Antibody-drug conjugates or ADCs have a significant impact on the treatment of cancer. This is demonstrated by the clinical activity of the recently approved Antibody-drug Conjugates such as brentuximab vedotin (Adcetris®; Seattle Genetics) for the treatment of Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) as well as Hodgkin lymphoma in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens and systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen and ado-trastuzumab emtansine (Kadcyla®/trastuzumab-MCC-DM1; Genentech/Roche) for the treatment of metastatic HER2+ breast cancer.

Cytotoxic Payload
DM1 is an analog of the maytansine, a microtubule inhibitor that by itself has limited clinical activity and high systemic toxicity. However, after conjugating DM1 to trastuzumab, the safety of the cytotoxic payload is improved while at the same time demonstrating clinical activity.

Results of a study by Thomas Pillow, Janet Tien, Kathryn Parsons-Reponte, Sunil Bhakta, Hao Li, et al, published in the October 9, 2014 edition of the Journal of Medicinal Chemistryshows that through chemical modification of the linker-drug and antibody engineering, the therapeutic activity of the trastuzumab maytansinoid ADCs can be further improved.

Based on their findings, the researchers report that these improvements include eliminating DM1 release in the plasma and increasing the drug load by engineering four cysteine residues into the antibody. The chemical synthesis of highly stable linker-drugs and the modification of cysteine residues of engineered site-specific antibodies resulted in a homogeneous ADC with increased therapeutic activity compared to the clinically approved trastuzumab-MCC-DM1 ADC.

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Published in: Journal of Medicinal Chemistry