A Novel T-Cell Engaging Bi-specific Antibody Targeting the Leukemia Antigen PR1/HLA-A2
| Autor: | Sijie Lu, Anna Sergeeva, Sumedha Pareek, Gheath Alatrash, Pariya Sukhumalchandra, Dongxing Zha, Hong He, Karen Clise-Dwyer, Amanda C. Herrmann, Jennifer M. Mehrens, Wilfredo Ruiz-Vasquez, Lisa S. St. John, Jeffrey J. Molldrem, Jin S. Im |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Cytotoxicity
Immunologic 0301 basic medicine lcsh:Immunologic diseases. Allergy re-directed cytotoxicity medicine.drug_class T-Lymphocytes medicine.medical_treatment Immunology CHO Cells acute myeloid leukemia Lymphocyte Activation Monoclonal antibody Immunotherapy Adoptive bi-specific antibody Cell Line 03 medical and health sciences Cricetulus 0302 clinical medicine Cancer immunotherapy Antigen Antibody Specificity Antigens Neoplasm hemic and lymphatic diseases Antibodies Bispecific HLA-A2 Antigen medicine Animals Humans Immunology and Allergy Cytotoxicity Original Research Antibody-dependent cell-mediated cytotoxicity cancer immunotherapy PR1 biology Chemistry Myeloid leukemia medicine.disease 3. Good health Leukemia Myeloid Acute Leukemia 030104 developmental biology Cancer research biology.protein Antibody lcsh:RC581-607 Protein Binding 030215 immunology |
| Zdroj: | Frontiers in Immunology Frontiers in Immunology, Vol 9 (2019) |
| ISSN: | 1664-3224 |
| Popis: | Despite substantial advances in the treatment of acute myeloid leukemia (AML), only 30% of patients survive more than 5 years. Therefore, new therapeutics are much needed. Here, we present a novel therapeutic strategy targeting PR1, an HLA-A2 restricted myeloid leukemia antigen. Previously, we have developed and characterized a novel T-cell receptor-like monoclonal antibody (8F4) that targets PR1/HLA-A2 and eliminates AML xenografts by antibody-dependent cellular cytotoxicity (ADCC). To improve the potency of 8F4, we adopted a strategy to link T-cell cytotoxicity with a bi-specific T-cell-engaging antibody that binds PR1/HLA-A2 on leukemia and CD3 on neighboring T-cells. The 8F4 bi-specific antibody maintained high affinity and specific binding to PR1/HLA-A2 comparable to parent 8F4 antibody, shown by flow cytometry and Bio-Layer Interferometry. In addition, 8F4 bi-specific antibody activated donor T-cells in the presence of HLA-A2+ primary AML blasts and cell lines in a dose dependent manner. Importantly, activated T-cells lysed HLA-A2+ primary AML blasts and cell lines after addition of 8F4 bi-specific antibody. In conclusion, our studies demonstrate the therapeutic potential of a novel bi-specific antibody targeting the PR1/HLA-A2 leukemia-associated antigen, justifying further clinical development of this strategy. |
| Databáze: | OpenAIRE |
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