Targeting two distinct epitopes on human CD73 with a bispecific antibody improves anticancer activity.

Autor:	Gammelgaard OL; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Terp MG; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Renn C; PharmaCenter Bonn, Pharmaceutical Sciences Bonn (PSB), Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn, Germany., Labrijn AF; Genmab BV, Utrecht, The Netherlands., Hamaker O; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Nielsen AY; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Vever H; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Hansen SW; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Gjerstorff MF; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.; Department of Oncology, Odense University Hospital, Odense, Denmark., Müller CE; PharmaCenter Bonn, Pharmaceutical Sciences Bonn (PSB), Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn, Germany., Parren PW; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Ditzel HJ; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark hditzel@health.sdu.dk.; Department of Oncology, Odense University Hospital, Odense, Denmark.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Sep; Vol. 10 (9).
DOI:	10.1136/jitc-2022-004554
Abstrakt:	Background: Immunosuppressive extracellular adenosine is generated by the enzymatic activity of CD73. In preclinical models, antibodies (Abs) targeting different epitopes on CD73 exert anticancer activity through distinct mechanisms such as inhibition of enzymatic activity, engagement of Fc receptors, and spatial redistribution of CD73. Methods: Using controlled Fab arm exchange, we generated biparatopic bispecific antibodies (bsAbs) from parental anti-CD73 Abs with distinct anticancer activities. The resulting anticancer activity was evaluated using in vitro and in vivo models. Results: We demonstrate that different anticancer activities can be combined in a biparatopic bsAb. Remarkably, the bsAb significantly improved the enzyme inhibitory activity compared with the parental Abs, which led to neutralization of adenosine-mediated T-cell suppression as demonstrated by proliferation and interferon gamma (IFN-γ) production and prolonged survival of tumor-bearing mice. Additionally, the bsAb caused more efficient internalization of cell surface CD73 and stimulated potent Fc-mediated engagement of human immune effector cells in vitro and in vivo. Conclusions: Our data collectively demonstrate that complementary anticancer mechanisms of action of distinct anti-CD73 Abs can be combined and enhanced in a biparatopic bsAb. The multiple mechanisms of action and superior activity compared with the monospecific parental Abs make the bsAb a promising candidate for therapeutic targeting of CD73 in cancer. This concept may greatly improve future Ab design. Competing Interests: Competing interests: All authors except AFL and PP declare no competing interests. AFL is an employee of Genmab, a biotechnology company that commercializes the DuoBody technology platform. He owns warrants and stock. PP is a co-inventor of patents relating to the DuoBody technology. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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