Targeting mutant p53-expressing tumours with a T cell receptor-like antibody specific for a wild-type antigen

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Mutant p53 protein accumulation is common in many cancers.
• Intracellular targets are challenging for conventional antibodies.
• Tumor cells present p53 peptides on their surface via MHC class I molecules.

Purpose of the Study:

• To engineer an antibody targeting p53-derived peptides on tumor cells.
• To evaluate the therapeutic potential of this antibody and its conjugates.

Main Methods:

• Engineering an affinity-matured human antibody (P1C1TM) specific for a p53 peptide-MHC complex.
• Testing P1C1TM's ability to differentiate between mutant and wild-type p53 expressing cells.
• Assessing antibody-dependent cellular cytotoxicity (ADCC) in vitro.
• Evaluating cytotoxic drug conjugates in vitro and in vivo.

Main Results:

• P1C1TM specifically recognizes the unmutated p53 peptide complexed with HLA-A24.
• P1C1TM distinguishes between mutant and wild-type p53 expressing HLA-A24+ cells.
• P1C1TM mediates antibody-dependent cellular cytotoxicity against mutant p53 expressing cells.
• PNU-159682-P1C1TM drug conjugates inhibit tumor cell growth in vitro and in vivo.

Conclusions:

• p53-associated peptide-MHCs are viable targets for cancer immunotherapy.
• Engineered antibodies like P1C1TM offer a strategy for targeting mutant p53 expressing tumors.
• Targeting p53 peptide-MHCs holds potential for novel cancer treatment approaches.