Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• HER2 is crucial for malignant phenotype in several cancers, making it a key therapeutic target.
• Approved HER2 antibodies (trastuzumab, pertuzumab) show efficacy, but combinations may offer superior inhibition by targeting non-overlapping epitopes.
• Trastuzumab and pertuzumab were not co-developed, suggesting potential for optimizing HER2 targeting strategies.

Purpose of the Study:

• To evaluate anti-HER2 antibody combinations for optimal epitope targeting and efficacious HER2 inhibition.
• To identify novel antibody combinations with superior anticancer activity.
• To investigate the efficacy of a tripartite antibody mixture targeting HER2.

Main Methods:

• Identification and testing of high-affinity antibodies targeting all four extracellular domains of HER2.
• In vitro evaluation of antibody combinations on HER2-dependent tumor cell lines.
• In vivo assessment of antibody mixture efficacy in relevant cancer models.

Main Results:

• A tripartite antibody mixture targeting HER2 subdomains I, II, and IV showed superior efficacy in vitro and in vivo compared to trastuzumab and pertuzumab.
• The tripartite mixture induced efficient HER2 internalization and degradation.
• Increased sensitivity was observed in cell lines with HER2 amplification and high EGFR levels.

Conclusions:

• The synergistic tripartite antibody targeting HER2 subdomains I, II, and IV demonstrates superior anticancer activity.
• This novel combination offers a promising strategy for enhanced HER2 inhibition in cancer therapy.
• Further optimization of HER2 targeting through multi-antibody combinations can improve clinical outcomes.