An Overview of ABBV-291: An Investigational CD79b-Targeting Antibody-Drug Conjugate for B-Cell Non-Hodgkin Lymphoma

1. Introduction to ABBV-291

ABBV-291 is an investigational therapeutic agent currently under development by AbbVie Inc..[1] It belongs to the class of antibody-drug conjugates (ADCs) and is being evaluated in early-stage clinical trials for the treatment of certain hematological malignancies.[1] The primary focus of ABBV-291 is to address the significant unmet medical need in patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Despite initial treatment successes with chemoimmunotherapy, which cures approximately 60% of patients with diffuse large B-cell lymphoma (DLBCL)—the most prevalent form of B-NHL—a substantial number of patients either do not respond to initial therapy or experience disease relapse. These individuals often face a poor prognosis and limited therapeutic alternatives, underscoring the urgent requirement for novel and effective treatments.[1]

The development of ABBV-291 aligns with AbbVie's broader strategic commitment to advancing its oncology portfolio. The company is actively pursuing a diverse pipeline of cancer therapies, encompassing various modalities such as small molecule inhibitors, immuno-oncology agents, and notably, antibody-drug conjugates.[5] AbbVie's presentations at major oncology conferences have highlighted key data from this expanding portfolio, featuring several ADC candidates, including ABBV-291, ABBV-400 (telisotuzumab adizutecan), and ABBV-706.[5] This pattern of concurrent ADC development, coupled with the company's stated intention to leverage "innovative platforms such as ADCs," points towards a deliberate and significant investment in ADC technology as a cornerstone of their oncology research and development strategy.[8] Furthermore, AbbVie has already achieved regulatory milestones with another ADC, EMRELIS (telisotuzumab vedotin-tllv), which has received FDA approval.[10] This existing experience within AbbVie in navigating the development, regulatory processes, and potential manufacturing scale-up for ADCs could confer advantages for the progression of ABBV-291.

2. Overview of ABBV-291: Characteristics and Mechanism of Action

ABBV-291 is classified as an antineoplastic agent and, more specifically, an antibody-drug conjugate (ADC).[1] ADCs represent a therapeutic strategy designed to selectively deliver highly potent cytotoxic agents to cancer cells by targeting specific antigens expressed on the tumor cell surface, thereby aiming to maximize efficacy at the tumor site while minimizing systemic toxicity.

The antibody component of ABBV-291 is engineered to target CD79b, a transmembrane protein that is part of the B-cell receptor (BCR) complex.[1] CD79b plays a crucial role in B-cell signaling and survival. Importantly, it is expressed on the surface of B-cells throughout their development and is found on most major subtypes of B-NHL, including its validated expression in DLBCL.[1] This expression profile makes CD79b an attractive and clinically validated target for ADC-based therapies in B-cell malignancies.

The cytotoxic component of ABBV-291 is a potent topoisomerase 1 inhibitor.[1] Topoisomerase 1 inhibitors are a class of chemotherapeutic drugs that function by interfering with the activity of topoisomerase I, an enzyme essential for DNA replication, transcription, and repair. Inhibition of this enzyme leads to the accumulation of DNA strand breaks, ultimately triggering apoptosis (programmed cell death) in rapidly dividing cancer cells.

The proposed mechanism of action for ABBV-291 follows the typical paradigm for ADCs. First, the anti-CD79b antibody component of ABBV-291 binds with high specificity to CD79b expressed on the surface of malignant B-cells. Upon binding, the ABBV-291-CD79b complex is internalized into the cancer cell, likely through receptor-mediated endocytosis. Once inside the cell, the linker connecting the antibody to the cytotoxic payload (the specifics of which are not detailed in the available information) is designed to be cleaved, releasing the active topoisomerase 1 inhibitor. This released payload then exerts its cytotoxic effect by inhibiting topoisomerase 1, leading to DNA damage and subsequent death of the B-NHL cell.[1] While detailed specifics of ABBV-291's linker are not provided, the general mechanism of CD79b-targeted ADCs involves payload release following internalization, as seen with polatuzumab vedotin, although its payload is monomethyl auristatin E (MMAE).[12]

Preclinical investigations have provided a strong rationale for advancing ABBV-291 into clinical trials. These studies have reportedly demonstrated robust antitumor activity.[1] Furthermore, preclinical models have suggested that ABBV-291 may achieve superior responses when compared to other anti-CD79b ADCs.[1] A significant aspect of its preclinical profile is the potential for a more favorable safety profile, particularly with respect to lower rates of key adverse events such as neuropathy, when compared to ADCs that utilize MMAE as their cytotoxic payload.[1] This potential for reduced neuropathy is a noteworthy feature, as MMAE-based ADCs, including the approved CD79b-targeting agent Polivy (polatuzumab vedotin), are associated with this toxicity.[1] The selection of a topoisomerase 1 inhibitor payload for ABBV-291, therefore, appears to be a strategic decision aimed at mitigating this known limitation of some established ADC technologies. If ABBV-291 can demonstrate comparable or enhanced efficacy alongside a clinically meaningful reduction in neuropathy, it could offer a significant therapeutic advantage.

