Abstract 1635: CBX-663, a first-in-class TCR-mimetic T-Cell Engager targeting the TERT peptide-HLA complex, mediates potent cytotoxicity <i>in vitro</i> and tumor inhibition <i>in vivo</i> in preclinical models of solid malignancies

Abstract While T-cell engager (TCE) therapies have demonstrated clear clinical benefit, their broader application remains limited by the restricted repertoire of tumor-specific surface antigens. Targeting HLA-restricted peptides (pHLA) derived from intracellular tumor antigens offers an opportunity to expand the reach of TCEs to solid tumors. Telomerase reverse transcriptase (TERT) represents such an intracellular target, as it is highly expressed in approximately 85-95% of human tumors. We have previously described CBX-663, a potent and specific TCR-mimetic (TCRm) TCE targeting the TERT540/HLA-A*02:01 complex, and its activity in hematologic cancer models. Here, we characterize its therapeutic potential in preclinical solid tumor models. CBX-663 consists of a single humanized CD3-binding domain and two fully human TCRm domains that recognize TERT540/HLA-A*02:01 in a bivalent format. CBX-663 binds TERT540 pHLA with sub-nM affinity and low-pM avidity, leading to potent T-cell-mediated cytotoxicity across multiple TERT- and HLA-A*02:01-positive solid tumor cell lines. Subsequent analysis revealed that responsive cell lines exhibit higher HLA-A*02:01 expression than non-responders. Notably, some of the highest responding cell lines carry TERT promoter mutations, which are well known to elevate TERT transcription and may increase pHLA presentation. CBX-663 achieved robust tumor control in a disseminated NSCLC COR-L23-A2 model using PBMC-humanized NSG mice and induced tumor growth delay in a subcutaneous NSCLC NCI-H1703 model established in humanized CD34+ (huCD34) mice. Additional efficacy studies are ongoing. To further characterize specificity, X-scan analysis of TERT540 peptide was conducted and revealed multiple residues critical for CBX-663 recognition of TERT540 pHLA. A screen of &amp;gt;6,000 human membrane proteins identified no detectable off-target interactions of CBX-663. In addition, no activity was observed against TERT- or HLA-A*02:01-negative cells, unrelated HLA alleles, or normal HLA-A*02:01-positive primary cells from diverse tissues. CBX-663 induced moderate cytokine release upon treatment of HLA-A*02:01-positive PBMCs in the absence of tumor cells, consistent with previously reported targeting of monocytes and B cells by TERT-directed T cell therapies in preclinical models. Cytokine induction with CBX-663 was markedly lower than that elicited by a CD123-targeting TCE tested under identical conditions. Importantly, repeat dosing of CBX-663 was well tolerated in non-tumor-bearing huCD34 mice reconstituted with human hematopoietic cells, with minimal cytokine release and transient changes in leukocyte populations. Collectively, these data support the therapeutic potential of CBX-663 in solid tumors. IND-enabling studies are currently underway. Citation Format: Yu Huang, Ricard Masia, Bhupal Ban, Qunyan Yu, Jennifer Helble, Jessica Jimenez, Delainey O’Connor, Preethi Sankaran, Christine A. Devlin, Melissa Bikowitz, Emily McNally, Sarah Jaffe, Tanzila Rahman, Alona Kulesha, Andrew Wolpert, Shawn O’Malley, Yue Li, Michael Jennings, Galina Gabriely, Mathilde A. Poussin, Daniel J. Powell, Nga Sze Amanda Mak, Tao Wang, Geraldine L. Paulus, Michi Schebesta, Benjamin Lee, Dmitri Wiederschain. CBX-663, a first-in-class TCR-mimetic T-Cell Engager targeting the TERT peptide-HLA complex, mediates potent cytotoxicity in vitro and tumor inhibition in vivo in preclinical models of solid malignancies [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 1635.