Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function

Benjamin Salzer, Christina M. Schueller, Charlotte U. Zajc, Timo Peters, Michael A. Schoeber, Boris Kovacic, Michelle C. Buri, Elisabeth Lobner, Omer Dushek, Johannes B. Huppa, Christian Obinger, Eva M. Putz, Wolfgang Holter, Michael W. Traxlmayr () and Manfred Lehner ()
Additional contact information
Benjamin Salzer: St. Anna Children’s Cancer Research Institute (CCRI)
Christina M. Schueller: St. Anna Children’s Cancer Research Institute (CCRI)
Charlotte U. Zajc: St. Anna Children’s Cancer Research Institute (CCRI)
Timo Peters: Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna
Michael A. Schoeber: St. Anna Children’s Cancer Research Institute (CCRI)
Boris Kovacic: St. Anna Children’s Cancer Research Institute (CCRI)
Michelle C. Buri: St. Anna Children’s Cancer Research Institute (CCRI)
Elisabeth Lobner: University of Natural Resources and Life Sciences
Omer Dushek: Sir William Dunn School of Pathology, University of Oxford
Johannes B. Huppa: Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna
Christian Obinger: Institute of Biochemistry, University of Natural Resources and Life Sciences
Eva M. Putz: St. Anna Children’s Cancer Research Institute (CCRI)
Wolfgang Holter: St. Anna Children’s Cancer Research Institute (CCRI)
Michael W. Traxlmayr: Christian Doppler Laboratory for Next Generation CAR T Cells
Manfred Lehner: St. Anna Children’s Cancer Research Institute (CCRI)

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ON-switch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity.

Date: 2020
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DOI: 10.1038/s41467-020-17970-3

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