The assertion from preclinical data that ABBV-291 "offers potential as a best-in-class treatment in DLBCL" and has demonstrated "superior responses compared with other anti-CD79b ADCs" sets a high benchmark.[1] However, it is crucial to recognize that preclinical findings do not always directly translate to clinical outcomes in humans. The competitive landscape includes established treatments like Polivy and other investigational agents such as SHR-A1912, which also employs a topoisomerase 1 inhibitor payload and is advancing through late-stage clinical trials.[11] Therefore, the forthcoming human clinical trial data for ABBV-291 will be paramount in substantiating these preclinical claims and determining its true therapeutic potential relative to existing and emerging competitors.

Detailed information regarding the specific chemical structure of the antibody, the linker technology, or the precise topoisomerase 1 inhibitor used in ABBV-291 is not publicly available in the provided documentation.[15] Similarly, specific patent details for the unique composition of ABBV-291 are not fully elucidated, though such proprietary information is typical for investigational compounds.[16]

Table 1: ABBV-291 - Key Drug Characteristics

Characteristic	Details
Drug Name	ABBV-291
Alternative Names	None specified
Developer/Sponsor	AbbVie Inc. 1
Drug Type	Antibody-Drug Conjugate (ADC) 1
Target Antigen	CD79b 1
Cytotoxic Payload	Topoisomerase 1 inhibitor 1
Proposed Indications (Clinical Trial)	Relapsed/Refractory B-cell Non-Hodgkin Lymphoma (including DLBCL, Follicular Lymphoma, Mantle Cell Lymphoma) 1

3. Therapeutic Indications

ABBV-291 is primarily being investigated for the treatment of adult patients diagnosed with relapsed or refractory (R/R) B-cell Non-Hodgkin Lymphoma (B-NHL).[1] This focus addresses a patient population with significant unmet medical needs, as these individuals have often exhausted standard therapeutic options or have diseases that are resistant to conventional treatments.

The ongoing Phase 1 clinical trial (NCT06667687) is designed to enroll patients with a range of B-NHL subtypes. However, the dose expansion and optimization phases of this study will specifically concentrate on evaluating ABBV-291 in patients with:

• Diffuse Large B-cell Lymphoma (DLBCL) [1]
• Follicular Lymphoma (FL) [1]
• Mantle Cell Lymphoma (MCL) [1]

While the expansion cohorts are focused on these three subtypes, the trial protocol also allows for the inclusion of patients with other B-NHL histologies, such as Marginal Zone Lymphoma (MZL) and Waldenstrom Macroglobulinemia (WM), during the initial dose-escalation phase.[19] Notably, Chronic Lymphocytic Leukemia (CLL) is an explicit exclusion criterion for this study.[1]

The rationale for targeting B-NHL with ABBV-291 is twofold. Firstly, as previously mentioned, there is a substantial unmet need, particularly in R/R DLBCL, where many patients ultimately succumb to their disease despite available therapies.[1] Secondly, the molecular target of ABBV-291, CD79b, is broadly expressed across most major subtypes of B-NHL and is considered a validated therapeutic target, especially in DLBCL.[1] The widespread expression of CD79b, a critical component of the B-cell receptor [20], across various B-NHL histologies provides a strong biological basis for investigating ABBV-291 in this diverse group of malignancies. This broad target expression suggests that if ABBV-291 demonstrates efficacy, its applicability could extend beyond the initial focus areas of DLBCL, FL, and MCL. Positive clinical signals observed in the broader B-NHL population during the dose-escalation phase could prompt AbbVie to explore indications in less common B-NHL subtypes in subsequent development, thereby potentially expanding its market reach. The current focus on DLBCL, FL, and MCL in the expansion cohorts likely reflects a strategic prioritization based on factors such as disease prevalence, the extent of unmet need, and existing preclinical or biological rationale.

The clinical trial (NCT06667687) is specifically designed for a heavily pre-treated patient population. Eligible participants must be relapsed or refractory to, or intolerant of, at least two or more prior lines of therapy and must have no other locally available therapies known to provide clinical benefit.[1] This focus on a challenging patient group means that demonstrating a meaningful clinical benefit would represent a significant therapeutic advance. Regulatory agencies often provide pathways for expedited review and approval for drugs that can address such high unmet needs. However, this patient population may also present with more comorbidities and a higher susceptibility to treatment-related adverse events, which will necessitate careful safety monitoring and evaluation throughout the trial.

