ASP-1002: A Novel Bispecific Antibody Targeting CLDN4 and CD137 for Solid Tumor Immunotherapy

I. Executive Summary

ASP-1002 is an investigational, first-in-human bispecific antibody currently under development by Astellas Pharma Inc..[1] It is engineered as a tetravalent IgG-scFv antibody designed to concurrently target Claudin 4 (CLDN4), a protein often overexpressed on the surface of various tumor cells, and CD137 (also known as 4-1BB), a potent co-stimulatory receptor found on T cells.[1] The primary therapeutic goal of ASP-1002 is to augment the host's anti-tumor immune response. This is achieved by creating a bridge between CLDN4-expressing cancer cells and CD137-bearing T cells, thereby triggering CD137-mediated co-stimulation, which in turn promotes T-cell activation, proliferation, and cytotoxic capabilities directed against the tumor.[1] A significant design characteristic of ASP-1002 is its "silent" Fc region, which is intended to minimize Fc/FcγR-mediated systemic toxicities that have been a concern with previous CD137-targeting agonistic antibodies.[2]

Preclinical investigations have yielded promising results, demonstrating that ASP-1002 can induce CLDN4-dependent activation of CD137, leading to enhanced interferon-gamma (IFNγ) production by T cells. Moreover, these studies have shown substantial anti-tumor efficacy, including instances of complete tumor regression in various murine cancer models.[2]

Building on these preclinical findings, ASP-1002 is currently being assessed in a Phase 1, open-label, multicenter clinical trial (NCT05719558; Astellas study ID: 1002-CL-0101). This study enrolls adult patients with locally advanced or metastatic solid tumors confirmed to express CLDN4.[1] The principal objectives of this initial human trial are to evaluate the safety and tolerability of ASP-1002, and to establish the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) for subsequent clinical development.[1]

ASP-1002 embodies a novel immunotherapeutic strategy for cancers characterized by CLDN4 expression. Its design, which focuses on achieving tumor-localized immune activation while incorporating features to potentially enhance its safety profile relative to earlier CD137-targeting agents, underscores its potential significance. The development of ASP-1002 is indicative of a strategic advancement in immuno-oncology towards bispecific antibodies that offer conditional activation of potent immune pathways, such as CD137 signaling. This conditional activation is contingent upon the antibody's binding to a tumor-associated antigen, thereby aiming for an improved therapeutic index by concentrating the immune response at the tumor site and reducing systemic immune-related adverse events.[2]

II. Introduction to ASP-1002

ASP-1002: A Novel Bispecific Antibody for Solid Tumor Immunotherapy

ASP-1002 is an investigational therapeutic agent identified as a bispecific antibody.[1] It is specifically engineered as a tetravalent IgG-scFv bispecific antibody.[2] This molecular architecture enables ASP-1002 to dually target Claudin 4 (CLDN4) and the CD137 co-stimulatory receptor.[1]

Developer: Astellas Pharma Inc.

The development of ASP-1002 is being conducted by Astellas Pharma Inc., a global pharmaceutical company.[1] This places ASP-1002 within a robust research and development framework, benefiting from the extensive resources and expertise of a major pharmaceutical entity.

Therapeutic Rationale: Addressing Unmet Needs in CLDN4-Expressing Cancers via CD137 Co-stimulation

The therapeutic rationale for ASP-1002 is founded on two key biological observations: the frequent overexpression of CLDN4 in a variety of solid tumors that are often challenging to treat, and the potent anti-tumor immune responses that can be elicited through agonistic engagement of the CD137 co-stimulatory pathway on T cells.[1]

Current cancer treatments, including checkpoint inhibitors (CPIs), have significantly advanced patient outcomes; however, a substantial proportion of patients do not achieve durable responses, underscoring the persistent unmet medical need for novel therapeutic strategies.[2] ASP-1002 represents such a strategy. Unlike traditional CD3-based T-cell engagers, which directly link T cells to tumor cells for immediate killing but can cause significant on-target, off-tumor toxicity if the target antigen is also expressed on normal tissues, ASP-1002 targets a co-stimulatory molecule (CD137).[2] This co-stimulation is intended to be conditional, primarily occurring when ASP-1002 binds to CLDN4 on tumor cells, thereby localizing and enhancing an existing or induced T-cell response against the cancer. This approach may offer a wider therapeutic window. The selection of CLDN4 as the tumor-associated antigen (TAA) paired with CD137 agonism is designed to deliver a "conditional" immune activation signal. This implies that potent T-cell co-stimulation is intended to occur predominantly when ASP-1002 simultaneously engages CLDN4 on a tumor cell and CD137 on a T cell, focusing the immune potentiation within the tumor microenvironment.

