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

Abstract

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 in vitro and in vivo; however, the ADC conjugated with a PBD payload (5T4-PBD) elicited more durable antitumor responses in vivo than the tubulysin conjugate in xenograft models. Likewise, the 5T4-PBD more potently inhibited the growth of 5T4-positive CSCs in vivo, 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 in vivo 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. Mol Cancer Ther; 16(8); 1576-87. ©2017 AACR.

• Authors: Jay Harper, Christopher Lloyd, Nazzareno Dimasi, Dorin Toader, Rose Marwood, Leeanne Lewis, David Bannister, Jelena Jovanovic, Ryan Fleming, Francois D'Hooge, Shenlan Mao, Allison M Marrero, Martin Korade 3rd, Patrick Strout, Linda Xu, Cui Chen, Leslie Wetzel, Shannon Breen, Lilian van Vlerken-Ysla, Sanjoo Jalla, Marlon Rebelatto, Haihong Zhong, Elaine M Hurt, Mary Jane Hinrichs, Keven Huang, Philip W Howard, David A Tice, Robert E Hollingsworth, Ronald Herbst, Adeela Kamal
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 16 Issue 8 Pg. 1576-1587 (08 2017) ISSN: 1538-8514 [Electronic] United States
• PMID: 28522587 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Immunoconjugates
• MEDI0641
• Pyrroles
• Tubulin Modulators
• pyrrolo(2,1-c)(1,4)benzodiazepine
• Benzodiazepines

Topics

• Animals
• Antibodies, Monoclonal (adverse effects, pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized (adverse effects, pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzodiazepines (adverse effects, pharmacology, therapeutic use)
• Cell Line, Tumor
• Humans
• Immunoconjugates (adverse effects, pharmacology, therapeutic use)
• Male
• Mice
• Mice, Nude
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Pyrroles (adverse effects, pharmacology, therapeutic use)
• Rats, Sprague-Dawley
• Tubulin Modulators (adverse effects, pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays