Engineering the avidity of nanobody-based bispecific diabodies and heavy chain antibodies to specifically target myeloma cells that co-express two membrane proteins

• Applicants: Professor Dr. Peter Bannas; Professor Dr. Friedrich Koch-Nolte
• Subject Area: Immunology ; Hematology, Oncology ; Clinical Immunology and Allergology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468337969

The underlying hypothesis of the proposed project is that more specific and effective targeting of myeloma cells can be achieved with bispecific nanobody-constructs that target two different tumor antigens. Nanobodies are soluble variable domains (VHH) derived from heavy chain antibodies (hcAbs) that naturally occur in camelids. Nanobody-dimers (diabodies) are suited for non-invasive in vivo imaging. Genetic fusion of a diabody to the hinge, CH2 and CH3 domains of human IgG1 yields soluble bispecific hcAbs. HcAbs can mark specific target antigens on tumor cells for attack by the immune system, e.g. by complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Cell surface ecto-enzymes such as CD38 and CD203 that hydrolyze NAD to anti-inflammatory adenosine are often upregulated on tumor cells and stromal cells, and thus, represent potential targets for diagnostic and therapeutic reagents (theranostics). SLAMF (Signaling Leukocyte Activation Molecule Family) protein 3 (CD229) is specifically overexpressed on myeloma cells and contributes to their malignant phenotype. The ecto-enzymes CD38 and CD203 and SLAMF3/CD229 represent promising targets for imaging and therapy of multiple myeloma. The goal of this project is to generate nanobody-based bispecific diabodies and heavy chain antibodies that co-target CD38 and CD203 or CD38 and CD229. We aim to engineer the avidity of these constructs so that they will preferentially target tumor cells that co-express both target antigens while sparing healthy cells that express only one of these targets. If successful, our results may pave the way for more potent theranostics for multiple myeloma and other malignancies.

• DFG Programme: Research Grants