Peptide-scFv antigen recognition domains effectively confer CAR T cell multiantigen specificity.

Autor:	Zoine JT; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Immadisetty K; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Structural Biology and Center of Excellence for Data Driven Discovery, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Ibanez-Vega J; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Moore SE; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Nevitt C; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Thanekar U; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Tian L; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Karouni A; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Chockley PJ; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Arthur B; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Sheppard H; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Klco JM; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Langfitt DM; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Krenciute G; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Gottschalk S; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Babu MM; Department of Structural Biology and Center of Excellence for Data Driven Discovery, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Velasquez MP; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: paulina.velasquez@stjude.org.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Feb 20; Vol. 5 (2), pp. 101422. Date of Electronic Publication: 2024 Feb 12.
DOI:	10.1016/j.xcrm.2024.101422
Abstrakt:	The emergence of immune escape is a significant roadblock to developing effective chimeric antigen receptor (CAR) T cell therapies against hematological malignancies, including acute myeloid leukemia (AML). Here, we demonstrate feasibility of targeting two antigens simultaneously by combining a GRP78-specific peptide antigen recognition domain with a CD123-specific scFv to generate a peptide-scFv bispecific antigen recognition domain (78.123). To achieve this, we test linkers with varying length and flexibility and perform immunophenotypic and functional characterization. We demonstrate that bispecific CAR T cells successfully recognize and kill tumor cells that express GRP78, CD123, or both antigens and have improved antitumor activity compared to their monospecific counterparts when both antigens are expressed. Protein structure prediction suggests that linker length and compactness influence the functionality of the generated bispecific CARs. Thus, we present a bispecific CAR design strategy to prevent immune escape in AML that can be extended to other peptide-scFv combinations. Competing Interests: Declaration of interests J.T.Z., P.J.C., D.M.L., G.K., S.G., and M.P.V. have patent applications in the field of immunotherapy. S.G. is a member of the Data and Safety Monitoring Board of Immatics, is on the Scientific Advisory Board of Be Biopharma, and has received honoraria from TESSA Therapeutics, Tidal, Catamaran Bio, and Sanofi within the last 2 years. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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