| Background | Lorvotuzumab mertansine (IMGN901, BB10901, huN901-DM1) is an antibody-drug conjugate (ADC) composed of the cytotoxic maytansinoid derivative, DM1, conjugated to the humanized N901 monoclonal antibody (lorvotuzumab, huN901), which binds CD56 with high affinity. DM1 conjugated to lorvotuzumab via a stable disulfide SPP linker (When DM1 is attached to an antibody with the SPP linker, it is mertansine; when it is attached with the thioether linker, SMCC, it is emtansine). It was developed by ImmunoGen, Inc. Lorvotuzumab mertansine is designed for the treatment of CD56 positive cancers (e.g. small-cell lung cancer, ovarian cancer). It has been granted orphan drug status for Merkel cell carcinoma and has reported encouraging Phase II results for small-cell lung cancer (SCLC). Once bound to CD56 on the surface of the target cell, the conjugate is internalized, the linker is cleaved, DM1 is released which in turn inhibits tubulin polymerization and results in cell death. Maytansine is a natural product, originally derived from the Ethiopian shrub Maytenus serrata. Maytansine inhibits tubulin polymerization, and is approximately 200-1,000 fold more cytotoxic than the Vinca alkaloids. Maytansine is clinically active but its narrow therapeutic window precluded further clinical development. Conjugation to an antibody and intracellular delivery could take advantage of the cytotoxic potency and expand the therapeutic window leading to greater tumor cell death with less overall toxicity. The maytansine derivative DM1 was developed specifically for use in ADCs. |
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