Affibody-based approaches as potential therapeutics for breast cancer: mechanisms, applications, and future perspectives

Breast cancer presents a significant therapeutic challenge due to the substantial molecular and genetic diversity among its subtypes, thereby necessitating the development of refined intervention strategies. Macromolecular therapies, such as monoclonal antibodies, are often hindered by suboptimal biodistribution, restricted tumor penetration, and off-target toxicity in advanced diseases. The advent of affibody technology, which utilizes engineered ∼7 kilodalton (kDa) scaffold proteins derived from Staphylococcus aureus protein A, introduces a distinct class of targeting agents designed to address several of these limitations. Affibody molecules exhibit favorable biophysical properties, including thermal stability, configurable binding affinities reaching picomolar ranges, rapid systemic clearance, compact molecular size, and modular engineering architecture that enables diverse therapeutic applications. This review explores potential affibody-based therapeutic strategies for breast cancer, with applications targeting human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3) serving as the most extensively characterized and translationally advanced model systems. Two principal modalities are emphasized: direct receptor antagonism and targeted payload delivery. The latter includes covalent affibody–drug conjugates, cytotoxic fusion proteins, radionuclide-conjugated variants for diagnostic imaging and targeted radionuclide therapy, and affibody-functionalized nanocarriers designed to enhance delivery efficiency. Although most affibody-based therapeutics remain at the preclinical stage, clinical development is most advanced in diagnostic imaging, particularly for HER2-targeted agents that have undergone evaluation in patients. Collectively, this review summarizes the current landscape of affibody-based therapeutic approaches and highlights their translational potential in breast cancer.