7KKH

P1A4 Fab in complex with ARS1620

Summary for 7KKH

• Entry DOI: 10.2210/pdb7kkh/pdb
• Descriptor: P1A4 Fab Light Chain, P1A4 Fab Heavy Chain, SODIUM ION, ... (5 entities in total)
• Functional Keywords: fab, antibody, antitumor protein, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 46682.18

Authors

Basu, K.,Rohweder, P.J.,Zhang, Z.,Bohn, M.-F.,Shokat, K.,Craik, C.S. (deposition date: 2020-10-27, release date: 2022-04-27, Last modification date: 2024-11-13)

Primary citation

Zhang, Z.,Rohweder, P.J.,Ongpipattanakul, C.,Basu, K.,Bohn, M.F.,Dugan, E.J.,Steri, V.,Hann, B.,Shokat, K.M.,Craik, C.S.
A covalent inhibitor of K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy.
Cancer Cell, 40:1060-1069.e7, 2022

PubMed Abstract: Immunotargeting of tumor-specific antigens is a powerful therapeutic strategy. Immunotherapies directed at MHC-I complexes have expanded the scope of antigens and enabled the direct targeting of intracellular oncoproteins at the cell surface. We asked whether covalent drugs that alkylate mutated residues on oncoproteins could act as haptens to generate unique MHC-I-restricted neoantigens. Here, we report that KRAS G12C mutant cells treated with the covalent inhibitor ARS1620 present ARS1620-modified peptides in MHC-I complexes. Using ARS1620-specific antibodies identified by phage display, we show that these haptenated MHC-I complexes can serve as tumor-specific neoantigens and that a bispecific T cell engager construct based on a hapten-specific antibody elicits a cytotoxic T cell response against KRAS G12C cells, including those resistant to direct KRAS G12C inhibition. With multiple K-RAS G12C inhibitors in clinical use or undergoing clinical trials, our results present a strategy to enhance their efficacy and overcome the rapidly arising tumor resistance.

PubMed: 36099883
DOI: 10.1016/j.ccell.2022.07.005

Experimental method

X-RAY DIFFRACTION (2 Å)