Preclinical Evaluation of MEDI0641, a Pyrrolobenzodiazepine-Conjugated Antibody-Drug Conjugate Targeting 5T4

• Published in: Molecular cancer therapeutics Vol. 16; no. 8; pp. 1576 - 1587
• Main Authors: Harper, Jay, Lloyd, Christopher, Dimasi, Nazzareno, Toader, Dorin, Marwood, Rose, Lewis, Leeanne, Bannister, David, Jovanovic, Jelena, Fleming, Ryan, D'Hooge, Francois, Mao, Shenlan, Marrero, Allison M, Korade, 3rd, Martin, Strout, Patrick, Xu, Linda, Chen, Cui, Wetzel, Leslie, Breen, Shannon, van Vlerken-Ysla, Lilian, Jalla, Sanjoo, Rebelatto, Marlon, Zhong, Haihong, Hurt, Elaine M, Hinrichs, Mary Jane, Huang, Keven, Howard, Philip W, Tice, David A, Hollingsworth, Robert E, Herbst, Ronald, Kamal, Adeela
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.08.2017
• Subjects: Animal models; Animals; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Benzodiazepines - adverse effects; Benzodiazepines - pharmacology; Benzodiazepines - therapeutic use; Biocompatibility; Cancer; Carcinoma; Cell Line, Tumor; Cell surface; Conjugation; Construction sites; Crosslinking; Cytotoxic agents; Cytotoxicity; Deoxyribonucleic acid; DNA; Drug delivery systems; Humans; Immunoconjugates - adverse effects; Immunoconjugates - pharmacology; Immunoconjugates - therapeutic use; In vivo methods and tests; Internalization; Male; Mice; Mice, Nude; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Payloads; Pyrroles - adverse effects; Pyrroles - pharmacology; Pyrroles - therapeutic use; Rats, Sprague-Dawley; Stem cell transplantation; Stem cells; Toxicology; Tubulin Modulators - adverse effects; Tubulin Modulators - pharmacology; Tubulin Modulators - therapeutic use; Tumor cells; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0825

Antibody-drug conjugates (ADC) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSC), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation. ADCs targeting 5T4 were constructed by site-specifically conjugating the antibody with payloads that possess different mechanisms of action, either a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer or a microtubule-destabilizing tubulysin, so that each ADC had a drug:antibody ratio of 2. The resulting ADCs demonstrated significant target-dependent activity and ; however, the ADC conjugated with a PBD payload (5T4-PBD) elicited more durable antitumor responses than the tubulysin conjugate in xenograft models. Likewise, the 5T4-PBD more potently inhibited the growth of 5T4-positive CSCs , which likely contributed to its superior antitumor activity. Given that the 5T4-PBD possessed both potent antitumor activity as well as anti-CSC activity, and thus could potentially target bulk tumor cells and CSCs in target-positive indications, it was further evaluated in non-GLP rat toxicology studies that demonstrated excellent stability with an acceptable safety profile. Taken together, these preclinical data support further development of 5T4-PBD, also known as MEDI0641, against 5T4 cancer indications. .