T-cell engineered with a fully humanized B-cell maturation antigen-specific T-cell antigen coupler receptor effectively target multiple myeloma.

Autor: Bezverbnaya K; McMaster Immunology Research Center, McMaster University, Hamilton, Canada; Department of Medicine, McMaster University, Hamilton, Canada., Hammill JA; McMaster Immunology Research Center, McMaster University, Hamilton, Canada; Department of Medicine, McMaster University, Hamilton, Canada; Center for Discovery in Cancer Research, McMaster University, Hamilton, Canada., Cummings D; McMaster Immunology Research Center, McMaster University, Hamilton, Canada; Department of Medicine, McMaster University, Hamilton, Canada; Center for Discovery in Cancer Research, McMaster University, Hamilton, Canada., Bojovic B; McMaster Immunology Research Center, McMaster University, Hamilton, Canada; Department of Medicine, McMaster University, Hamilton, Canada; Center for Discovery in Cancer Research, McMaster University, Hamilton, Canada., Groisman B; McMaster Immunology Research Center, McMaster University, Hamilton, Canada., Baker CL; McMaster Immunology Research Center, McMaster University, Hamilton, Canada; Department of Medicine, McMaster University, Hamilton, Canada; Center for Discovery in Cancer Research, McMaster University, Hamilton, Canada., Aarts C; McMaster Immunology Research Center, McMaster University, Hamilton, Canada; Department of Medicine, McMaster University, Hamilton, Canada; Center for Discovery in Cancer Research, McMaster University, Hamilton, Canada., Hayes DL; Triumvira Immunologics, Hamilton, Canada., Rill D; Triumvira Immunologics, Hamilton, Canada., Xu SX; Triumvira Immunologics, Hamilton, Canada., Bader AG; Triumvira Immunologics, Hamilton, Canada., Helsen CW; McMaster Immunology Research Center, McMaster University, Hamilton, Canada; Triumvira Immunologics, Hamilton, Canada., Bramson JL; McMaster Immunology Research Center, McMaster University, Hamilton, Canada; Department of Medicine, McMaster University, Hamilton, Canada; Center for Discovery in Cancer Research, McMaster University, Hamilton, Canada; Office of the Vice Dean, Research, Faculty of Health Sciences, McMaster University, Hamilton, Canada. Electronic address: bramsonj@mcmaster.ca.
Jazyk: angličtina
Zdroj: Cytotherapy [Cytotherapy] 2023 May; Vol. 25 (5), pp. 490-501. Date of Electronic Publication: 2023 Feb 11.
DOI: 10.1016/j.jcyt.2023.01.002
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest DLH, DR, SXX, AGB and CWH are employees of Triumvira Immunologics, which holds commercial rights to the TAC technology and BCMA-TAC receptor described herein. JLB is a paid consultant for Triumvira Immunologics and holds shares in the company. JAH, DC, BB, BG, CLB and CA are employees of McMaster University and have been supported by a sponsored research agreement with Triumvira Immunologics.
(Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: