Novel formats of antibody conjugates: recent advances in payload diversity, conjugation, and linker chemistry

ABSTRACT

Introduction

In the field of bioconjugates, the focus on antibody – drug conjugates (ADCs) with novel payloads beyond the traditional categories of potent cytotoxic agents is increasing. These innovative ADCs exhibit various molecular formats, ranging from small-molecule payloads, such as immune agonists and proteolytic agents, to macromolecular payloads, such as oligonucleotides and proteins.

Areas Covered

This review offers an in-depth exploration of unconventional strategies for designing conjugates with novel mechanisms of action and notable examples of approaches that show promising prospects. Representative examples of novel format payloads and their classification, attributes, and appropriate conjugation techniques are discussed in detail.

Expert opinion

The existing basic technologies used to manufacture ADCs can be directly applied to synthesize novel formatted conjugates. However, a wide variety of new payloads require the creation of customized technologies adapted to the unique characteristics of these payloads. Consequently, fundamental technologies, such as conjugation methods aimed at achieving high drug – antibody ratios and developing stable crosslinkers, are likely to become increasingly important research areas in the future.

KEYWORDS:

• Antibody–drug conjugates
• bispecific antibodies
• novel format conjugates
• payload linker
• site-specific conjugation

Acknowledgments

The authors thank Dr. Akira Chiba, Mr. Hiroki Imai, and Dr. Tatsuya Okuzumi from Ajinomoto Co., Inc. for helpful discussions and suggestions in this review.

Article highlights

• Antibody – drug conjugates (ADCs) with novel payloads that extend beyond traditional potent cytotoxic agents have become the focus in the field of bioconjugates.

• This review discusses unconventional strategies for designing conjugates with novel mechanisms of action and presents promising approaches with representative examples.

• These innovative ADCs include various molecular formats, from small-molecule payloads, such as immune agonists and proteolytic agents, to macromolecular payloads, such as oligonucleotides and chemically generated bispecific antibodies.

• Existing technologies for ADC production can be directly used to synthesize these novel formatted conjugates; however, the diversity of new payloads demands the development of custom technologies to cater to their unique characteristics.

• Fundamental technologies, such as conjugation methods aimed at a homogeneous drug-antibody ratio and the creation of stable crosslinkers, are likely to become key research areas in the future.

• This review also offers insights into the prospective directions of the ADC field.

Declaration of interest

The authors are employees with stocks or stock options in Ajinomoto Co., Inc. or Ajinomoto Bio-Pharma Services. T. Fujii is an ADC researcher at Ajinomoto Co., Inc., and Yutaka Matsuda is an ADC project manager at Ajinomoto Bio-Pharma Services. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in the manuscript, apart from those disclosed.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14712598.2023.2276873

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.