Development of a PRAME pMHC targeted T cell engager for solid tumor therapy

Area of Science:

• Immunology and Cancer Therapeutics
• Molecular Biology and Structural Biology

Background:

• Bispecific T cell engager (TCE) therapies show promise in hematological cancers but face challenges in solid tumors due to limited antigen selectivity.
• On-target, off-tumor toxicities arise from tumor-associated antigens expressed in healthy tissues, hindering TCE efficacy in solid tumors.

Purpose of the Study:

• To identify a highly tumor-restricted antigen for TCE therapy to overcome selectivity issues in solid tumors.
• To characterize the cancer-testes antigen Preferentially Expressed Antigen in Melanoma (PRAME) and its presented peptide PRAME425 as a potential TCE target.

Main Methods:

• Developed a TCR-mimic (TCRm) antibody screening cascade prioritizing T cell-dependent cellular cytotoxicity assays over traditional pMHC binding assays for specificity determination.
• Discovered anti-PRAME425 pMHC TCRm antibodies with TCR-like binding geometry, confirmed by cryo-electron microscopy structure of the antibody complexed with PRAME425/HLA-A*02:01.
• Formatted discovered TCRm antibodies into potent TCEs to assess tumor cell killing efficacy.

Main Results:

• Identified PRAME425 presented by MHCI as a highly selective tumor antigen for TCE development.
• Discovered novel TCRm antibodies that selectively bind PRAME425 pMHC without significant off-target recognition.
• Demonstrated PRAME425 pMHC-specific killing of tumor cells using the developed TCEs.

Conclusions:

• PRAME425 pMHC is a promising and highly selective target for developing novel TCEs against solid tumors.
• The developed TCRm antibodies and TCEs represent a new class of biologics for targeted cancer therapy, minimizing off-tumor effects.