4. Clinical Development Program: Focus on NCT06667687

ABBV-291 is currently in Phase 1 of clinical development.[1] The cornerstone of its early clinical evaluation is the first-in-human study identified by the clinical trial identifier NCT06667687.[1] The official title of this study is "A phase 1 first-in-human study evaluating safety, pharmacokinetics, and efficacy of ABBV-291, a CD79b-targeting antibody-drug conjugate, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma," with similar descriptions such as "Study to Evaluate Adverse Events, Change in Disease Activity, and How Intravenously Infused ABBV-291 Moves Through the Body in Adult Participants With Non-Hodgkin's Lymphoma" also being used.[1]

This is an open-label, multicenter study, reflecting standard practice for early-phase oncology trials, and is structured in multiple parts to systematically evaluate ABBV-291 [1]:

• Part 1: Dose Escalation: This part aims to enroll up to approximately 45 patients. It employs a Bayesian Optimal Interval (BOIN) design, a model-based adaptive method that can be more efficient in identifying the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) compared to traditional rule-based designs like the 3+3 method. To enhance safety, the administration of ABBV-291 for the first two patients at each of the initial two dose levels is staggered by at least 24 hours.
• Part 2: Dose Expansion and Optimization: This part is planned to enroll approximately 120 patients and is further divided:
• Dose Expansion: ABBV-291 will be evaluated at the Recommended Phase 1 Expansion Dose (RP1ED), determined in Part 1, in specific cohorts of patients with DLBCL and FL.
• Dose Optimization: For patients with MCL, ABBV-291 will be evaluated at two or more dose levels. This suggests that a more tailored dosing strategy might be necessary for this particular subtype, or that further refinement of the optimal dose is required.

The primary objectives of the NCT06667687 study are to assess the safety and tolerability of ABBV-291 and to determine its RP1ED.[1] Secondary objectives include evaluating the preliminary efficacy of ABBV-291 in the specified subsets of R/R B-NHL (DLBCL, FL, MCL). Efficacy endpoints will include Objective Response Rate (ORR), Duration of Response (DoR), and Progression-Free Survival (PFS). Another key secondary objective is to characterize the pharmacokinetic (PK) profile of ABBV-291, determining how the drug is absorbed, distributed, metabolized, and excreted by the body.[1]

Exploratory objectives are also incorporated into the study design, notably to investigate the potential association between various biomarkers and clinical outcomes, including safety, efficacy, and PK parameters.[1] This emphasis on biomarker analysis, coupled with the requirement for baseline tumor tissue via biopsy for immunohistochemistry (IHC) testing and the potential for on-treatment biopsies in certain cohorts [19], signals a robust effort to understand which patients are most likely to benefit from ABBV-291 and the underlying mechanisms of response or resistance. Such biomarker-driven insights are crucial for targeted therapies like ADCs. For instance, the conditional allowance for enrolling patients previously treated with a CD79b-targeting therapy, provided a new tumor biopsy is collected post-therapy [19], suggests an interest in evaluating ABBV-291 in patients who may have developed resistance to other CD79b agents or in characterizing the target antigen after such treatments. Findings from these biomarker analyses could inform patient selection strategies in later-phase trials, potentially enhancing the probability of clinical success and helping to define a more precise therapeutic niche for ABBV-291.

Key inclusion criteria for the study include adult patients (≥18 years) with a documented diagnosis of B-NHL (excluding CLL), measurable disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (indicating patients are fully ambulatory and capable of light work or more), and disease that is relapsed or refractory to, or intolerant of, at least two prior lines of systemic therapy.[1] Patients must also have no other available therapies that are known to provide clinical benefit. For Part 2, specific histological confirmation of DLBCL, FL, or MCL according to World Health Organization (WHO) criteria is required.[19]

Key exclusion criteria include a history of interstitial lung disease (ILD) or pneumonitis that required treatment with systemic steroids, or any current evidence of active ILD or pneumonitis.[19] Prior treatment with other CD79b-directed agents within 4 weeks (or 5 half-lives) before the first dose of ABBV-291 is also an exclusion, unless a new tumor biopsy is obtained after the most recent CD79b-targeting therapy. Treatment with other anticancer therapies (chemotherapy, radiotherapy, small molecules, investigational agents, biologics) within 14 days (or at least 5 half-lives, whichever is shorter) prior to the first dose of study treatment is prohibited.[19]

ABBV-291 is administered intravenously (IV).[1] Patients will continue treatment until documented disease progression, unacceptable toxicity, or other protocol-defined discontinuation criteria are met. Safety evaluations are comprehensive and include ongoing monitoring of adverse events (AEs), assessment of dose-limiting toxicities (DLTs) for 35 days from the initial dose in the dose-escalation phase, and regular checks of vital signs, electrocardiograms (ECGs), and clinical laboratory parameters.[1]

The NCT06667687 study, sponsored by AbbVie, Inc., is actively enrolling participants at multiple sites globally.[1] The trial was officially posted on clinical trial registries around October 31, 2024.[18] The adaptive and efficient trial design, utilizing BOIN methodology and distinct cohorts for different B-NHL subtypes, aims to maximize the information gathered from this early-phase study. This approach can potentially accelerate the decision-making process for subsequent, larger trials and help identify promising patient subgroups early in development.

