Comprehensive Report on Acasunlimab (GEN1046/BNT311): An Investigational PD-L1 x 4-1BB Bispecific Antibody for Cancer Immunotherapy

[1]

1. Executive Summary

Acasunlimab (GEN1046/BNT311) is an investigational, first-in-class, Fc-silenced human immunoglobulin G1 (IgG1) bispecific antibody meticulously engineered to dually target programmed death-ligand 1 (PD-L1) and the co-stimulatory receptor 4-1BB (CD137).[1] Developed utilizing Genmab's proprietary DuoBody® technology, Acasunlimab is designed to provide conditional 4-1BB co-stimulation that is dependent on its binding to PD-L1, typically within the tumor microenvironment (TME). This mechanism aims to enhance T-cell and Natural Killer (NK)-cell mediated anti-tumor activity while concurrently mitigating the potential for systemic toxicities that have been associated with conventional 4-1BB agonistic antibodies.[1]

Extensive preclinical investigations have substantiated Acasunlimab's proposed mechanism of action, demonstrating potent anti-tumor activity and superior immune activation when compared to monospecific antibody counterparts, including in models resistant to checkpoint inhibitors (CPIs).[2] The clinical development program, now primarily spearheaded by Genmab following BioNTech's strategic decision to opt-out of further co-development in August 2024 [13], has concentrated on evaluating Acasunlimab in patients with advanced solid tumors. A significant focus has been on metastatic non-small cell lung cancer (mNSCLC), particularly in patients whose disease has progressed following prior CPI therapy, an area of substantial unmet medical need.

Initial data from the Phase 2 GCT1046-04 trial (NCT05117242) in this mNSCLC patient population have been encouraging. Specifically, Acasunlimab administered in combination with pembrolizumab every six weeks (Q6W) demonstrated a median overall survival (mOS) of 17.5 months and a 12-month OS rate of 69%.[17] These promising results, coupled with a manageable safety profile where liver-related toxicities were noted but generally low-grade and reversible, have supported the advancement of Acasunlimab into a pivotal Phase 3 trial. The ABBIL1TY NSCLC-06 study (NCT06635824) is currently enrolling patients to compare the Acasunlimab-pembrolizumab Q6W combination against docetaxel in the second-line plus setting for PD-L1-positive mNSCLC.[3]

Acasunlimab represents a novel immunotherapeutic strategy. Its development navigates a competitive landscape of PD-L1 x 4-1BB bispecific antibodies, each employing distinct engineering approaches to optimize the risk-benefit profile of 4-1BB agonism. If the promising efficacy and manageable safety observed in Phase 2 trials are confirmed in the ongoing Phase 3 study, Acasunlimab could offer a significant therapeutic advancement for patients with CPI-refractory cancers.

2. Introduction

The Evolving Landscape of Cancer Immunotherapy:

The advent of immune checkpoint inhibitors (ICIs), particularly those targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, has fundamentally transformed the treatment paradigm for a multitude of malignancies. These agents have demonstrated the capacity to induce durable clinical responses and improve overall survival in a subset of patients.33 However, the efficacy of PD-1/PD-L1 blockade is not universal. A substantial proportion of patients exhibit primary resistance, failing to respond to initial ICI therapy, while others develop acquired resistance after an initial period of benefit.34 These challenges underscore a significant unmet medical need and drive the pursuit of novel therapeutic strategies designed to overcome resistance mechanisms and broaden the population of patients who can benefit from immunotherapy.

Rationale for Dual Targeting: PD-L1 and 4-1BB:

One promising avenue to enhance anti-tumor immunity involves the simultaneous modulation of multiple immune pathways. The combination of PD-L1 blockade with agonism of co-stimulatory receptors on immune cells has garnered considerable interest.

PD-L1, frequently upregulated on tumor cells and other cells within the tumor microenvironment (TME), binds to its receptor PD-1 on T-cells, delivering an inhibitory signal that dampens T-cell activity and facilitates immune evasion by the tumor.1 Antagonizing this interaction can "release the brakes" on the anti-tumor T-cell response.

Concurrently, 4-1BB (CD137 or TNFRSF9) serves as a critical inducible co-stimulatory receptor expressed on activated T-cells, Natural Killer (NK) cells, and other immune cell subsets.1 Engagement of 4-1BB by its natural ligand or agonistic antibodies provides a potent "accelerator" signal, promoting immune cell proliferation, survival, effector functions (such as cytokine production and enhanced cytolytic activity), and the establishment of immunological memory.1

The observation that PD-1 and 4-1BB are often co-expressed on tumor-infiltrating lymphocytes (TILs) provides a compelling biological rationale for dual targeting.7 It is hypothesized that such a strategy could synergistically enhance anti-tumor immunity, particularly in immune-excluded ("cold") tumors or in tumors that have become refractory to single-agent CPI therapy.

Introducing Acasunlimab (GEN1046/BNT311):

Acasunlimab (GEN1046/BNT311) is an investigational, first-in-class bispecific antibody engineered to dually engage PD-L1 and 4-1BB.1 A key design feature of Acasunlimab is its conditional 4-1BB agonism, which is dependent on the antibody's binding to PD-L1. This mechanism is intended to localize the potent 4-1BB co-stimulation to the PD-L1-rich TME, thereby enhancing tumor-specific immune responses while potentially mitigating the systemic toxicities, notably hepatotoxicity, that have been observed with earlier generations of systemic 4-1BB agonistic antibodies.1

Unmet Medical Need in Advanced Non-Small Cell Lung Cancer (NSCLC):

Patients with metastatic NSCLC who experience disease progression on or after first-line CPI-containing regimens face a particularly challenging prognosis with limited effective therapeutic options. Standard second-line treatments, such as docetaxel-based chemotherapy, offer modest clinical benefit and are often associated with significant toxicity.34 Consequently, there is a substantial unmet need for novel immunotherapies like Acasunlimab that can overcome resistance and provide durable clinical benefit in this patient population. The development of Acasunlimab, with its dual mechanism aimed at reinvigorating exhausted T-cells and enhancing immune surveillance within the TME, directly addresses this critical therapeutic gap. The strategy of combining PD-L1 blockade with conditional 4-1BB agonism is designed to convert immunologically "cold" tumors into "hot," T-cell-inflamed environments, or to reactivate T-cells that have become dysfunctional due to chronic antigen exposure and inhibitory signals within the tumor.

3. Acasunlimab: Drug Profile and Mechanism of Action

• Nomenclature: Acasunlimab is the International Nonproprietary Name (INN) for this investigational agent. It is also widely recognized by its development codes GEN1046 (Genmab) and BNT311 (BioNTech). Given its bispecific nature and proprietary generation technology, it is sometimes referred to as DuoBody®-PD-L1x4-1BB.1
• Developer(s) and Collaboration History: Acasunlimab was initially developed as part of a global strategic collaboration between Genmab A/S and BioNTech SE, which commenced in 2015 and was expanded in 2022 to include novel monospecific antibody candidates.3 However, in August 2024, BioNTech announced its strategic decision to opt-out of further co-development and potential commercialization of Acasunlimab, citing reasons related to its internal portfolio strategy. Consequently, Genmab assumed sole responsibility for the program's continued global development and future commercialization efforts. Under the revised agreement, BioNTech remains eligible for certain developmental milestones and tiered single-digit royalties on net sales.13 This shift in development leadership, despite what BioNTech acknowledged as an "encouraging clinical profile" 13, places the full responsibility and potential future rewards for Acasunlimab with Genmab. Genmab's commitment is underscored by its plans to advance the molecule into late-stage development, positioning Acasunlimab as a key wholly-owned asset.14 This strategic pivot highlights the substantial financial and strategic considerations inherent in late-stage oncology drug development and can reflect differing risk appetites or resource allocation priorities between collaborating entities.
• Therapeutic Class: Acasunlimab is classified as an antineoplastic agent, specifically a bispecific monoclonal antibody, and falls under the broad category of immunotherapy.3
• Molecular Design and Proprietary Technologies:
• Bispecific Antibody Nature: Acasunlimab is a recombinant, human IgG1 bispecific antibody engineered to concurrently bind two distinct molecular targets: human PD-L1 and human 4-1BB (CD137).[1]
• Genmab's DuoBody® Technology Platform:
• Mechanism: The DuoBody® platform is a proprietary technology developed by Genmab for the efficient generation of stable, IgG-like bispecific antibodies. The process involves the co-expression of two different parental IgG1 antibodies, each targeting one of the desired antigens (PD-L1 and 4-1BB in the case of Acasunlimab). These parental antibodies incorporate specific, matched point mutations in their CH3 domains. Under controlled in vitro redox conditions, these antibodies are mixed, leading to the dissociation of the homodimers into half-molecules (heavy-chain/light-chain pairs). The engineered mutations in the CH3 domains then preferentially drive the reassembly of these half-molecules into functional heterodimeric bispecific antibodies, with high yield and purity (typically >95%), while minimizing the formation of unwanted homodimers or other byproducts. This process effectively mimics a natural IgG Fab-arm exchange process but in a controlled manner.[4]
• Advantages: This platform produces bispecific antibodies that maintain the structural and pharmacokinetic characteristics of conventional monoclonal antibodies, including a long plasma half-life. The resulting bispecific antibodies are stable and possess good manufacturability. A key advantage is the prevention of light chain mispairing, a common issue with other bispecific antibody formats, which contributes to the high purity of the final product.[51]
• Fc-Silenced IgG1 Backbone:
• Rationale: Acasunlimab is constructed on an Fc-silenced (also referred to as Fc-inert) IgG1 backbone.[1] This modification is critical for its intended mechanism and safety profile. The Fc region of a standard IgG1 antibody can interact with Fc gamma receptors (FcγRs) expressed on various immune cells, triggering effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). While beneficial for some therapeutic antibodies, these effector functions can be detrimental for others, particularly for agonistic antibodies targeting co-stimulatory receptors like 4-1BB. Non-specific activation of 4-1BB through FcγR-mediated cross-linking can lead to widespread, systemic immune activation and associated toxicities, most notably hepatotoxicity, which has been a significant challenge in the development of previous 4-1BB agonistic antibodies.[33]
• Benefit: By incorporating Fc-silencing mutations (e.g., LALA-PG mutations, which abrogate binding to FcγRs and C1q), the effector functions of the Acasunlimab Fc region are minimized.[55] This design ensures that the 4-1BB agonistic activity of Acasunlimab is primarily, if not exclusively, driven by the cross-linking event mediated by its binding to PD-L1 on target cells within the TME. This localized activation strategy aims to maximize the therapeutic effect at the tumor site while reducing the risk of off-target, systemic immune-related adverse events.[7] The strategic combination of the DuoBody® platform for robust bispecific antibody generation with Fc-silencing for enhanced safety represents a sophisticated protein engineering approach. This design directly addresses the historical toxicity concerns associated with 4-1BB agonism, aiming to decouple the potent immune stimulation from widespread systemic effects, thereby potentially widening the therapeutic index.
• Detailed Mechanism of Action (MoA):
• PD-L1 Blockade: One arm of Acasunlimab binds to PD-L1, which is often expressed on tumor cells and antigen-presenting cells within the TME. This binding blocks the interaction between PD-L1 and its receptor PD-1 on T-cells. The PD-1/PD-L1 pathway is a major inhibitory checkpoint that normally serves to dampen T-cell responses and prevent autoimmunity, but tumors exploit this pathway to evade immune destruction. By disrupting this interaction, Acasunlimab removes an important "brake" on T-cell activity, thereby restoring or enhancing the ability of T-cells to recognize and attack cancer cells.[1]
• Conditional 4-1BB Co-stimulation: The other arm of Acasunlimab binds to the 4-1BB receptor on activated T-cells and NK cells. Crucially, the agonistic (activating) signal delivered through 4-1BB is conditional and dependent on the simultaneous binding of Acasunlimab's PD-L1 arm to PD-L1-expressing cells. This co-engagement, leading to the cross-linking of 4-1BB receptors on the immune cell surface, is believed to be necessary for potent 4-1BB signaling. This mechanism is designed to "press the accelerator" on the immune response, but primarily in the context of the TME where PD-L1 is present. This localized co-stimulation leads to enhanced proliferation, survival, cytokine production (e.g., IFNγ, IL-2), and cytotoxic effector functions of T-cells and NK cells specifically directed against the tumor.[1]
• Synergistic Anti-Tumor Effect: The concurrent PD-L1 blockade and tumor-localized 4-1BB agonism are intended to work synergistically. By removing an inhibitory signal while simultaneously providing a strong co-stimulatory signal in the presence of tumor antigen (often presented on PD-L1 expressing cells), Acasunlimab aims to generate a more potent and durable anti-tumor immune response than could be achieved by targeting either pathway alone or through the simple combination of two separate monospecific antibodies. This is particularly relevant for overcoming resistance to single-agent CPIs and for treating tumors with an immune-suppressive microenvironment.

4. Preclinical Development

The preclinical development of Acasunlimab provided a strong foundation for its advancement into clinical trials, demonstrating its unique mechanism of action and potent anti-tumor activity.

• In Vitro Studies:
• Acasunlimab (GEN1046) consistently demonstrated superior capabilities in stimulating immune responses compared to clinically approved PD-(L)1 monospecific antibodies. This included enhanced T-cell proliferation, increased production of key pro-inflammatory cytokines such as interferon-gamma (IFNγ) and interleukin-2 (IL-2), and more potent antigen-specific T-cell-mediated cytotoxicity against tumor cells in various human T-cell culture systems.[2]
• The drug was shown to promote crucial interactions between dendritic cells (DCs) and T-cells, a fundamental step in initiating and amplifying adaptive immune responses.[2]
• Critically, the 4-1BB agonistic activity of Acasunlimab was confirmed to be dependent on PD-L1 cross-linking, validating the conditional activation mechanism designed to localize immune stimulation.[4]
• In studies involving dysfunctional T-cells, the combination of Acasunlimab with pembrolizumab (an anti-PD-1 antibody) was shown to reinvigorate these T-cells, further supporting the rationale for combination therapy in the clinic.[8]
• In Vivo Studies (Syngeneic and Humanized Mouse Models):
• Acasunlimab, or its corresponding murine surrogate antibodies, exhibited potent anti-tumor activity across a range of transplantable mouse tumor models. Notably, efficacy was observed even in models that were resistant to PD-(L)1 monotherapy, suggesting its potential to overcome existing resistance mechanisms.[2]
• In several models, such as the MC38 colon adenocarcinoma model, Acasunlimab treatment led to durable complete tumor regressions. Furthermore, mice that achieved complete regression were often protected from tumor rechallenge, indicating the induction of long-lasting immunological memory.[8]
• The combination of Acasunlimab (or its surrogate) with anti-PD-1 antibodies (such as pembrolizumab surrogates) demonstrated synergistic anti-tumor effects, resulting in enhanced tumor growth inhibition and improved survival compared to either agent alone.[8]
• Mechanistic Insights from Preclinical Work:
• Immunohistochemical and flow cytometric analyses of tumors and lymphoid organs from treated animals revealed increased infiltration of CD3+ and CD8+ T-cells into the TME.[8]
• Acasunlimab treatment led to enhanced clonal expansion of tumor-specific CD8+ T-cells, particularly in tumor-draining lymph nodes, indicating a focused adaptive immune response.[8]
• A key finding was the potentiation of the IL-2 signaling pathway and an increase in the proportion of GZMB+ (Granzyme B-positive) stem-like CD8+ T-cells (e.g., PD-1+TCF1+TIM3-) within the TME. These stem-like T-cells are considered crucial for maintaining a durable anti-tumor response due to their self-renewal capacity and ability to differentiate into effector T-cells.[7]
• Transcriptomic analyses indicated a favorable modulation of the TME, with enrichment of pathways related to antigen presentation, IFN signaling, macrophage activation, and Th1/Th2 cell activation, alongside inhibition of immunosuppressive IL-10 signaling.[8] Radiomic features from CT images were also found to correlate with a tumor microenvironment favorable for immunotherapy in NSCLC patients treated with Acasunlimab.[62]
• Safety and Tolerability in Non-Human Primates (NHP):
• Crucially, Acasunlimab was reported to be well-tolerated in cynomolgus monkeys at dose levels up to 30 mg/kg. Importantly, no significant liver enzyme elevations (a hallmark toxicity of earlier systemic 4-1BB agonists) were observed in these NHP studies.[9] This preclinical safety finding was pivotal in supporting the progression of Acasunlimab into human clinical trials, suggesting that its conditional activation mechanism and Fc-silenced design might successfully mitigate systemic toxicities.

