Among antibody–drug conjugate (ADC) payloads, monomethyl auristatin E (MMAE), linked through a valine–citrulline p-aminobenzylcarbamate (VC-PAB) linker, is one of the most widely used in clinical applications. It serves as the cytotoxic payload in brentuximab vedotin (Adcetris®), which contains approximately four drug molucules per antibody. This ADC was the second to be approved by the U.S. FDA in 2011 (developed by Seagen/Takeda) for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma.
MMAE inhibits cell division by blocking the polymerization of tubulin, leading to cell cycle arrest and apoptosis. The VC-PAB linker remains stable in extracellular fluid but is specifically cleaved by cathepsin B once internalized into tumor cells, thereby releasing the active drug and triggering its antimitotic mechanism. Although VC-PAB is a clinically validated linker, it introduces significant hydrophobicity to MMAE, making it difficult to achieve high drug-to-antibody ratios (DARs) without causing aggregation or loss of stability.
The AqT-MMAE (CM81303) drug asset is currently available for partner evaluation. It uses reduced-thiol conjugation chemistry with a releasable VC-PAB linker, enabling efficient loading of up to eight drug molecules per antibody with minimal aggregation and improved stability.