Maleimide Linkers: The State of ADC Linker Chemistry
Antibody-drug conjugates depend on one small, unglamorous piece of chemistry to hold the whole therapeutic together: the linker joining a potent cytotoxic payload to a targeting antibody. Among the chemistries available for this task, maleimide-thiol conjugation remains the dominant choice. A 2025 review reported that ten of the fifteen commercialised ADCs rely on maleimide conjugation to attach their payloads, a reflection of how well the reaction's fast kinetics and thiol selectivity suit large-scale, reproducible manufacturing. This dominance has made maleimide chemistry a natural focus for continued refinement, and the field has responded with real ingenuity. Work on spacer design, ring-hydrolysis control, and next-generation Michael acceptors has steadily improved conjugate stability in circulation, extending the time payloads stay attached until the ADC reaches its intended target. Far from being a limitation, this ongoing optimisation shows how much headroom still exists in a chemistry that already underpins most of the ADC market, and it is exactly this kind of iterative, structure-led improvement that keeps maleimide linkers at the centre of new conjugate design. That progress continues to translate into new medicines. Telisotuzumab vedotin, approved by the FDA in May 2025 for c-Met overexpressing non-small cell lung cancer, uses a cleavable maleimidocaproyl-valine-citrulline-PABC linker to attach MMAE, the same well-established linker-payload combination used in brentuximab vedotin. Its approval is a strong reminder that a mature, well-understood conjugation chemistry can still deliver clinically meaningful therapies when paired with the right target and payload, and that the steady refinements happening across the field now are setting up the next wave of approvals. Explore our range of building blocks using the advanced search tools at https://lnkd.in/eVbfw6Ua 1. Recent Advances in Peptide Linkers for Antibody-Drug Conjugates https://lnkd.in/eQshwTGh 2. Systematic Evaluation of Maleimide Spacer Impact on Drug-Linker Deconjugation in Antibody-Drug Conjugates Ex Vivo and In Vivo https://lnkd.in/eR\_24BtA 3. Linker substitution influences succinimide ring hydrolysis equilibrium impacting the stability of attachment to antibody-drug conjugates https://lnkd.in/evDueWgF