Abstract
B-cell maturation antigen (BCMA) is a clinically validated target for multiple myeloma.
T-cell engineered with chimeric antigen receptors (CARs) directed against BCMA have
demonstrated robust therapeutic activity in clinical trials, but toxicities remain
a significant concern for a subset of patients, supporting continued investigation
of other engineered T-cell platforms that may offer equal efficacy with an improved
toxicity profile. The authors recently described a BCMA-specific, T-cell-centric synthetic
antigen receptor, the T-cell antigen coupler (TAC) receptor, that can be used to engineer
T-cell with robust anti-myeloma activity. Here the authors describe the creation of
a fully humanized BCMA-specific TAC receptor. Single-chain variable fragments (scFvs)
were developed from BCMA-specific F(ab)s that were identified in a fully human phage
display library. Twenty-four configurations of the F(ab)s were evaluated in a medium-throughput
screening using primary T-cell, and a single F(ab), TRAC 3625, emerged as the most
robust following in vitro and in vivo evaluation. An optimized BCMA-specific TAC receptor was developed through iterations
of the BCMA-TAC design that evaluated a next-generation TAC scaffold sequence, different
domains connecting the TAC to the 3625 scFv and different orientations of the TRAC
3625 heavy and light variable regions.
Key Words
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Article info
Publication history
Published online: February 11, 2023
Accepted:
January 8,
2023
Received:
July 29,
2022
Publication stage
In Press Corrected ProofIdentification
Copyright
© 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.