Table 2: Overview of Clinical Trial NCT06667687

Parameter	Details
Trial ID	NCT06667687 1
Phase	Phase 1 1
Official Title (example)	"A Phase 1 First-In-Human Study Evaluating Safety, Pharmacokinetics, and Efficacy of ABBV-291 in Patients With Relapsed/Refractory B-cell Non-Hodgkin Lymphoma" 1
Status	Recruiting 16
Sponsor	AbbVie Inc. 1
Primary Objectives	Assess safety/tolerability of ABBV-291; Determine Recommended Phase 1 Expansion Dose (RP1ED) 1
Secondary Objectives	Evaluate preliminary efficacy (Objective Response Rate, Duration of Response, Progression-Free Survival) in R/R B-NHL subsets (DLBCL, FL, MCL); Characterize Pharmacokinetics (PK) 1
Study Design	Open-label, multicenter, dose-escalation (BOIN methodology), dose-expansion, and dose-optimization 1
Key Inclusion Criteria (Summary)	Adults ≥18 years, confirmed R/R B-NHL (excluding CLL), ≥2 prior lines of therapy, ECOG performance status 0–1, measurable disease, no other appropriate locally available standard therapies 1
Key Exclusion Criteria (Summary)	Prior CD79b-targeting therapy (conditional on new biopsy), active interstitial lung disease/pneumonitis, recent other anticancer therapies 19
Investigated Subgroups (Expansion/Optimization)	Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL) 1

5. Preliminary Clinical Data (Anticipated)

The first public disclosure of human clinical data for ABBV-291 from the ongoing Phase 1 study (NCT06667687) is anticipated at the American Society of Clinical Oncology (ASCO) Annual Meeting scheduled between May 30 and June 3, 2025. AbbVie has announced that a poster presentation (Abstract #5579, Poster Board #477) detailing this study will take place on Sunday, June 1, 2025.[8]

Based on the primary and secondary objectives of the NCT06667687 trial [1], the initial data presentation is expected to cover several key categories:

• Safety and Tolerability: This will likely be a major focus of the initial report. Data will include the types, frequencies, and severity of adverse events (AEs) observed across different dose levels. Information on dose-limiting toxicities (DLTs) encountered during the dose-escalation phase will be crucial for understanding the drug's safety profile and for the determination of the Maximum Tolerated Dose (MTD), if reached, and the Recommended Phase 1 Expansion Dose (RP1ED). A particularly critical aspect of the safety data will be the incidence and severity of neuropathy. Given the preclinical hypothesis that ABBV-291's topoisomerase 1 inhibitor payload might lead to lower rates of neuropathy compared to MMAE-payload ADCs [1], this specific adverse event will be closely scrutinized. A demonstrably favorable neuropathy profile compared to historical data for agents like Polivy would be a significant differentiating factor for ABBV-291 and could position it as a safer alternative, especially for patients at risk for or with pre-existing neuropathy, or those considered for long-term treatment.
• Pharmacokinetics (PK): The presentation is expected to include initial pharmacokinetic parameters, such as maximum concentration (Cmax​), area under the curve (AUC), and half-life, determined using noncompartmental analysis methods. These data will help in understanding the drug's behavior in the human body and inform dosing schedules.
• Preliminary Efficacy: While early-phase trials primarily focus on safety, preliminary efficacy signals are also highly anticipated. This may include the Objective Response Rate (ORR) in the overall patient population and potentially within specific B-NHL subtypes enrolled (DLBCL, FL, MCL). Data on the Duration of Response (DoR) for any responding patients and, if the follow-up is sufficient, initial trends in Progression-Free Survival (PFS) might also be presented. Response evaluations are conducted according to disease-specific standardized criteria.

The preliminary efficacy data, particularly ORR and DoR, will inevitably be compared, albeit informally, to the established efficacy of existing therapies for R/R B-NHL and other CD79b-targeting ADCs. For instance, Polatuzumab vedotin has demonstrated efficacy in R/R DLBCL [11], and SHR-A1912, another ADC with a topoisomerase 1 inhibitor payload, has reported promising ORRs (59-61% as monotherapy in R/R B-NHL in early data, and a 73.0% ORR when combined with R-GemOx in R/R DLBCL in a Phase 1b/2 study).[11] For ABBV-291 to support its preclinical "best-in-class" aspiration [1], it would ideally need to demonstrate efficacy that is at least comparable, if not superior, to these benchmarks, alongside any demonstrated safety advantages. Even early-phase efficacy signals that are competitive, when combined with a favorable safety profile (especially regarding neuropathy), would build significant confidence for continued and potentially accelerated development.

6. Regulatory Status and Designations

ABBV-291 is currently an investigational drug. As such, it has not yet received marketing approval from major regulatory authorities, including the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[2] Its status is that of a compound undergoing clinical evaluation to determine its safety and efficacy.

As of the latest available information (December 2024), ABBV-291 has not been granted Orphan Drug Designation by the FDA or EMA.[2] Orphan Drug Designation is a status assigned to drugs and biologics intended for the safe and effective treatment, diagnosis, or prevention of rare diseases or disorders, typically defined as those affecting fewer than 200,000 people in the United States, or meeting specific criteria related to prevalence and lack of satisfactory treatments in the European Union. While certain subtypes of B-NHL are considered rare, an overarching designation for B-NHL might not be applicable unless development is focused on specific, qualifying rare subtypes. Nevertheless, the potential for future regulatory designations remains. Should Phase 1/2 clinical data demonstrate significant promise, particularly in R/R B-NHL subtypes with high unmet medical needs or in rarer forms of the disease, AbbVie could pursue designations such as Breakthrough Therapy Designation from the FDA or PRIME (PRIority MEdicines) status from the EMA. Such designations are intended to expedite the development and review of drugs that show potential to provide substantial improvements over available therapies for serious conditions. AbbVie has a track record of obtaining such designations for other oncology products, for example, EMRELIS (telisotuzumab vedotin-tllv) received Breakthrough Therapy Designation from the FDA [10], indicating the company's familiarity with these programs. Achieving such a designation for ABBV-291 could significantly accelerate its development pathway.