III. Mechanism of Action

Dual Targeting Strategy

ASP-1002 employs a dual-targeting strategy, simultaneously engaging two distinct molecular entities:

• Claudin 4 (CLDN4): CLDN4 is a member of the claudin family of proteins, which are essential components of tight junctions that regulate paracellular permeability.[1] Its expression is significantly upregulated in a diverse range of epithelial cancers, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), colorectal cancer (CRC), prostate adenocarcinoma (PA), ovarian cancer (OC), and triple-negative breast cancer (TNBC).[1] This overexpression in malignant tissues, compared to more restricted or lower expression in some normal tissues, provides a basis for tumor-targeted therapy.[2] The differential expression levels and accessibility of CLDN4 on tumor cells versus normal cells are critical determinants for achieving a favorable therapeutic index.
• CD137 (4-1BB): CD137, also known as 4-1BB, is a potent co-stimulatory receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily. It is primarily expressed on activated CD4+ and CD8+ T cells, as well as on other immune cells such as natural killer (NK) cells, regulatory T cells, dendritic cells, and mast cells.[1] Agonistic signaling through CD137 plays a critical role in enhancing various aspects of T-cell function, including proliferation, survival, cytokine production (notably IFNγ), and the development of cytotoxic effector functions. These enhancements contribute to a more robust and sustained anti-tumor immune response.[1] Furthermore, CD137 signaling is implicated in the generation and maintenance of long-term memory T cells, which could be crucial for preventing tumor recurrence.[7]

Molecular Design of ASP-1002

ASP-1002 possesses specific molecular features designed to optimize its therapeutic activity and safety:

• Bispecific, tetravalent IgG-scFv antibody structure: ASP-1002 is constructed as a tetravalent antibody, likely incorporating two antigen-binding fragments (Fabs) from a standard IgG structure for one target, and two single-chain variable fragments (scFvs) for the other. This tetravalency allows for the simultaneous binding of two CLDN4 molecules on a tumor cell and two CD137 molecules on a T cell.[2] Such multivalent binding can enhance the avidity of interaction with target cells and promote receptor clustering, which is often critical for potent downstream signaling, particularly for co-stimulatory receptors like CD137.
• Significance of the silent Fc region: A key aspect of ASP-1002's design is the incorporation of a "silent" Fc region.[2] The Fc region of an antibody typically interacts with Fcγ receptors (FcγRs) on various immune cells, which can lead to antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or non-specific immune cell activation. For agonistic antibodies targeting co-stimulatory molecules like CD137, FcγR-mediated crosslinking can lead to widespread, systemic T-cell activation and associated toxicities, such as hepatotoxicity, which has been a significant hurdle in the development of previous CD137 agonists. By engineering the Fc region to be "silent" (i.e., to have minimal or no binding to FcγRs), ASP-1002 aims to prevent these off-target effects and improve its safety profile.

Proposed Immunological Cascade

The proposed mechanism by which ASP-1002 mediates its anti-tumor effects involves a sequence of molecular and cellular interactions:

1. ASP-1002, upon administration, circulates and seeks out CLDN4-expressing tumor cells. The CLDN4-binding arms of the antibody attach to CLDN4 molecules on the surface of these cancer cells.
2. Concurrently, the CD137-binding arms of ASP-1002 engage CD137 receptors expressed on nearby activated T cells. This dual binding effectively tethers the T cell to the tumor cell.
3. The co-ligation of CLDN4 on the tumor cell and CD137 on the T cell, facilitated by the bispecific antibody, leads to the clustering of CD137 receptors on the T-cell surface. In the context of a primary T-cell activation signal (e.g., T-cell receptor engagement with a tumor antigen presented by MHC molecules), this CD137 clustering delivers a potent co-stimulatory signal.
4. This co-stimulation significantly amplifies T-cell activation, leading to enhanced T-cell proliferation, increased survival of effector T cells, augmented production of pro-inflammatory cytokines like IFNγ, and an upregulation of cytotoxic machinery. Ultimately, this results in a more effective and targeted killing of the CLDN4-expressing tumor cells by the activated T cells.[1]

