Selective Blockade of the Ubiquitous Checkpoint Receptor CD47 Is Enabled by Dual-Targeting Bispecific Antibodies.
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.
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Elie
E
Dheilly
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Valéry
V
Moine
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Lucile
L
Broyer
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Susana
S
Salgado-Pires
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Zoë
Z
Johnson
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Anne
A
Papaioannou
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Laura
L
Cons
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Sébastien
S
Calloud
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Stefano
S
Majocchi
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Robert
R
Nelson
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
François
F
Rousseau
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Walter
W
Ferlin
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Marie
M
Kosco-Vilbois
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland.
Nicolas
N
Fischer
Novimmune SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Switzerland. Electronic address: kmasternak@novimmune.com.
Krzysztof
K
Masternak
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D051928:CD47 Antigen / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000090204:Mesothelin; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D051928:CD47 Antigen; C000715528:Msln protein, mouse; D000090204:Mesothelin
CD19; CD47; bispecific antibody; cancer immunotherapy; immune checkpoint; macrophage; mesothelin; phagocytosis; pharmacokinetics