A first-in-class precision antibody conjugate targeting EGFR, mTOR, and PI3K to treat head and neck cancers

Area of Science:

• Oncology
• Pharmacology
• Bioconjugation Chemistry

Background:

• Head and neck squamous cell carcinoma (HNSCC) shows poor response to cetuximab due to PI3K/AKT/mTOR pathway activation.
• Existing PI3K/mTOR inhibitors face clinical limitations due to dose-limiting toxicities.

Purpose of the Study:

• To develop a targeted therapy for HNSCC by conjugating a PI3K/mTOR inhibitor to cetuximab.
• To evaluate the efficacy and safety of the novel antibody-drug conjugate PAC-XL in preclinical HNSCC models.

Main Methods:

• Development of PAC-XL, an antibody-drug conjugate linking BGT226 to cetuximab via a cleavable linker.
• Assessment of PAC-XL's binding, uptake, trafficking, and payload release characteristics.
• Evaluation of PAC-XL's efficacy in PIK3CA-altered HNSCC cell lines and xenograft models, comparing it to cetuximab, BGT226, and alpelisib.

Main Results:

• PAC-XL demonstrated preserved EGFR binding, efficient uptake, and enzyme-dependent drug release.
• The conjugate induced potent, PI3K/mTOR-dependent cytotoxicity and apoptosis in HNSCC models.
• PAC-XL achieved complete regressions in xenografts with improved tolerability, reducing hyperglycemia and weight loss.

Conclusions:

• Targeted delivery of PI3K/mTOR inhibitors via antibody-drug conjugates is a viable strategy for HNSCC.
• PAC-XL offers enhanced efficacy and reduced systemic toxicity in preclinical models of HNSCC.
• This approach holds promise for improving treatment outcomes in patients with head and neck cancers.