An overview of process development for antibody-drug conjugates produced by chemical conjugation technology

ABSTRACT

Introduction: We discuss chemical conjugation strategies for antibody-drug conjugates (ADCs) from an industrial perspective and compare three promising chemical conjugation technologies to produce site-specific ADCs.

Areas covered: Currently, nine ADCs are commercially approved and all are produced by chemical conjugation technology. However, seven of these ADCs contain a relatively broad drug distribution, potentially limiting their therapeutic indices. In 2019, the first site-specific ADC was launched on the market by Daiichi-Sankyo. This achievement, and an analysis of clinical trials over the last decade, indicates that current industrial interest in the ADC field is shifting toward site-specific conjugation technologies. From an industrial point of view, we aim to provide guidance regarding established conjugation methodologies that have already been applied to scale-up stages. With an emphasis on highly productive, scalable, and synthetic process robustness, conjugation methodologies for ADC production is discussed herein.

Expert opinion: All three chemical conjugation technologies described in this review have various advantages and disadvantages, therefore drug developers can utilize these depending on their biological and/or protein targets. The future landscape of the ADC field is also discussed.

KEYWORDS:

• Antibody-drug Conjugate
• chemical conjugation
• process development
• site-specific conjugation
• chemistry manufacturing and control

Article highlights

• Currently, nine ADCs are commercially approved and all are produced by chemical conjugation technology.

• To date, the development of scalable and robust ADC processes remains a highly challenging task for drug developers and contract development and manufacturing organizations (CDMOs) However, there are limited review articles reporting from the straightforward CMC (chemistry, manufacturing, and control) perspective.

• In this review, chemical conjugation strategies for antibody-drug conjugates (ADCs) were discussed from an industrial perspective.

• Comparison of three promising chemical conjugation technologies to produce site-specific ADCs was described.

• Finally, the future direction of the ADC field was predicted.

This box summarizes key points contained in the article.

Acknowledgments

The authors wish to thank our colleagues from Ajinomoto Bio-Pharma Services, Inc. and Ajinomoto Co., Inc., as follows: Ms. Monica Leung, Ms. Zhala Tawfiq, and Dr. Tomohiro Fujii for technical assistance for native cysteine conjugation study; Mr. Bert Barbosa, Dr. Shigeo Hirasawa and Dr. Tatsuya Okuzumi for helpful discussions and suggestions in this review; Dr. Kei Yamada for many helpful initial studies on AJICAP® technology.

Declaration of interest

The authors are employees with stock or stock options in Ajinomoto Co., Inc. or Ajinomoto Bio-Pharma Services. Y. Matsuda is ADC researcher at Ajinomoto Co., Inc.; B. A. Mendelsohn is director 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 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 work was supported by Ajinomoto Co., Inc.