Antibody-drug conjugates: Recent advances in linker chemistry

Antibody-drug conjugates (ADCs) are gradually revolutionizing clinical cancer therapy. The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects, and so has a major influence on the fate of ADCs. An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor. However, existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity. This defect is becoming an increasingly important factor that restricts the development of ADCs. The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers. The present review summarizes the advance of the chemical trigger, linker‒antibody attachment and linker‒payload attachment over the last 5 years, and describes the ADMET properties of ADCs. This work also helps clarify future developmental directions for the linkers.

Consideration of antibody drug conjugates development and regulation / 药学学报

Antibody drug conjugates (ADCs), as they combine the targetability of monoclonal antibody and cytotoxicity of small molecules, are a growing class of therapeutics for cancer. The key factor of ADCs development is the accurate selection of parameters including tumor target, monoclonal antibody, cytotoxic payload, and linkage strategy of antibody to payload. Here, we summarize the main elements in the structural design and the development of ADCs, as well as the regulatory consideration of product manufacturing and control, which would be helpful for the research and development of ADCs.

Advanced research and technology development of antibody-drug conjugates / 药学学报

Although numbers of naked antibodies showing clinical efficacy as single agents, their therapeutic effect is limited. Chemotherapy is very effective but with relatively large side effects, so conjugation of small chemotherapeutic drugs to antibodies is one of the important methods to enhance therapeutic potential of antibodies. Antibody-drug conjugates (ADCs) represent a promising therapeutic approach for cancer patients by combining the antigen-targeting specificity of monoclonal antibodies (mAbs) with the cytotoxic potency of chemotherapeutic drugs. These modified antibodies are expected to selectively deliver chemotherapeutic drugs to tumor cells and provide sustained clinical benefit to cancer patients, at the same time, minimizing systemic toxicity. ADCs are expected to bring together the benefits of highly potent drugs on the one hand and selective binders of specific tumor antigens on the other hand. However, designing an ADC is very complex, requiring thoughtful combination of antibody, linker, and payload drugs in the context of a target and a defined cancer indication. Although many challenges remain, recent clinical success has generated intense interest in this therapeutic class.