A new anti-CXCR4 antibody

The type-4 C-X-C-motif chemokine receptor (CXCR4) is expressed in a large variety of human cancers including hematological malignancies, and this receptor and its ligand, stromal-cell-derived factor-1 (SDF-1), play a crucial role in cancer progression. We generated a humanized immunoglobulin-G1 monoclonal antibody, hz515H7, which binds human CXCR4, efficiently competes for SDF-1 binding, and induces a conformational change in CXCR4 homodimers. Furthermore, it inhibits both CXCR4 receptor-mediated G-protein activation and β-arrestin-2 recruitment following CXCR4 activation. The binding of the hz515H7 antibody to CXCR4 inhibits the SDF-1-induced signaling pathway, resulting in reduced phosphorylation of downstream effectors such as Akt, Erk1/2, p38 and GSK3β. Hz515H7 also strongly inhibits cell migration and proliferation and, while preserving normal blood cells, induces both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against neoplastic cells. In mouse xenograft models, hz515H7 displays anti-tumor activities with multiple hematological tumor cell lines, with its Fc-mediated effector functions proving essential in this context. Furthermore hz515H7 binds to primary tumor cells from acute myeloid leukemia and multiple myeloma patients. Collectively, our results demonstrate two major mechanisms of action, making hz515H7 unique in this regard. Its potential as a best-in-class molecule is currently under investigation in a phase I clinical trial.

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