Trastuzumab and pertuzumab are FDA-approved monoclonal antibodies that target different epitopes of the Her2 receptor; they are used in combination with each other to treat metastatic breast cancer in patients that overexpress Her2. However, in the majority of breast cancer patients, the tumors do not express Her2 to a sufficiently high enough level to be able to respond to this treatment. A Her2-targeted antibody that can more efficiently internalize and down-regulate the receptor, disrupt cell signaling, and “turn off” this receptor would have the potential to address patients that do not overexpress Her2; this would extend the treatment to a new and significantly larger patient population that is currently not eligible for this biological therapy.
To this end, Zyngenia Inc. is developing trastuzumab-based therapeutics that contain additional anti-Her2 and/or Her1 modular recognition domains. One such Zybody targets two distinct Her2 epitopes, resulting in more effective binding and more efficient receptor internalization when compared with the parent mAb, which only binds to a single epitope.
This Zybody more effectively disrupts cell signaling but also enhances the delivery of drug conjugates into the cell, which is important for the treatment of metastatic breast cancer. Additionally, Zyngenia Inc. is developing a trastuzumab/anti-Her2-based therapeutic that also targets a single EGFR epitope, resulting in more efficient internalization of both EGFR and Her2, as well as the down-regulation of the EGFR-mediated resistance pathways.