The comprehensive preclinical data package for Acasunlimab strongly supported its proposed mechanism of action. The findings indicated that the conditional 4-1BB agonism, tethered to PD-L1 engagement, could effectively enhance anti-tumor immunity, particularly when combined with PD-1 blockade, potentially overcoming CPI resistance. The ability to induce complete tumor regressions and establish immune memory in animal models, coupled with a favorable safety profile in NHPs (especially the lack of hepatotoxicity), provided a robust rationale for advancing Acasunlimab into clinical investigation for patients with advanced cancers.

5. Clinical Development Program

Acasunlimab has undergone an extensive clinical development program, progressing from first-in-human Phase 1 studies to a pivotal Phase 3 trial. The program has primarily focused on patients with advanced solid tumors, with a particular emphasis on mNSCLC following progression on prior CPI therapy.

Table 1: Summary of Key Clinical Trials for Acasunlimab (GEN1046/BNT311)

This table provides a consolidated overview of the main clinical trials involving Acasunlimab, facilitating an understanding of its developmental trajectory, target indications, and current status.

NCT ID	EudraCT ID(s)	Phase	Official Title/Brief Description	Target Indication(s)	Key Design Features (Monotherapy/Combination, Key Drugs, Dosing Regimens if specified)	Status (as of latest snippet)	Sponsor(s)
NCT03917381	2018-003402-63; 2023-509059-15	1/2	First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety of GEN1046 in Subjects With Malignant Solid Tumors (GCT1046-01)	Advanced/Metastatic Solid Tumors (including NSCLC, Endometrial, Urothelial, TNBC, HNSCC, Cervical Cancer)	Dose escalation (GEN1046 mono); Dose expansion (GEN1046 mono; GEN1046 + pembrolizumab +/- chemo; GEN1046 + docetaxel)	Active, Not Recruiting (Primary Completion Apr 2025) 62	Genmab 62
NCT04937153	-	1	GEN1046 Safety and PK in Subjects With Advanced Solid Malignancies (Japanese patients) (GCT1046-02)	Advanced/Metastatic Solid Tumors	GEN1046 monotherapy or in combination with pembrolizumab	Active, Not Recruiting (Primary Completion Oct 2024) 69	Genmab 20
NCT05117242	2021-001928-17	2	A Phase 2, Multicenter, Randomized, Open-Label Trial of GEN1046 as Monotherapy and in Combination With Pembrolizumab in Subjects With Relapsed/Refractory Metastatic Non-Small Cell Lung Cancer (GCT1046-04)	Relapsed/Refractory Metastatic NSCLC (PD-L1+)	Arm A: GEN1046 mono (100mg Q3W x2 -> 500mg Q6W); Arm B: GEN1046 (100mg) + Pembrolizumab (200mg) Q3W; Arm C: GEN1046 (100mg) + Pembrolizumab (400mg) Q6W	Recruitment Complete (Primary Completion Dec 2024) 73	Genmab/BioNTech (Genmab now sole lead) 2
NCT06046274	2022-502453-33-00	2	A Phase 2 Exploratory, Multicenter, Open-Label Trial to Determine the Safety and Preliminary Clinical Activity of GEN1046 in Combination With Anticancer Agents in Subjects With Advanced Endometrial Cancer (GCT1046-05)	Advanced Endometrial Cancer	GEN1046 + Pembrolizumab (2 cohorts based on prior CPI)	Withdrawn 3	Genmab 3
NCT06635824	2024-512998-27-00; jRCT2051240178	3	A Prospective, Open-Label, Randomized, Phase 3 Trial of Acasunlimab (GEN1046) in Combination With Pembrolizumab Versus Docetaxel in Subjects With PD-L1 Positive Metastatic Non-Small Cell Lung Cancer After Treatment With a PD-1/PD-L1 Inhibitor and Platinum-Containing Chemotherapy (ABBIL1TY NSCLC-06 / GCT1046-06)	PD-L1+ Metastatic NSCLC (post-CPI and platinum chemo)	Arm A: Acasunlimab (100mg) + Pembrolizumab (400mg) Q6W; Arm B: Docetaxel (75 mg/m²) Q3W	Recruiting (Est. completion 2027-2029) 3	Genmab 3

• Detailed Discussion of Individual Trials:
• NCT03917381 (GCT1046-01): First-in-Human Phase 1/2 Safety and Efficacy Study
• Study Design and Objectives: This foundational open-label, multi-center trial was designed in two parts: a dose-escalation phase (Phase 1) to determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of Acasunlimab monotherapy, followed by dose-expansion cohorts (Phase 2a) to further evaluate safety and preliminary efficacy of Acasunlimab as monotherapy and in combination with pembrolizumab (+/- chemotherapy) or docetaxel in patients with various advanced/metastatic solid tumors refractory to standard therapies.[62] Key tumor types in expansion cohorts included NSCLC, endometrial cancer, urothelial carcinoma, triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), and cervical cancer.[40]
• Enrollment and Status: The dose-escalation part enrolled 61 patients across nine dose levels (25-1200 mg Q3W) as of June 2020.[9] The trial is currently active but not recruiting, with an estimated primary completion date of April 2025 and a target enrollment of 429 participants for all parts.[62]
• Endpoints: Primary endpoints included DLTs and adverse events (AEs) for the dose-escalation part, and Objective Response Rate (ORR) per RECIST v1.1 for the expansion cohorts. Secondary endpoints encompassed pharmacokinetic (PK) parameters, further safety assessments, and other measures of anti-tumor activity (e.g., Duration of Response, Progression-Free Survival).[64]
• Key Results (Phase 1 Dose-Escalation, published Feb 2022 [9], data cut-off June 2020): The MTD was not reached. Based on safety, PK/PD, and preliminary efficacy, 100 mg Q3W was selected as an expansion dose.[9] A Disease Control Rate (DCR) of 65.6% (40/61 patients) was observed across all dose levels in a heavily pretreated population.[6] Partial Responses (PRs) were noted in patients with TNBC, ovarian cancer, and, significantly, in NSCLC patients previously treated with CPIs.[6] The safety profile was generally manageable, with the most common treatment-related AEs (TRAEs) being transaminase elevations (all grades 24.6%; Grade 3-4: 9.8%), hypothyroidism (16.4%; Grade 3-4: 1.6%), and fatigue (13.1%; Grade 3-4: 1.6%).[6] Pharmacodynamic analyses confirmed target engagement and immune activation in peripheral blood.[6] This initial study provided critical validation of Acasunlimab's manageable safety and showed early signals of clinical activity, particularly the responses in CPI-experienced NSCLC patients, which strongly supported its further investigation in this challenging setting.
• NCT04937153 (GCT1046-02): Phase 1 Safety and PK Study in Japanese Patients
• Study Design and Objectives: This open-label, dose-escalation Phase 1 trial was conducted in Japan to evaluate the safety, tolerability, DLTs, and PK of Acasunlimab administered as monotherapy or in combination with pembrolizumab in Japanese patients with advanced or metastatic solid tumors for whom no standard therapy was available.[2]
• Enrollment and Status: The trial enrolled 18 participants and is listed as active, not recruiting, with an estimated primary completion in October 2024 and study completion in December 2024.[69]
• Endpoints: Primary endpoints focused on safety (DLTs, AEs) and PK parameters (Cmax, Tmax, AUC, t1/2, Cthrough). Secondary endpoints included immunogenicity (ADA) and preliminary efficacy.[69]
• Key Results (JSMO 2025 Poster Presentation): In the Acasunlimab monotherapy arm (n=15 efficacy-evaluable), stable disease (SD) was observed in 40% of patients (6/15).[72] Pharmacokinetic data indicated approximate dose-proportional exposure, and pharmacodynamic assessments showed dose-dependent increases in biomarkers like soluble 4-1BB, indicative of target engagement.[69] The findings from this study are important for understanding the drug's behavior in the Japanese patient population, which is crucial for global registration strategies.
• NCT05117242 (GCT1046-04): Phase 2 Randomized Study in Relapsed/Refractory mNSCLC
• Study Design and Objectives: This randomized, open-label, multicenter Phase 2 trial (EudraCT 2021-001928-17) was designed to evaluate the safety and efficacy of Acasunlimab as monotherapy versus Acasunlimab in combination with pembrolizumab in patients with PD-L1-positive (Tumor Proportion Score ≥1%) mNSCLC who had progressed on or after at least one prior line of systemic therapy containing an anti-PD-1/PD-L1 inhibitor.[2] Patients were randomized to one of three arms: Arm A (Acasunlimab 100 mg Q3W for 2 cycles, then 500 mg Q6W), Arm B (Acasunlimab 100 mg Q3W + pembrolizumab 200 mg Q3W), or Arm C (Acasunlimab 100 mg Q6W + pembrolizumab 400 mg Q6W).[18]
• Enrollment and Status: 113 patients were randomized. Recruitment is complete, and the estimated primary completion date is December 2024.[73]
• Endpoints: The primary endpoint was ORR per RECIST v1.1. Key secondary endpoints included OS, PFS, DoR, Time to Response (TTR), and safety.[18]
• Key Results (Presented at ASCO 2024; data cut-off March/May 2024 for PD-L1+ efficacy-evaluable patients, n=62 for ORR, n=80 for OS): [17]
• Arm C (Acasunlimab + Pembrolizumab Q6W): Demonstrated the most favorable outcomes with a mOS of 17.5 months and a 12-month OS rate of 69%. The ORR was 30% (confirmed ORR 17%), and DCR was 75%.
• Arm A (Acasunlimab Monotherapy): mOS was 5.5 months, with an ORR of 31% (confirmed ORR 13%) and DCR of 50%.
• Arm B (Acasunlimab + Pembrolizumab Q3W): mOS was 8.6 months, with an ORR of 21% (confirmed ORR 18%) and DCR of 59%.
• Anti-tumor activity was noted across different PD-L1 TPS levels (1-49% and ≥50%) and irrespective of the duration of prior CPI treatment. The safety profile was generally manageable, with TRAEs being primarily Grade 1-2. Liver-related events, fatigue, asthenia, and diarrhea were among the most common TRAEs in the combination arms. Notably, the Q6W combination regimen (Arm C) was associated with a lower incidence of Grade ≥3 TRAEs and treatment-related liver events, as well as lower discontinuation rates compared to the Q3W regimen or monotherapy. Transaminase elevations were generally asymptomatic and manageable with standard interventions. The pronounced mOS of 17.5 months in the Q6W combination arm, within a heavily pre-treated CPI-refractory NSCLC population, is a clinically significant finding. This outcome, coupled with a more favorable safety profile, strongly supported the selection of the Q6W regimen for further development. The data suggest that less frequent, but still potent, immune stimulation might achieve a better therapeutic balance, potentially by mitigating T-cell exhaustion that could arise from more continuous co-stimulation.
• NCT06046274 (GCT1046-05): Phase 2 Study in Advanced Endometrial Cancer
• Study Design and Objectives: This was planned as an open-label, multicenter, exploratory Phase 2 trial to evaluate the safety and preliminary clinical activity of Acasunlimab in combination with pembrolizumab in patients with advanced (unresectable, recurrent, and/or metastatic) endometrial cancer who had failed prior standard first-line treatment. The trial was designed with two cohorts based on prior CPI exposure.[3]
• Status: The trial was withdrawn prior to enrollment.[76] Cohort A (CPI-naive) was noted as closed in some records.[76]
• Reason for Withdrawal: While specific reasons for this trial's withdrawal are not explicitly detailed in most snippets, Genmab's broader portfolio prioritization strategy, which involved terminating some early-stage clinical programs that did not meet their criteria for "KYSO® (knock-your-socks-off) antibody-based medicines" [21], likely played a role. Furthermore, Genmab is advancing another asset, rinatabart sesutecan (Rina-S), in endometrial cancer, with plans for a Phase 3 study.[78] This suggests a strategic decision to focus resources on what might be perceived as a more promising candidate or approach for this specific indication. The withdrawal of this trial, therefore, likely reflects a strategic portfolio decision rather than a specific safety or efficacy concern with Acasunlimab in this context at such an early stage.
• NCT06635824 (GCT1046-06 / ABBIL1TY NSCLC-06): Pivotal Phase 3 Study in PD-L1+ mNSCLC
• Study Design and Objectives: This is an ongoing, multicenter, randomized, open-label, international Phase 3 trial (EudraCT 2024-512998-27-00; jRCT2051240178). The study is designed to evaluate the efficacy and safety of Acasunlimab (100 mg) in combination with pembrolizumab (400 mg) administered Q6W, compared to docetaxel (75 mg/m² Q3W, standard of care) in participants with PD-L1-positive (TPS ≥1%) mNSCLC who have experienced disease progression on or after treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy (administered either concomitantly or sequentially).[3]
• Enrollment and Status: The trial is currently recruiting, with an estimated enrollment of 702 patients. The study commenced in February 2025, and the estimated trial duration for each participant may be up to 5 years, encompassing screening, up to 2 years of treatment, and follow-up periods.[3]
• Endpoints: The primary endpoint is Overall Survival (OS). Key secondary endpoints include Progression-Free Survival (PFS), confirmed ORR, DoR, safety, and patient-reported quality of life (QoL) measures.[25]
• This pivotal Phase 3 trial is critical for determining the definitive clinical benefit of Acasunlimab in combination with pembrolizumab in a challenging, CPI-refractory mNSCLC population. Its design directly builds upon the encouraging OS signal and favorable safety profile observed with the Q6W regimen in the Phase 2 GCT1046-04 study. A positive outcome could establish this combination as a new standard of care for these patients.

6. Clinical Efficacy

The clinical efficacy of Acasunlimab, particularly when combined with pembrolizumab, has shown promise in heavily pre-treated patient populations with advanced solid tumors, most notably in mNSCLC.

