A review of conjugation technologies for antibody drug conjugates

Abstract

Antibody-drug conjugates (ADCs) have gained significant attention in biotherapeutics after several years of steady development. Among the multiple factors influencing ADC design, the conjugation method is one of the most critical parameters. This review classifies conjugation strategies into three categories: non-specific, site-specific but non-selective, and fully site-specific and selective methods. The characteristics; advantages and disadvantages; chemistry, manufacturing, and controls (CMC) potential; and clinical status of each conjugation strategy are discussed in detail. The site-specific and selective methods will yield more homogeneous ADC, which may influence the stability and pharmacokinetics (PK) profile of the ADC and then influence the final therapeutic outcome. Additionally, the review also explores challenges and future directions for developing novel conjugation strategies. This review presents the most prevalent conjugation techniques, providing a valuable resource for researchers in selecting conjugation technologies and advancing ADC development.

Keywords: affinity peptide conjugation; antibody–drug conjugate (ADC); cysteine conjugation; enzymatic-tag conjugation; glycan remodeling conjugation; lysine conjugation; non-canonical amino acids (ncAAs) conjugation.

Figure 1

Scheme of site-specific conjugation techniques and interchain cysteine conjugation process. (A) Illustration of site-specific conjugation techniques, highlighting key reaction mechanisms and conjugation sites. (B) Illustration of interchain cysteine conjugation process with different strategies of (i) cysteine conjugation, (ii) WuXiDAR4, and (iii) re-bridge.