Antibody drug conjugates under investigation in phase I and phase II clinical trials for gastrointestinal cancer

ABSTRACT

Introduction: Antibody drug conjugates (ADCs) represent a developing class of anticancer therapeutics which are designed to selectively deliver a cytotoxic payload to tumors, while limiting systemic toxicity to healthy tissues. There are several ADCs which are currently in various stages of clinical development for the treatment of gastrointestinal malignancies.

Areas covered: We discuss the biologic rationale and review the clinical experience with ADCs in the treatment of gastrointestinal malignancies, summarizing the pre-clinical and phase I/II clinical trial data that have been completed or are ongoing.

Expert opinion: While there have been significant advances in the development of ADCs since they were first introduced, several challenges remain. These challenges include (i) the selection of an ideal antigen target which is tumor specific and internalized upon binding, (ii) selection of an antibody which has high affinity for its antigen target and low immunogenicity, (iii) selection of a potent payload which is cytotoxic at sub-nanomolar concentrations, and (iv) optimal design of a linker to confer ADC stability with limited off-site toxicity. Efforts are ongoing to address these issues and innovate the ADC technology to improve the safety and efficacy of these agents.

KEYWORDS:

• Adenocarcinoma
• antibody drug conjugate
• cholangiocarcinoma
• colorectal cancer
• drug conjugates
• esophageal cancer
• gastric cancer
• gastrointestinal malignancies
• immunoconjugates
• pancreatic cancer

Article Highlights

• Antibody drug conjugates are an emerging class of anticancer therapeutics which are designed to selectively deliver cytotoxic agents directly to tumors, while limiting systemic toxicity to healthy tissues.

• Antibody drug conjugates are comprised of a monoclonal antibody and a cytotoxic payload attached via a linker peptide. These agents are engineered to preferentially bind to tumor cells, leading to internalization and intracellular release of the cytotoxic payload, resulting in cell death.

• Several challenges have been met in the development of antibody drug conjugates, including premature release of the payload, resulting in off-target side effects and dose limiting toxicity.

• An optimal target antigen should be overexpressed in tumor tissue and have limited to no expression in normal healthy tissues and should be internalized upon antibody binding to ensure delivery of the cytotoxic agents to the tumor cells of interest.

• The linker used to attach the cytotoxic payload to the monoclonal antibody must be stable enough to ensure that the antibody drug conjugate can circulate intact, while labile enough that it can be cleaved to release the payload once internalized within the tumor cell of interest.

• Further research aimed at elucidating factors influencing antigen internalization, identifying novel cytotoxic payloads, linkage optimization strategies, and site-specific conjugation are needed to improve the efficacy and safety of these agents to hopefully result in more efficacious treatment options for cancer patients.

This box summarizes key points contained in the article.

Declaration of interest

WA Messersmith has received funding from Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Immunomedics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This article was not funded.