• Metastatic Non-Small Cell Lung Cancer (mNSCLC) - NCT05117242 (ASCO 2024 Data): The Phase 2 GCT1046-04 trial provided the most compelling efficacy data to date for Acasunlimab in patients with PD-L1-positive mNSCLC who had progressed after prior CPI therapy.17
• Combination Therapy (Acasunlimab + Pembrolizumab Q6W - Arm C): This regimen demonstrated a median OS of 17.5 months, with a 12-month OS rate of 69%. The ORR was 30% (confirmed ORR 17%), and the DCR was 75%. These results were observed in a cohort of centrally confirmed PD-L1+ efficacy-evaluable patients.
• Combination Therapy (Acasunlimab + Pembrolizumab Q3W - Arm B): This arm showed a mOS of 8.6 months, an ORR of 21% (confirmed ORR 18%), and a DCR of 59%.
• Monotherapy (Acasunlimab - Arm A): Acasunlimab alone yielded a mOS of 5.5 months, an ORR of 31% (confirmed ORR 13%), and a DCR of 50%. The superior mOS observed with the Q6W combination regimen (Arm C) compared to the Q3W combination (Arm B) or monotherapy (Arm A), despite somewhat similar ORRs in some comparisons, is a noteworthy finding. This suggests that the less frequent dosing schedule for the combination might lead to more durable responses or a more sustained beneficial impact on the tumor immune microenvironment, potentially by avoiding T-cell exhaustion that could be associated with more frequent or continuous 4-1BB co-stimulation. The durability of response is a critical factor in this refractory patient population.
• Advanced Solid Tumors - NCT03917381 (Phase 1 Dose Escalation): In the initial dose-escalation phase of this first-in-human trial, which included heavily pretreated patients with various advanced solid tumors, Acasunlimab monotherapy demonstrated a DCR of 65.6% (40 out of 61 patients). Confirmed PRs were observed in patients with TNBC and ovarian cancer. Importantly, unconfirmed PRs were also reported in patients with NSCLC who had previously progressed on anti-PD-(L)1 therapy, providing an early signal of activity in this resistant setting.6
• Advanced Solid Tumors in Japanese Patients - NCT04937153 (JSMO 2025 Data): Preliminary data from the Phase 1 study in Japanese patients indicated that Acasunlimab monotherapy resulted in stable disease in 40% (6 out of 15) of efficacy-evaluable patients.72

Table 2: Summary of Key Efficacy Results for Acasunlimab (GEN1046) in Clinical Trials

This table consolidates the primary efficacy outcomes reported from the key clinical trials of Acasunlimab.

Trial ID (Study Name)	Indication	Patient Subgroup	Treatment Arm	N (evaluable)	ORR (Confirmed %)	DCR (%)	mOS (months)	12-mo OS (%)	mPFS (months)	Source(s)
NCT05117242 (GCT1046-04)	mNSCLC (PD-L1+)	Post-CPI	Acasunlimab + Pembro Q6W (Arm C)	25 (ORR) / ~27 (OS)	30% (17%)	75%	17.5	69%	6-mo PFS: 33%	17
NCT05117242 (GCT1046-04)	mNSCLC (PD-L1+)	Post-CPI	Acasunlimab + Pembro Q3W (Arm B)	22 (ORR) / ~27 (OS)	21% (18%)	59%	8.6	-	6-mo PFS: 18%	17
NCT05117242 (GCT1046-04)	mNSCLC (PD-L1+)	Post-CPI	Acasunlimab Mono (Arm A)	16 (ORR) / ~26 (OS)	31% (13%)	50%	5.5	-	6-mo PFS: 0%	17
NCT03917381 (GCT1046-01)	Advanced Solid Tumors	Heavily Pretreated	Acasunlimab Mono (Dose Escalation)	61	PRs noted*	65.6%	-	-	-	6
NCT04937153 (GCT1046-02)	Advanced Solid Tumors (Japanese)	Heavily Pretreated	Acasunlimab Mono	15	-	SD in 40%	-	-	-	72

• PRs in TNBC, Ovarian, NSCLC (uPR)

The collective efficacy data, particularly the mOS of 17.5 months achieved with the Acasunlimab plus pembrolizumab Q6W regimen in CPI-experienced mNSCLC patients, are encouraging and form the basis for the ongoing Phase 3 investigation. This level of activity in such a difficult-to-treat population suggests that Acasunlimab's dual mechanism may indeed be overcoming some of the resistance pathways that limit the effectiveness of single-agent CPIs.

7. Safety and Tolerability

The safety and tolerability profile of Acasunlimab has been evaluated across its clinical development program, both as monotherapy and in combination with pembrolizumab.

• Overall Safety Profile: Acasunlimab has generally demonstrated a manageable safety profile, with most treatment-related adverse events (TRAEs) being Grade 1 or 2 in severity.[9] The safety profile appears consistent with the mechanisms of PD-L1 inhibition and 4-1BB co-stimulation.
• Most Common Treatment-Related Adverse Events (TRAEs):
• In the Phase 2 GCT1046-04 trial (mNSCLC, Acasunlimab + Pembrolizumab Q6W - Arm C), the most common TRAEs (all grades) included liver-related events (such as transaminase elevations, ~18.4%), fatigue (~8.2%), asthenia (~12.2%), and diarrhea (~10.2%).[18]
• In the Phase 1 GCT1046-01 trial (Acasunlimab monotherapy, dose escalation), the most frequent TRAEs (all grades; Grade ≥3) were transaminase elevation (24.6%; 9.8%), hypothyroidism (16.4%; 1.6%), and fatigue (13.1%; 1.6%).[6] Other reported TRAEs in this study included asthenia, nausea, and anemia.[19]
• Serious Adverse Events and Dose-Limiting Toxicities (DLTs):
• In the GCT1046-01 dose-escalation phase, DLTs occurred in 9.8% (6/61) of patients. These included Grade 4 febrile neutropenia (n=2), Grade 3 immune-mediated nephritis (n=1), Grade 3 ALT increase (n=1), Grade 3 AST/ALT increase (n=1), and Grade 3 transaminase elevation (n=1). The MTD was not reached in this study.[6]
• In the GCT1046-04 Phase 2 trial, the Q6W combination regimen (Arm C) was associated with a lower incidence of Grade ≥3 TRAEs and treatment-related liver events compared to the Q3W combination regimen (Arm B) or Acasunlimab monotherapy (Arm A).[18] This observation was a key factor in selecting the Q6W regimen for the Phase 3 trial.
• Management of Adverse Events:
• Transaminase elevations, a notable AE consistent with immune-mediated liver effects, were reported as generally asymptomatic and manageable with standard interventions such as corticosteroids and/or treatment delay or discontinuation.[6] These events tended to resolve more rapidly in patients treated with the Q6W combination therapy.[19]
• Discontinuation Rates: Treatment discontinuation rates due to AEs varied across studies and treatment arms. The Q6W combination arm in GCT1046-04 reportedly had lower discontinuation rates compared to the Q3W arm.[19]

The safety profile of Acasunlimab, particularly the occurrence of liver enzyme elevations, aligns with the immune-mediated effects anticipated from potent T-cell activating agents like 4-1BB agonists. However, the conditional activation mechanism conferred by PD-L1 binding, coupled with the Fc-silenced design, appears to mitigate the severe systemic toxicities, especially hepatotoxicity, that plagued earlier, non-conditional 4-1BB agonists.[33] The observation that the Q6W dosing schedule for the combination therapy offers a more favorable tolerability profile is significant, suggesting that intermittent but potent immune stimulation may be key to maximizing the therapeutic window. This careful balance between robust immune activation and manageable toxicity is paramount for the successful clinical application of such agents.

Table 3: Common Treatment-Related Adverse Events (TRAEs) for Acasunlimab (GEN1046) from Key Clinical Trials (Incidence ≥10% All Grades or any Grade ≥3 in at least one arm/study shown)

Trial ID	Treatment Arm	Adverse Event Term	Frequency (All Grades %)	Frequency (Grade ≥3 %)	Source(s)
NCT03917381 (GCT1046-01)	Acasunlimab Mono (Dose Escal.)	Transaminase Elevation	24.6	9.8	6
		Hypothyroidism	16.4	1.6	6
		Fatigue	13.1	1.6	6
NCT05117242 (GCT1046-04)	Acasunlimab Mono (Arm A)	Asthenia	22.7	-	19
		Diarrhea	18.2	-	19
		Nausea	18.2	-	19
		Anemia	13.6	-	19
		Liver-related events	13.6	-	19
NCT05117242 (GCT1046-04)	Acasunlimab + Pembro Q3W (Arm B)	Liver-related events	28.6	-	19
		Fatigue	21.4	-	19
		Asthenia	12.0	-	19
		Diarrhea	12.0	-	19
NCT05117242 (GCT1046-04)	Acasunlimab + Pembro Q6W (Arm C)	Liver-related events	18.4	(Lower than Arm B)	19
		Asthenia	12.2	-	19
		Diarrhea	10.2	-	19
		Fatigue	8.2	-	19

Note: Specific Grade ≥3 frequencies for all events in all arms of NCT05117242 were not consistently detailed in the snippets; "Lower than Arm B" for liver events in Arm C is qualitative based on snippet text.

8. Pharmacokinetics and Pharmacodynamics

The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of Acasunlimab have been characterized in early-phase clinical trials, providing insights into its disposition and biological activity in humans.

• Pharmacokinetics (PK):
• Data from the Phase 1/2 GCT1046-01 trial and the Phase 1 GCT1046-02 trial in Japanese patients have contributed to understanding Acasunlimab's PK.[6]
• Key PK parameters evaluated include maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma concentration-time curve (AUC), elimination half-life (t1/2), total body clearance (CL), and volume of distribution (Vd).[64]
• Acasunlimab has demonstrated approximately dose-proportional kinetics across the dose ranges studied [[80] (general expectation for well-behaved antibodies), specific confirmation for Acasunlimab in [69]].
• In the GCT1046-01 study, the mean terminal half-life of Acasunlimab was reported to range from 2.3 to 10.3 days across different dose levels.[9] This half-life supports intermittent dosing schedules, such as Q3W or Q6W, as explored in clinical trials.
• Pharmacodynamics (PD):
• Evidence of target engagement and immune activation by Acasunlimab has been consistently observed in clinical trials.
• Dose-dependent increases in peripheral blood levels of soluble 4-1BB (s4-1BB), a biomarker indicative of 4-1BB receptor engagement and activation, have been reported [[9] (general PD marker for 4-1BB agonists)].
• Treatment with Acasunlimab has also led to increases in markers of T-cell activation and proliferation, such as the proportion of Ki-67+ CD8+ T-cells, and elevated levels of IFNγ and CXCL10 in peripheral blood.[6]
• In combination therapy with pembrolizumab, a more pronounced increase in CD8 T-cell proliferation was observed compared to Acasunlimab monotherapy, supporting the synergistic potential of the combination.[18]
• Pharmacodynamic results from the GCT1046-04 trial indicated that intermittent 4-1BB engagement (as with the Q6W schedule) might reduce chronic T-cell stimulation, potentially mitigating T-cell dysfunction by allowing for resting intervals and resetting T-cell function.[70]
• Immunogenicity:
• The development of anti-drug antibodies (ADAs) to Acasunlimab has been monitored in clinical trials.[64] The specific incidence rates and clinical impact of ADAs were not extensively detailed in the provided snippets, but this is a standard assessment for biologic therapies.

The PK profile of Acasunlimab, characterized by dose-proportional exposure and a half-life permitting Q3W or Q6W dosing, appears suitable for clinical development. The PD data provide in-human validation of its proposed mechanism of action, demonstrating clear target engagement of 4-1BB and downstream immune activation, consistent with preclinical observations. The finding that intermittent dosing might preserve T-cell function is particularly relevant for optimizing long-term efficacy and managing potential immune-related toxicities.

9. Regulatory Status and Future Directions

• Current Global Development Stage: Acasunlimab is in late-stage clinical development. The most advanced program is the pivotal Phase 3 ABBIL1TY NSCLC-06 trial (NCT06635824) for patients with previously treated PD-L1-positive mNSCLC.3
• Regulatory Designations (FDA/EMA): The provided research snippets did not explicitly mention any specific Orphan Drug, Fast Track, Breakthrough Therapy, or PRIME designations granted to Acasunlimab (GEN1046/BNT311) by the FDA or EMA.3 While some snippets discuss such designations for other drugs or general FDA/EMA processes, none directly attribute these to Acasunlimab.
• Genmab's Strategic Vision for Acasunlimab:
• Following BioNTech's exit from the co-development agreement in August 2024, Genmab assumed sole responsibility for the continued global development and potential commercialization of Acasunlimab.[13]
• Genmab has positioned Acasunlimab as a key late-stage, wholly-owned asset within its pipeline, alongside other promising candidates like Rina-S.[14]
• The company has expressed confidence in Acasunlimab's potential and is committed to advancing it through late-stage development, with plans to initiate the Phase 3 NSCLC trial in the second half of 2024 (now actively recruiting).[14]
• Genmab projects a significant commercial opportunity for Acasunlimab, with potential peak sales exceeding $1 billion in the NSCLC indication alone.[48] The estimated commercial launch is anticipated between 2029 and 2030, contingent on successful trial outcomes and regulatory approvals.[21]
• Future Development Plans:
• The primary focus is the successful execution and completion of the pivotal Phase 3 ABBIL1TY NSCLC-06 trial (NCT06635824).
• Genmab anticipates providing an additional Phase 2 data update for Acasunlimab in NSCLC during 2025.[21]
• While the endometrial cancer trial (NCT06046274) was withdrawn [76], potentially due to portfolio prioritization [45], exploration in other solid tumor indications could be considered in the future, depending on emerging data and strategic alignment. Genmab's full ownership and commitment to Acasunlimab, particularly in the context of promising Phase 2 data in a high unmet need population (CPI-refractory NSCLC), signals a strong belief in the drug's therapeutic and commercial potential. The successful execution of the ongoing Phase 3 trial will be paramount in realizing this potential.

10. Competitive Landscape for PD-L1 x 4-1BB Bispecific Antibodies

The development of bispecific antibodies targeting both PD-L1 and 4-1BB is an active and competitive area within oncology research. Several companies are exploring this dual-targeting strategy, employing various molecular formats and engineering approaches to optimize efficacy and safety.[11]

Table 4: Selected PD-L1 x 4-1BB Bispecific Antibodies in Clinical Development

This table provides a snapshot of key competitors to Acasunlimab in the PD-L1 x 4-1BB bispecific antibody space, based on the information available in the provided research snippets.