ABBV-291 is classified as a New Molecular Entity (NME).[2] This classification is standard for novel investigational drugs that contain an active moiety not previously approved by the regulatory authority. NME status can have implications for market exclusivity periods upon potential approval.

AbbVie's experience with the regulatory processes for other ADCs, notably the successful navigation of EMRELIS to an accelerated FDA approval [10], demonstrates an established in-house expertise. This prior experience with ADC development, including managing regulatory interactions and understanding the data requirements for expedited pathways (such as accelerated approval based on ORR and DoR from Phase 2 studies), could be advantageously leveraged for ABBV-291. This familiarity may help streamline the regulatory strategy and interactions for ABBV-291, potentially contributing to a more efficient path toward approval if the clinical data prove compelling.

7. Competitive Landscape and Market Positioning

CD79b has emerged as a clinically validated and attractive therapeutic target in B-cell malignancies. Its expression on most major subtypes of B-NHL and its integral role as a component of the B-cell receptor complex provide a strong rationale for its targeting.[1] The development of ABBV-291 occurs within an active and competitive field of CD79b-targeting antibody-drug conjugates.

Key competitors in this space include:

• Polatuzumab Vedotin (Polivy; developed by Roche/Genentech): This is currently the most established CD79b-targeting ADC.
• Payload: Monomethyl auristatin E (MMAE), an auristatin derivative that acts as a microtubule inhibitor.[11]
• Status: Approved by regulatory authorities in multiple regions. Its indications include use in combination with R-CHP (rituximab, cyclophosphamide, doxorubicin, prednisone) for previously untreated DLBCL and in combination with bendamustine and rituximab for R/R DLBCL after at least two prior therapies.[11]
• Mechanism: Polatuzumab vedotin binds to CD79b on B-cells, leading to internalization of the ADC. Lysosomal proteases then cleave the linker, releasing MMAE, which binds to tubulin and inhibits microtubule polymerization, causing cell cycle arrest and apoptosis.[12]
• Noteworthy Issue: Peripheral neuropathy is a recognized and clinically significant adverse event associated with its MMAE payload, which can be dose-limiting and impact quality of life.[1]
• SHR-A1912 (developed by Jiangsu HengRui): This ADC is another significant player targeting CD79b.
• Payload: Topoisomerase 1 (Topo1) inhibitor.[11]
• Status: It is in late-stage clinical development, with a Phase 3 trial underway evaluating SHR-A1912 in combination with R-GemOx (rituximab, gemcitabine, oxaliplatin) versus R-GemOx alone in patients with R/R DLBCL. A Phase 1/2 trial is also exploring its use in first-line patient populations.[11]
• Clinical Data: Early Phase 1 data in the R/R setting indicated an ORR of 59% in DLBCL patients and 61% across all B-NHL subtypes treated with monotherapy. One report mentioned a 100% ORR in DLBCL at a 3.6mg/kg dose, though the sample size for this specific dose was not detailed in the provided information.[11] More recent data from a Phase 1b/2 study (NCT06104553) of SHR-A1912 (at 1.8 mg/kg) combined with R-GemOx in 37 R/R DLBCL patients showed an ORR of 73.0% and a Complete Response (CR) rate of 51.4%. The most common Grade ≥3 treatment-emergent adverse events were hematological toxicities.[20]
• NBT508 (developed by NewBio Therapeutics): This is an earlier-stage CD79b-targeting ADC.
• Payload: MMAE (auristatin).[11]
• Status: Currently in Phase 1 clinical trials for R/R B-cell non-Hodgkin's lymphoma.[11]

ABBV-291 aims to differentiate itself within this competitive field primarily through its payload. The use of a topoisomerase 1 inhibitor is hypothesized to offer an improved safety profile, particularly a lower incidence and severity of neuropathy, when compared to MMAE-based ADCs like Polivy and NBT508.[1] This potential safety advantage, if clinically validated, could be a major distinguishing factor. Furthermore, AbbVie's preclinical data suggested that ABBV-291 might offer superior antitumor responses compared to other anti-CD79b ADCs [1], a claim that awaits substantiation in human trials.

The concurrent development of ABBV-291 and SHR-A1912, both employing topoisomerase 1 inhibitor payloads, highlights an emerging trend in the ADC field. This suggests a broader industry effort to identify and utilize payloads that can overcome known limitations of earlier ADC technologies, such as the neurotoxicity associated with MMAE. AbbVie itself is exploring Topo1i payloads in other ADC candidates within its pipeline, such as ABBV-400 (telisotuzumab adizutecan) and ABBV-969 [6], indicating a strategic investment in this payload class. The clinical performance and safety outcomes of these Topo1 inhibitor-based ADCs will be critical in determining if they can offer a better benefit-risk profile and potentially displace MMAE-based ADCs for targets where toxicity is a significant concern.