The core of ASP-1002's mechanism relies on "conditional agonism." Potent CD137-mediated co-stimulation is intended to be spatially restricted and significantly amplified primarily when ASP-1002 is bound to CLDN4 on tumor cells. This localized activation is fundamental to the drug's proposed efficacy and its potential for an improved safety profile compared to systemic CD137 agonists. The bispecific nature ensures that the powerful immune-enhancing signals are delivered preferentially within the tumor microenvironment, directly where T cells encounter the cancer cells they are programmed to eliminate, thereby minimizing systemic immune activation and associated adverse events.

IV. Preclinical Profile of ASP-1002

Preclinical studies have been instrumental in establishing the foundational efficacy and mechanism of action for ASP-1002, providing the necessary support for its advancement into clinical trials.

In Vitro Studies

Laboratory-based experiments have demonstrated the CLDN4-dependent activity of ASP-1002:

• CLDN4-dependent CD137 activation: In specialized reporter assays, ASP-1002 was shown to activate CD137, and the degree of this activation correlated directly with the level of CLDN4 expression on the cancer cells used in the co-culture system.[2] This finding is crucial as it supports the intended mechanism of action, where the bispecific antibody's ability to stimulate T cells via CD137 is contingent upon its engagement with CLDN4 on tumor cells.
• Enhancement of T-cell effector functions: When T cells were co-cultured with cancer cells expressing CLDN4, the addition of ASP-1002 led to a marked increase in the production of IFNγ by the T cells. IFNγ is a critical cytokine involved in anti-tumor immunity, promoting the activation of various immune cells and enhancing tumor cell killing. Importantly, this enhancement of IFNγ production was not observed when T cells were co-cultured with cancer cells that did not express CLDN4, further underscoring the CLDN4-specificity of ASP-1002's action.[2]

In Vivo Efficacy

Studies in animal models have provided evidence of ASP-1002's anti-tumor activity:

• Humanized mouse models: In mice engrafted with human immune systems (humanized mice) and bearing human lung cancer cells, ASP-1002 treatment exhibited anti-tumor efficacy.[2] These models are valuable because they allow for the assessment of therapeutic agents that target human immune cells, like ASP-1002, in a more physiologically relevant in vivo context.
• Syngeneic mouse models: Perhaps more strikingly, complete tumor regression was observed in syngeneic mouse models.[2] These models utilized human CLDN4-overexpressing mouse tumor cell lines (MC38 colorectal cancer cells or B16F10 melanoma cells) implanted into immunocompetent mice that were genetically engineered to express human CD137 (human CD137 knock-in mice). The achievement of complete tumor regressions in these models is a strong indicator of potent, immune-mediated anti-tumor activity and suggests that ASP-1002 can effectively harness the immune system to eradicate established tumors. The consistency of activity across different tumor cell lines (lung, colorectal, melanoma) points towards a potentially broad applicability in various CLDN4-expressing malignancies.

Pharmacokinetics

Pharmacokinetic (PK) properties of ASP-1002 were assessed in cynomolgus monkeys, including the determination of its elimination half-life.[2] While specific PK parameters such as the exact half-life duration, clearance rates, and volume of distribution are not detailed in the available information, these data are vital for informing the selection of appropriate dosing regimens and schedules for human clinical trials. Understanding how the drug is absorbed, distributed, metabolized, and excreted is fundamental to optimizing its therapeutic effect and minimizing potential toxicities.