Drug Name (Code)	Developer(s)	Key Design Features	Highest Development Phase	Key Targeted Indication(s)	Brief Summary of Reported Efficacy/Safety (if available)	Source(s)
Acasunlimab (GEN1046/BNT311)	Genmab (formerly with BioNTech)	DuoBody® IgG1, Fc-silenced, bivalent for PD-L1 and 4-1BB	Phase 3	mNSCLC (post-CPI), other solid tumors	mOS 17.5 mo (combo with pembro Q6W in Ph2 NSCLC); manageable safety, liver enzyme elevations noted.	1
MCLA-145	Merus	Biclonics® platform, full-length human IgG1, binds PD-L1 and CD137	Phase 1	HNSCC, Solid Tumors, B-cell Lymphomas	Preclinical: PD-L1 dependent CD137 activation, T-cell activation, tumor growth inhibition. Clinical data not detailed in snippets.	37
INBRX-105	Inhibrx	Tetravalent (2 PD-L1 sdAbs, 2 4-1BB sdAbs)	Terminated (formerly Phase 1/2)	PD-L1 expressing tumors	Program terminated.	90
FS222	F-star Therapeutics (invoX Pharma)	mAb²™ tetravalent (bivalent for PD-L1, bivalent for CD137)	Phase 1	Melanoma, Ovarian, NSCLC, TNBC, other solid tumors	Preclinical: potent, PD-L1 dependent CD137 activation, T-cell activation, tumor regression. Clinical data: robust PD activity in FIH study.	37
ABL503 (Ragistomig)	ABL Bio / I-Mab Biopharma	Fc-silent IgG1 fused with anti-4-1BB scFv (Grabody-T platform)	Phase 1b	Solid Tumors	Phase 1 (ASCO 2024): ORR 25% at 5mg/kg (3/12 PRs), CBR 75% at 5mg/kg. Manageable safety, DLTs observed.	37
PRS-344/S095012	Pieris Pharmaceuticals / Servier	PD-L1 antibody - 4-1BB Anticalin fusion (Mabcalin), tetravalent "2+2"	Phase 1	Advanced Solid Tumors	Phase 1 (AACR 2025): Significant toxicity (hematologic, HLH, liver injury). OBI pretreatment reduced ADAs but worsened hepatic toxicity. Limited responses.	33
ATG-101	Antengene	Tetravalent "2+2" PD-L1 x 4-1BB	Phase 1 (PROBE trial)	Solid Tumors, B-NHL, TNBC, CRC	Phase 1: PR in MSS CRC, durable SD. Good safety, no liver toxicities reported. Dose escalation ongoing/completing H1 2025.	37
BH3120	Hanmi Pharmaceutical / Beijing Hanmi	Heterodimeric bispecific (Pentambody platform)	Phase 1 (mono & combo with pembrolizumab)	Advanced/Metastatic Solid Tumors	Preclinical: TME-focused 4-1BB activation, favorable safety. Phase 1 dose escalation ongoing, no DLTs reported up to cohort 3 (1 mg/kg) as of Nov 2024.	38

• Differentiation Factors: The competitive landscape is characterized by varied molecular engineering strategies. Key differentiating factors include:
• Valency and Format: Molecules range from IgG-like bispecifics (e.g., Acasunlimab, MCLA-145) to tetravalent constructs (e.g., INBRX-105, FS222, ATG-101) and fusion proteins (e.g., PRS-344/S095012). The number and arrangement of binding domains for PD-L1 and 4-1BB can significantly influence avidity, signaling potency, and PK/PD properties.
• Fc Engineering: Most candidates, including Acasunlimab, utilize Fc-silenced backbones to mitigate non-specific FcγR-mediated activation and associated toxicities.[1] This is a critical design choice to improve the therapeutic index of 4-1BB agonism.
• Binding Affinities and Epitopes: The specific affinities for PD-L1 and 4-1BB, as well as the epitopes recognized, can impact the conditional activation properties and overall efficacy. For instance, ATG-101 is reported to have greater affinity for PD-L1 than 4-1BB, potentially enhancing tumor targeting before 4-1BB engagement.[37]
• Proprietary Technology Platforms: Companies leverage unique platforms (e.g., Genmab's DuoBody®, Merus' Biclonics®, F-star's mAb²™, ABL Bio's Grabody-T, Hanmi's Pentambody, Pieris' Anticalin®) which confer distinct structural and functional characteristics to their respective molecules.

Acasunlimab (GEN1046) stands out due to its advancement into Phase 3 development for NSCLC, supported by encouraging Phase 2 overall survival data. Its DuoBody® IgG1 format with Fc-silencing represents a well-characterized approach to bispecific antibody engineering. However, the field remains dynamic, with several competitors demonstrating promising early clinical activity (e.g., ABL503, ATG-101). The challenges encountered by some candidates, such as the termination of INBRX-105 and the toxicity issues observed with PRS-344/S095012 [90], highlight the complexities of safely and effectively harnessing 4-1BB co-stimulation, even with conditional activation strategies. The ultimate success of these agents will depend on demonstrating a compelling risk-benefit profile in larger, controlled trials.

11. Conclusion

Acasunlimab (GEN1046/BNT311) has emerged as a promising investigational bispecific antibody, thoughtfully designed to combine PD-L1 checkpoint blockade with conditional 4-1BB co-stimulation. Its Fc-silenced IgG1 architecture, derived from Genmab's DuoBody® platform, aims to deliver potent, tumor-localized immune activation while mitigating the systemic toxicities that have challenged previous 4-1BB agonistic approaches.

Preclinical studies have robustly supported its mechanism of action, demonstrating superior T-cell activation and anti-tumor efficacy compared to monospecific antibodies, including in CPI-resistant models. The clinical development program, now under the sole stewardship of Genmab, has yielded encouraging results, particularly in heavily pretreated patients with metastatic NSCLC. The Phase 2 GCT1046-04 trial highlighted a clinically meaningful median overall survival of 17.5 months when Acasunlimab was combined with pembrolizumab on a Q6W schedule, in a patient population with limited therapeutic options. This efficacy was accompanied by a safety profile deemed manageable, with liver enzyme elevations being the most notable immune-related adverse event, generally low-grade and reversible.

The initiation of the pivotal Phase 3 ABBIL1TY NSCLC-06 trial (NCT06635824) represents a critical step towards potentially establishing Acasunlimab as a new therapeutic option for patients with PD-L1-positive mNSCLC who have progressed on prior CPI and platinum-based chemotherapy. A positive outcome in this trial could address a significant unmet medical need.

While Acasunlimab's journey has seen a strategic shift with BioNTech's exit from co-development, Genmab's commitment to advancing this wholly-owned asset underscores a strong belief in its potential. The competitive landscape for PD-L1 x 4-1BB bispecifics is active, with various molecular formats and engineering strategies being explored. Acasunlimab's relatively advanced clinical stage and the promising survival data in NSCLC position it as a leading candidate.

Key challenges remain, including the confirmation of efficacy and safety in the larger Phase 3 setting, long-term management of potential immune-related adverse events, and navigating the evolving treatment paradigms in oncology. Nevertheless, Acasunlimab's innovative design and encouraging clinical data to date suggest it holds considerable therapeutic promise. If its benefits are substantiated in ongoing and future trials, Acasunlimab could become a valuable addition to the armamentarium against difficult-to-treat cancers, offering new hope to patients with advanced disease.

12. References

1 NCI Drug Dictionary. Definition of Acasunlimab.

2 MedChemExpress. Acasunlimab (GEN1046).

25 Clinical Trials EU. Acasunlimab: A Promising New Treatment for Non-Small Cell Lung Cancer.

49 DrugBank. Acasunlimab (DB18932).

73 AbbVie Clinical Trials. Safety and Efficacy Study of GEN1046 as a Single Agent or in Combination With Pembrolizumab for Treatment of Recurrent (Non-small Cell) Lung Cancer (GCT1046-04).

4 Kuick Research. Acasunlimab (GEN1046) Clinical Trials Insight.

64 AbbVie Clinical Trials. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (GCT1046-01).

40 Pharmaceutical Technology. Acasunlimab by BioNTech for Non-Small Cell Lung Cancer: Likelihood of Approval.

41 Genmab. Pipeline.

17 FirstWord Pharma. Investigational Acasunlimab (DuoBody-PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity in Phase 2 Trial...

65 Georgia CancerInfo. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (NCT03917381).

19 BusinessWire. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity in Phase 2 Trial... (June 1, 2024).

1 NCI Drug Dictionary. Acasunlimab (Code name: BNT 311).

39 AdisInsight (Springer). Acasunlimab - BioNTech/Genmab.

19 BusinessWire. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab....19

42 Genmab and BioNTech Expand Global Strategic Collaboration to Develop and Commercialize Novel Immunotherapy Candidates. (August 5, 2022).

13 Pharmaceutical Technology. BioNTech exits PD-L1 development with Genmab as Q2 revenues drop. (August 5, 2024).

75 BioNTech SE. BioNTech to Present Clinical Data Updates for Next-Generation Immunotherapies at ASCO 2024. (May 21, 2024).

130 BioNTech SE. BioNTech to Present Clinical and Preclinical Data Updates from its Oncology Pipeline at the SITC 35th Annual Meeting. (October 14, 2020).

1 NCI Drug Dictionary. Definition of Acasunlimab..1

2 MedChemExpress. Acasunlimab (GEN1046)..2

5 PMC. Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046)... (Feb 17, 2022).

6 PMC. Preclinical Characterization and Phase I Trial Results....5

131 PMC. Anti-PD-L1-Based Bispecific Antibodies Targeting Co-Inhibitory and Co-Stimulatory Molecules for Cancer Immunotherapy.

132 BioNTech SE. Genmab and BioNTech Expand Global Strategic Collaboration....42

40 Pharmaceutical Technology. Acasunlimab by BioNTech for Non-Small Cell Lung Cancer....40

25 Clinical Trials EU. Acasunlimab: A Promising New Treatment for Non-Small Cell Lung Cancer..25

66 Journal for ImmunoTherapy of Cancer. 412 First-in-human phase I/IIa trial to evaluate the safety and initial clinical activity of DuoBody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors. (2020).

133 Patsnap Synapse. BNT113 (E6/E7 RNA liposomal vaccine). (Note: This snippet is about BNT113, not Acasunlimab/BNT311, but was returned for a BNT311 query).

134 BusinessWire. Genmab to Showcase Data in Various Patient Populations to be Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting. (May 23, 2024).

73 AbbVie Clinical Trials. Safety and Efficacy Study of GEN1046... (GCT1046-04)..73

25 Clinical Trials EU. Acasunlimab: A Promising New Treatment for Non-Small Cell Lung Cancer..25

64 AbbVie Clinical Trials. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (GCT1046-01)..64

29 Genmab. Clinical Trials Privacy Policy GCT1046-06 (NCT06635824).

135 Patsnap Synapse. BioNTech to present clinical updates for next-gen immunotherapies at ASCO 2024. (May 21, 2024).

19 BusinessWire. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab....19

7 PMC. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity... (April 10, 2025).

18 ASCO Publications. Acasunlimab (DuoBody-PD-L1x4-1BB) alone or in combination with pembrolizumab (pembro) in patients (pts) with previously treated metastatic non-small cell lung cancer (mNSCLC): Initial results of a randomized, open-label, phase 2 trial. (JCO 2024 42:16_suppl, 2533-2533).

67 My Cancer Genome. Clinical Trial: NCT03917381 - GEN1046 Safety Trial in Patients With Malignant Solid Tumors.

63 CenterWatch. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (NCT03917381).

71 DAP Studies. Study's details - GEN1046 Safety and PK in Subjects With Advanced Solid Malignancies (NCT04937153).

69 Ngram. GEN1046 Safety and PK in Subjects With Advanced Solid Malignancies (NCT04937153).

26 Veeva CTV. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06) (NCT06635824).

27 Georgia CancerInfo. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel... (NCT06635824).

136 Siteman Cancer Center. A Prospective, Open-Label, Randomized, Phase 3 Trial of Acasunlimab (GEN1046) in Combination With Pembrolizumab Versus Docetaxel... (NCT06635824). (Note: Snippet is about NSCLC trial, not endometrial).

76 NCI. GEN1046 in Combination With Anticancer Agents for the Treatment of Advanced Endometrial Cancer (NCT06046274).

64 AbbVie Clinical Trials. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (NCT03917381)..64

9 ResearchGate. Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046)... (Feb 2022, Cancer Discovery).

73 AbbVie Clinical Trials. Safety and Efficacy Study of GEN1046... (NCT05117242)..73

19 BusinessWire. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab....19

28 UVA Health. A Prospective, Open-Label, Randomized, Phase 3 Trial of Acasunlimab (GEN1046) in Combination With Pembrolizumab Versus Docetaxel... (NCT06635824).

10 ResearchGate. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity... (JITC 2025)..7

26 Veeva CTV. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority... (NCT06635824)..26

25 Clinical Trials EU. Acasunlimab: A Promising New Treatment for Non-Small Cell Lung Cancer..25

29 Genmab. Clinical Trials Privacy Policy GCT1046-06 (NCT06635824)..29

77 Veeva CTV. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (NCT03917381).

68 NCI. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (NCI-2020-03735 / NCT03917381).

62 Larvol Delta. Acasunlimab (GEN1046) / Genmab - Radiomics and TME. (AACR 2025).

69 Ngram. GEN1046 Safety and PK in Subjects With Advanced Solid Malignancies (NCT04937153)..69

6 PMC. Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046)... (Feb 17, 2022, Cancer Discovery)..5

39 AdisInsight (Springer). Acasunlimab - BioNTech/Genmab..3

81 BioSpace. BioNTech Outlines 2024 Strategic Priorities... (Jan 2024).

33 AACR Journals. The PD-L1/4-1BB Bispecific Antibody Anticalin PRS-344/S095012... (Clinical Cancer Research 2022).

37 PMC. The tetravalent PD-L1×4-1BB bispecific antibody ATG-101 activates 4-1BB+ T cells... (Cancer Research 2024).

64 AbbVie Clinical Trials. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (GCT1046-01)..64

6 PMC. Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046)... (Feb 17, 2022, Cancer Discovery)..5

8 PubMed. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity... (JITC 2025 Apr 10).

73 AbbVie Clinical Trials. Safety and Efficacy Study of GEN1046... (GCT1046-04)..73

28 UVA Health. A Prospective, Open-Label, Randomized, Phase 3 Trial of Acasunlimab (GEN1046)... (NCT06635824)..28

11 JITC. Acasunlimab (DuoBody-PD-L1×4-1BB) combined with PD-1 blockade elicits complementary immune-modulatory effects... (2025)..7

26 Veeva CTV. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority... (NCT06635824)..26

27 Georgia CancerInfo. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority... (NCT06635824)..27

76 NCI. GEN1046 in Combination With Anticancer Agents for the Treatment of Advanced Endometrial Cancer (NCT06046274)..76

44 Clinical Trials Arena. Genmab and BioNTech report data from Phase II GCT1046-04 trial for mNSCLC. (June 3, 2024).

7 PMC. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025)..7

29 Genmab. Clinical Trials Privacy Policy GCT1046-06 (NCT06635824)..29

69 Ngram. GEN1046 Safety and PK in Subjects With Advanced Solid Malignancies (NCT04937153)..69

70 Larvol Sigma. Acasunlimab (GEN1046) / Genmab - NewsTrac.

43 Genmab. Genmab Annual Report 2024. (Feb 12, 2025).

14 BioSpace. Genmab Takes Full Control of Acasunlimab Development Program. (August 5, 2024).

1 NCI Drug Dictionary. Definition of Acasunlimab..1

20 GlobeNewswire. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity... (June 1, 2024).

37 PMC. The tetravalent PD-L1×4-1BB bispecific antibody ATG-101 activates 4-1BB+ T cells... (Cancer Res 2024). (Competitor ATG-101).

33 AACR Journals. The PD-L1/4-1BB Bispecific Antibody Anticalin PRS-344/S095012... (Clin Cancer Res 2022). (Competitor PRS-344).

29 Genmab. Clinical Trials Privacy Policy GCT1046-06 (NCT06635824)..29

3 Patsnap Synapse. Acasunlimab Drug Profile.

21 Genmab. Genmab Investor Update ASCO 2024. (June 2024).

20 GlobeNewswire. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab....20

7 PMC. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025)..7

10 ResearchGate. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade... (JITC 2025)..7

8 PubMed. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025 Apr 10)..8

11 JITC. Acasunlimab combined with PD-1 blockade elicits complementary immune-modulatory effects... (JITC 2025)..7

47 Genmab. Genmab Q1 2025 Interim Report. (May 8, 2025).

43 Genmab. Genmab Annual Report 2024..43

37 PMC. The tetravalent PD-L1×4-1BB bispecific antibody ATG-101....37 (Competitor ATG-101).

38 NCI. Clinical Trials Using Anti-4-1BB/PD-L1 Bispecific Antibody BH3120. (Competitor BH3120).

82 FDA. FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma. (Jan 16, 2025) (Not Acasunlimab related).

43 Genmab. Genmab Annual Report 2024..43

83 EMA. EU/3/24/2966 - orphan designation for treatment of gastric cancer (Bemarituzumab). (Not Acasunlimab).

19 BusinessWire. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab....19

7 PMC. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025)..7

3 Patsnap Synapse. Acasunlimab Drug Profile..3

88 Pharmaceutical Technology. MCLA-145 by Merus for Head And Neck Squamous Cell Carcinoma (HNSC): Likelihood of Approval. (Competitor MCLA-145).

