A Novel Antibody-Drug Conjugate That Induces Long-Term Tumor Regression And Anticancer Stem Cell Activity

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAAntibody-drug conjugates (ADCs) selectively deliver cytotoxic agents to tumors and provide the potential for increased clinical benefit to cancer patients. We have developed an ADC consisting of an antibody against a target expressed on the surface of tumor cells that is site-specifically conjugated with a pyrrolobenzodiazepine (PBD) dimer payload (PBD-ADC). The tumor-associated antigen is overexpressed in many carcinomas, on both bulk tumor cells and cancer stem cells (CSCs), while normal tissue expression is limited, thus making it an ideal ADC target. The PBD payload was selected due to its picomolar potency and because, unlike tubulin inhibitors, it could be cytotoxic to CSCs as well as bulk tumor cells. The PBD-ADC is significantly efficacious in target-positive in vivo tumor models of gastric, breast and lung carcinomas, inducing long-term tumor regressions and demonstrates greater potency compared to ADCs conjugated with either tubulysin or auristatin payloads, both tubulin inhibitors. Additionally, the PBD-ADC significantly reduced the CSC population of tumors in vivo, unlike ADCs bearing tubulin inhibitor payloads. The PBD-ADC appears to be efficacious against tumors that have acquired resistance to a tubulysin-based ADC, however possible mechanisms of resistance to this PBD-ADC are being investigated. Collectively, this novel ADC represents a promising therapy that may deliver durable clinical responses in indications with unmet medical need.Citation Format: Jay W. Harper, Chris Lloyd, Shenlan Mao, Xin Lin, Nazzareno Dimasi, Phil Howard, Ellen Ou0027Connor, David Farkas, Christopher Barton, Jeff Smith, Helen Zhong, Tracy Chen, Mary Jane Hinrichs, Marlon Rebelatto, Xiang-Qing Yu, Susan Spitz, Andrew Pierce, Dominic Lai, Hurt Elaine, Lilian van Vlerken-Ysla, Jalla Sanjoo, Katy Miller, Karen McCullough, Priya Kannan, Simon Thompson, Parthiv Mahadevia, Chris Martin, Robert Hollingsworth, Adeela Kamal. A novel antibody-drug conjugate that induces long-term tumor regression and anticancer stem cell activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 948. doi:10.1158/1538-7445.AM2015-948