Continuous Processing for Manufacturing of Antibody–Drug Conjugates (ADCs)

Antibody-drug conjugates (ADCs) are a promising and emerging class of biotherapeutics that combine the targeting precision of monoclonal antibodies (mAbs) with the cytotoxic potency of small-molecule drugs. Their manufacturing, however, requires conjugation of the mAb with the pertinent small molecule drug, a step typically is inefficient, incurring wastage of both the mAb and the drug. In addition, ADC manufacturing is challenged by precise control of drug-to-antibody ratio (DAR), aggregation, safe handling of cytotoxic payloads, among other factors. In this work, we present a novel approach for continuous conjugation of the mAb and the drug, by utilizing a coiled flow inverter reactor (CFIR) to facilitate the thiol-maleimide conjugation at interchain cysteines residues in the mAb. As an initial step, the process parameters for reducing thiol groups and the conjugation steps were screened, followed by optimization of the significant parameters (concentration of mAb and drug/linker payload, reaction duration, and temperature) using design of experiments (DoE) methodology. The performance of the CFIR was then compared to that of traditional batch conjugation. We demonstrate that the CFIR offers 64.40% higher productivity, 70% lower cost of production, and a safer alternative to the traditional batch conjugation, while producing clinically relevant DAR. This work illustrates the potential of continuous processing to transform ADC manufacturing by enabling more efficient, scalable, and sustainable production platforms.