Overall Preclinical Rationale for Clinical Translation

The collective preclinical evidence indicates that ASP-1002 can selectively activate T cells in a manner dependent on the presence of CLDN4 on target cells. This targeted activation translates into potent anti-tumor activity both in vitro and, significantly, in vivo, including complete tumor eradication in some models. These robust preclinical findings provide a compelling scientific rationale for the ongoing Phase 1 clinical evaluation of ASP-1002 (NCT05719558) in patients with CLDN4-expressing solid tumors.[2] The data suggest that ASP-1002 has the potential to be a novel and effective immunotherapeutic agent.

V. Clinical Development: The NCT05719558 Phase 1 Study (1002-CL-0101)

The clinical development of ASP-1002 is currently centered on a first-in-human Phase 1 study designed to assess its safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity.

• Study Overview:
• Official Title: "A Study of ASP1002 in Adults for Treatment of Solid Tumors".[4]
• ClinicalTrials.gov Identifier: NCT05719558.[1]
• Astellas Study ID: 1002-CL-0101.[4]
• Phase: Phase 1.[1]
• Current Status: The trial is actively recruiting participants across multiple sites in the United States as of early 2023/late 2024.[1]
• Sponsor: Astellas Pharma Inc. (or its global development arm, Astellas Pharma Global Development, Inc.).[1]
• Objectives:
• Primary Objectives: The foremost goals are to evaluate the safety and tolerability profile of ASP1002 in patients with CLDN4-expressing solid tumors. This involves identifying any dose-limiting toxicities (DLTs) and establishing the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) for future studies.[1]
• Secondary Objectives: These include characterizing the pharmacokinetic (PK) profile of ASP1002 (how the drug is absorbed, distributed, metabolized, and eliminated by the body). Additionally, the study aims to gather preliminary evidence of anti-tumor activity by assessing confirmed Objective Response Rate (ORR), Duration of Response (DOR), and Disease Control Rate (DCR) according to both immune-related Response Evaluation Criteria in Solid Tumors (iRECIST) and standard RECIST 1.1. The incidence and expression levels of CLDN4 in tumor tissues, as determined by immunohistochemistry (IHC), will also be evaluated.[1]
• Study Design:
• This is a first-in-human, open-label, multicenter study.[1] "Open-label" means that both the investigators and participants are aware of the treatment being administered.
• The study is structured in two main parts [1]:
• Part 1 (Dose Escalation): In this part, ASP1002 will be administered intravenously (IV) at escalating dose levels. The initial dosing schedule mentioned is once weekly (Q1W) on Days 1, 8, and 15 of a 21-day cycle.[1] However, other schedules such as every other week (Q2W) or every 3 weeks (Q3W), within 21-day or 28-day cycles, are also being considered.[4] Cohorts involving multiple participants will be enrolled at doses of 10 mg and above.[1] The primary aim of this part is to determine the MTD and/or identify candidate RP2D regimens.
• Part 2 (Dose Expansion): Once the RP2D(s) are determined from Part 1, this part will enroll additional patients into tumor-specific cohorts. Approximately 40 patients per dose level, per tumor type, are planned for this expansion phase.[1] The focus will be on tumor types that showed confirmed complete response (CR) or partial response (PR) during the dose escalation phase, with specific mention of NSCLC, UC, and CRC.[1]
• Patient Population:
• General Criteria: Eligible participants are adults (18 years of age or older) with a histologically or cytologically confirmed diagnosis of a locally advanced or metastatic solid tumor that expresses CLDN4.[1] Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a predicted life expectancy of at least 12 weeks.[1]
• Prior Treatment: Patients must have experienced disease progression on, been intolerant to, or refused available standard therapies, or have no standard therapies that are likely to provide clinical benefit. There is no specified limit on the number of prior lines of therapy.[4]
• Tumor Types:
• Dose Escalation (Part 1): Eligible tumor types include NSCLC (adenocarcinoma, squamous cell carcinoma, and adenosquamous carcinoma; large cell and sarcomatoid carcinoma are excluded), urothelial carcinoma (UC), colorectal cancer (CRC), prostate adenocarcinoma (PA), epithelial ovarian cancer (OC), or triple-negative breast cancer (TNBC). Any tumor with a neuroendocrine histology component is exclusionary.[1]
