Multimeric Antibody formats targeting GPCR NETworks in leukemic cells (MAGNETIC)

G protein coupled receptor proteins (GPCRs) are promising targets for treatment of cancer, immune and inflammatory diseases. Thus far, this class of receptors has been primarily targeted by small molecules. The potential for therapeutic antibodies directed at GPCRs has recently become recognized as antibody-based GPCR modulation is reportedly longer lasting and with higher specificity compared to conventional small molecule approaches. In this consortium we aim to develop and test the next-generation of GPCR-targeting biopharmaceuticals; multimeric antibody formats targeting GPCRs in leukemic cells (MAGNETIC). CXCR4 as target for leukemia – The chemokine receptor CXCR4, belonging to the class of GPCRs, plays a central role in the pathobiology of the most common leukemia in the Western World, chronic lymphocytic leukemia (CLL). Recently, it has become clear that CLL tumor cells migrate into the lymph node compartment via CXCR4, where they actively create a protective tumor microenvironment (TME) by subverting adjacent cells. Within this TME, complex signalling occurs resulting in leukemic cell proliferation but also in expression of different anti-apoptotic proteins. Migration and adhesion into the lymph node compartment is dictated by CXCR4 mediated signalling. CXCR4 exists as monomer, dimer and higher order oligomer complexes, in particular when overexpressed. Antibodies and their fragments targeting and inhibiting CXCR4 complexes have a great potential for clinical intervention of leukemia and serve as important tools in fundamental research. Inhibition of CXCR4 can prevent the migration of CLL cells to lymph node compartments and thereby reduce the formation of a protective TME. In addition, preliminary data have indicated that targeting CXCR4 with nanobody-Fc constructs is more effective in destroying CLL cells via antibody dependent cellular cytotoxic (ADCC) responses compared to the commonly used monoclonal antibody Rituximab (anti-CD20). In this MAGNETIC consortium we will take a dual approach to target CXCR4 function in CLL by: (i) targeting CXCR4 using different antibody formats (multimeric, bispecific) to alter GPCR complex formation and inhibit downstream signalling; (ii) immunomodulation (via T-cell or NK-cell engagers) of CXCR4-overexpressing leukemic cells and will examine which approach has therapeutic potential. The MAGNETIC consortium – In this multi-partner project, the MAGNETIC consortium taps on the complementary expertise of Vrije Universiteit Amsterdam (GPCR assays, chemokine receptors, nanobodies) and University of Utrecht (structural biology, (phospho)proteomics), for detailed functional and structural characterisation of antibodies targeting GPCR complexes and associated modulatory effects. We will focus and build on available antibodies and nanobodies targeting the CXCR4, a chemokine receptor that plays an important role in inflammatory and immunological disorders and cancer. Involvement of the Amsterdam University Medical Centers will allow us to test the different formats on patient material from e.g. chronic lymphocytic leukemia (CLL) patients. As primary tumor cells are readily available and can be manipulated in vitro, this disease also serves as a model for primary malignancies. Strategic partnerships with two SMEs, QVQ and argenx, will enable the development and delivery of novel and functional antibody formats needed in this challenging and highly translational project. This collaborative alliance directly connects structural rearrangements of GPCRs by novel antibody formats with altered signalling function and has relevant therapeutic potential. From fundamental insights to therapeutic impact – Together, the MAGNETIC team will deliver novel antibody formats (multimeric, bispecific antibodies, mAb-fusion and antibody-drug conjugates) that target aberrant GPCR signalling, provide comprehensive understanding for the cellular consequences and therapeutic applications. This next generation of GPCR targeting antibody-based formats holds great therapeutic potential as future medicines. Given the large number of GPCRs (~700), for which no selective small molecules have been identified, this project is expected to device novel biologics that effectively inhibit aberrant GPCR function in diverse pathological states.