Kinetic Studies of the Partial Reduction and Conjugation Reactions in an Antibody-Drug Conjugate (ADC) Synthesis

Subramanya Nayak and Steve Richter of AbbVie discusses thier work investigating the synthesis of antibody-drug conjugates (ADCs) through the partial reduction of native interchain disulfide bonds in antibodies, followed by covalent conjugation of cysteine thiol groups to small-molecule therapeutics. This process yields a heterogeneous mixture of ADCs characterized by varying drug-to-antibody ratios (DAR), which in turn influences their pharmacological properties, stability, and therapeutic index.

Key kinetic studies reveal that the partial reduction of disulfide bonds is the rate-limiting step in ADC synthesis, notably slower than the subsequent conjugation reactions. Importantly, once a disulfide bond in the heavy chains is reduced, remaining bonds are preferentially targeted, leading to different reduction rates among positional isomers. This results in a diverse product distribution. The researchers developed kinetic models to understand how different process parameters affect this distribution, providing insights into optimizing ADC synthesis for desired DAR profiles and improved therapeutic efficacy.

Nayak, S., & Richter, S. M. (2023). Kinetic studies of the partial reduction and conjugation reactions in an Antibody-Drug conjugate (ADC) synthesis. Organic Process Research & Development, 27(11), 2091–2099. https://doi.org/10.1021/acs.oprd.3c00264