Prospects and progress of antibody-drug conjugates in solid tumor therapies

ABSTRACT

Introduction: Antibody-drug conjugates (ADCs) for targeted chemotherapy have evolved in the past 2–3 decades to become a validated clinical cancer therapy modality. While considerable strides have been made in treating hematological tumors, challenges remain in the more difficult-to-treat solid cancers.

Areas covered: The current model for a successful ADC uses a highly potent cytotoxic drug as the payload, with stringent linker requirements and limited substitutions. In solid tumor treatment, a number of ADCs have not progressed beyond Phase I clinical trials, indicating a need to optimize additional factors governing translational success. In this regard, insights from mathematical modeling provide a number of pointers relevant to target antigen and antibody selection. Together with the choice of targets, these can be expected to complement the gains made in ADC design towards the generation of better therapeutics.

Expert opinion: While highly potent microtubule inhibitors continue to dominate the current ADC landscape, there are promising data with other drugs, linkers, and targets that suggest a more flexible model for a successful ADC is evolving. Such changes will undoubtedly lead to the consideration of new targets and constructs to overcome some of the unique natural barriers that impede the delivery of cytotoxic agents in solid tumor.

KEYWORDS:

• Antibody-drug conjugates
• clinical development
• drug-antibody ratio
• solid cancers
• therapeutic index

Article highlights

• Antibody-drug conjugates (ADCs) have evolved to be a validated clinical therapy modality, but a plug-and-play approach of conjugating specific drug-linker combinations to different antibodies has limitations for solid tumor therapies.

• Binding-site barrier is an impediment to uniform penetration of ADC in a tumor mass, and multiple solutions to overcome this could be factored into designing effective ADCs.

• ADC toxicity manifests by the release of the potent drug by general antibody processing throughout the body and by normal tissues expressing the targeted antigen, thereby impacting the therapeutic index and clinical utility.

• Potentially successful ADCs, based on either highly potent or moderately potent cytotoxic payloads, which are undergoing clinical evaluation, illustrate different ways of designing useful ADCs.

• ADC efficacy can be expected to be augmented in the clinic by combination with chemotherapy or immunotherapy, based on promising preclinical data.

This box summarizes key points contained in the article.

Declaration of interest

This paper was supported by Immunomedics Inc. DM Goldenberg is the founder, chairman and chief scientific officer of Immunomedics with patents, stock and stock options in the same entity. SV Govindan is an employee of Immunomedics with patents and stock options, and RM Sharkey is an employee of Immunomedics with stock options. 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.