However, the promising efficacy data from SHR-A1912, especially its 73% ORR in combination therapy for R/R DLBCL [20], and the established market presence of Polivy, create a high benchmark. For ABBV-291, which is at an earlier stage of development, to achieve its "best-in-class" aspiration, it will need to demonstrate not just non-inferiority but clear and clinically meaningful advantages in efficacy, safety, or applicability to specific patient populations. The preclinical assertion of "superior responses" will require robust clinical validation to be compelling in this dynamic landscape.

Table 3: Competitive Landscape of Key CD79b-Targeting ADCs

Project Name	Company	Payload Type	Highest Development Status	Key Indication(s) (R/R B-NHL Focus)
Polivy (Polatuzumab Vedotin)	Roche/Genentech	MMAE (Auristatin)	Approved	DLBCL / B-NHL 11
SHR-A1912	Jiangsu HengRui	Topo1 inhibitor	Phase 3	R/R DLBCL 11
NBT508	NewBio Therapeutics	MMAE (Auristatin)	Phase 1	R/R B-NHL 11
ABBV-291	AbbVie	Topo1 inhibitor	Phase 1	R/R B-NHL (DLBCL, FL, MCL) 1

8. Developer Overview: AbbVie Inc.

AbbVie Inc. is a global biopharmaceutical company with a pronounced commitment to the discovery and development of innovative medicines, particularly in therapeutic areas with high unmet medical needs. Oncology is a core strategic focus for AbbVie, with substantial investment in building a comprehensive portfolio and a robust pipeline aimed at addressing difficult-to-treat solid tumors and blood cancers.[5] The company's mission in oncology is to elevate standards of care and deliver transformative therapies to patients worldwide.[5]

AbbVie's oncology pipeline is characterized by its breadth and the diversity of its therapeutic modalities. The company is actively advancing investigational agents that include small molecule therapeutics, antibody-drug conjugates (ADCs), immuno-oncology-based therapies, multispecific antibodies, and novel CAR-T platforms.[5] This multi-pronged approach allows AbbVie to target various cancer pathways and tumor types. Recent announcements have showcased progress with several investigational molecules, such as the ADCs telisotuzumab adizutecan (ABBV-400) and ABBV-706, the bispecific antibody pivekimab sunirine (PVEK), another ADC ABBV-969, and the antibody ABBV-514, reflecting the dynamism of their research efforts.[6]

Within its ADC platform, AbbVie has demonstrated growing expertise and has achieved notable regulatory success. EMRELIS™ (telisotuzumab vedotin-tllv), a c-Met-directed ADC utilizing an MMAE payload, received accelerated approval from the U.S. FDA for certain types of non-small cell lung cancer, marking AbbVie's first internally developed solid tumor medicine to gain such approval.[10] This success underscores the company's capability in advancing complex ADC molecules through clinical development and regulatory review.

ABBV-291 represents a key component of AbbVie's strategy in the hematologic malignancy space. It specifically leverages the company's ADC platform by combining a validated B-cell target (CD79b) with a next-generation payload (topoisomerase 1 inhibitor) to address the challenges in R/R B-NHL. The development of ABBV-291 is indicative of a strategic evolution in AbbVie's ADC payload selection. While EMRELIS incorporates an MMAE payload, several newer ADCs in AbbVie's pipeline, including ABBV-291, ABBV-400 (telisotuzumab adizutecan, a c-Met directed ADC with a Top1i payload), and ABBV-969 (a STEAP1/PSMA dual-targeted ADC with a Top1i payload), utilize topoisomerase 1 inhibitors.[1] This shift suggests a deliberate move to explore payloads with potentially improved safety and tolerability profiles, such as reduced neuropathy, or those that may offer efficacy against different tumor types or resistance mechanisms. This diversification enhances AbbVie's ADC technological capabilities, enabling a more tailored approach to ADC design based on specific tumor biology and clinical requirements, and reflects an adaptation to broader industry trends in ADC innovation.

Furthermore, AbbVie's extensive experience in developing, manufacturing, and navigating the regulatory landscape for multiple ADCs (EMRELIS, ABBV-400, ABBV-706, ABBV-291, ABBV-969) fosters an internal accumulation of knowledge and platform-specific expertise. This internal synergy is valuable, as common challenges in ADC development—such as optimizing linker stability, payload conjugation chemistry, ensuring scalable and consistent manufacturing, and managing class-specific or payload-specific toxicities—can be addressed more effectively. Lessons learned from one ADC program, for example, in managing toxicities or in regulatory interactions for EMRELIS, can directly inform and potentially de-risk the development pathways for other candidates like ABBV-291. The company's emphasis on its "innovative platforms such as ADCs" [8] underscores this integrated approach. This internal cross-learning and platform synergy could translate into more efficient and successful development trajectories for AbbVie's entire ADC portfolio, including ABBV-291, potentially leading to accelerated timelines and an increased probability of bringing impactful new medicines to patients.

