TCR-mimic antibody-drug conjugates targeting intracellular tumor-specific mutant antigen KRAS G12V mutation

Area of Science:

• Oncology
• Immunology
• Drug Development

Background:

• Antibody-drug conjugates (ADCs) face limitations due to on-target, off-tumor side effects.
• Tumor-specific mutant antigens (TSMAs) present an ideal target for safer ADCs.
• Intracellular mutant proteins can be presented on the cell surface via human leukocyte antigen class I (HLA I) complexes.

Purpose of the Study:

• To develop novel TCR-mimic ADCs (TCRm-ADCs) targeting intracellular TSMAs.
• To evaluate the efficacy and safety of TCRm-ADCs targeting the KRAS G12V mutation.

Main Methods:

• Generation of two TCRm-ADCs, 2E8-MMAE and 2A5-MMAE.
• Targeting the KRAS G12V/HLA-A*0201 complex.
• In vitro and in vivo evaluation of antitumor activity and toxicity.

Main Results:

• Both TCRm-ADCs demonstrated specific antitumor activity.
• The developed TCRm-ADCs showed no obvious toxicity in preclinical models.
• Successful targeting of the KRAS G12V/HLA-A*0201 complex was achieved.

Conclusions:

• The study validates TCRm-ADCs as a strategy for targeting intracellular TSMAs.
• This approach improves the safety profile of antibody-based cancer therapies.
• TCRm-ADCs offer a novel strategy for precision medicine in cancer treatment.