Development of AO-176, a Next-Generation Humanized Anti-CD47 Antibody with Novel Anticancer Properties and Negligible Red Blood Cell Binding
| Autor: | Pamela T. Manning, Ronald R. Hiebsch, Daniel S. Pereira, Benjamin J. Capoccia, Robyn J Puro, Michael J. Donio, Myriam N. Bouchlaka, William A. Frazier, Karr Robert W |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Erythrocytes T-Lymphocytes Mice Nude Apoptosis CD47 Antigen Antibodies Monoclonal Humanized Mice 03 medical and health sciences 0302 clinical medicine Immune system Phagocytosis Antigen Neoplasms Tumor Cells Cultured Signal-regulatory protein alpha Animals Humans Receptors Immunologic Cell Proliferation Antibody-dependent cell-mediated cytotoxicity Mice Inbred BALB C Innate immune system biology Cell growth Chemistry CD47 Antigens Differentiation Xenograft Model Antitumor Assays Immunity Innate Macaca fascicularis 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Female Antibody |
| Zdroj: | Molecular Cancer Therapeutics. 19:835-846 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | Inhibitors of adaptive immune checkpoints have shown promise as cancer treatments. CD47 is an innate immune checkpoint receptor broadly expressed on normal tissues and overexpressed on many tumors. Binding of tumor CD47 to signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells triggers a “don't eat me” signal that inhibits phagocytosis enabling escape of innate immune surveillance. Blocking CD47/SIRPα interaction promotes phagocytosis reducing tumor burden in numerous xenograft and syngeneic animal models. We have developed a next-generation humanized anti-CD47 antibody, AO-176, that not only blocks the CD47/SIRPα interaction to induce tumor cell phagocytosis, but also induces tumor cytotoxicity in hematologic and solid human tumor cell lines, but not normal noncancerous cells, by a cell autonomous mechanism (not ADCC). AO-176 also binds preferentially to tumor versus many normal cell types. In particular, AO-176 binds negligibly to RBCs in contrast to tumor cells, even at high concentrations up to 200 μg/mL and does not agglutinate RBCs up to 1 mg/mL in vitro. These properties are expected not only to decrease the antigen sink, but also to minimize on-target clinical adverse effects observed following treatment with other reported RBC-binding anti-CD47 antibodies. When tested in cynomolgus monkeys, AO-176 was well tolerated with no adverse effects. Finally, we show that AO-176 demonstrates dose-dependent antitumor activity in tumor xenograft models. Taken together, the unique properties and antitumor activity of our next-generation anti-CD47 antibody, AO-176, distinguishes it from other CD47/SIRPα axis targeting agents in clinical development. |
| Databáze: | OpenAIRE |
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