The human epidermal growth factor receptor pathways play a critical role in cancer, in which dysregulated signaling results in tumor growth and metastases. The “Her” family consists of four structurally related receptors: Her1 (EGFR), Her2, Her3, and Her4. In many cancers, over-expression and autocrine stimulation of Her1/EGFR occurs. Thus, the EGFR receptor is important to tumor growth and is an attractive target for cancer therapy.
Cetuximab is an FDA-approved monoclonal antibody directed against Her1/EGFR that can be effective in treating head, neck, and colorectal cancers. The effectiveness of cetuximab appears to be related to its ability to block autocrine growth signals by antagonizing ligand binding to the receptor and by clearing Her1/EGFR from the surface of tumor cells. Frequently, patients either do not respond to cetuximab, or the drug loses its effectiveness when tumor cells “escape” the inhibitory activity of the antibody. Researchers have demonstrated that cancer cells can escape cetuximab treatment due to ineffective clearance of Her1/EGFR from the tumor surface and through resistance pathways mediated by the upregulation of other growth factor receptors, including other Her family members such as Her3. A single multi-specific, multi-valent biotherapeutic should be capable of shutting down these key tumor escape mechanisms while simultaneously and synergistically exploiting the micro-environment that the tumor needs to survive. This approach has the potential to be significantly more broadly effective than current combination-based treatments.
To this end, Zyngenia Inc. is developing cetuximab-based bi- and tri-specific Zybody therapeutics that have the ability to bind two different epitopes of Her1/EGFR, as well as Her3. The engagement of Her1/EGFR at two different sites enhances receptor cross-linking and clearance, and blocking of Her3 eliminates an important tumor resistance mechanism. Zyngenia Inc. is developing these Zybodies initially for applications in head and neck cancer, non-small cell lung cancer, and colorectal cancer. Preclinical data show that these multi- and bi-specific therapeutics are superior inhibitors of Her receptor activation, intracellular signaling, and tumor proliferation.