Anti-BCMA chimeric antigen receptors with fully human heavy-chain-only antigen recognition domains

Norris Lam, Nathan D. Trinklein, Benjamin Buelow, George H. Patterson, Namrata Ojha and James N. Kochenderfer ()
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Norris Lam: Center for Cancer Research, Surgery Branch
Nathan D. Trinklein: TeneoBio, Inc. 7999 Gateway Blvd
Benjamin Buelow: TeneoBio, Inc. 7999 Gateway Blvd
George H. Patterson: National Institute of Biomedical Imaging and Bioengineering
Namrata Ojha: National Institute of Biomedical Imaging and Bioengineering
James N. Kochenderfer: Center for Cancer Research, Surgery Branch

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Chimeric antigen receptor (CAR)-expressing T cells targeting B-cell maturation antigen (BCMA) have activity against multiple myeloma, but improvements in anti-BCMA CARs are needed. We demonstrated recipient anti-CAR T-cell responses against a murine single-chain variable fragment (scFv) used clinically in anti-BCMA CARs. To bypass potential anti-CAR immunogenicity and to reduce CAR binding domain size, here we designed CARs with antigen-recognition domains consisting of only a fully human heavy-chain variable domain without a light-chain domain. A CAR designated FHVH33-CD8BBZ contains a fully human heavy-chain variable domain (FHVH) plus 4-1BB and CD3ζ domains. T cells expressing FHVH33-CD8BBZ exhibit similar cytokine release, degranulation, and mouse tumor eradication as a CAR that is identical except for substitution of a scFv for FHVH33. Inclusion of 4-1BB is critical for reducing activation-induced cell death and promoting survival of T cells expressing FHVH33-containing CARs. Our results indicate that heavy-chain-only anti-BCMA CARs are suitable for evaluation in a clinical trial.

Date: 2020
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DOI: 10.1038/s41467-019-14119-9

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