9. Summary and Future Outlook

ABBV-291 is a novel, investigational antibody-drug conjugate developed by AbbVie Inc., characterized by its targeting of the CD79b antigen on B-cells and its delivery of a potent topoisomerase 1 inhibitor payload. It is currently being evaluated in a global, multicenter Phase 1 clinical trial (NCT06667687) involving adult patients with various subtypes of relapsed or refractory B-cell Non-Hodgkin Lymphoma, with specific expansion cohorts planned for Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), and Mantle Cell Lymphoma (MCL).

The primary therapeutic goal for ABBV-291 is to provide a new and effective treatment option for patients with heavily pre-treated B-NHL who have limited or no satisfactory alternatives. Based on its proposed mechanism of action and supporting preclinical data, a key potential advantage of ABBV-291 lies in its topoisomerase 1 inhibitor payload. This payload class is hypothesized to offer an improved safety and tolerability profile, particularly with a lower incidence or severity of neuropathy, compared to ADCs utilizing monomethyl auristatin E (MMAE)-based payloads, while aiming to maintain or enhance antitumor efficacy.

The ongoing Phase 1 trial is crucial for establishing the foundational clinical profile of ABBV-291. It is designed to meticulously assess its safety, tolerability, and pharmacokinetic properties, and to determine a Recommended Phase 1 Expansion Dose (RP1ED). Preliminary efficacy data will also be gathered. The first presentation of human clinical data from this study is anticipated at the ASCO Annual Meeting in June 2025.[8] Positive outcomes from this Phase 1 study, particularly demonstrating a manageable safety profile and encouraging signs of antitumor activity, would be essential for AbbVie to advance ABBV-291 into later-stage Phase 2 and potentially Phase 3 clinical trials.

The future development and potential market positioning of ABBV-291 will be influenced by several factors. The competitive landscape is dynamic, with an approved CD79b-targeting ADC (Polatuzumab Vedotin) and other investigational agents, notably SHR-A1912 (also a topoisomerase 1 inhibitor ADC), in advanced stages of development.[11] The initial Phase 1 data for ABBV-291 will therefore be critically evaluated, not only for its intrinsic merits but also in the context of these existing and emerging competitors. Given AbbVie's preclinical "best-in-class" aspiration for ABBV-291 [1] and the presence of a Phase 3 competitor utilizing a similar payload technology, the imperative for compelling early clinical data is substantial. A strong data readout could significantly bolster confidence and accelerate development, whereas modest or ambiguous results might necessitate a re-evaluation of its competitive standing and development strategy within AbbVie's extensive oncology pipeline.

Biomarker analyses from the NCT06667687 trial are also expected to play a significant role. Identifying specific patient populations or biological markers that predict response or resistance to ABBV-291 could help refine its therapeutic niche and optimize patient selection in future studies.

AbbVie's long-term commitment to ABBV-291 will likely be contingent on these early clinical signals and how the drug aligns with the company's broader oncology strategy and ADC platform capabilities. Positive data that reinforce the potential benefits of their Topo1i payload technology and demonstrate clear efficacy in defined B-NHL populations would encourage continued investment. Even if ABBV-291 does not achieve blockbuster status, it could still become a valuable therapeutic option for specific patient segments if it offers a distinct and favorable benefit-risk profile. Its development will also contribute valuable knowledge and experience to AbbVie's overall ADC platform, informing future research and development efforts in this promising class of cancer therapeutics.