89 Dana-Farber Cancer Institute. A Phase 1...Study of MCLA-145 in Participants With Select Advanced or Metastatic Solid Tumors (NCT03922204). (Competitor MCLA-145).

90 Inhibrx. Inhibrx Announces Dosing of First Patient in Phase 1 Dose-Escalation Study of INBRX-105... (Feb 19, 2019). (Competitor INBRX-105).

91 My Cancer Genome. INBRX-105. (Competitor INBRX-105).

92 Pharmaceutical Technology. FS-222 by F-star Therapeutics for Melanoma: Likelihood of Approval. (Competitor FS222).

93 F-star Therapeutics. F-star Therapeutics Announces First Patient Dosed in FS222 Phase 1 Clinical Trial. (Sept 2022). (Competitor FS222).

94 ABL Bio. ABL503 (Ragistomig) Pipeline. (Competitor ABL503).

95 My Cancer Genome. ABL503. (Competitor ABL503).

96 AACR Journals. Abstract CT078: Results of a phase 1 first-in-human study of PRS-344/S095012... (Cancer Res 2025). (Competitor PRS-344).

97 Clinical Trials EU. PRS-344/S095012: A Promising New Treatment for Solid Tumors. (Competitor PRS-344).

98 Pharmaceutical Technology. ATG-101 by Antengene for Triple-Negative Breast Cancer (TNBC): Likelihood of Approval. (Competitor ATG-101).

99 PMC. Atg101 is a novel component of the Atg1 complex that functions in the initiation of autophagy. (Note: This is about the Atg101 gene, not the drug ATG-101).

100 Patsnap Synapse. Hanmi Pharmaceutical and Beijing Hanmi Progress BH3120 Cancer Immunotherapy Trials. (Dec 3, 2024). (Competitor BH3120).

101 Hanmi Pharmaceutical. BH3120 (PD-L1/4-1BB BsAb) Pipeline. (Competitor BH3120).

137 EU CTR. Clinical trials for 2018-003402-63 (GCT1046-01).

138 EU CTR. Clinical trials - Regulation EU No 536/2014. (General info).

139 EU CTR. Clinical trials for 2021-001928-17 (GCT1046-04).

140 EU CTR. EudraCT Number: 2021-001928-17 (GCT1046-04 Portugal).

29 Genmab. Clinical Trials Privacy Policy GCT1046-06 (NCT06635824 / EudraCT 2024-512998-27-00)..29

26 Veeva CTV. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority... (NCT06635824 / EudraCT 2024-512998-27-00)..26

141 EU CTR. Search for clinical trials - EMA. (General search page).

142 Mauriziano Hospital. EU Regulation No 536/2014. (General info).

43 Genmab. Genmab Annual Report 2024..43

3 Patsnap Synapse. Acasunlimab Drug Profile..3

39 AdisInsight (Springer). Acasunlimab - BioNTech/Genmab..39

44 Clinical Trials Arena. Genmab and BioNTech report data from Phase II GCT1046-04 trial for mNSCLC..44

102 Patsnap Synapse. MCLA-145 Drug Profile. (Competitor MCLA-145).

103 ResearchGate. Abstract 539: A bispecific Fc-silenced IgG1 antibody (MCLA-145) requires PD-L1 binding to activate CD137. (Cancer Res 2019). (Competitor MCLA-145).

104 JITC. 742 Phase 1/2 study of the bispecific 4–1BB and PD-L1 antibody INBRX-105... (2023). (Competitor INBRX-105).

105 Inhibrx. INBRX_105_SITC_TiP_Poster_SUBMISSION_16Oct2023.pdf. (Competitor INBRX-105).

106 AACR Journals. FS222, a CD137/PD-L1 Tetravalent Bispecific Antibody, Exhibits Low Toxicity and Antitumor Activity... (Clin Cancer Res 2020). (Competitor FS222).

107 JITC. 668 FS222 is a CD137/PD-L1 tetravalent, bispecific antibody which elicits robust pharmacodynamic activity... (2023). (Competitor FS222).

108 ABL Bio. ABL503, PD-L1x4-1BB bispecific antibody via tumor-immune cell interaction... (Poster). (Competitor ABL503).

109 ABL Bio. ABL Bio To Present Phase 1 Data for ABL503 (Ragistomig) at ASCO 2024. (May 24, 2024). (Competitor ABL503).

110 PMC. The PD-L1/4-1BB Bispecific Antibody–Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation... (Clin Cancer Res 2022). (Competitor PRS-344).

96 AACR Journals. Abstract CT078: Results of a phase 1 first-in-human study of PRS-344/S095012... (Cancer Res 2025)..96

111 Larvol Clin. A Study ATG-101 in Patients With Metastatic/Advanced Solid Tumors and Mature B-cell Non-Hodgkin Lymphomas (NCT04986865). (Competitor ATG-101).

112 PubMed. ATG-101 Is a Tetravalent PD-L1×4-1BB Bispecific Antibody That Stimulates Antitumor Immunity... (Cancer Res 2024). (Competitor ATG-101).

101 Hanmi Pharmaceutical. BH3120 (PD-L1/4-1BB BsAb) Pipeline..101

113 JITC. 698 A phase I, open-label, multinational, multicenter, dose escalation and expansion study of BH3120 (4–1BB x PD-L1 BsAb)... (2024). (Competitor BH3120).

73 AbbVie Clinical Trials. Safety and Efficacy Study of GEN1046... (NCT05117242)..73

64 AbbVie Clinical Trials. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (NCT03917381)..62

74 CenterWatch. Safety and Efficacy Study of GEN1046... (NCT05117242).

19 BusinessWire. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab....19

61 MedChemExpress. Acasunlimab (GEN1046) (Japanese)..2

20 GlobeNewswire. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab....19

30 AbbVie Clinical Trials. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority... (NCT06635824).

31 Georgia CancerInfo. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority... (NCT06635824)..27

29 Genmab. Clinical Trials Privacy Policy GCT1046-06 (NCT06046274). (Note: This is for GCT1046-06, but snippet mentions GCT1046-05 / NCT06046274 for endometrial cancer).

76 NCI. GEN1046 in Combination With Anticancer Agents for the Treatment of Advanced Endometrial Cancer (NCT06046274)..76

84 Oncology News Central. Oncology Drugs Fast Tracked by the FDA in February 2025. (General, not Acasunlimab).

14 BioSpace. Genmab Takes Full Control of Acasunlimab Development Program..14

85 EMA. EU/3/22/2731 - orphan designation for treatment of small cell lung cancer (Serplulimab). (Not Acasunlimab).

15 Genmab. Genmab Takes Full Control of Acasunlimab Development Program..14

88 Pharmaceutical Technology. MCLA-145 by Merus....88 (Competitor MCLA-145).

114 GlobeNewswire. Merus Announces Financial Results for the Fourth Quarter and Full Year 2023... (Feb 28, 2024). (Competitor MCLA-145).

115 Inhibrx Investor Room. Inhibrx Reports Fourth Quarter and Fiscal Year 2024 Financial Results. (March 17, 2025). (Competitor INBRX-105 terminated).

116 PR Newswire. Inhibrx Reports Fourth Quarter and Fiscal Year 2024 Financial Results..115 (Competitor INBRX-105 terminated).

92 Pharmaceutical Technology. FS-222 by F-star Therapeutics....92 (Competitor FS222).

117 Larvol Delta. FS222 / F-star Therapeutics - NewsTrac. (Competitor FS222).

118 ABL Bio. ABL Bio and I-Mab Presented Encouraging Phase 1 Clinical Data for ABL111... (Sept 20, 2024). (About ABL111, mentions ABL503).

119 ABL Bio. ABL Bio To Present Phase 1 Data for ABL503 (Ragistomig) at ASCO 2024. (May 24, 2024). (Competitor ABL503).

120 AccessWire. Pieris Pharmaceuticals and Servier Announce Dosing of First Patient in Phase 1/2 Trial of 4-1BB/PD-L1 Bispecific PRS-344/S095012. (Competitor PRS-344).

97 Clinical Trials EU. PRS-344/S095012: A Promising New Treatment for Solid Tumors..97

98 Pharmaceutical Technology. ATG-101 by Antengene for Triple-Negative Breast Cancer....98 (Competitor ATG-101).

121 BioSpace. Antengene Announces IND Approval in China for the Phase I Study of ATG-101... (March 9, 2022). (Competitor ATG-101).

122 Hanmi Pharmaceutical. Hanmi Pharmaceutical and Beijing Hanmi Progress BH3120 Cancer Immunotherapy Trials. (May 13, 2025). (Competitor BH3120).

123 Business Korea. Hanmi Pharmaceutical to Present 11 Preclinical Research Findings at AACR 2025. (April 14, 2025). (Competitor BH3120).

73 AbbVie Clinical Trials. Safety and Efficacy Study of GEN1046... (NCT05117242)..73

64 AbbVie Clinical Trials. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (NCT03917381)..62

7 PMC. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025)..7

43 Genmab. Genmab Annual Report 2024..43

50 Patsnap Synapse. What are the primary areas of focus for Genmab? (DuoBody tech).

51 Genmab US. Antibody Science - DuoBody Technology.

57 Arcus Bio. Fc-silent antibody. (General info on Fc-silencing).

58 Ichor.bio. Fc-silenced antibodies. (General info on Fc-silencing).

7 PMC. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025)..7

40 Pharmaceutical Technology. Acasunlimab by BioNTech for Non-Small Cell Lung Cancer....40

11 JITC. Acasunlimab combined with PD-1 blockade elicits complementary immune-modulatory effects... (JITC 2025)..7

36 Innovations in Pharmaceutical Technology. 4-1BB Antibodies in Oncology Clinical Trials: A Review. (May 2025).

86 Aptitude Health. Most FDA and EMA Oncology Drug Approvals in Q1 2025... (General regulatory news).

87 Lymphoma Hub. EMA approves acalabrutinib combination for patients with previously untreated MCL. (May 6, 2025) (Not Acasunlimab).

10 ResearchGate. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025)..7

143 Genmab. Genmab to Highlight New Data Evaluating Late-Stage Oncology Portfolio at the 2025 ASCO Annual Meeting. (May 22, 2025).

47 Genmab. Genmab Q1 2025 Interim Report..47

19 BusinessWire. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab....19

21 Genmab. Genmab Investor Update ASCO 2024. (June 2024).

22 Oncology Pipeline. ASCO 2024 – acasunlimab impresses on overall survival. (June 2024).

52 FirstWord Pharma. Genmab to Highlight New Data Evaluating Late-Stage Oncology Portfolio at ASCO 2025..143

53 BioSpace. Genmab to Highlight New Data Evaluating Late-Stage Oncology Portfolio at ASCO 2025..52

59 PMC. Silencing Fc domains in T Cell–Engaging Bispecific Antibodies... (July 2020). (General Fc-silencing).

60 Creative Biolabs. Bispecific Antibodies: Expanding the Frontiers of Targeted Immunotherapy. (General bispecifics, Fc-silencing).

8 PubMed. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025 Apr 10)..8

12 JITC. 719 Acasunlimab combined with PD-1 blockade elicits complementary immune-modulatory effects... (SITC 2024 Abstract).

34 PMC. Second-Line Treatment for Advanced or Metastatic Non-Small Cell Lung Cancer... (Nov 2024). (Unmet need NSCLC).

35 AJMC. Unmet Needs in NSCLC Treatment. (Unmet need NSCLC).

16 Patsnap Synapse. BioNTech halts development of Genmab-collaborated bispecific antibody acasunlimab. (Aug 2024).

15 Genmab. Genmab Takes Full Control of Acasunlimab Development Program..14

36 Innovations in Pharmaceutical Technology. 4-1BB Antibodies in Oncology Clinical Trials: A Review..36

33 AACR Journals. The PD-L1/4-1BB Bispecific Antibody Anticalin PRS-344/S095012....33 (Competitor PRS-344).

124 PRNewswire. I-Mab Announces Portfolio Prioritization of Givastomig... (March 2025). (Competitor ABL503 update).

125 ASCO Publications. Phase 1 trial safety and efficacy of ragistomig (ABL503/TJ-L14B)... (JCO 2024). (Competitor ABL503).

98 Pharmaceutical Technology. ATG-101 by Antengene....98 (Competitor ATG-101).

126 BioSpace. Antengene Presents Encouraging Clinical Data from Four Pipeline Programs at the 2023 R&D Day. (Nov 16, 2023). (Competitor ATG-101).

12 JITC. Acasunlimab combined with PD-1 blockade elicits complementary immune-modulatory effects....12

23 OncoDaily. Giannis Mountzios: Top 10 Abstracts from WCLC 2024. (Refers to Acasunlimab WCLC24 presentation).

55 Frontiers in Immunology. mRNA-encoded bispecific antibodies for cancer immunotherapy. (May 2024). (General Fc-silencing, 4-1BB).

56 Cellular & Molecular Biology Letters. An Fc-muted bispecific antibody targeting PD-L1 and 4-1BB induces antitumor immune activity... (May 2023). (General Fc-muting, 4-1BB).

3 Patsnap Synapse. Acasunlimab Drug Profile..3

15 Genmab. Genmab Takes Full Control of Acasunlimab Development Program..14

127 Larvol Clin. A Study ATG-101 in Patients With Metastatic/Advanced Solid Tumors... (NCT04986865)..111

128 Larvol Clin. Givastomig (TJ-CD4B / ABL111) Clinical Trial Updates. (Competitor ABL111, mentions ABL503).

129 Antengene. Antengene Announces 2024 Full-Year Financial Results... (March 21, 2025). (Competitor ATG-101 update).

111 Larvol Clin. A Study ATG-101 in Patients With Metastatic/Advanced Solid Tumors... (NCT04986865)..111

47 Genmab. Genmab Q1 2025 Interim Report..47

48 Genmab. Genmab Full Year 2024 Financial Results Conference Call Transcript. (Feb 12, 2025).

54 Evitria. Bispecific Antibodies. (General DuoBody info).

51 Genmab US. Antibody Science - DuoBody Technology..51

80 PMC. Clinical and Translational Relevance of ATOR-1017... (May 2025). (Different 4-1BB drug, but relevant for PD markers).

