Chimeric Antigen Receptors Directed at Mutant KRAS Exhibit an Inverse Relationship Between Functional Potency and Neoantigen Selectivity.

Autor:	Tokatlian T; Research, A2 Biotherapeutics, Agoura Hills, California., Asuelime GE; Research, A2 Biotherapeutics, Agoura Hills, California., Naradikian MS; Research, A2 Biotherapeutics, Agoura Hills, California., Mock JY; Research, A2 Biotherapeutics, Agoura Hills, California., Daris ME; Research, A2 Biotherapeutics, Agoura Hills, California., Martin AD; Research, A2 Biotherapeutics, Agoura Hills, California., Toledo Warshaviak D; Research, A2 Biotherapeutics, Agoura Hills, California., Kamb A; Research, A2 Biotherapeutics, Agoura Hills, California., Hamburger AE; Research, A2 Biotherapeutics, Agoura Hills, California.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2022 Jan 28; Vol. 2 (1), pp. 58-65. Date of Electronic Publication: 2022 Jan 28 (Print Publication: 2022).
DOI:	10.1158/2767-9764.CRC-21-0165
Abstrakt:	Neoantigens are among the most intriguing potential immuno-oncology targets because, unlike many cancer targets that are expressed on normal tissues, they are by definition restricted to cancer cells. Medicines directed at common neoantigens such as mutant KRAS are especially interesting because they may offer the convenience and cost of an off-the-shelf therapy. However, all common KRAS mutations produce proteins that differ from the wild type at a single amino acid, creating challenges for molecular discrimination. We have undertaken an effort to optimize single-chain variable fragments (scFv) against peptide/major histocompatibility antigen complexes composed of HLA-A*11 and either G12V- or G12D-mutant KRAS peptides. These scFvs could in principle be used in chimeric antigen receptor (CAR) T-cell therapies for selected patients whose tumors bear either of these mutations. Here we show that optimization of such CARs involves a trade-off between potency and selectivity. We further show that targeting this family without high selectivity engenders risks of cross-reactivity against other members of the G-protein family to which KRAS belongs. Significance: We report an effort to generate high potency, selective CARs directed at mutant KRAS peptides. Although the heavily optimized CARs maintain high selectivity against wild-type KRAS, they lose selectivity against other KRAS-related peptides derived from human proteins. To our knowledge, this work is the first to examine the trade-off between potency and selectivity with regard to KRAS pMHC-directed CARs, illustrating the challenge to achieve both sufficient potency and high selectivity. Competing Interests: T. Tokatlian reports personal fees from A2 Biotherapeutics during the conduct of the study; personal fees from A2 Biotherapeutics outside the submitted work; in addition, T. Tokatlian has a patent to Polypeptides targeting KRAS and methods of use thereof pending. G.E. Asuelime reports personal fees from A2 Biotherapeutics during the conduct of the study; other from A2 Biotherapeutics outside the submitted work; in addition, G.E. Asuelime has a patent to Polypeptides targeting KRAS and methods of use thereof pending. M.S. Naradikian reports personal fees from A2 Biotherapeutics during the conduct of the study; personal fees from A2 Biotherapeutics outside the submitted work; in addition, M.S. Naradikian has a patent to Polypeptides targeting KRAS and methods of use thereof pending. J.-Y. Mock reports personal fees from A2 Biotherapeutics during the conduct of the study; personal fees from A2 Biotherapeutics outside the submitted work; in addition, J. Mock has a patent to Polypeptides targeting KRAS and methods of use thereof pending. M.E. Daris reports personal fees from A2 Biotherapeutics during the conduct of the study; personal fees from A2 Biotherapeutics outside the submitted work; in addition, M.E. Daris has a patent to Polypeptides targeting KRAS and methods of use thereof pending. A.D. Martin reports personal fees from A2 Biotherapeutics during the conduct of the study; personal fees from A2 Biotherapeutics outside the submitted work; in addition, A.D. Martin has a patent to Polypeptides targeting KRAS and methods of use thereof pending. D. Toledo Warshaviak reports personal fees from a. A2 Biotherapeutics during the conduct of the study; personal fees from A2 Biotherapeutics outside the submitted work; in addition, D. Toledo Warshaviak has a patent to Polypeptides targeting KRAS and methods of use thereof pending. A. Kamb reports personal fees from A2 Biotherapeutics during the conduct of the study; personal fees from A2 Biotherapeutics outside the submitted work; in addition, A. Kamb has a patent to Polypeptides targeting KRAS and methods of use thereof pending. A.E. Hamburger reports personal fees from A2 Biotherapeutics during the conduct of the study; personal fees from A2 Biotherapeutics outside the submitted work; in addition, A.E. Hamburger has a patent to Polypeptides targeting KRAS and methods of use thereof pending. (© 2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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