• Dose Expansion (Part 2): This part will enroll patients with NSCLC, UC, CRC, or any other tumor type that demonstrated a confirmed response (CR or PR) during the dose escalation phase.[1]
• Biomarker Requirement: All enrolled patients must have tumors that express CLDN4, as determined by methods specified in the protocol (likely IHC).[1] Accessible archival tumor tissue (less than 6 months old) or a fresh biopsy is mandatory for confirming CLDN4 expression prior to study intervention. An on-treatment biopsy is also planned.[1]
• Measurable Disease: Participants must have at least one measurable lesion as defined by RECIST v1.1 criteria. Lesions in previously irradiated areas can be considered measurable if progression has been demonstrated in those lesions.[1]
• Key Exclusion Criteria (Selected): Patients weighing less than 40 kg; unresolved Grade ≥2 toxicity from prior therapies; symptomatic or uncontrolled CNS metastases (though stable, treated CNS metastases may be permissible under specific conditions); significant cardiovascular comorbidities (e.g., recent myocardial infarction, unstable angina, symptomatic congestive heart failure, LVEF < 45%); QTcF interval > 470ms; uncontrolled HIV infection (patients with CD4+ T cell counts ≥350 cells/μL and no recent AIDS-defining opportunistic infections may be eligible); active hepatitis B (unless HBV DNA is undetectable) or C infection; prior bone marrow or solid organ transplant; major surgery within 28 days without full recovery; recent investigational, antineoplastic, or immunotherapy (within 21 days); systemic corticosteroid use (>10 mg/day prednisone equivalent) or other immunosuppressive therapy within 14 days (with exceptions for physiologic replacement, single doses, or premedication for imaging); prior discontinuation of immunomodulatory therapy due to life-threatening Grade ≥3 immune-related AEs; other active malignancy requiring therapy; prior anti-CD137 therapy; and receipt of a live vaccine within 28 days.[4]
• Intervention:
• Drug: ASP1002.[1]
• Administration: Administered as an intravenous (IV) infusion.[1] Infusion duration may range from 15 minutes to 2 hours, depending on the dose.[9]
• Dosing Schedule: This will be determined during the dose escalation phase. Mentioned schedules include Q1W on Days 1, 8, and 15 of a 21-day cycle, or potentially Q2W or Q3W in 21-day or 28-day cycles.[1]
• Duration of Treatment: Patients may continue treatment for up to 2 years, or until disease progression, unacceptable toxicity, patient withdrawal, initiation of other cancer treatment, or if they do not return for treatment.[4]
• Key Outcome Measures:
• Primary Outcome Measures:
• Safety and tolerability of ASP1002, primarily assessed through the incidence and severity of Dose-Limiting Toxicities (DLTs), adverse events (AEs), serious AEs (SAEs), and changes in laboratory parameters, vital signs, ECGs, physical examinations, and ECOG performance status.[1]
• Secondary Outcome Measures:
• Pharmacokinetic profile of ASP1002 (e.g., Cmax, AUC, half-life).[1]
• Preliminary anti-tumor activity, including confirmed Objective Response Rate (ORR), Duration of Response (DOR), and Disease Control Rate (DCR), assessed using both iRECIST and RECIST v1.1 criteria.[1] For the dose expansion phase, specific minimum numbers of responders are defined to establish activity in NSCLC (4 responders), CRC (3 responders), and UC (7 responders) cohorts.[1]
• Incidence rate and expression levels of CLDN4 in tumor tissue, evaluated by IHC.[1]
• Study Timelines:
• Actual Study Start Date: March 2023.[4]
• Estimated Study Completion Date: May 2028.[4]
• Patients will have safety follow-up visits within 7 days, and at 30 and 90 days post-treatment, with overall follow-up for up to 1 year after the last dose of ASP1002.[1]
• Table: Summary of NCT05719558 Clinical Trial Design

Feature	Details
Trial Identifier	NCT05719558 / 1002-CL-0101 1
Phase	1 1
Title	A Study of ASP1002 in Adults for Treatment of Solid Tumors 9
Sponsor	Astellas Pharma Inc. 1
Primary Objectives	Evaluate safety, tolerability; determine MTD/RP2D 1
Key Secondary Obj.	PK profile; preliminary efficacy (ORR, DOR, DCR); CLDN4 expression 1
Study Design	Open-label, multicenter, two-part (Part 1: Dose Escalation; Part 2: Dose Expansion) 1
Patient Population	Adults with locally advanced or metastatic CLDN4-expressing solid tumors (specific types for escalation: NSCLC, UC, CRC, PA, OC, TNBC; specific types in expansion based on response) 1
Intervention	ASP1002 administered intravenously at escalating doses and varying schedules 1
Status	Recruiting 4
Est. Enrollment	210 participants 4
Est. Completion	May 2028 4