Works cited

1. A phase 1 first-in-human study evaluating safety, pharmacokinetics, and efficacy of ABBV-291, a CD79b-targeting antibody-drug conjugate, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. - ASCO Publications, accessed June 9, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS7093
2. ABBV 291 - AdisInsight - Springer, accessed June 9, 2025, https://adisinsight.springer.com/drugs/800080326
3. Likelihood of Approval and Phase Transition Success Rate Model – ABBV-291 in Diffuse Large B-Cell Lymphoma - GlobalData, accessed June 9, 2025, https://www.globaldata.com/store/report/abbv-291-in-diffuse-large-b-cell-lymphoma-loa-innovation-and-trend-analysis/
4. A phase 1 first-in-human study evaluating safety, pharmacokinetics, and efficacy of ABBV-291, a CD79b-targeting antibody-drug co, accessed June 9, 2025, https://ascopubs.org/doi/pdf/10.1200/JCO.2025.43.16_suppl.TPS7093
5. AbbVie Features New Data Across Difficult-to-Treat Solid Tumors and Blood Cancers at ASCO 2025, Highlighting Breadth and Depth of its Oncology Portfolio, accessed June 9, 2025, https://investingnews.com/abbvie-features-new-data-across-difficult-to-treat-solid-tumors-and-blood-cancers-at-asco-2025-highlighting-breadth-and-depth-of-its-oncology-portfolio/
6. AbbVie Showcases Early Pipeline and Scientific Advances in Oncology at AACR Annual Meeting 2025 - PR Newswire, accessed June 9, 2025, https://www.prnewswire.com/news-releases/abbvie-showcases-early-pipeline-and-scientific-advances-in-oncology-at-aacr-annual-meeting-2025-302411497.html
7. AbbVie's Oncology Pipeline Shows Breakthrough Potential in Rare and Refractory Cancers: A Strategic Investment Opportunity - AInvest, accessed June 9, 2025, https://www.ainvest.com/news/abbvie-oncology-pipeline-shows-breakthrough-potential-rare-refractory-cancers-strategic-investment-opportunity-2505/
8. AbbVie Features New Data Across Difficult-to-Treat Solid Tumors and Blood Cancers at ASCO 2025, Highlighting Breadth and Depth of its Oncology Portfolio, accessed June 9, 2025, https://news.abbvie.com/2025-05-27-AbbVie-Features-New-Data-Across-Difficult-to-Treat-Solid-Tumors-and-Blood-Cancers-at-ASCO-2025,-Highlighting-Breadth-and-Depth-of-its-Oncology-Portfolio
9. AbbVie Features New Data Across Difficult-to-Treat Solid Tumors and Blood Cancers at ASCO 2025, Highlighting Breadth and Depth of its Oncology Portfolio - PR Newswire, accessed June 9, 2025, https://www.prnewswire.com/news-releases/abbvie-features-new-data-across-difficult-to-treat-solid-tumors-and-blood-cancers-at-asco-2025-highlighting-breadth-and-depth-of-its-oncology-portfolio-302464933.html
10. U.S. FDA Approves EMRELIS for Adults With Previously Treated Advanced Non-Small Cell Lung Cancer With High c-Met Protein Overexpression - Investing News Network, accessed June 9, 2025, https://investingnews.com/u-s-fda-approves-emrelis-for-adults-with-previously-treated-advanced-non-small-cell-lung-cancer-with-high-c-met-protein-overexpression/
11. HengRui challenges with a Polivy follow-on | ApexOnco - Oncology Pipeline, accessed June 9, 2025, https://www.oncologypipeline.com/apexonco/hengrui-challenges-polivy-follow
12. go.drugbank.com, accessed June 9, 2025, https://go.drugbank.com/drugs/DB12240#:~:text=Once%20the%20antibody%20component%20binds,effects%20against%20malignant%20B%20cells.
13. Polatuzumab vedotin: Uses, Interactions, Mechanism of Action, accessed June 9, 2025, https://go.drugbank.com/drugs/DB12240
14. Broadening the Therapeutic Window of ADCs Using Site-Specific Bioconjugation Showcased by an MMAE-Containing Peptide Linker in a CD79b-Targeting ADC - AACR Journals, accessed June 9, 2025, https://aacrjournals.org/mct/article/24/6/803/762661/Broadening-the-Therapeutic-Window-of-ADCs-Using
15. ABBV-CLS-7262 (Fosigotifator THAM sodium) | Eukaryotic Initiation Factor (eIF) Activator, accessed June 9, 2025, https://www.medchemexpress.com/abbv-cls-7262.html
16. ABBV-291 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed June 9, 2025, https://synapse.patsnap.com/drug/760c2516a73b4aa1bc2bea195e63a1c0
17. ALLERGAN USA, INC. v. MSN LABORATORIES PRIVATE LTD - U.S. Court of Appeals for the Federal Circuit, accessed June 9, 2025, https://www.cafc.uscourts.gov/opinions-orders/24-1061.OPINION.8-13-2024_2366074.pdf
18. ABBV-291 - MedPath, accessed June 9, 2025, https://trial.medpath.com/drug/a8d646091c7d44bc/abbv-291
19. Study to Evaluate Adverse Events, Change in Disease Activity, and How Intravenously Infused ABBV-291 Moves Through the Body in Adult Participants With Non-Hodgkin's Lymphoma - ClinConnect, accessed June 9, 2025, https://clinconnect.io/trials/NCT06667687
20. CD79b-targeted antibody-drug conjugate (ADC) SHR-A1912 in combination with rituximab, gemcitabine, and oxaliplatin (R-GemOx) in relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL): Data from a phase 1b/2 study. - ASCO Publications, accessed June 9, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.7013
21. ABBV-291 / AbbVie - LARVOL DELTA, accessed June 9, 2025, https://delta.larvol.com/Products/?ProductId=df8467fa-2ed6-4cc9-90d2-941984cae91e
22. CD79b-targeted antibody-drug conjugate (ADC) SHR-A1912 in combination with rituximab, gemcitabine, and oxaliplatin (R-GemOx) in relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL): Data from a phase 1b/2 study. - ResearchGate, accessed June 9, 2025, https://www.researchgate.net/publication/392303977_CD79b-targeted_antibody-drug_conjugate_ADC_SHR-A1912_in_combination_with_rituximab_gemcitabine_and_oxaliplatin_R-GemOx_in_relapsed_or_refractory_rr_diffuse_large_B-cell_lymphoma_DLBCL_Data_from_a_phas
23. Polatuzumab Vedotin-Piiq - Drug Targets, Indications, Patents - Patsnap Synapse, accessed June 9, 2025, https://synapse.patsnap.com/drug/cb6f4ca492c34c78a244c0071d5b9977
24. AbbVie Reports Full-Year and Fourth-Quarter 2024 Financial Results, accessed June 9, 2025, https://investors.abbvie.com/news-releases/news-release-details/abbvie-reports-full-year-and-fourth-quarter-2024-financial