Antibody prodrugs for cancer

ABSTRACT

Introduction: The toxicity of potent new biological therapies for cancer has limited their utility. By improving tumor specificity, antibody prodrugs can widen or even create a therapeutic window for anticancer agents that are difficult or impossible to use otherwise because of poor tolerability.

Areas covered: This review will describe the current status of the field of antibody prodrugs, focusing on Probody^TM therapeutics, including the principles behind their design, application to a variety of different antibody-based therapies, preclinical examples of their activity and safety, and early results of Phase 1 trials.

Expert opinion: Proof of concept for the antibody prodrug approach, which is defined as demonstration of potent antitumor activity with improved safety, has been extensively established preclinically as well as preliminarily in early clinical trials in human patients. However, experience with antibody prodrugs is limited, and important challenges remain. Principal among them are how to design the molecules to provide the most effective protection from toxicities while preserving efficacy, how to optimize clinical pharmacology, and how to determine which among the many possible clinical applications is the best use of this promising technology.

KEYWORDS:

• Antibody
• cancer
• antibody prodrug
• tumor microenvironment
• protease

Article Highlights

• Antibody prodrugs are masked antibodies engineered to be pharmacologically inactive until they are activated by proteases in the diseased tissue microenvironment.

• A variety of different formats have been reported, but all are intended to widen the therapeutic window for potent therapies that are otherwise difficult to use because of poor tolerability, or to create a therapeutic window for undruggable targets.

• Preclinical proof of concept has been extensively reported, and early clinical trial results suggest that the technology performs as designed in human patients.

• There is potential for the technology to be useful in therapeutic areas beyond oncology, and for other protein therapeutics besides antibodies.

• Future work should focus on better understanding the optimal design and use of antibody prodrugs.

This box summarizes key points contained in the article.

Declaration of interest

The author is an employee and stockholder of CytomX Therapeutics, Inc. The author has 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 apart from those disclosed.

Reviewer Disclosures

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

Additional information

Funding

This paper was not funded.