An overview of site-specific methods for achieving antibody drug conjugates with homogenous drug to antibody ratio

ABSTRACT

Introduction

Antibody drug conjugates (ADCs) have emerged as a potent tool in cancer treatment, where cytotoxic drugs are linked to antibodies targeting specific antigens. While conventional ADC synthesis methods have seen success as commercials therapeutics, there is a growing interest in next-generation ADCs, looking at homogeneity of the drug-to-antibody ratio.

Areas covered

The article provides a high-level overview for achieving said homogeneity by site-directed conjugations via encompassing engineered amino acids, enzyme-mediated strategies, peptide sequences, affinity peptides, and beyond. As the field rapidly evolves with multiple ADCs in clinical trials and the advent of biosimilars, the article explores the benefits and challenges in both conventional and non-platform ADC technologies.

Expert opinion

The choice of site selection approach must be based on multiple criteria as discussed in this report. Two ADCs made from conjugation to engineered cysteines have been approved by regulatory agencies which have contributed to the excitement in this space. For the others, though successful as proof-of-concept, the true test of merit will be determined as these technologies advance into the clinic. The promise of improving the therapeutics index and decreasing toxicities will continue to drive progress in this area.

KEYWORDS:

• Antibody drug conjugate
• engineered antibody
• affinity peptides
• non-natural amino acid
• glycan conjugate
• enzyme mediated conjugation
• homogeneous DAR

Article highlights

• The ADC field is still in its early stages of growth. The opportunity to vary one or more parts that make up an ADC such as the antibody backbone, linker and, drug paves the way for an immense amount of scientific ingenuity and creativity in finding the next ‘magic bullet.’

• Early development data suggest that site-specific conjugates improve safety, efficacy, and tolerability by improving clearance and reducing off-target and dose-dependent toxicities.

• Antibodies are often modified at specific sites to carry either natural or non-natural amino acids. These amino acid side chains provide the chemical handles needed for conjugation.

• Substrate selectivity of enzyme can be harnessed for drug attachment to either a glycan sugar residue or native amino acid.

• Small peptide sequences that show affinity by non-covalent interactions to a segment of the antibody have been leveraged to enhance proximity-based conjugations to certain amino acids.

• For a broader picture, alternatives to achieving homogeneity have been discussed briefly, including via conventional methods and purification.

• Summary of all approved ADCs and an outlook for the advancement of both homogenous and heterogenous ADCs are provided.

Declaration of interest

DV Hingorani works for Seagen but any views in this paper do not necessarily reflect those of the company. 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 or other relationships to disclose.

Acknowledgments

I would like to acknowledge the efforts of Joshua Hunter, John Valliere-Douglass, Howard Clarke, Nomalie Jaya, Srinath Thirumalairajan, Carol Krantz, and Phil Tsai for their constructive review and unwavering support through the writing process. Additionally, my sincere thanks to Rajappa Vaidyanathan for his mentorship which inspired this manuscript.

Additional information

Funding

This paper was not funded.