Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis
| Autor: | Julia Abdullah, Diala Ghazal, Muctarr Sesay, John C. Fisk, Karamveer Birthare, Anthony W. Gebhard, Jing Ying Eng, Swetha Tati, Joseph Jessee, Stephen T. Koury, James R. Olson, David Moreno, Olga V. Glinskii, Taylor Chrisikos, Sally A. Quataert, Loukia G. Karacosta, Vladislav V. Glinsky, Susan Morey, Kate Rittenhouse-Olson, Fatma Zazala, Padraic Philbin |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment Humanized antibody lcsh:RC254-282 Targeted therapy 03 medical and health sciences 0302 clinical medicine Breast cancer Antigen Cancer immunotherapy medicine Triple-negative breast cancer biology Thomsen-Friedenreich Antigen business.industry medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Molecular biology 3. Good health 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Antibody business Corrigendum |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 19, Iss 9, Pp 716-733 (2017) Neoplasia (New York, N.Y.) |
| ISSN: | 1522-8002 1476-5586 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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