1139 - Novel TCR-Mimic ADC Targeting Intracellular KRAS G12D/HLA-A11 pMHC: A Synergistic Strategy to Overcome Radioresistance and Enhance Antitumor Immunity in Pancreatic Cancer

03:50pm - 03:55pm ET

Room 160

Presenter(s)

K. S. Clifford Chao, MD - China Medical University Hospital, Taichung, Taichung

K. S. C. Chao¹, C. C. Chao², W. Z. Hong², H. Y. Chang², J. Y. Chen¹, Y. W. Jiang¹, and K. C. Y. Huang¹; ¹China Medical University, Taichung, Taiwan, ²NDV therapeutics, HsinChu, Taiwan

Purpose/Objective(s): Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stroma and prevalent KRAS-G12D mutations, both of which contribute to pronounced resistance to radiotherapy (RT). While conventional antibody-drug conjugates (ADCs) target surface antigens, their efficacy is often hampered by off-tumor toxicities and limited target accessibility. Here, we developed a TCR-mimic antibody-drug conjugate (TCRm-ADC) specifically targeting the intracellular KRAS-G12D mutation presented by HLA-A*11, aiming to evaluate its potential to sensitize PDAC to RT.

Materials/Methods: A high-affinity TCR-mimic (TCRm) antibody specific to the KRAS-G12D/HLA-A11 complex was identified via phage display and validated through ELISA and cell-based assays. The specificity and safety of the TCRm-ADC were confirmed both in vitro and in vivo. Utilizing humanized HLA-A11/hB2M transgenic mice and PDAC xenograft models, we investigated the synergistic effects of TCRm-ADC combined with low-dose RT, focusing on tumor growth kinetics, metastatic burden, and tumor microenvironment (TME) remodeling.

Results: The TCRm-ADC exhibited potent, antigen-specific antitumor activity against the KRAS-G12D/HLA-A11 complex with a favorable safety profile and no observable systemic toxicity. Notably, TCRm-ADC significantly suppressed tumor progression and reduced lung metastasis. Furthermore, low-dose RT was found to significantly upregulate the surface density of the KRAS-G12D/HLA-A11 complex, thereby enhancing TCRm-ADC efficacy. This combination therapy demonstrated robust synergistic effects, not only inhibiting tumor growth but also profoundly reshaping the TME by eliciting potent antitumor immunity and increasing immune cell infiltration in the transgenic model.

Conclusion: Our study presents a novel therapeutic strategy to target the "undruggable" intracellular KRAS-G12D mutation. By combining TCRm-ADC with radiotherapy, we effectively overcame radioresistance and modulated the immunosuppressive TME in PDAC. These findings support the clinical translation of TCR-mimic-based conjugates as a precision medicine approach to expand the therapeutic window of RT for KRAS-mutated malignancies.