The adaptive nature of this Phase 1 trial, particularly the dose expansion phase that focuses on specific tumor types demonstrating early responses and sets predefined minimum responder numbers [1], reflects a contemporary approach to early-phase oncology drug development. This design allows for a more rapid identification of promising signals of efficacy in distinct patient populations, which can then inform more targeted and efficient subsequent Phase 2 studies. Such a strategy is particularly valuable for a therapeutic agent like ASP-1002, which targets a biomarker (CLDN4) present across a range of diverse cancer histologies.

VI. Safety and Tolerability Profile (Anticipated and Monitored)

The safety and tolerability of ASP-1002 are paramount in its early clinical development, given the potent immunostimulatory pathways it aims to modulate.

• Anticipated Safety Considerations based on Mechanism:
• CD137 Agonism: CD137 is a powerful co-stimulatory molecule. While its activation is desirable for anti-tumor immunity, excessive or uncontrolled systemic agonism can trigger a broad immune response, potentially leading to immune-related adverse events (irAEs). These can manifest as cytokine release syndrome, autoimmune-like phenomena affecting various organs, and hepatotoxicity, which have been observed with other CD137-targeting agents.[2]
• CLDN4 Targeting: CLDN4, while overexpressed in many tumors, is also present in some normal epithelial tissues.[2] If binding of ASP-1002 to CLDN4 on normal cells is sufficient to cause cell damage, or if the "silent Fc" region is not entirely inert and leads to some level of off-tumor immune cell engagement, on-target, off-tumor toxicities could occur.
• Design Features to Mitigate Toxicity:
• Silent Fc Region: A critical design element of ASP-1002 is its engineered silent Fc region. This modification is intended to abrogate binding to Fcγ receptors (FcγRs) on immune cells, thereby preventing FcγR-mediated crosslinking and subsequent non-specific activation of T cells or other immune cells. This feature aims to reduce the risk of systemic toxicities, particularly hepatotoxicity, that have plagued some earlier CD137 agonistic antibodies.[2]
• Conditional Agonism: The bispecific nature of ASP-1002 is designed to promote CD137 activation primarily when the antibody is also bound to CLDN4 on tumor cells. This "conditional" or "tumor-targeted" agonism seeks to concentrate potent immune stimulation within the tumor microenvironment, thereby sparing normal tissues from widespread immune activation and reducing the likelihood of systemic irAEs.
• Safety Findings from Preclinical Studies:
• Preclinical safety studies are essential for proceeding to human trials. A Korean patent application (KR20230171465A) mentions that an anti-CLDN4-anti-CD137 bispecific antibody (presumably related to or representing ASP1002) was shown to be safely administered to monkeys.[12] While the snippet does not provide specific details on the observed safety profile in non-human primates (e.g., types of adverse events, dose-response relationships for toxicity), such studies are crucial for establishing an initial safety margin and informing the starting dose and safety monitoring plan in human trials.
• Monitoring Strategies in Phase 1 Trial (NCT05719558):
• The primary endpoint of the NCT05719558 study is explicitly focused on safety and tolerability. This involves rigorous monitoring for DLTs, AEs, SAEs, and changes in laboratory parameters (hematology, chemistry, liver function tests), vital signs, electrocardiograms (ECGs), physical examinations, and ECOG performance status.[1]
• Given the mechanism of action, close surveillance for potential irAEs, including but not limited to cytokine release syndrome, autoimmune manifestations, and organ-specific toxicities (e.g., hepatitis, pneumonitis, colitis), is anticipated.
• The study protocol includes safety follow-up visits within 7 days of treatment cessation, and subsequently at 30 and 90 days post-treatment. Long-term safety follow-up extends for up to 1 year after the last dose of ASP1002, ensuring comprehensive data collection on any delayed adverse events.[1]

The careful design of ASP-1002, particularly the incorporation of a silent Fc region and the principle of CLDN4-dependent CD137 activation [2], coupled with a meticulous dose-escalation strategy in the Phase 1 trial [1], reflects a concerted effort to harness the potent anti-tumor effects of CD137 agonism while mitigating the systemic toxicities observed with earlier generations of CD137-targeting antibodies. The success of this approach hinges on identifying a therapeutic window where robust, tumor-localized immune activation can be achieved without inducing unacceptable dose-limiting systemic side effects.

