Trastuzumab-DM1 (T-DM1; trastuzumab emtansine) iscomposed of the humanized antibody trastuzumab and DM1, a maytansinoidderivative, linked with a nonreducible thioether linker,N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC, designatedMCC after conjugation). Maytansinoids are natural products that are potent antimitotic agents,which like the vinca alkaloids prevent microtubule assembly. Due in part to their impressive potency,maytansinoids were investigated as drugs for conjugation to monoclonalantibodies. Derivatives of maytansinoids were synthesized to allow chemicalconjugation to proteins using disulfide linkers. The realization that theendocytic pathway is not reducing and our empirical experimental observationsled us to conclude that the more stable thioether linkage was better suited formaytansinoid coupling to trastuzumab. Early promisingclinical data were recently generated in patients whose tumors have progressedon HER2-directed therapies.

Trastuzumab emtansine (T-DM1) for the
treatment of HER2-positive breast cancer

242nd National Meeting (2011)

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Trastuzumab emtansine (T-DM1) for the treatment of HER2-positive breast cancer