The medicinal chemistry evolution of antibody–drug conjugates

Abstract

Antibody-drug conjugates (ADCs) comprise of 3 components of wildly differing sizes: antibody (150,000 Da), linker (typically <500 Da)and payload (typically <500Da). While the drug-linker makes up only a small percent...

Late-Stage Desulfurization Enables Rapid and Efficient Solid-Phase Synthesis of Cathepsin-Cleavable Linkers for Antibody–Drug Conjugates

“…The majority of clinically approved ADCs employ protease-cleavable peptide-based linkers, such as valine-citrulline (Val-Cit) and valine-alanine (Val-Ala) to attach the payload to the antibody. , This class of cleavable linkers has shown adequate stability in the serum and effective payload release in targeted cancerous cells …”

“…31,32 This class of cleavable linkers has shown adequate stability in the serum and effective payload release in targeted cancerous cells. 33 Dubowchik et al were the first to report the detailed solution-phase synthesis of the maleimidocaproyl-L-valine-Lcitrulline-para-aminobenzyl alcohol p-nitrophenyl carbonate (MC-Val-Cit−PABC-PNP) linker. 34 Subsequently, Senter et al followed Dubowchic's chemistry to synthesize the MC-Val-Cit−PABC-PNP linker and used it to conjugate the antimitotic agent monomethyl auristatin E (MMAE) to a CD30-directed antibody, cAC10, leading to the creation of Brentuximab vedotin (ADCETRIS) (Figure 2A).…”