Independent, Previous Senior Vice President and Head of Translational Sciences at Bayer Pharmaceuticals
With many antibody-drug conjugates (ADCs) in preclinical and clinical development, these remarkable compounds have attracted the attention of researchers and pharmaceutical companies. To grasp the significance of ADCs, it is important to understand how they work. They consist of three main components: a monoclonal antibody, a cytotoxic drug payload, and a linker. The monoclonal antibody is designed to specifically recognize antigens overexpressed on the surface of cancer cells, allowing for selective targeting. The cytotoxic payload is often a potent chemotherapy drug that is highly effective at killing cancer cells. Finally, the linker serves as a bridge between the two other components, maintaining stability during circulation while releasing the payload upon internalization. All 3 components are critical and to find the right mix resulting in the right balance between efficacy and safety is now the major challenge. In this context, payload classes are getting pretty creative. Small molecules, protein toxins, peptides, and enzymes are being joined by alpha, beta, and gamma-emitting radioisotopes/radionuclides. The jury is still out who will finally find the best compound, i.e. the best mix between antibody, payload and linker. The ones who will effectively incorporate the learnings from the successes and failures into their development strategy may be the winners.
Dowdy Jackson
7mo
Very nice article. I think many companies that are new to ADCs don't appear to have taken the path to scale their ADC manufacturing to support late stage clinical studies and beyond into consideration. Many CDMOs are equipped to deal with known linker-payloads and the analytics. The issue will be when novel linker-payloads are being developed and new analytical.methods need to be developed. They will need substantial lead time with the CDMOs to get on into the queue. You mentioned Ambrx. I was the project leader for ARX517 before Ambrx changed directions away from ADCs and led the inlicensing efforts between Ambrx and Agensys/Astellas. Ambrx's ADC technology has some significant challenges compared to other site-specific ADC technologies that need to be considered. While ARX517 has shown promise in prostate cancer, the failure rate for early stage ADCs is still significant. I love the interest in ADCs and we will see who's still standing when the dust clears.
Thank you for re-sharing our article with Matthew Pillar! It's been fascinating to see the creative exploration of different payload classes, which underscores the ongoing innovation in ADC design. Indeed, the journey to finding the optimal ADC formulation is an evolving process, guided by both successes and failures. Excited for the future!
Chief Executive Officer at Strategic Decisions Group (SDG)
7moThanks for calling this out. This explosion of creativity is providing an enormous opportunity for young (bio)chemists, finding ways to synthesize the actives. There is so much work to do!