pH-switchable shark-derived single domain antibodies for biomedical applications

• Applicant: Professor Dr. Harald Kolmar
• Subject Area: Biochemistry
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398463564

For decades, antibodies have been irreplaceable molecules for various applications encompassing the field of diagnostics as well as therapy. The high specificity for a cognate antigen combined with Fc-mediated immune effector functions renders antibodies auspicious tools for medical applications. In addition to antibodies with the classical composition of heavy and light chains, the adaptive immune repertoire of sharks also includes a heavy-chain only isotype named IgNAR, where antigen binding is mediated exclusively by a small and highly stable domain referred to as vNAR. In recent years, vNAR fragments have evolved as promising, target-binding scaffolds that can be tailored for applications in medicine and biotechnology. These domains comprise beneficial properties such as high affinity and specificity, small size, high physicochemical stability and a low cost of production. In the proposed project we set out to generate and utilize pH-responsive vNAR domains for biotherapeutic applications. Such pH-switchable vNAR domains might be attractive for the specific targeting of antigens in the acidic tumor microenvironment. As such, variants comprising higher affinity for a tumor-associated antigen at acidic pH but significantly lower affinity under physiological conditions could reduce off-target effects which are often observed for conventional antibody therapeutics. In addition, pH-dependent and anti-idiotypic vNAR variants will be developed aimed at increasing the on-target efficacy of already available therapeutic antibodies. These masking vNARs comprise high affinity for the antibody at physiological pH, but low affinity under slightly acidic conditions. This effect would block the therapeutic antibody in healthy tissue, while being unmasked upon reaching the acidic tumor microenvironment.

• DFG Programme: Research Grants