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

Odd L. Gammelgaard, Mikkel G. Terp, Christian Renn, Aran F. Labrijn, Oliver Hamaker, Aaraby Y. Nielsen, Henriette Vever, Soren Wk Hansen, Morten F. Gjerstorff, Christa E. Müller, Paul Whi Parren, Henrik J. Ditzel

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Abstract

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.

Original languageEnglish
Article numbere004554
JournalJournal for immunotherapy of cancer
Volume10
Issue number9
Number of pages32
ISSN2051-1426
DOIs
Publication statusPublished - 12. Sep 2022

Bibliographical note

Publisher Copyright:
© 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.

Keywords

  • adenosine
  • antibody formation
  • immunotherapy

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