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A101-VC-MMAE

Development stage: Preclinical
Lead developer: National Cancer Institute
Modality: Nanobodies (VHH) → Antibody Fragments → Engineered Antibody Formats → Antibody-Based Therapeutics, Cytotoxic ADCs → Antibody-Drug Conjugates (ADCs) → Antibody Conjugates → Antibody-Based Therapeutics
Administration: Intravenous

Overview

A101-VC-MMAE is a mesothelin (MSLN)-targeted nanobody-drug conjugate (NDC) developed for the treatment of pancreatic ductal adenocarcinoma (PDAC). It consists of a camelid-derived VHH nanobody (A101) that binds to MSLN with high affinity, conjugated to the cytotoxic microtubule inhibitor monomethyl auristatin E (MMAE) via a cathepsin-cleavable valine-citrulline (VC) linker. The nanobody format is specifically designed to improve tumor penetration within the dense stroma of the pancreatic tumor microenvironment compared to traditional antibody-drug conjugates. Upon binding to MSLN on the surface of cancer cells, the conjugate is internalized, and the VC linker is cleaved by intracellular proteases to release MMAE, which inhibits tubulin polymerization and induces cell death. Preclinical studies have demonstrated its efficacy in MSLN-positive tumor models, although related constructs with alternative linkers are also being explored for potentially superior specificity.

Other names: A101-valine-citrulline-MMAEA-101-valine-citrulline-MMAEA 101-valine-citrulline-MMAE

Targets

MesothelinTUBB (Tubulin (alpha and beta subunits))

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