VII. Discussion and Future Perspectives

ASP-1002 emerges as a thoughtfully designed bispecific antibody with the potential to address unmet needs in the treatment of various CLDN4-expressing solid tumors. Its development reflects key advancements in immuno-oncology and antibody engineering.

• Potential Positioning of ASP-1002:
• For patients with CLDN4-positive solid tumors who have exhausted or are unsuitable for current standard-of-care therapies, ASP-1002 could represent a novel therapeutic avenue.[1] The initial clinical trial targets several common and aggressive cancer types, including NSCLC, UC, and CRC, where new treatment options are continually sought.
• The mechanism of action, centered on direct T-cell co-stimulation at the tumor site, may offer advantages in tumors that are immunologically "cold" or have developed resistance to checkpoint inhibitors by providing a distinct pathway for T-cell activation and tumor attack.
• Significance of Targeting the CLDN4/CD137 Axis:
• The strategy of linking a tumor-associated antigen (CLDN4) with a potent T-cell co-stimulatory molecule (CD137) is a rational approach to enhance the specificity and efficacy of immunotherapy.[1] CLDN4 provides the tumor-targeting anchor, while CD137 engagement delivers a powerful activation signal to T cells already in the vicinity or recruited to the tumor.
• Successful clinical development of ASP-1002 would not only provide a new treatment option but also validate this specific dual-targeting strategy, potentially encouraging the development of other bispecific antibodies that leverage similar conditional co-stimulation concepts for different TAAs or co-stimulatory pathways.
• Challenges and Next Steps:
• A critical challenge will be the precise identification of the optimal CLDN4 expression threshold required for patient selection to ensure that the therapy is directed towards patients most likely to benefit. The Phase 1 trial includes IHC assessment of CLDN4, which will be vital in this regard.[1]
• Despite design features aimed at mitigating toxicity, the potential for on-target, off-tumor adverse events remains a consideration if CLDN4 is expressed at functionally relevant levels on critical normal tissues and if the conditional agonism is not perfectly restricted. The silent Fc region is designed to minimize this, but careful monitoring is essential.[2]
• The immediate next step is the successful completion of the dose escalation part of the Phase 1 study to determine the RP2D and the optimal dosing schedule.[1] This will pave the way for the dose expansion cohorts.
• Future development will likely focus on expanding into specific tumor types that show promising signals in the Phase 1 trial. While the current study evaluates ASP-1002 as a monotherapy, there is a strong rationale in immuno-oncology for exploring combination therapies. For instance, CD137 agonists have been studied in combination with checkpoint inhibitors [7], and such combinations could be explored for ASP-1002 in later stages if monotherapy activity and safety are established. Astellas' FY2024 pipeline update and financial results do not specifically mention ASP-1002 by name in the publicly presented highlights, which is common for early-phase assets, but they do emphasize their focus on oncology and innovative modalities.[13]

VIII. Conclusions

ASP-1002 is an innovative, first-in-human bispecific antibody developed by Astellas Pharma Inc., targeting CLDN4 on tumor cells and the co-stimulatory molecule CD137 on T cells. Its tetravalent IgG-scFv structure and silent Fc region are designed to promote potent, tumor-localized T-cell activation while minimizing systemic toxicities associated with earlier CD137 agonists.

Preclinical studies have demonstrated CLDN4-dependent CD137 activation, enhanced T-cell effector functions, and significant in vivo anti-tumor efficacy, including complete tumor regressions in relevant animal models. These findings provide a strong rationale for its clinical investigation.

