9WJ6
An integrated in silico-in vitro workflow for discovering high-affinity, selective antibodies to the KRAS(G12D)-MHC I complex
Summary for 9WJ6
| Entry DOI | 10.2210/pdb9wj6/pdb |
| Descriptor | Peptide from GTPase KRas, N-terminally processed, C8K10D5-1 Fab Light chain, HLA class I antigen, ... (5 entities in total) |
| Functional Keywords | mhc class i, tcr-like antibody, fab, hla-c*08:02, immune system |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 10 |
| Total formula weight | 196787.24 |
| Authors | |
| Primary citation | Ahn, S.,Oh, T.S.,Suh, S.,Jeon, J.Y.,Lah, S.,Ryu, K.,Choi, S.,Kim, H.,Lee, E.G.,Lee, H.,Lee, J.,Kim, Y.,Kim, S.,Park, S.R.,Yoo, H.,Choi, S.Y.,Lee, J.E.,Kim, D.K.,Ku, B.M.,Jung, W.,Ahn, M.J.,Jung, J.U.,Kim, Y.S.,Oh, B.H.,Jeong, B.S. Discovery of TCR-like antibodies to the KRAS G12D neoantigen via in silico-in vitro workflow. Mol.Ther., 2026 Cited by PubMed Abstract: Antibodies that recognize peptide-loaded class I major histocompatibility complex (MHC) molecules could enable therapeutic targeting of intracellular oncogenic proteins, yet their discovery has been hampered by the small size of peptide antigens and the need for allele-specific recognition. Here, we describe an integrated in silico-in vitro workflow for generating high-affinity, selective antibodies to Kirsten rat sarcoma viral oncogene homolog (KRAS) G12D presented by human leukocyte antigen (HLA)-C∗08:02, a clinically validated cancer neoantigen. In the in silico stage, multiple human antibody-derived variable fragments optimally docked to the target were generated, followed by limited sequence design of complementarity-determining regions (CDRs). In the in vitro stage, limited CDR diversity was introduced to construct a yeast surface-displayed library, which was subjected to iterative selection. This workflow yielded KRAS G12D/HLA-C∗08:02-specific antibodies with high affinity. Comprehensive specificity profiling using a phage display library confirmed the absence of human off-target reactivity, and in silico analysis predicted low immunogenicity. When reformatted as chimeric antigen receptors or bispecific T cell engagers, these antibodies mediated selective cytotoxicity against target-positive cells. Together, these findings establish a practical design-to-function pipeline for T cell receptor (TCR)-like antibody discovery and demonstrate the feasibility of therapeutically targeting KRAS G12D-driven malignancies. PubMed: 42237541DOI: 10.1016/j.ymthe.2026.05.032 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (4.54 Å) |
Structure validation
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