Selective targeting of oncogenic hotspot mutations of the HER2 extracellular domain

Area of Science:

• Oncology
• Immunology
• Structural Biology

Background:

• Oncogenic mutations in cell-surface receptor extracellular domains (ECD) can act as tumor-specific antigens.
• HER2 (Human Epidermal growth factor Receptor 2) is a receptor tyrosine kinase with known oncogenic mutations in its ECD.
• Developing therapeutics that selectively target mutated proteins while sparing wild-type is a significant challenge.

Purpose of the Study:

• To develop novel antibodies that selectively target common oncogenic mutations (S310F and S310Y) in the HER2 ECD.
• To investigate the mechanism of antibody binding and its effect on HER2 dimerization and function.
• To evaluate the therapeutic potential of these antibodies in preclinical cancer models.

Main Methods:

• Combinatorial library screening and structure-guided design were employed to generate selective antibodies.
• Cryogenic-electron microscopy (cryo-EM) was used to determine the structures of HER2 mutants and antibody-bound complexes.
• In vitro and in vivo assays were performed to assess the efficacy of antibody-mediated cancer cell killing and tumor growth inhibition.

Main Results:

• Antibodies selective for HER2 S310F and S310Y mutations were successfully developed.
• Structural analysis revealed antibodies mimic HER2 dimerization arms, inhibiting receptor dimerization.
• Antibody-T cell engagers demonstrated selective killing of HER2 S310F-driven cancer cells in vitro and reduced tumor growth in vivo.

Conclusions:

• HER2 ECD mutations represent actionable targets for antibody-based therapeutics.
• The developed antibodies show promise for selective targeting of HER2-mutated cancers.
• These findings support further clinical development of these novel antibody therapeutics.