The Payload Revolution: Redefining the Future of Antibody-Drug Conjugates (ADCs)
Curator: Dr. Sudipta Saha, Ph. D.
Antibody-Drug Conjugates (ADCs) are at the forefront of targeted cancer therapy. While much attention has focused on antibody engineering and linker technology, the real breakthrough may lie in the payload—the cytotoxic compound delivered to tumor cells.
Historically, ADC payloads have relied on microtubule inhibitors like MMAE and MMAF, and topoisomerase I inhibitors such as SN-38 and Exatecan. These payloads are potent but limited in diversity, making differentiation difficult in a crowded therapeutic landscape.
The next wave of innovation introduces unconventional payloads with novel mechanisms:
- ISACs (Immune-Stimulating ADCs) activate the immune system locally.
- Protein degraders eliminate cancer-critical proteins without inhibiting them directly.
- Urease-based and membrane-disrupting agents affect the tumor microenvironment.
- RNA polymerase inhibitors and peptide-based payloads offer precision with reduced systemic toxicity.
This shift also places new demands on linker design. Linkers must now accommodate payloads with diverse chemical properties and release them selectively at the tumor site. A payload–linker mismatch could compromise both safety and efficacy.
Ultimately, the focus is shifting toward payloads not just as cytotoxins, but as precision-guided interventions. This evolution could redefine how ADCs are developed and positioned in treatment regimens, enabling breakthroughs in resistant and heterogeneous cancers. The ADC revolution is payload-powered—and the future belongs to those who can innovate at the molecular level.
References:
https://www.nature.com/articles/s41573-022-00590-3
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10301933
https://www.cell.com/fulltext/S0092-8674(22)01299-7
https://ascopubs.org/doi/full/10.1200/JCO.22.02474
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257482
2012pharmaceutical
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