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Neoplasia. 2017 Sep;19(9):716-733. doi: 10.1016/j.neo.2017.07.001. Epub 2017 Aug 19.

Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and InVitro Efficacy Analysis.

Neoplasia (New York, N.Y.)

Swetha Tati, John C Fisk, Julia Abdullah, Loukia Karacosta, Taylor Chrisikos, Padraic Philbin, Susan Morey, Diala Ghazal, Fatma Zazala, Joseph Jessee, Sally Quataert, Stephen Koury, David Moreno, Jing Ying Eng, Vladislav V Glinsky, Olga V Glinskii, Muctarr Sesay, Anthony W Gebhard, Karamveer Birthare, James R Olson, Kate Rittenhouse-Olson

Affiliations

  1. For-Robin, Inc., Buffalo, NY. Electronic address: [email protected].
  2. For-Robin, Inc., Buffalo, NY. Electronic address: [email protected].
  3. Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, Buffalo, NY; For-Robin, Inc., Buffalo, NY; Department of Microbiology and Immunology, University at Buffalo, Buffalo, NY. Electronic address: [email protected].
  4. For-Robin, Inc., Buffalo, NY. Electronic address: [email protected].
  5. Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, Buffalo, NY; For-Robin, Inc., Buffalo, NY. Electronic address: [email protected].
  6. Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, Buffalo, NY. Electronic address: [email protected].
  7. Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, Buffalo, NY. Electronic address: [email protected].
  8. For-Robin, Inc., Buffalo, NY. Electronic address: [email protected].
  9. For-Robin, Inc., Buffalo, NY. Electronic address: [email protected].
  10. For-Robin, Inc., Buffalo, NY. Electronic address: [email protected].
  11. For-Robin, Inc., Buffalo, NY. Electronic address: [email protected].
  12. Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, Buffalo, NY. Electronic address: [email protected].
  13. Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, Buffalo, NY. Electronic address: [email protected].
  14. Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, Buffalo, NY. Electronic address: [email protected].
  15. Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO; Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO. Electronic address: [email protected].
  16. Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO. Electronic address: [email protected].
  17. Goodwin Biotechnology, Inc., Plantation, FL. Electronic address: [email protected].
  18. Goodwin Biotechnology, Inc., Plantation, FL. Electronic address: [email protected].
  19. For-Robin, Inc., Buffalo, NY; Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY. Electronic address: [email protected].
  20. Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, Buffalo, NY; For-Robin, Inc., Buffalo, NY. Electronic address: [email protected].

PMID: 28830009 PMCID: PMC5565633 DOI: 10.1016/j.neo.2017.07.001

Abstract

JAA-F11 is a highly specific mouse monoclonal to the Thomsen-Friedenreich Antigen (TF-Ag) which is an alpha-O-linked disaccharide antigen on the surface of ~80% of human carcinomas, including breast, lung, colon, bladder, ovarian, and prostate cancers, and is cryptic on normal cells. JAA-F11 has potential, when humanized, for cancer immunotherapy for multiple cancer types. Humanization of JAA-F11, was performed utilizing complementarity determining regions grafting on a homology framework. The objective herein is to test the specificity, affinity and biology efficacy of the humanized JAA-F11 (hJAA-F11). Using a 609 target glycan array, 2 hJAA-F11 constructs were shown to have excellent chemical specificity, binding only to TF-Ag alpha-linked structures and not to TF-Ag beta-linked structures. The relative affinity of these hJAA-F11 constructs for TF-Ag was improved over the mouse antibody, while T20 scoring predicted low clinical immunogenicity. The hJAA-F11 constructs produced antibody-dependent cellular cytotoxicity in breast and lung tumor lines shown to express TF-Ag by flow cytometry. Internalization of hJAA-F11 into cancer cells was also shown using a surface binding ELISA and confirmed by immunofluorescence microscopy. Both the naked hJAA-F11 and a maytansine-conjugated antibody (hJAA-F11-DM1) suppressed in vivo tumor progression in a human breast cancer xenograft model in SCID mice. Together, our results support the conclusion that the humanized antibody to the TF-Ag has potential as an adjunct therapy, either directly or as part of an antibody drug conjugate, to treat breast cancer, including triple negative breast cancer which currently has no targeted therapy, as well as lung cancer.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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