FDA Clears Phase 1/2 Study for Novel CDH17-Targeting ADC in Advanced GI Cancers

The US FDA has granted investigational new drug (IND) clearance for 7MW4911, a first-in-class CDH17-targeting antibody-drug conjugate (ADC) developed by Mabwell.¹ This regulatory milestone enables the company to initiate a phase 1/2 clinical trial to evaluate the safety, pharmacokinetics, and preliminary efficacy of the drug in patients with advanced colorectal cancer and other advanced gastrointestinal (GI) tumors. The clearance positions 7MW4911 as a promising new therapeutic candidate for a patient population with significant unmet needs.

A Novel Mechanism for a Clinically Relevant Target

7MW4911 is an ADC engineered using Mabwell’s proprietary IDDC™ platform. The drug is designed to selectively deliver a potent cytotoxic payload to cancer cells that express cadherin-17 (CDH17).^1,2 CDH17 is a pancancer target with limited expression in normal tissues but is frequently overexpressed in various GI malignancies, including colorectal, gastric, and pancreatic cancers. Its aberrant expression is associated with tumor metastasis and poor prognosis, making it an ideal candidate for targeted therapy.

The drug's highly optimized structure is comprised of three critical components. The first is Mab0727, a highly specific CDH17 monoclonal antibody with rapid internalization properties. This antibody is crucial for binding to the target antigen on the tumor cell surface and facilitating the drug's entry. The second component is a novel cleavable linker, designed to ensure the precise release of the cytotoxic payload only within the tumor microenvironment, thereby minimizing systemic toxicity. The final element is the MF-6 payload, a proprietary DNA topoisomerase I inhibitor. This payload is notable for its ability to overcome multidrug resistance (MDR), a major challenge in oncology, and for its superior plasma stability and potent bystander effect. The bystander effect is a key advantage of this payload, as it allows the drug to kill neighboring tumor cells even if they have low or no CDH17 expression, potentially leading to more comprehensive tumor eradication.

Preclinical Data Highlight Broad Efficacy and Safety Profile

The IND clearance follows the publication of robust preclinical data. The findings underscore several key advantages that support the clinical investigation of 7MW4911.

The drug’s molecular design, which features a homogeneous drug-to-antibody ratio (DAR = 4, >95%), ensures exceptional plasma stability. This stability is critical for reducing off-target toxicities and maintaining consistent drug exposure. In preclinical models, 7MW4911 demonstrated broad antitumor efficacy, showing significant tumor regression across a variety of patient-derived xenograft (PDX) and cell-derived xenograft (CDX) models. This efficacy was observed not only in typical GI cancers but also in tumors with challenging genetic profiles, such as those with RAS/BRAF mutations and diverse Consensus Molecular Subtypes (CMS), which are often resistant to standard therapies.

A particularly compelling finding was 7MW4911's ability to overcome MDR. The drug outperformed commonly used ADC payloads like MMAE and DXd in models of ABC transporter-mediated multidrug resistance. This suggests that 7MW4911 could be an effective treatment option for patients who have relapsed or progressed after receiving other ADC therapies. Furthermore, its activity in tumors with low-to-moderate CDH17 expression extends its potential clinical utility to a broader patient population.

Preclinical safety assessments also yielded encouraging results. Studies in mice demonstrated limited tissue distribution, and pharmacokinetics in cynomolgus monkeys showed a controllable half-life with no drug accumulation. A wide therapeutic window was observed, with no significant toxicity signals, suggesting a favorable safety profile for human trials.

The Road Ahead: Phase 1/2 Clinical Investigation

With the IND clearance now secured, Mabwell will proceed with the phase 1/2 clinical study in the United States. This trial aims to systematically evaluate the drug's safety, tolerability, and optimal dosing, while also providing initial insights into its clinical efficacy in patients with advanced GI malignancies. The drug's IND application has also been accepted by China's National Medical Products Administration (NMPA), indicating a parallel development pathway in both major markets.

The initiation of this trial represents a significant step forward in the development of targeted therapies for advanced GI cancers, diseases that remain a leading cause of cancer-related mortality worldwide. The promising preclinical data suggest that 7MW4911 could offer a much-needed treatment alternative for patients who have exhausted other options, particularly those with difficult-to-treat or drug-resistant tumors.

REFERENCES:

1. Mabwell's CDH17-targeting ADC 7MW4911 Receives IND Clearance from FDA. News release. August 19, 2025. Accessed August 20, 2025. https://tinyurl.com/3u842ub8

2. Pipeline. Mabwell. Accessed August 19, 2025. https://tinyurl.com/3v9eanve