Antibody-drug conjugates (ADCs) are formed by covalent biochemical conjugation of monoclonal antibodies (mAb) with payload drugs through small molecular linkers. They are regarded as an emerging class of drugs designed for high-specificity targeting and destruction of cancer cells, since the specificity of mAb to tumor cells allows small-molecule drugs to target tumor tissues, effectively reducing the high toxicity of traditional small-molecule drugs and improving overall treatment efficiency.
ADC manufacturing consists of multiple steps that can be divided into three distinct stages: cGMP production of the antibody, organic synthesis of the drug-linker complex, and conjugation to form an ADC. And then the conjugated antibodies undergo extensive purification and are finished as ADC products upon the completion of fill-finishing. At current, there are no general guidelines for individual ADC strategies, and ADC manufacturers could design and select appropriate strategies evaluated based on the efficacy and toxicity of an individual ADC construct.
ADC manufacturing begins with the parent monoclonal antibody (mAb). Many manufacturers will design and screen mAbs at an early stage to make the molecule robust enough for the manufacturing environment, formulation, and dosage requirements. To achieve robustness against the more demanding process conditions inherent in ADC processes, mAbs destined for ADC production are being further optimized. Such enhanced requirements are likely to lead to further technological advances in mAb expression and processing.
The second step is performed on the organic synthesis chemistry pipeline in R&D and cGMP environments, which can enable researchers prepare regular or highly tailored linker molecules bearing different release mechanisms, modify payload drugs for proper conjugation chemistry, prepare new payload derivatives for drug development, and formulate the drug-linker complex for ADC manufacturing. ADC conjugation is achieved in cGMP certified reactors after small-scale conjugation protocol verification. The therapeutic impurities are removed utilizing advanced filtering devices such as ultrafiltration and tangential flow filtration (TFF) systems. The ADC products are purified using single-use chromatography systems and finished by filling them into aseptic vials via the cGMP sterile filling pipeline.
However, the unique nature of ADC presents challenges in its large-scale production. To be more specific, ADCs must be manufactured in a Current Good Manufacturing Process (cGMP) aseptic environment whilst also ensuring containment of the highly toxic drug compounds to protect operators and the wider environment, which presents significant operational difficulties. What’s more, efficiently linking a unique, tumor-targeted mAb to a potent, cell-killing cytotoxic small molecule drug is only the beginning—meeting ADC manufacturing needs requires a comprehensive portfolio of products and wide-ranging expertise in small and large molecule development, manufacturing, and testing.
Nowadays, ADCs demonstrated great potential for the treatment of cancers, and simultaneously require unique supporting infrastructure to meet biopharmaceutical industry standards for safe, effective, and reliable manufacturing. To further enhance ADC efficacy, improved drug platforms and linker technologies are in development. In addition to new cytotoxic agent development, future ADC manufacturing should also focus on novel linkers that can be cleaved efficiently and provide adequate stability to deliver the cytotoxic agent. Moreover, there also continue to be developments in the areas of manufacturing and scale-up for this technology, given the cytotoxicity of the drug and the challenges associated with manufacturing the antibody variants.