24 BioNTech. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity... (June 1, 2024).

7 PMC. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025)..7

8 PubMed. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025 Apr 10)..8

72 Larvol Clin. GEN1046 Safety and PK in Subjects With Advanced Solid Malignancies (NCT04937153) JSMO 2025 results.

61 MedChemExpress. Acasunlimab (GEN1046) (Japanese)..2

45 Seeking Alpha. Genmab A/S (GMAB) Q1 2025 Earnings Conference Call Transcript. (May 8, 2025).

46 GuruFocus. Q4 2024 Genmab A/S Earnings Call Transcript. (Feb 12, 2025).

7 PMC. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025)..7

64 AbbVie Clinical Trials. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (NCT03917381)..62

73 AbbVie Clinical Trials. Safety and Efficacy Study of GEN1046... (NCT05117242)..73

74 CenterWatch. Safety and Efficacy Study of GEN1046... (NCT05117242).

28 UVA Health. A Prospective, Open-Label, Randomized, Phase 3 Trial of Acasunlimab (GEN1046)... (NCT06635824)..28

32 Larvol Clin. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority... (NCT06635824).

63 CenterWatch. GEN1046 Safety Trial in Patients With Malignant Solid Tumors (NCT03917381)..63

144 I-Mab Biopharma. I-Mab Announces Portfolio Prioritization... (May 2025). (Mentions ABL111, not Acasunlimab directly).

8 PubMed. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025 Apr 10)..8

145 Antibody Society. DuoBody Technology. (General, not Acasunlimab specific).

78 Oncology Pipeline. SGO 2025: Genmab's Advantage Looks Profound (Rina-S). (Mentions Genmab's endometrial cancer strategy with Rina-S).

79 HRA UK. GCT1046-05 Research Summary (NCT06046274).

146 DrugBank. Endometrial Carcinoma (DBCOND0029860). (General info, not Acasunlimab specific).

49 DrugBank. Acasunlimab (DB18932)..49

10 ResearchGate. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody... (JITC 2025)..7

147 MDPI. Bispecific Antibodies in Non-Small Cell Lung Cancer... (April 2024). (General review, not Acasunlimab specific).

43 Genmab. Genmab Annual Report 2024..43

21 Genmab. Genmab Investor Update ASCO 2024..21

148 PMC. 4-1BB antibodies in oncology clinical trials: a review. (May 2025).

36 Innovations in Pharmaceutical Technology. 4-1BB Antibodies in Oncology Clinical Trials: A Review..36

The other snippets 149 are not relevant to Acasunlimab.

The S_B snippets were largely inaccessible or not directly relevant.

The plan to create the detailed report based on the Step 2 outline and these analyzed snippets is sound.# Comprehensive Report on Acasunlimab (GEN1046/BNT311): An Investigational PD-L1 x 4-1BB Bispecific Antibody for Cancer Immunotherapy

[1]

1. Executive Summary

Acasunlimab (GEN1046/BNT311) is an investigational, first-in-class, Fc-silenced human immunoglobulin G1 (IgG1) bispecific antibody meticulously engineered to dually target programmed death-ligand 1 (PD-L1) and the co-stimulatory receptor 4-1BB (CD137).[1] Developed utilizing Genmab's proprietary DuoBody® technology, Acasunlimab is designed to provide conditional 4-1BB co-stimulation that is dependent on its binding to PD-L1, typically within the tumor microenvironment (TME). This mechanism aims to enhance T-cell and Natural Killer (NK)-cell mediated anti-tumor activity while concurrently mitigating the potential for systemic toxicities that have been associated with conventional 4-1BB agonistic antibodies.[1]

Extensive preclinical investigations have substantiated Acasunlimab's proposed mechanism of action, demonstrating potent anti-tumor activity and superior immune activation when compared to monospecific antibody counterparts, including in models resistant to checkpoint inhibitors (CPIs).[2] The clinical development program, now primarily spearheaded by Genmab following BioNTech's strategic decision to opt-out of further co-development in August 2024 [13], has concentrated on evaluating Acasunlimab in patients with advanced solid tumors. A significant focus has been on metastatic non-small cell lung cancer (mNSCLC), particularly in patients whose disease has progressed following prior CPI therapy, an area of substantial unmet medical need.

Initial data from the Phase 2 GCT1046-04 trial (NCT05117242) in this mNSCLC patient population have been encouraging. Specifically, Acasunlimab administered in combination with pembrolizumab every six weeks (Q6W) demonstrated a median overall survival (mOS) of 17.5 months and a 12-month OS rate of 69%.[17] These promising results, coupled with a manageable safety profile where liver-related toxicities were noted but generally low-grade and reversible, have supported the advancement of Acasunlimab into a pivotal Phase 3 trial. The ABBIL1TY NSCLC-06 study (NCT06635824) is currently enrolling patients to compare the Acasunlimab-pembrolizumab Q6W combination against docetaxel in the second-line plus setting for PD-L1-positive mNSCLC.[3]

Acasunlimab represents a novel immunotherapeutic strategy. Its development navigates a competitive landscape of PD-L1 x 4-1BB bispecific antibodies, each employing distinct engineering approaches to optimize the risk-benefit profile of 4-1BB agonism. If the promising efficacy and manageable safety observed in Phase 2 trials are confirmed in the ongoing Phase 3 study, Acasunlimab could offer a significant therapeutic advancement for patients with CPI-refractory cancers.

2. Introduction

The Evolving Landscape of Cancer Immunotherapy:

The advent of immune checkpoint inhibitors (ICIs), particularly those targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, has revolutionized the treatment paradigm for a multitude of malignancies. These agents have demonstrated the capacity to induce durable clinical responses and improve overall survival in a subset of patients.33 However, the efficacy of PD-1/PD-L1 blockade is not universal. A substantial proportion of patients exhibit primary resistance, failing to respond to initial ICI therapy, while others develop acquired resistance after an initial period of benefit.34 These challenges underscore a significant unmet medical need and drive the pursuit of novel therapeutic strategies designed to overcome resistance mechanisms and broaden the population of patients who can benefit from immunotherapy.

Rationale for Dual Targeting: PD-L1 and 4-1BB:

One promising avenue to enhance anti-tumor immunity involves the simultaneous modulation of multiple immune pathways. The combination of PD-L1 blockade with agonism of co-stimulatory receptors on immune cells has garnered considerable interest.

PD-L1, frequently upregulated on tumor cells and other cells within the tumor microenvironment (TME), binds to its receptor PD-1 on T-cells, delivering an inhibitory signal that dampens T-cell activity and facilitates immune evasion by the tumor.1 Antagonizing this interaction can "release the brakes" on the anti-tumor T-cell response.

Concurrently, 4-1BB (CD137 or TNFRSF9) serves as a critical inducible co-stimulatory receptor expressed on activated T-cells, Natural Killer (NK) cells, and other immune cells.1 Engagement of 4-1BB by its natural ligand or agonistic antibodies provides a potent "accelerator" signal, promoting immune cell proliferation, survival, effector functions (such as cytokine production and enhanced cytolytic activity), and the establishment of immunological memory.1

The observation that PD-1 and 4-1BB are often co-expressed on tumor-infiltrating lymphocytes (TILs) provides a compelling biological rationale for dual targeting.7 It is hypothesized that such a strategy could synergistically enhance anti-tumor immunity, particularly in immune-excluded ("cold") tumors or in tumors that have become refractory to single-agent CPI therapy.

Introducing Acasunlimab (GEN1046/BNT311):

Acasunlimab (GEN1046/BNT311) is an investigational, first-in-class bispecific antibody engineered to concurrently bind PD-L1 and 4-1BB.1 A key design feature of Acasunlimab is its conditional 4-1BB agonism, which is dependent on the antibody's binding to PD-L1. This mechanism is intended to localize the potent 4-1BB co-stimulation to the PD-L1-rich TME, thereby enhancing tumor-specific immune responses while potentially mitigating the systemic toxicities, notably hepatotoxicity, that have been observed with earlier generations of systemic 4-1BB agonistic antibodies.1

Unmet Medical Need in Advanced NSCLC:

Patients with mNSCLC who progress on or after first-line CPI-containing regimens face a particularly challenging prognosis with limited effective therapeutic options. Standard second-line treatments, such as docetaxel-based chemotherapy, offer modest clinical benefit and are often associated with significant toxicity.34 There is a pressing need for novel therapies that can overcome resistance and provide durable clinical benefit in this setting. The development of Acasunlimab, with its dual mechanism aimed at reinvigorating exhausted T-cells and enhancing immune surveillance within the TME, directly targets this critical therapeutic gap. Its design aims to convert immunologically "cold" tumors into "hot," T-cell-inflamed environments or to reactivate T-cells that have become dysfunctional due to chronic antigen exposure and inhibitory signals within the tumor, a common scenario in CPI-refractory disease.

3. Acasunlimab: Drug Profile and Mechanism of Action

• Nomenclature: Acasunlimab is the International Nonproprietary Name (INN) for this investigational agent. It is also widely recognized by its development codes GEN1046 (Genmab) and BNT311 (BioNTech). Given its bispecific nature and proprietary generation technology, it is sometimes referred to as DuoBody®-PD-L1x4-1BB.1
• Developer(s) and Collaboration History: Acasunlimab was initially developed as part of a global strategic collaboration between Genmab A/S and BioNTech SE, which commenced in 2015 and was expanded in 2022 to include novel monospecific antibody candidates.3 However, in August 2024, BioNTech announced its strategic decision to opt-out of further co-development and potential commercialization of Acasunlimab, citing reasons related to its internal portfolio strategy. Consequently, Genmab assumed sole responsibility for the program's continued global development and future commercialization efforts. Under the revised agreement, BioNTech remains eligible for certain developmental milestones and tiered single-digit royalties on net sales.13 This transition to Genmab's sole ownership, despite what BioNTech acknowledged as an "encouraging clinical profile" 13, underscores the significant financial and strategic commitments required for late-stage development. Genmab's decision to fully invest highlights their strong conviction in Acasunlimab's potential, positioning it as a key wholly-owned asset 14, a strategic pivot likely reflecting differing risk appetites or resource allocation priorities between the former collaborators rather than a fundamental flaw in the drug's potential.
• Therapeutic Class: Acasunlimab is classified as an antineoplastic agent, specifically a bispecific monoclonal antibody, and falls under the broad category of immunotherapy.3
• Molecular Design and Proprietary Technologies:
• Bispecific Antibody Nature: Acasunlimab is a recombinant, human IgG1 bispecific antibody that dually targets human PD-L1 and human 4-1BB (CD137).[1]
• Genmab's DuoBody® Technology Platform:
• Mechanism: The DuoBody® platform is a proprietary technology developed by Genmab for the efficient generation of stable, IgG-like bispecific antibodies. The process involves the co-expression of two different parental IgG1 antibodies, each targeting one of the desired antigens (PD-L1 and 4-1BB in the case of Acasunlimab). These parental antibodies incorporate specific, matched point mutations in their CH3 domains. Under controlled in vitro redox conditions, these antibodies are mixed, leading to the dissociation of the homodimers into half-molecules (heavy-chain/light-chain pairs). The engineered CH3 domains then preferentially drive the reassembly of these half-molecules into functional heterodimeric bispecific antibodies, with high purity (typically >95%) and preventing light chain mispairing.[4] This process effectively mimics a natural IgG Fab-arm exchange process but in a controlled and efficient manner.
• Advantages: This platform produces bispecific antibodies that retain the structural and pharmacokinetic properties of conventional IgG antibodies, including a long plasma half-life. The resulting bispecific antibodies are stable and possess good manufacturability. A key advantage is the prevention of light chain mispairing, a common issue with other bispecific antibody formats, which contributes to the high purity of the final product.[51] The DuoBody® technology is thus crucial for Acasunlimab's design, enabling the creation of a stable and manufacturable bispecific antibody with the desired dual-targeting functionality and the capacity for Fc-silencing. This technological underpinning is a key differentiator for Genmab's bispecific antibody pipeline, addressing historical manufacturing challenges for such complex molecules.
• Fc-Silenced IgG1 Backbone:
• Rationale: Acasunlimab is constructed on an Fc-silenced (also referred to as Fc-inert) IgG1 backbone.[1] This modification is critical for its intended mechanism and safety profile. The Fc region of a standard IgG1 antibody can interact with Fc gamma receptors (FcγRs) expressed on various immune cells, triggering effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). While beneficial for some therapeutic antibodies, these effector functions can be detrimental for others, particularly for agonistic antibodies targeting co-stimulatory receptors like 4-1BB. Non-specific activation of 4-1BB through FcγR-mediated cross-linking can lead to widespread, systemic immune activation and associated toxicities, most notably hepatotoxicity, which has been a significant challenge in the development of previous 4-1BB agonistic antibodies.[33]
• Benefit: By incorporating Fc-silencing mutations (e.g., LALA-PG mutations, which abrogate binding to FcγRs and C1q), the effector functions of the Acasunlimab Fc region are minimized.[55] This design ensures that the 4-1BB agonistic activity of Acasunlimab is primarily, if not exclusively, driven by the cross-linking event mediated by its binding to PD-L1 on target cells within the TME. This localized activation strategy aims to maximize anti-tumor efficacy while minimizing systemic side effects, thereby improving the therapeutic window [[33]

