What are the challenges involved in the strategies for future antibody-drug conjugate discovery and development for oncology?

ABSTRACT

Introduction

There have been significant advances in the therapeutic strategies based on monoclonal antibodies. These advances, including the modification of their format, their production, and their functionalization. have further improved their efficacy and, particularly in oncology, have helped to overcome several limitations. Nevertheless, the efficacy and safety profile of antibody drug conjugates is not yet optimal.

Area Covered

This article primarily summarizes the challenges that need to be addressed during the development of various strategies for the discovery of antibody-drug conjugates in oncology. The authors further provide their expert opinion and perspectives for the future/

Expert opinion

Addressing the challenges discussed in this perspective, such as by improving the specificity of targeting cancer cells, the selective site-specific conjugation of cytotoxic drugs to antibodies and developing different strategies to overcome the problem of drug resistance will likely generate a new class of ADCs and bring more value to the concept of ADCs, particularly in the treatment of cancer patients

KEYWORDS:

• Antibody drug conjugates
• Mabs
• linker
• cytotoxic
• payloads
• tumor-specific
• strategies

Article highlights

• The activity of an ADC will depend on the target, payload selection, and linker as well as on the tumor microenvironment.

• The main challenge is to enhance the therapeutic index of ADCs while reducing the on-target and off-target toxicities.

• Drug-to-antibody ratio (DAR) plays an important role in the pharmacokinetics and pharmacodynamics of ADCs.

• The utilization of molecular imaging could be vital in the development of ADCs.

• ADC therapies in combination with chemotherapy could make the treatment cost-effective.

• The homogeneous ADCs obtained by the new approaches of site-specific conjugation (SSC) techniques are exciting prospects for the future.

Declaration of interest

The authors have no 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

One referee declares that they are affiliated with Clinical Cancer Research, NEXT Madrid, and the Quirónsalud Madrid University Hospital. They also have a consultancy/advisory role with Puma Biotechnology; Ideaya Biosciences; Loxo Oncology, CytomX Therapeutics; Guidepoint; Oncoart. They also declare that they are on an independent data monitoring committee for Nanobiotix and the Steering Committee of CytomX Therapeutics. Furthermore, the referee has received speaker’s honoraria from Eli Lilly and Company, Merck Sharp and Dohme, SOLTI, and TACTICS and travel/inscription/accommodation honoraria from Bayer Healthcare. The referee’s institution has also received financial support for clinical trials from: AbbVie, ACEO, Adaptaimmune, Amcure, Amgen, Amunix, AstraZeneca, Bristol-Myers Squibb, Cytomx, GlaxoSmithKline, Genentech/Roche, H3, Incyte, Janssen Pharmaceuticals, Kura, Eli Lilly and Company, Loxo Oncology, Nektar, Macrogenics, Menarini, Merck and Co, Merus, Nanobiotix, Novartis, Pfizer Inc, PharmaMar, Principia, Puma Biotechnology, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Takeda, Incyte, Innovio, Merck Sharp and Dohme, PsiOxus, Seattle Genetics, Mersana, Daiichi Sankyo, Nektar Therapeutics, Astellas, ORCA, Boston Therapeutics, Dynavax, DebioPharm, Boehringer Ingelheim, Regeneron, Millennium Pharmaceuticals, Synthon, Spectrum, Rigontec, and Zenith.

Additional information

Funding

This paper was not funded.