Engineered antibodies that stabilize drug-modified KRAS^G12C neoantigens enable selective and potent cross-HLA...

Area of Science:

• Oncology
• Immunology
• Structural Biology

Background:

• Covalent inhibitors of KRAS oncoprotein show initial efficacy but lack durable responses.
• Covalently modified oncoproteins form MHC-restricted hapten-peptides (p*MHC) on cancer cells, presenting an opportunity for targeted therapy combined with immunotherapy.
• Existing evidence for KRAS^G12C-derived p*MHCs is indirect, necessitating direct identification and quantification.

Purpose of the Study:

• To identify and quantify synthetic neoantigens derived from KRAS^G12C.
• To develop engineered antibodies for targeting these synthetic neoantigens to overcome drug resistance.
• To investigate the potential of synthetic neoantigens as actionable targets in cancer immunotherapy.

Main Methods:

• Immunopeptidomics was employed to identify and quantify KRAS^G12C-derived p*MHCs.
• A T cell-engaging bispecific antibody, AETX-R114, was developed with high affinity for sotorasib-modified KRAS^G12C peptides presented by HLA-A3 supertype alleles.
• AETX-R302 was developed to target divarasib-modified KRAS^G12C peptides on HLA-A2 and A3 supertypes.
• Cryo-electron microscopy (Cryo-EM) was used for structure determination.

Main Results:

• AETX-R114 significantly increased the half-life and presentation of p*MHCs, leading to potent killing of resistant cancer cells in vitro and in vivo.
• AETX-R302 demonstrated the ability to recognize modified KRAS^G12C peptides across HLA-A2 and A3 supertypes.
• Cryo-EM revealed the structural basis for overcoming HLA supertype restriction.

Conclusions:

• Engineered antibodies can effectively target synthetic neoantigens, transforming them into viable cancer immunotherapy targets.
• This approach offers a strategy to overcome drug resistance in KRAS-mutated cancers.
• The study highlights the therapeutic potential of combining targeted therapy with engineered antibodies for cancer treatment.