Site-Specific Trastuzumab Maytansinoid Antibody鈥揇rug Conjugates with Improved Therapeutic Activity through Linker and Antibody Engineering

详细信息    查看全文

• 作者：Thomas H. Pillow ; Janet Tien ; Kathryn L. Parsons-Reponte ; Sunil Bhakta ; Hao Li ; Leanna R. Staben ; Guangmin Li ; Josefa Chuh ; Aimee Fourie-O鈥橠onohue ; Martine Darwish ; Victor Yip ; Luna Liu ; Douglas D. Leipold ; Dian Su ; Elmer Wu ; Susan D. Spencer ; Ben-Quan Shen ; Keyang Xu ; Katherine R. Kozak ; Helga Raab ; Richard Vandlen ; Gail D. Lewis Phillips ; Richard H. Scheller ; Paul Polakis ; Mark X. Sliwkowski ; John A. Flygare ; Jagath R. Junutula
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：57
• 期：19
• 页码：7890-7899
• 全文大小：497K
• ISSN：1520-4804

文摘

Antibody鈥揹rug conjugates (ADCs) have a significant impact toward the treatment of cancer, as evidenced by the clinical activity of the recently approved ADCs, brentuximab vedotin for Hodgkin lymphoma and ado-trastuzumab emtansine (trastuzumab-MCC-DM1) for metastatic HER2+ breast cancer. DM1 is an analog of the natural product maytansine, a microtubule inhibitor that by itself has limited clinical activity and high systemic toxicity. However, by conjugation of DM1 to trastuzumab, the safety was improved and clinical activity was demonstrated. Here, we report that through chemical modification of the linker鈥揹rug and antibody engineering, the therapeutic activity of trastuzumab maytansinoid ADCs can be further improved. 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鈥揹rugs 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 ADC, trastuzumab-MCC-DM1.