Works cited

1. Definition of Acasunlimab - NCI Drug Dictionary, accessed May 23, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/acasunlimab
2. Acasunlimab (GEN1046) | Bispecific Antibody - MedchemExpress.com, accessed May 23, 2025, https://www.medchemexpress.com/acasunlimab.html
3. Acasunlimab - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 23, 2025, https://synapse.patsnap.com/drug/4492c0932eaa446180af5394c7390841
4. Acasunlimab (GEN1046) Clinical Trials Insight - Kuick Research, accessed May 23, 2025, https://www.kuickresearch.com/acasunlimab-gen1046-clinical-trials-insight-clinical
5. pmc.ncbi.nlm.nih.gov, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9662884/#:~:text=DuoBody%2DPD%2DL1%C3%974,1BB%20stimulation%20in%20one%20molecule.
6. Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors - PubMed Central, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9662884/
7. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity via complementary immune modulatory effects - PMC - PubMed Central, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11987116/
8. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity via complementary immune modulatory effects - PubMed, accessed May 23, 2025, https://pubmed.ncbi.nlm.nih.gov/40216443/
9. (PDF) Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients With Advanced Refractory Solid Tumors - ResearchGate, accessed May 23, 2025, https://www.researchgate.net/publication/358727005_Preclinical_Characterization_and_Phase_I_Trial_Results_of_a_Bispecific_Antibody_Targeting_PD-L1_and_4-1BB_GEN1046_in_Patients_With_Advanced_Refractory_Solid_Tumors
10. (PDF) Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity via complementary immune modulatory effects - ResearchGate, accessed May 23, 2025, https://www.researchgate.net/publication/390718047_Acasunlimab_an_Fc-inert_PD-L14-1BB_bispecific_antibody_combined_with_PD-1_blockade_potentiates_antitumor_immunity_via_complementary_immune_modulatory_effects?_tp=eyJjb250ZXh0Ijp7InBhZ2UiOiJqb3VybmFsIiwicHJldmlvdXNQYWdlIjoic2NpZW50aWZpY0NvbnRyaWJ1dGlvbnMiLCJzdWJQYWdlIjoib3ZlcnZpZXcifX0
11. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity via complementary immune modulatory effects | Journal for ImmunoTherapy of Cancer, accessed May 23, 2025, https://jitc.bmj.com/content/13/4/e011377
12. 719 Acasunlimab combined with PD-1 blockade elicits complementary immune-modulatory effects and enhances anti-tumor activity in preclinical models | Journal for ImmunoTherapy of Cancer, accessed May 23, 2025, https://jitc.bmj.com/content/12/Suppl_2/A821
13. BioNTech exits PD-L1 development with Genmab as Q2 revenues ..., accessed May 23, 2025, https://www.pharmaceutical-technology.com/news/biontech-exits-pd-l1-development-with-genmab-as-q2-revenues-drop/
14. Genmab Takes Full Control of Acasunlimab Development Program - BioSpace, accessed May 23, 2025, https://www.biospace.com/genmab-takes-full-control-of-acasunlimab-development-program
15. Genmab Takes Full Control of Acasunlimab Development Program, accessed May 23, 2025, https://ir.genmab.com/news-releases/news-release-details/genmab-takes-full-control-acasunlimab-development-program/
16. BioNTech halts development of Genmab-collaborated bispecific antibody acasunlimab, accessed May 23, 2025, https://synapse.patsnap.com/article/biontech-halts-development-of-genmab-collaborated-bispecific-antibody-acasunlimab
17. Investigational Acasunlimab (DuoBody-PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity in Phase 2 Trial in Patients with Previously Treated Metastatic Non-small Cell Lung Cancer (mNSCLC) - FirstWord Pharma, accessed May 23, 2025, https://firstwordpharma.com/story/5862821
18. Acasunlimab (DuoBody-PD-L1x4-1BB) alone or in combination with pembrolizumab (pembro) in patients (pts) with previously treated, accessed May 23, 2025, https://ascopubs.org/doi/pdf/10.1200/JCO.2024.42.16_suppl.2533
19. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity in Phase 2 Trial in Patients with Previously Treated Metastatic Non-small Cell Lung Cancer (mNSCLC) - Business Wire, accessed May 23, 2025, https://www.businesswire.com/news/home/20240601902871/en/Investigational-Acasunlimab-DuoBody--PD-L1x4-1BB-in-Combination-with-Pembrolizumab-Demonstrates-Meaningful-Clinical-Activity-in-Phase-2-Trial-in-Patients-with-Previously-Treated-Metastatic-Non-small-Cell-Lung-Cancer-mNSCLC
20. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity, accessed May 23, 2025, https://ml-eu.globenewswire.com/Resource/Download/2415ad8b-e418-4af8-b659-d059d53b5490
21. Leading antibody science for better futures., accessed May 23, 2025, https://ir.genmab.com/static-files/0a7a7302-59d4-45fc-b6b7-5caa33222e07
22. ASCO 2024 – acasunlimab impresses on overall survival | ApexOnco - Oncology Pipeline, accessed May 23, 2025, https://www.oncologypipeline.com/apexonco/asco-2024-acasunlimab-impresses-overall-survival
23. Giannis Mountzios: 10 exciting compounds that will shape lung cancer in 2025 - Oncodaily, accessed May 23, 2025, https://oncodaily.com/drugs/giannis-mountzios214773
24. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity in Phase 2 Trial in Patients with Previously Treated Metastatic Non-small Cell Lung Cancer (mNSCLC) | BioNTech, accessed May 23, 2025, https://investors.biontech.de/news-releases/news-release-details/investigational-acasunlimab-duobodyr-pd-l1x4-1bb-combination/
25. Acasunlimab: A Promising New Treatment for Non-Small Cell Lung Cancer - Clinical trials, accessed May 23, 2025, https://clinicaltrials.eu/inn/acasunlimab/
26. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06) - ClinicalTrials.Veeva, accessed May 23, 2025, https://ctv.veeva.com/study/trial-to-evaluate-acasunlimab-and-pembrolizumab-combination-superiority-over-standard-of-care-doceta
27. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06), accessed May 23, 2025, https://www.georgiacancerinfo.org/trialDetailPrint.aspx?trialID=5748
28. A Prospective, Open-Label, Randomized, Phase 3 Trial of Acasunlimab (GEN1046) in Combination With Pembrolizumab Versus Docetaxel in Subjects With PD-L1 Positive Metastatic Non-Small Cell Lung Cancer After Treatment With a PD-1/PD-L1 Inhibitor and Platinum-Containing Chemotherapy | UVA Health, accessed May 23, 2025, https://uvahealth.com/clinicaltrials/prospective-open-label-randomized-phase-3-trial-acasunlimab-gen1046-combination
29. GCT1046-06 Trial of Acasunlimab (Gen1046; DuoBody®-PD-L1x4-1BB) - Genmab, accessed May 23, 2025, https://www.genmab.com/privacy/clinical-trials-privacy-policy-gct1046-06
30. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06), accessed May 23, 2025, https://www.abbvieclinicaltrials.com/study/?id=GCT1046-06
31. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06) - Georgia CORE, accessed May 23, 2025, https://www.georgiacancerinfo.org/clinical-trials/detail/5748
32. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06), accessed May 23, 2025, https://clin.larvol.com/trial-detail/NCT06635824
33. The PD-L1/4-1BB Bispecific Antibody–Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner - AACR Journals, accessed May 23, 2025, https://aacrjournals.org/clincancerres/article/28/15/3387/707095/The-PD-L1-4-1BB-Bispecific-Antibody-Anticalin
34. Addressing the unmet need in NSCLC progression with advances in second-line therapeutics - PMC, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11700623/
35. Unmet Needs in NSCLC Treatment - American Journal of Managed Care, accessed May 23, 2025, https://www.ajmc.com/view/unmet-needs-in-nsclc-treatment
36. 4-1BB Antibodies in Oncology Clinical Trials: A Review - Allen Press, accessed May 23, 2025, https://meridian.allenpress.com/innovationsjournals-JIPO/article/8/2/121/506216/4-1BB-Antibodies-in-Oncology-Clinical-Trials-A
37. ATG-101 Is a Tetravalent PD-L1×4-1BB Bispecific Antibody That Stimulates Antitumor Immunity through PD-L1 Blockade and PD-L1–Directed 4-1BB Activation - PubMed Central, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11094422/
38. Clinical Trials Using Anti-4-1BB/PD-L1 Bispecific Antibody BH3120 - NCI, accessed May 23, 2025, https://www.cancer.gov/research/participate/clinical-trials/intervention/anti-4-1bb-pd-l1-bispecific-antibody-bh3120
39. Acasunlimab - BioNTech/Genmab - AdisInsight - Springer, accessed May 23, 2025, https://adisinsight.springer.com/drugs/800054549
40. Acasunlimab by BioNTech for Non-Small Cell Lung Cancer: Likelihood of Approval, accessed May 23, 2025, https://www.pharmaceutical-technology.com/data-insights/acasunlimab-biontech-non-small-cell-lung-cancer-likelihood-of-approval/
41. Pipeline | Genmab, accessed May 23, 2025, https://www.genmab.com/antibody-science/pipeline
42. Genmab and BioNTech Expand Global Strategic Collaboration to Develop and Commercialize Novel Immunotherapy Candidates, accessed May 23, 2025, https://ir.genmab.com/news-releases/news-release-details/genmab-and-biontech-expand-global-strategic-collaboration/
43. Leading Antibody Science for Better Futures, accessed May 23, 2025, https://ir.genmab.com/static-files/1a422c1a-382d-4c62-921a-1733164cf253
44. Genmab and BioNTech report data from Phase II GCT1046-04 trial for mNSCLC, accessed May 23, 2025, https://www.clinicaltrialsarena.com/news/genmab-data-phase-ii-gct1046/
45. Genmab A/S (GMAB) Q1 2025 Earnings Conference Call Transcript | Seeking Alpha, accessed May 23, 2025, https://seekingalpha.com/article/4787609-genmab-a-s-gmab-q1-2025-earnings-conference-call-transcript
46. Q4 2024 Genmab A/S Earnings Call Transcript - GuruFocus, accessed May 23, 2025, https://www.gurufocus.com/stock/WBO:GMAB/transcripts/2695185
47. Genmab Interim Report, accessed May 23, 2025, https://ir.genmab.com/static-files/e17c16da-89cb-4e68-a34e-9222da5e4098
48. Leading antibody science for better futures., accessed May 23, 2025, https://ir.genmab.com/static-files/83c918b1-8bf5-4181-9424-a4143ebf52ac
49. Acasunlimab: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed May 23, 2025, https://go.drugbank.com/drugs/DB18932
50. What are the primary areas of focus for Genmab? - Patsnap Synapse, accessed May 23, 2025, https://synapse.patsnap.com/article/what-are-the-primary-areas-of-focus-for-genmab
51. Unique Technology Platforms For Developing Antibody Medicines | Genmab US, accessed May 23, 2025, https://www.us.genmab.com/research/antibody-science
52. Genmab to Highlight New Data Evaluating Late-Stage Oncology Portfolio at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting - FirstWord Pharma, accessed May 23, 2025, https://firstwordpharma.com/story/5965643
53. Genmab to Highlight New Data Evaluating Late-Stage Oncology Portfolio at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting - BioSpace, accessed May 23, 2025, https://www.biospace.com/press-releases/genmab-to-highlight-new-data-evaluating-late-stage-oncology-portfolio-at-the-2025-american-society-of-clinical-oncology-asco-annual-meeting
54. Bispecific Antibodies: A Comprehensive Overview - evitria, accessed May 23, 2025, https://www.evitria.com/bispecific-antibodies/bispecific-antibodies/
55. Effective cancer immunotherapy combining mRNA-encoded bispecific antibodies that induce polyclonal T cell engagement and PD-L1-dependent 4-1BB costimulation - Frontiers, accessed May 23, 2025, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1494206/full
56. (PDF) An Fc-muted bispecific antibody targeting PD-L1 and 4-1BB induces antitumor immune activity in colorectal cancer without systemic toxicity - ResearchGate, accessed May 23, 2025, https://www.researchgate.net/publication/371172519_An_Fc-muted_bispecific_antibody_targeting_PD-L1_and_4-1BB_induces_antitumor_immune_activity_in_colorectal_cancer_without_systemic_toxicity
57. Fc-Silent Antibody | Pursuing a Known Target in a New Way - Arcus Biosciences, accessed May 23, 2025, https://arcusbio.com/editorials/fc-silent-antibody/
58. Fc Silenced Antibodies - ichorbio, accessed May 23, 2025, https://ichor.bio/fc-silenced-antibodies
59. pmc.ncbi.nlm.nih.gov, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7398503/#:~:text=Our%20results%20showed%20that%20Fc,splenic%20engraftment%20and%20renal%20infiltration.
60. Bispecific Antibodies: Expanding the Frontiers of Targeted Immunotherapy - Biointron, accessed May 23, 2025, https://www.biointron.com/blog/bispecific-antibodies-expanding-the-frontiers-of-targeted-immunotherapy.html
61. Acasunlimab (GEN1046) | Bispecific Antibody - MedchemExpress.com, accessed May 23, 2025, https://www.medchemexpress.com/acasunlimab.html?locale=ja-JP
62. acasunlimab (GEN1046) / Genmab - LARVOL DELTA, accessed May 23, 2025, https://delta.larvol.com/products/?ProductId=adf0a7c8-61de-47bf-844e-401d41e040b4&Index=0
63. GEN1046 Safety Trial in Patients With Malignant Solid Tumors | Clinical Research Trial Listing - CenterWatch, accessed May 23, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT03917381/gen1046-safety-trial-in-patients-with-malignant-solid-tumors
64. GEN1046 Safety Trial in Patients With Malignant Solid Tumors, accessed May 23, 2025, https://www.abbvieclinicaltrials.com/study/?id=GCT1046-01
65. Clinical Trial Details | GCI, accessed May 23, 2025, https://www.georgiacancerinfo.org/trialDetailPrint.aspx?trialID=4968
66. 412 First-in-human phase I/IIa trial to evaluate the safety and initial clinical activity of DuoBody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors | Journal for ImmunoTherapy of Cancer, accessed May 23, 2025, https://jitc.bmj.com/content/8/Suppl_3/A250.2
67. Clinical Trial: NCT03917381 - My Cancer Genome, accessed May 23, 2025, https://www.mycancergenome.org/content/clinical_trials/NCT03917381/
68. GEN1046 Safety Trial in Patients With Malignant Solid Tumors - NCI, accessed May 23, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-03735
69. GEN1046 Safety and PK in Subjects With Advanced Solid Malignancies - ngram, accessed May 23, 2025, https://www.ngram.com/trials/NCT04937153
70. acasunlimab (GEN1046) News - LARVOL Sigma, accessed May 23, 2025, https://sigma.larvol.com/product.php?e1=783388&tab=newstrac
71. GEN1046 Safety and PK in Subjects With Advanced Solid Malignancies, accessed May 23, 2025, https://dev-cr.dapstudies.com/find-trials/Study/NCT04937153
72. GEN1046 Safety and PK in Subjects With Advanced Solid Malignancies - LarvolClin, accessed May 23, 2025, https://clin.larvol.com/trial-detail/NCT04937153
73. Safety and Efficacy Study of GEN1046 as a Single Agent or in Combination With Pembrolizumab for Treatment of Recurrent (Non-small Cell) Lung Cancer, accessed May 23, 2025, https://www.abbvieclinicaltrials.com/study/?id=GCT1046-04
74. Safety and Efficacy Study of GEN1046 as a Single Agent or in Combination With Pembrolizumab for Treatment of Recurrent (Non-small Cell) Lung Cancer | Clinical Research Trial Listing - CenterWatch, accessed May 23, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT05117242/safety-and-efficacy-study-of-gen1046-as-a-single-agent-or-in-combination-with-pembrolizumab-for-treatment-of-recurrent-non-small-cell-lung-cancer
75. BioNTech to Present Clinical Data Updates for Next-Generation Immunotherapy Candidates at the ASCO Annual Meeting 2024, accessed May 23, 2025, https://investors.biontech.de/news-releases/news-release-details/biontech-present-clinical-data-updates-next-generation/
76. GEN1046 in Combination With Anticancer Agents for the Treatment of Advanced Endometrial Cancer - NCI, accessed May 23, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-09673
