9O55

Structure of a synthetic antibody (RM010) in complex with a class I MHC presenting a hapten-peptide conjugate

This is a non-PDB format compatible entry.

Summary for 9O55

• Entry DOI: 10.2210/pdb9o55/pdb
• EMDB information: 70124
• Descriptor: MHC class I antigen, GTPase KRas, N-terminally processed, RM010 Fab heavy chain, ... (5 entities in total)
• Functional Keywords: complex, fab, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 46923.38

Authors

Hu, Z.,Rajak, E.,Maso, L.,Koide, S. (deposition date: 2025-04-09, release date: 2025-07-23, Last modification date: 2025-08-13)

Primary citation

Maso, L.,Rajak, E.,Hattori, T.,Hu, Z.,Koide, A.,Neel, B.G.,Koide, S.
Generation of actionable, cancer-specific neoantigens from KRAS(G12C) with adagrasib.
Proc.Natl.Acad.Sci.USA, 122:e2509012122-e2509012122, 2025

PubMed Abstract: Effective immune therapy against cancer ideally should target a cancer-specific antigen, an antigen that is present exclusively in cancer cells. However, there is a paucity of cancer-specific antigens that are endogenously produced. HapImmune™ technology utilizes covalent inhibitors directed to an intracellular cancer driver to create cancer-specific neoantigens in the form of drug-peptide conjugates presented by class I MHC molecules. Our previous study with sotorasib, an FDA-approved covalent inhibitor of KRAS(G12C), demonstrated that drug-treated cells produce such neoantigens and can be killed by T cell engagers directed against the drug-peptide/MHC complex. Thus, this technology can unite targeted and immune therapies. In the present study, we examined whether this approach could generalize to another FDA-approved KRAS(G12C) inhibitor, adagrasib, whose chemical structure and cysteine reactivity differ substantially from sotorasib. We developed antibodies selective to adagrasib-KRAS(G12C) peptides presented by HLA-A*03 and A*11 that also show cross-reactivity to other KRAS(G12C) inhibitors presented in the same manner. Cryoelectron microscopy structures revealed a mode of adagrasib-peptide/HLA recognition distinctly different from that of sotorasib-directed HapImmune antibodies. The antibodies in a bispecific T cell engager format killed adagrasib-resistant lung cancer cells upon adagrasib treatment. These results support the broad applicability of the HapImmune approach for creating actionable cancer-specific neoantigens and offer candidates for therapeutic development.

PubMed: 40737322
DOI: 10.1073/pnas.2509012122

Experimental method

ELECTRON MICROSCOPY (2.88 Å)