Cynthia Tope Chemistry Department University of Georgia Wednesday, August 15, 2018 - 11:15am Chemistry Building, Room 400 Analytical Seminar HER2-positive breast cancers affect roughly 25% of patients and are extremely aggressive. While treatments specifically targeting the HER2 receptors are quite successful, they require an accurate diagnosis of HER2 overexpression. Current detection methods of immunohistochemical staining (IHC) and fluorescent in situ hybridization (FISH) do not give a global view of the cancer. They are limited to the metastases biopsied and may lead to misdiagnosis. While the use of antibodies as specific protein binders is very useful for ex vivo detection methods such as IHC, their slow clearance rate from non-specific tissue and high-blood retention limits their use in vivo, making HER2 quantification impossible. Ample research is being done to produce protein binders, such as affibodies, that can overcome these limitations. Affibodies are a classification of synthetic protein binders derived from the IgG binding domain of Staphylococcal protein A. By varying thirteen specific residues of the parent protein, and through additional affinity maturation, a second-generation affibody, denoted ZHER2, has been determined to bind HER2 with high affinity (22 pM) using SPR. ZHER2 has also been shown to bind HER2 in a site separate from that of drugs that target HER2, as shown in X-ray crystal structures. Through further engineering of the Z-domain scaffold, ZHER2 has been better optimized to limit binding to IgG’s and increase stability. ABY-025, the newly optimized affibody, has recently undergone phase I/II clinical studies, where it has been shown to quantitatively determine HER2 expression in vivo, allowing for the diagnosis of HER-positive metastases without the need for invasive biopsies.