77. GEN1046 Safety Trial in Patients With Malignant Solid Tumors - ClinicalTrials.Veeva, accessed May 23, 2025, https://ctv.veeva.com/study/gen1046-safety-trial-in-patients-with-malignant-solid-tumors
78. SGO 2025 – Genmab's advantage looks Profound | ApexOnco - Oncology Pipeline, accessed May 23, 2025, https://www.oncologypipeline.com/apexonco/sgo-2025-genmabs-advantage-looks-profound
79. GCT1046-05 - NHS Health Research Authority, accessed May 23, 2025, https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/gct1046-05/
80. First-in-human, multicenter, open-label, phase I study of ATOR-1017 (evunzekibart), a 4-1BB antibody, in patients with advanced solid malignancies - PMC, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11784162/
81. BioNTech Outlines 2024 Strategic Priorities at the 42nd Annual J.P. Morgan Healthcare Conference - BioSpace, accessed May 23, 2025, https://www.biospace.com/biontech-outlines-2024-strategic-priorities-at-the-42nd-annual-j-p-morgan-healthcare-conference
82. FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma, accessed May 23, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-bendamustine-and-rituximab-previously-untreated-mantle-cell-lymphoma
83. EU/3/24/2966 - orphan designation for treatment of gastric cancer | European Medicines Agency (EMA), accessed May 23, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-24-2966
84. Oncology Drugs Fast-Tracked by the FDA in February 2025, accessed May 23, 2025, https://www.oncologynewscentral.com/drug/oncology-drugs-fast-tracked-by-the-fda-in-february-2025
85. EU/3/22/2731 - orphan designation for treatment of small cell lung cancer, accessed May 23, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-22-2731
86. Most FDA and EMA Oncology Drug Approvals in Q1 2025 Were New Indications for Biologics and Biosimilars - Aptitude Health, accessed May 23, 2025, https://www.aptitudehealth.com/oncology-news/most-fda-and-ema-oncology-drug-approvals-in-q1-2025-were-new-indications-for-biologics-and-biosimilars/
87. EMA approves acalabrutinib combination for patients with previously untreated MCL, accessed May 23, 2025, https://lymphomahub.com/medical-information/ema-approves-acalabrutinib-combination-for-patients-with-previously-untreated-mcl
88. MCLA-145 by Merus for Head And Neck Squamous Cell Carcinoma (HNSC): Likelihood of Approval - Pharmaceutical Technology, accessed May 23, 2025, https://www.pharmaceutical-technology.com/data-insights/mcla-145-merus-head-and-neck-squamous-cell-carcinoma-hnsc-likelihood-of-approval/
89. A Phase 1, Open-Label, Dose-Escalation, Safety, Tolerability, and ..., accessed May 23, 2025, https://www.dana-farber.org/clinical-trials/19-093
90. News Releases - Inhibrx | Investors, accessed May 23, 2025, https://inhibrxbiosciences.investorroom.com/2019-02-19-Inhibrx-Announces-Dosing-of-First-Patient-in-Phase-1-Dose-Escalation-Study-of-INBRX-105-a-Novel-Multispecific-PD-L1-and-4-1BB-Antibody
91. inbrx-105 - My Cancer Genome, accessed May 23, 2025, https://www.mycancergenome.org/content/drugs/inbrx-105/
92. FS-222 by F-star Therapeutics for Melanoma: Likelihood of Approval, accessed May 23, 2025, https://www.pharmaceutical-technology.com/data-insights/fs-222-f-star-therapeutics-melanoma-likelihood-of-approval/
93. F-star Therapeutics Announces First Patient Dosed in FS222 Phase 1 Clinical Trial, accessed May 23, 2025, https://f-star.com/wp-content/uploads/2022/09/F-star-Therapeutics-Announces-First-Patient-Dosed-in-FS222-Phase-1-Clinical-Trial.pdf
94. Pipeline - ABL503 - ABL Bio, accessed May 23, 2025, https://www.ablbio.com/en/company/pipeline07
95. abl503 - My Cancer Genome, accessed May 23, 2025, https://www.mycancergenome.org/content/drugs/abl503/
96. Abstract CT078: Results of a phase 1 first-in-human study of PRS ..., accessed May 23, 2025, https://aacrjournals.org/cancerres/article/85/8_Supplement_2/CT078/761427/Abstract-CT078-Results-of-a-phase-1-first-in-human?searchresult=1
97. PRS-344/S095012: A Promising New Treatment for Solid Tumors - Clinical trials, accessed May 23, 2025, https://clinicaltrials.eu/inn/prs-344/
98. ATG-101 by Antengene for Triple-Negative Breast Cancer (TNBC): Likelihood of Approval, accessed May 23, 2025, https://www.pharmaceutical-technology.com/data-insights/atg-101-antengene-triple-negative-breast-cancer-tnbc-likelihood-of-approval/
99. The autophagy-related gene Atg101 in Drosophila regulates both neuron and midgut homeostasis - PMC - PubMed Central, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6462509/
100. Hanmi Pharmaceutical and Beijing Hanmi Progress BH3120 Cancer Immunotherapy Trials, accessed May 23, 2025, https://synapse.patsnap.com/blog/hanmi-pharmaceutical-and-beijing-hanmi-progress-bh3120-cancer-immunotherapy-trials
101. BH3120 | Pipeline | Hanmi Pharmaceutical, accessed May 23, 2025, https://www.hanmipharm.com/science/pipeline/focused/bh3120.hm
102. MCLA-145 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 23, 2025, https://synapse.patsnap.com/drug/8661cdced1b044ff8329bf4a9938268d
103. Abstract 539: A bispecific Fc-silenced IgG1 antibody (MCLA-145) requires PD-L1 binding to activate CD137 | Request PDF - ResearchGate, accessed May 23, 2025, https://www.researchgate.net/publication/335051801_Abstract_539_A_bispecific_Fc-silenced_IgG1_antibody_MCLA-145_requires_PD-L1_binding_to_activate_CD137
104. 742 Phase 1/2 study of the bispecific 4–1BB and PD-L1 antibody INBRX-105 alone and in combination with pembrolizumab in select solid tumors | Journal for ImmunoTherapy of Cancer, accessed May 23, 2025, https://jitc.bmj.com/content/11/Suppl_1/A836
105. Agonism of 4-1BB is dependent on engagement of INBRX-105 with cell surface PD-L14, accessed May 23, 2025, https://inhibrxbiosciences.investorroom.com/download/INBRX_105_SITC_TiP_Poster_SUBMISSION_16Oct2023.pdf
106. FS222, a CD137/PD-L1 Tetravalent Bispecific Antibody, Exhibits Low Toxicity and Antitumor Activity in Colorectal Cancer Models - AACR Journals, accessed May 23, 2025, https://aacrjournals.org/clincancerres/article/26/15/4154/82490/FS222-a-CD137-PD-L1-Tetravalent-Bispecific
107. 668 FS222 is a CD137/PD-L1 tetravalent, bispecific antibody which elicits robust pharmacodynamic activity in advanced solid tumor patients in a FIH study | Journal for ImmunoTherapy of Cancer, accessed May 23, 2025, https://jitc.bmj.com/content/12/Suppl_2/A766
108. The PD-L1 x 4-1BB Bispecific Antibody ABL503 Shows - Potent Anti-Tumor Effect through Tumor-Directed T Cell Activation, accessed May 23, 2025, https://www.ablbio.com/ctrlDownload/document_download/board/576
109. ABL Bio's ABL503 Patent Issued in Indonesia and China, accessed May 23, 2025, https://ablbio.com/en/company/news_view/738
110. The PD-L1/4-1BB Bispecific Antibody–Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner - PMC, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9662934/
111. A Study ATG-101 in Patients With Metastatic/Advanced Solid Tumors and Mature B-cell Non-Hodgkin Lymphomas - Cancer Trial Results, accessed May 23, 2025, https://clin.larvol.com/trial-detail/NCT04986865
112. ATG-101 Is a Tetravalent PD-L1×4-1BB Bispecific Antibody That Stimulates Antitumor Immunity through PD-L1 Blockade and PD-L1-Directed 4-1BB Activation - PubMed, accessed May 23, 2025, https://pubmed.ncbi.nlm.nih.gov/38501978/
113. 698 A phase I, open-label, multinational, multicenter, dose escalation and expansion study of BH3120 (4–1BB x PD-L1 BsAb) in patients with advanced or metastatic solid tumors | Journal for ImmunoTherapy of Cancer, accessed May 23, 2025, https://jitc.bmj.com/content/12/Suppl_2/A800
114. Merus Announces Financial Results for the Fourth Quarter and Full Year 2023 and Provides Business Update - GlobeNewswire, accessed May 23, 2025, https://www.globenewswire.com/news-release/2024/02/28/2837467/37568/en/Merus-Announces-Financial-Results-for-the-Fourth-Quarter-and-Full-Year-2023-and-Provides-Business-Update.html
115. Inhibrx Reports Fourth Quarter and Fiscal Year 2024 Financial Results - Mar 17, 2025, accessed May 23, 2025, https://inhibrxbiosciences.investorroom.com/2025-03-17-Inhibrx-Reports-Fourth-Quarter-and-Fiscal-Year-2024-Financial-Results
116. Inhibrx Reports Fourth Quarter and Fiscal Year 2024 Financial Results - PR Newswire, accessed May 23, 2025, https://www.prnewswire.com/news-releases/inhibrx-reports-fourth-quarter-and-fiscal-year-2024-financial-results-302403351.html
117. FS222 / Sino Biopharm - LARVOL DELTA, accessed May 23, 2025, https://delta.larvol.com/Products/?ProductId=1fb47c34-ed7f-4649-9b51-a6bcc8268fde
118. News - ABL Bio, accessed May 23, 2025, https://www.ablbio.com/en/company/news/9?
119. News - ABL Bio, accessed May 23, 2025, http://www.ablbio.com/en/company/news/18?
120. Pieris Pharmaceuticals and Servier Announce Dosing of First Patient in Phase 1/2 Trial of 4-1BB/PD-L1 Bispecific PRS-344/S095012, accessed May 23, 2025, https://www.accessnewswire.com/newsroom/en/biotechnology/pieris-pharmaceuticals-and-servier-announce-dosing-of-first-patient-in-phase-12-trial-671610
121. Antengene Announces IND Approval in China for the Phase I Study of ATG-101 (PD-L1/4-1BB Bispecific Antibody) for the Treatment of Solid Tumors and Non-Hodgkin Lymphoma - FirstWord Pharma, accessed May 23, 2025, https://firstwordpharma.com/story/5522561
122. Hanmi Pharmaceutical Seeks New Frontiers in Cancer Immunotherapy with mRNA Platform, accessed May 23, 2025, https://www.hanmipharm.com/about/investor-relations/press/detail-1982.hm
123. Hanmi Pharmaceutical to Present Next-Generation Cancer Therapies at AACR, accessed May 23, 2025, https://www.businesskorea.co.kr/news/articleView.html?idxno=239818
124. I-Mab Announces Portfolio Prioritization of Givastomig (CLDN18.2 x 4-1BB Bispecific Antibody) as Lead Clinical Program - BioSpace, accessed May 23, 2025, https://www.biospace.com/press-releases/i-mab-announces-portfolio-prioritization-of-givastomig-cldn18-2-x-4-1bb-bispecific-antibody-as-lead-clinical-program
125. Phase 1 trial safety and efficacy of ragistomig, a bispecific antibody targeting PD-L1 and 4-1BB, in advanced solid tumors., accessed May 23, 2025, https://ascopubs.org/doi/pdf/10.1200/JCO.2024.42.16_suppl.2529
126. Antengene Presents Encouraging Clinical Data from Four Pipeline Programs at the 2023 R&D Day - BioSpace, accessed May 23, 2025, https://www.biospace.com/antengene-presents-encouraging-clinical-data-from-four-pipeline-programs-at-the-2023-r-and-amp-d-day
127. This is a Study to Evaluate the Safety and Tolerability of ABL503, and to Determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of ABL503 in Subjects with Any Progressive Locally Advanced or Metastatic Solid Tumors - LarvolClin, accessed May 23, 2025, https://clin.larvol.com/trial-detail/NCT04762641
128. Study of TJ033721 (givastomig) in Subjects with Advanced or Metastatic Solid Tumors, accessed May 23, 2025, https://clin.larvol.com/trial-detail/NCT04900818
129. Antengene Announces 2024 Full-Year Financial Results, Proprietary Programs Advancing to Pivotal Trials with Accelerating Multi-market Revenue Ramp Up, accessed May 23, 2025, https://antengene.com/newsinfo/422
130. BioNTech to Present Data from BNT311 (GEN1046) and BNT131 (SAR441000) Programs at SITC 35th Annual, accessed May 23, 2025, https://biontechse.gcs-web.com/node/8621/pdf
131. Anti-PD-L1-Based Bispecific Antibodies Targeting Co-Inhibitory and Co-Stimulatory Molecules for Cancer Immunotherapy - PubMed Central, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10819708/
132. BioNTech and Genmab Expand Global Strategic Collaboration to Develop and Commercialize Novel Immunotherapy Candidates, accessed May 23, 2025, https://investors.biontech.de/news-releases/news-release-details/biontech-and-genmab-expand-global-strategic-collaboration/
133. BNT-113 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 23, 2025, https://synapse.patsnap.com/drug/61f4e53fe42c479c8d3c834621765532
134. Genmab to Showcase Data in Various Patient Populations to be Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting - Business Wire, accessed May 23, 2025, https://www.businesswire.com/news/home/20240523620002/en/Genmab-to-Showcase-Data-in-Various-Patient-Populations-to-be-Presented-at-the-American-Society-of-Clinical-Oncology-ASCO-Annual-Meeting
135. BioNTech to Present Clinical Updates for Next-Gen Immunotherapies at ASCO 2024, accessed May 23, 2025, https://synapse.patsnap.com/article/biontech-to-present-clinical-updates-for-next-gen-immunotherapies-at-asco-2024
136. 202410203 - Siteman Cancer Center, accessed May 23, 2025, https://siteman.wustl.edu/clinical-trial/202410203/
137. Search for 2018-003402-63 - Clinical Trials register, accessed May 23, 2025, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003402-63
138. Clinical trials - Regulation EU No 536/2014 - European Commission - Public Health, accessed May 23, 2025, https://health.ec.europa.eu/medicinal-products/clinical-trials/clinical-trials-regulation-eu-no-5362014_en
139. Search for 2021-001928-17 - Clinical Trials register, accessed May 23, 2025, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2021-001928-17
140. PT - EU Clinical Trials Register, accessed May 23, 2025, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-001928-17/PT
141. Search for clinical trials - EMA - CTIS, accessed May 23, 2025, https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2022-501863-41-00
142. CLINICAL TRIAL AGREEMENT FOR THE DRUG(S) CONTRATTO PER LA CONDUZIONE DELLA SPERIMENTAZIONE CLINICA SU MEDICINALI BETWEEN TRA Azi, accessed May 23, 2025, https://www.mauriziano.it/flex/FixedPages/Common/AttachDownload.php?D=czo0OToiUHJvdnZlZGltZW50by1ERy05MjctMjAyMy9NT0RFTExPX0NPTlZFTlpJT05FLnBkZiI7&P=czo4MToiL3Zhci93d3cvdmhvc3RzL3d3dy5tYXVyaXppYW5vLml0L2ZsZXgvQXBwRGF0YS9SZWRhdGlvbmFsL0RlbGliZXJlRGV0ZXJtaW5lRmlsZXMvIjs=
143. Genmab to Highlight New Data Evaluating Late-Stage Oncology Portfolio at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting | Morningstar, accessed May 23, 2025, https://www.morningstar.com/news/business-wire/20250522461621/genmab-to-highlight-new-data-evaluating-late-stage-oncology-portfolio-at-the-2025-american-society-of-clinical-oncology-asco-annual-meeting
144. I-Mab Biopharma, accessed May 23, 2025, https://www.i-mabbiopharma.com/static-files/47411f69-3b59-4860-8abc-5590a4c2767f
145. Distribution of general development status category - YAbS database - The Antibody Society, accessed May 23, 2025, https://db.antibodysociety.org/db0/results_target?sort=-isotype_fc&page=35
146. Solid Tumors (DBCOND0029860) | DrugBank Online, accessed May 23, 2025, https://go.drugbank.com/conditions/DBCOND0029860
147. Unveiling the Synergistic Potential: Bispecific Antibodies in Conjunction with Chemotherapy for Advanced Non-Small-Cell Lung Cancer Treatment - MDPI, accessed May 23, 2025, https://www.mdpi.com/1718-7729/32/4/206
148. 4-1BB Antibodies in Oncology Clinical Trials: A Review - PMC, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11936102/
149. BL-M07D1, a novel HER2 antibody-drug conjugate, in subjects with locally advanced or metastatic HER2 expressing breast cancer and other solid tumors: Results from a phase 1 study - SystImmune, accessed May 23, 2025, https://systimmune.com/documents/BL-M07D1-101-SABCS-2023-Poster-20231114-Final.pdf
150. About the Ozempic (semaglutide) shortage | Therapeutic Goods Administration (TGA), accessed May 23, 2025, https://www.tga.gov.au/safety/shortages/information-about-major-medicine-shortages/about-ozempic-semaglutide-shortage