Affibodies: Synthetic Protein Binders for Imaging HER2-Positive Breast Cancers

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.