The ongoing Phase 1 clinical trial (NCT05719558) is crucial for establishing the safety, tolerability, MTD, and RP2D of ASP-1002 in patients with various CLDN4-expressing advanced solid tumors. The study's adaptive design, incorporating dose expansion cohorts in specific tumor types based on early responses, aims to efficiently identify signals of clinical activity.

The development of ASP-1002 exemplifies a sophisticated approach in immuno-oncology, aiming to overcome the limitations of previous therapies by enhancing specificity and engineering safety features into a potent immune-activating agent. If successful, ASP-1002 could offer a significant new therapeutic option for patients with a range of difficult-to-treat CLDN4-expressing cancers, potentially validating a novel strategy for bispecific antibody design and CD137 co-stimulation. The outcomes of the current Phase 1 study are eagerly awaited by the oncology community.

Works cited

1. Phase 1 study of ASP1002, a bispecific antibody targeting claudin 4 ..., accessed May 19, 2025, https://ascopubs.org/doi/pdf/10.1200/JCO.2024.42.16_suppl.TPS2670
2. jitc.bmj.com, accessed May 19, 2025, https://jitc.bmj.com/content/jitc/12/Suppl_2/A1482.full.pdf
3. Abstracts & Presentations - ASCO Meeting Program Guide, accessed May 19, 2025, https://meetings.asco.org/abstracts-presentations/search?q=Jianning%20Yang%20
4. A Study of ASP1002 in Adults for Treatment of Solid Tumors - NCI, accessed May 19, 2025, https://www.cancer.gov/clinicaltrials/NCI-2023-03815
5. 1002-CL-0101 - Details | Astellas Clinical Trials, accessed May 19, 2025, https://www.clinicaltrials.astellas.com/study/1002-CL-0101/
6. Clinical Trials Using Anti-CLDN4/Anti-CD137 Bispecific Antibody ASP1002 - NCI, accessed May 19, 2025, https://www.cancer.gov/research/participate/clinical-trials/intervention/anti-cldn4-anti-cd137-bispecific-antibody-asp1002?pn=1
7. Role Of CD137 In Cancer Therapy - BioSpace, accessed May 19, 2025, https://www.biospace.com/press-releases/role-of-cd137-in-cancer-therapy
8. Claudin 1, 4, 6 and 18 isoform 2 as targets for the treatment of cancer (Review) - PMC, accessed May 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11414526/
9. A Study of ASP1002 in Adults for Treatment of Solid Tumors (NCT05719558) - CareAcross, accessed May 19, 2025, https://www.careacross.com/clinical-trials/trial/NCT05719558
10. Trials Today, accessed May 19, 2025, https://www.trialstoday.org/search/results?status=recruiting&gender=&age=&zip=&radius=25&condition=&healthy=&type=&interventionalpurpose=&observationalmodel=&query=University%20of%20Iowa%20Neurology&page=eJyLVspLrShR0lHycw4xMDUxMDA1NFLS0bWEARxMQwM9YxNLC2MLHUNzQxNTI0MzAxDQUcpLLjEwMbSwNDE3VIoFAOcOFLw-
11. 1002-CL-0101: A Phase 1 Study of ASP1002 in participants with Metastatic or Locally Advanced Solid Tumors - HealthPartners Institute, accessed May 19, 2025, https://www.healthpartners.com/institute/research/studies/1002-cl-0101-a-phase-1-study-of-asp1002-in-participants-with-metastatic-or-locally-advanced-solid-tumors/
12. KR20230171465A - Anti-CLDN4-anti-CD137 bispecific antibody - Google Patents, accessed May 19, 2025, https://patents.google.com/patent/KR20230171465A/en
13. R&D Pipeline, accessed May 19, 2025, https://www.astellas.com/en/system/files/7e354c3866/3q2024_pip_en.pdf
14. FY2024 Financial Results - Astellas Pharma Inc., accessed May 19, 2025, https://www.astellas.com/en/system/files/534ea626b9/4q2024_pre_en.pdf
15. Financial results for the first nine months of the fiscal year 2024 (FY2024) - Astellas Pharma Inc., accessed May 19, 2025, https://www.astellas.com/en/system/files/235dfe0339/3q2024_sup_en.pdf