Abstract KRAS amplification has emerged as a shared mechanism of resistance to KRAS-targeted therapies, including KRASG12C and KRAS-multi small molecule inhibitors. Wild-type KRAS allele amplification also defines a subset of aggressive gastroesophageal cancers with poor outcomes. To exploit this alteration, we sought a mutation-agnostic, HLA-A*02:01-restricted KRAS pMHC antigen selectively presented in KRAS-amplified tumors. Using peptide prediction COR-L23*, 555; HSKTC*, 1432) and undetectable or 10 CPC in non-amplified cell lines (A375, NCI-H661, ND; NCI-H520*, 9). A*02:01-negative lines (*) were A*02:01-engineered. KRAS pathway inhibition further increased antigen levels: treatment of 10 nM RMC-7977 in COR-L23 cells (G12V; KRAS CN=16), produced a 2.5× rise in surface HLA and an 8-fold increase in kAMP.A2, reaching ∼4,000 CPC at 48 h. KRAS amplification thereby establishes an exploitable pMHC therapeutic window—analogous to gp100 or PRAME—that is further broadened by KRAS inhibition. Importantly, NRAS 4 min), supporting kAMP.A2 as a selective TCE target with minimal paralog cross-reactivity. Screening our ultra-large human naïve antibody library with phage/yeast display and stringent counter-selection yielded the TCR-mimicking antibody PK313, exhibiting high affinity (KD = 5.3 nM) and strict specificity confirmed by SPR as well as by X-scan and healthy-tissue pMHC libraries (102 COR-L23*, 150 pM; HSKTC*, 160 pM) and showed enhanced activity with KRAS inhibitors. Structure-guided maturation is underway to advance PK313 toward development candidate nomination. Our data demonstrate that KRAS amplification—whether intrinsic or emerging under therapeutic pressure—creates a robust, tumor-amplified pMHC antigen with exceptional potential for therapeutic exploitation. PK313 enables selective targeting of KRAS-amplified tumors as a monotherapy or in combination with KRAS small molecule inhibitors to enhance treatment durability and provides a therapeutic strategy for A*02:01 patients (∼42% in US population), who are currently excluded from A*03/A*11 KRAS-mutant neoantigen TCR-T/CAR-T/TCE programs. Citation Format: Lorenzo Maso, Diamond N. Mensah, Angelina Pizzo, Sergio A. Rodriguez-Aponte, Samantha Sze, Weifeng Liu, Sean T. Toenjes, Paul Da Silva Jardine, Christoph Rader, Lauren E. Stopfer. KRAS amplification creates a targetable pMHC antigen for T cell engager therapy to overcome KRAS inhibitor resistance abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4413.
Maso et al. (Fri,) studied this question.
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