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HLA-A∗02-gated safety switch for cancer therapy has exquisite specificity for its allelic target antigen

Mock, Jee-Young and Winters, Aaron and Riley, Timothy P. and Bruno, Richele and Naradikian, Martin S. and Sharma, Shruti and Jette, Claudia A. and Elshimali, Ryan and Gahrs, Casey and Toledo-Warshaviak, Dora and West, Anthony P., Jr. and Kamb, Alexander and Hamburger, Agnes E. (2022) HLA-A∗02-gated safety switch for cancer therapy has exquisite specificity for its allelic target antigen. Molecular Therapy - Oncolytics, 27 . pp. 157-166. ISSN 2372-7705. PMCID PMC9619369. doi:10.1016/j.omto.2022.09.010.

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Innovative cell-based therapies are important new weapons in the fight against difficult-to-treat cancers. One promising strategy involves cell therapies equipped with multiple receptors to integrate signals from more than one antigen. We developed a specific embodiment of this approach called Tmod, a two-receptor system that combines activating and inhibitory inputs to distinguish between tumor and normal cells. The selectivity of Tmod is enforced by the inhibitory receptor (blocker) that recognizes an antigen, such as an HLA allele, whose expression is absent from tumors because of loss of heterozygosity. Although unwanted cross-reactivity of the blocker likely reduces efficacy rather than safety, it is important to verify the blocker’s specificity. We have tested an A∗02-directed blocker derived from the PA2.1 mouse antibody as a safety mechanism paired with a mesothelin-specific activating CAR in our Tmod construct. We solved the crystal structure of humanized PA2.1 Fab in complex with HLA-A∗02 to determine its binding epitope, which was used to bioinformatically select specific class I HLA alleles to test the blocker’s functional specificity in vitro. We found that this A∗02-directed blocker is highly specific for its cognate antigen, with only one cross-reactive allele (A∗69) capable of triggering comparable function.

Item Type:Article
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URLURL TypeDescription CentralArticle
Mock, Jee-Young0000-0002-4656-3357
Winters, Aaron0000-0002-0962-8000
Naradikian, Martin S.0000-0003-1926-0382
Jette, Claudia A.0000-0002-5085-8027
Elshimali, Ryan0000-0002-6482-7256
West, Anthony P., Jr.0000-0003-4213-5184
Kamb, Alexander0000-0002-8675-6620
Hamburger, Agnes E.0000-0002-2679-3673
Additional Information:Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) We thank Dr. Peter Parham for identifying and characterizing the original mouse anti-HLA A∗02 antibody PA2.1, Dr. Pamela J. Bjorkman for supporting this work, Mark Daris for molecular biology and construct strategy, Kiran Deshmukh and Dr. Breanna DiAndreth for assistance with Jurkat cell assays, and Dr. Talar Tokatlian for helpful discussions and comments on the manuscript. Tmod is a trademark of A2 Biotherapeutics, Inc. Author contributions. A.E.H. and A.K. conceived and designed the study. J.-Y.M., A.W., T.P.R., R.B., M.S.N., S.S., C.A.J., R.E., C.G., D.T.-W., and A.P.W. conducted experiments and/or analyzed data. A.K., A.E.H., J.Y.M., and A.W. wrote the manuscript. A.E.H. and A.K. supervised the project. Data availability statement. Raw data will be made available upon reasonable request. Declaration of interests. A.E.H., A.K., J.-Y.M., A.W., T.P.R., R.B., M.S.N., S.S., C.J., R.E., C.G., and D.T.-W. are current or former employees and shareholders of A2 Biotherapeutics, Inc.
PubMed Central ID:PMC9619369
Record Number:CaltechAUTHORS:20221205-666301600.15
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ID Code:118240
Deposited By: Research Services Depository
Deposited On:06 Jan 2023 21:52
Last Modified:06 Jan 2023 21:52

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