ADAPTs, Small, Bispecific Affinity Proteins with Tunable Pharmacokinetic Properties Developed for Clinical Applications

摘要

As knowledge of complex diseases increases, the need for new, specific and sensitive drugs is apparent. Targeting disease-associated molecular abnormalities with high specificity is one of the most promising approaches in order to diagnose and treat heterogeneous diseases. Alternative protein scaffolds have lately gained a lot of interest as alternatives to the dominating antibodies for binding to disease-related targets. ADAPTs are small affinity proteins derived from the albumin-binding domain (ABD) of streptococcal protein G and represent a novel group of scaffold proteins. These new affinity molecules possess valuable properties including small size (46 aa), high affinity and specificity, high thermal stability and solubility as well as straightforward generation. Moreover, we have engineered this scaffold with the ability to bind different targets while retaining its inherent affinity for serum albumin. This unique feature allows for the in vivo pharmacokinetic properties to be finely adapted for a given application. ADAPTs with retained affinity for albumin will have the capability to increase the serum half-life of the molecules, which is beneficial in therapeutic applications, whereas ADAPTs without affinity for albumin is more suitable for diagnostic applications. We have previously developed bispecific ADAPTs with affinity for TNF-α and two cancer-associated receptor tyrosine kinases, HER2 and HER3. In this study we engineered a monospecific ADAPT molecule with affinity towards HER2 for use as an in vivo molecular imaging agent. The engineered molecule was investigated in HER2-positive xenograft mouse models and demonstrated high, specific and HER2-dependent uptake in tumors together with high tumor-to-normal tissue ratios. This non-invasive imaging agent represents a very promising tool for personalized breast-cancer diagnostics with the possibility to identify patients that may benefit from an anti-HER2 therapy. In conclusion, the ADAPT scaffold can be used to develop target specific proteins towards disease-associated molecules and holds great potential as a diagnostic and therapeutic tool for various diseases.