Selective Blockade of the Ubiquitous Checkpoint Receptor CD47 Is Enabled by Dual-Targeting Bispecific Antibodies.

Abstract

CD47 is a ubiquitously expressed immune checkpoint receptor that is often upregulated in cancer. CD47 interacts with its counter-receptor SIRPα on macrophages and other myeloid cells to inhibit cancer cell phagocytosis and drive immune evasion. To overcome tolerability and "antigen sink" issues arising from widespread CD47 expression, we generated dual-targeting bispecific antibodies that selectively block the CD47-SIRPα interaction on malignant cells expressing a specific tumor-associated antigen; e.g., CD19 or mesothelin. These bispecific κλ bodies are fully human, native IgG1 molecules, combining tumor targeting and selective CD47 blockade with immune activating mechanisms mediated by the Fc portion of the antibody. CD47-neutralizing κλ bodies efficiently kill cancer cells in vitro and in vivo but interact only weakly with healthy cells expressing physiological levels of CD47. Accordingly, a κλ body administered to non-human primates showed a typical IgG pharmacokinetic profile and was well tolerated. Importantly, κλ bodies preserve their tumoricidal capabilities in the presence of a CD47 antigen sink. Thus, dual-targeting κλ bodies allow for efficacious yet safe targeting of CD47 in cancer. Such a bispecific design could be applied to limit the extent of neutralization of other ubiquitously expressed therapeutic targets.

• Authors: Elie Dheilly, Valéry Moine, Lucile Broyer, Susana Salgado-Pires, Zoë Johnson, Anne Papaioannou, Laura Cons, Sébastien Calloud, Stefano Majocchi, Robert Nelson, François Rousseau, Walter Ferlin, Marie Kosco-Vilbois, Nicolas Fischer, Krzysztof Masternak
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 25 Issue 2 Pg. 523-533 (02 01 2017) ISSN: 1525-0024 [Electronic] United States
• PMID: 28153099 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Bispecific
• Antigens, Neoplasm
• Antineoplastic Agents
• CD47 Antigen
• Msln protein, mouse
• Mesothelin

Topics

• Animals
• Antibodies, Bispecific (immunology, pharmacology)
• Antibody-Dependent Cell Cytotoxicity (immunology)
• Antigens, Neoplasm (immunology)
• Antineoplastic Agents (pharmacology)
• CD47 Antigen (immunology, metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Humans
• Mesothelin
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Molecular Targeted Therapy
• Neoplasms (drug therapy, immunology, metabolism)
• Phagocytosis (immunology)
• Protein Binding (immunology)
• Xenograft Model Antitumor Assays