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Behind the Journey of ADCs by Raffaele Colombo

Raffaele Colombo/LinkedIn

Oct 27, 2024, 11:29

Behind the Journey of ADCs by Raffaele Colombo

Raffaele Colombo posted on X about recent paper by him as first author titled “The Journey of Antibody–Drug Conjugates: Lessons Learned from 40 Years of Development” published on Cancer Discovery by AACR.

Authors: Raffaele Colombo, Paolo Tarantino, Jamie R. Rich, Patricia M. LoRusso, Elisabeth G.E. de Vries

“~400 ADCs have entered clinical development since the 1980s! We represented them by the year they first entered the clinic, divided by payload classes. To capture their status, we created a spiral table, which took some patience…

None of the approved ADCs (to date) is fully stable in circulation There are 2 types of linker instabilities: 1) linker-drug instabilities, which release free drug 2) antibody-linker instabilities, which release the whole drug-linker.

ADC (in)stabilities are well studied and understood preclinically, but we have limited clinical data

For approved ADCs. figure below:
blue arrows = mAb-linker instabilities
purple arrows = linker-drug instabilities
red atoms = cleavable linker
green atoms = self-immolative group

In this recent publication, the authors compared the changes of DAR (drug-to-antibody ratio) over time for vedotin and mafodotin ADCs in clinical samples vs in vitro plasma stability (!!)
ADC-E = vedotin = MC-ValCit-PABC-MMAE
ADC-F = mafodotin = MC-MMAF

In addition to intrinsic deconjugation rates, faster clearance of the higher DAR species (for certain more hydrophobic payloads, not necessarily for all types of payloads) may contribute to apparent greater DAR reduction over time in vivo (open system) vs in vitro (close system)

In vivo DAR over time = drug loss from deconjugation (either antibody-drug instabilities and/or linker-drug instabilities) + faster clearances of higher DAR species (unique for each ADC based on the overall properties as result of the combination of antibody, linker, and drug)

Reduced DAR over time for ADC-F (MMAF) appeared to be driven predominantly by deconjugation, while for ADC-E (MMAE) by both deconjugation and faster elimination of higher DAR species. Of note, higher odd-loaded species tended to deconjugate faster than even-loaded species.”

Raffaele Colombo, a leading figure in the pharmaceutical industry is the Associate Director of Medicinal Chemistry at Zymeworks Inc.. His leadership and scientific acumen drive the discovery and optimization of novel drug candidates and advancing the treatment landscape for various diseases.