293 Discovery and characterization of a first-in-class de novo AI-designed TCR-mimetic-CAR targeting HLA-A2:01+ PRAME+ cancers

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Background The application of T and NK-cell therapies to solid tumors remains a challenge due to the limited repertoire of suitable tumor-specific surface antigens. Targeting HLA-restricted peptides (pHLA) derived from intracellular oncoproteins provides an opportunity to unlock the cancer proteome for T-cell-based immunotherapies.PRAME (Preferentially Expressed Antigen in Melanoma) is a cancer-testis antigen whose expression is highly upregulated in various hematological and solid tumors, while being absent in most normal healthy tissues. To leverage this differential expression, we have developed PRM-CAR-T, a T cell therapy engineered to express a Chimeric Antigen Receptor (CAR) built from a high-affinity T-cell receptor mimic (TCRm) that recognizes the PRAME-derived peptide SLLQHLIGL presented by HLA-A*02:01.Methods PRM-CAR candidates were discovered using VISTA-Ab a novel generative model of antibodies trained on over 300M observed antibodies, and manufactured using variational synthesis, so that over 100M functional scFv candidates could be screened simultaneously against 30+ dextramers, yielding over 2000 PRAME-specific candidates.Results In vitro, prioritized candidate PRM-CAR-T and PRM-CAR-NKT cells demonstrated potent, antigen-specific activation, proliferation, and polyfunctional cytokine release (IFN−γ, TNF−α) when co-cultured with PRAME-positive cancer cell lines. This resulted in robust, dose-dependent killing of target cells with varying antigen densities.The specificity of the engineered receptor is critical for safety. The risk of off-target reactivity was assessed by challenging PRM-CAR cells with a panel of human peptides identified in silico for their similarity to the target SLLQHLIGL peptide. No meaningful cross-reactivity was observed. Furthermore, PRM-CAR-T and PRM-CAR-NKT cells showed no activity against target-negative cancer cells, including a PRAME-knockout cell line, or a broad panel of normal human primary cells derived from various tissues, confirming the high specificity of the therapy.Conclusions In summary, these data provide strong in vitro evidence for the potency and specificity of PRM-CAR cells. This novel, TCRm-based CAR therapy, represents a promising new treatment modality for HLA-A2:01-positive patients with PRAME-positive malignancies.

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