Anti-DM1/4 polyclonal antibody

Early clinical development in the field of targeted delivery of cytotoxic drugs to tumors using antibodies failed to achieve effective, well-tolerated anticancer products. In recent years, several new highly potent cell-killing agents, such as thiol derivatives of the potent antimitotic microtubule agent maytansine, developed by ImmunoGen, are being utilized to make a new generation of antibody-drug conjugates (ADCs). Several antibody-maytansinoid conjugates (AMCs) have shown encouraging efficacy in clinical trials, including trastuzumab-DM1 (T-DM1), which targets HER2+ breast cancer, SAR-3419, which targets CD19 expressed on B-cell malignancies, and IMGN-901, which targets CD56 expressed on both solid tumors (small cell lung cancer and other neuroendocrine tumor types) and hematological tumors, including multiple myeloma. Besides their demonstrated efficacy in phase I and/or phase II clinical studies, these AMCs are well tolerated, with no clinically significant myelosuppression, suggesting that AMC compounds are well suited for evaluation in combination treatment regimens. Maytansinoids are payloads for antibody-mediated delivery that are realizing the promise of ADCs for improved targeted therapy in cancer patients. Copyright ? 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We determined in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymerizing agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was determined in mouse breast cancer models, and toxicity was assessed in rats as measured by body weight loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concentrations of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was observed on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addition, trastuzumab-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clinical development.