Abstract P1-10-15: Development of humanized anti-CD47 monoclonal antibodies with differentiated functional profiles

Autor: Pamela T. Manning, Robyn J Puro, S Chanda, RW Karr, Benjamin J. Capoccia, Michael J. Donio, Ronald R. Hiebsch, K. J. M. Liu, K Crowley
Rok vydání: 2018
Předmět:
Zdroj: Cancer Research. 78:P1-10
ISSN: 1538-7445
0008-5472
Popis: CD47 is a cell surface transmembrane protein that binds to signal regulatory protein alpha (SIRPα) on macrophages and results in a “don't eat me” signal that inhibits phagocytosis. Breast cancer cells, both primary and metastatic, frequently overexpress CD47 and exploit this pathway to evade macrophage-mediated destruction. Anti-CD47 monoclonal antibodies (mAbs) block the CD47/SIRPα interaction and promote tumor cell destruction via phagocytosis. Anti-CD47 mAbs also contribute to an anti-tumor T-cell response in immune-competent mice. Therefore, anti-CD47 antibodies represent a new class of immune checkpoint inhibitors that modulate both the innate and adaptive immune systems. CD47 is expressed on multiple cell types, including tumor cells and normal cells. Many anti-CD47 mAbs block the CD47/SIRPα interaction and cause phagocytosis of tumor cells, but do not directly induce the death of human tumor cells. Tioma has created new humanized anti-CD47 mAbs with novel and differentiated functional profiles to enhance functional heterogeneity. Ti-104, Ti-176 and Ti-108 block the binding of SIRPα to CD47 and increase phagocytosis of human tumor cells. They also induce cell death of human hematological and solid tumor cell lines (including breast cancer lines) in a cell autonomous manner. Cell death was determined by an increase in phosphatidylserine-positive/7AAD-positive tumor cells assessed by flow cytometry following incubation in media containing anti-CD47 mAb or a negative control immunoglobulin. In vitro, these mAbs bind to human tumor cell lines with apparent binding affinities ranging from low pM to low nM, depending on the cell line and method of analysis (solid-phase or cell-based ELISA, flow cytometry or surface plasmon resonance). In vitro, Ti-104 and Ti-108 bind to human RBCs, whereas Ti-176 has markedly reduced binding to human and cynomolgus monkey RBCs. In a four-week (once-weekly dosing) exploratory safety study in cynomolgus monkeys with Ti-176 and Ti-108, no dose-limiting toxicity or gross pathological or microscopic findings were identified after an initial dose of 5 mg/kg (Week 1) followed by doses of 50 mg/kg (Weeks 2, 3, and 4). Ti-176 treatment resulted in minimal decrease in red cell mass, hemoglobin and hematocrit, which corresponded in vitro to markedly reduced binding to cynomolgus monkey RBCs. Ti-108 caused transient reduction of RBC parameters comparable to some previously reported anti-CD47 mAbs. Ti-104, Ti-176 and Ti-108 showed potent, dose-dependent efficacy in multiple mouse tumor models, including in the MDA-MB-231 triple-negative breast cancer orthotopic model. These data provide the preclinical rationale for further evaluation of Ti-104, Ti-176 and Ti-108 as breast cancer treatments. Citation Format: Karr RW, Liu K, Hiebsch R, Capoccia B, Donio M, Crowley K, Puro R, Chanda S, Manning P. Development of humanized anti-CD47 monoclonal antibodies with differentiated functional profiles [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-15.
Databáze: OpenAIRE
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