Targeting a neoantigen derived from a common TP53 mutation.

Area of Science:

• Immunology
• Oncology
• Structural Biology

Background:

• TP53 (tumor protein p53) is the most frequently mutated cancer driver gene.
• Targeting mutated tumor suppressor genes, including TP53, remains a significant challenge in cancer therapy due to the lack of available drugs.

Purpose of the Study:

• To identify a highly specific antibody for the common TP53 R175H mutation presented on the cell surface.
• To develop an immunotherapeutic agent based on this antibody for targeting difficult-to-treat cancers.

Main Methods:

• Identification of an antibody with high specificity for the TP53 R175H mutation in complex with human leukocyte antigen-A (HLA-A).
• Elucidation of the structural basis for antibody specificity.
• Engineering the antibody into a bispecific single-chain diabody for therapeutic application.
• In vitro and in vivo (mice) testing of the bispecific antibody's efficacy in activating T cells and lysing cancer cells.

Main Results:

• An antibody was identified that specifically recognizes the TP53 R175H neoantigen presented by HLA-A on cancer cells.
• The bispecific single-chain diabody effectively activated T cells to lyse cancer cells presenting the target neoantigen, even at low complex densities.
• Demonstrated in vitro and in vivo efficacy of the immunotherapeutic approach.

Conclusions:

• A novel bispecific antibody targeting the common TP53 R175H mutation has been developed.
• This approach shows promise for treating cancers with mutations that are conventionally difficult to target.
• The strategy offers a potential new avenue for cancer immunotherapy.