Abstract 5462: MEDI3185, a potent anti-CXCR4 antibody, inhibits tumor cell migration, signaling and tumor growth in preclinical models.

Abstract

The chemokine receptor CXCR4 is a seven-transmembrane G-protein coupled receptor that mediates chemotaxis and cell migration upon stimulation via its ligand, stromal-derived factor 1 (SDF-1), also called CXCL12. CXCR4 is normally expressed on bone marrow stem and progenitor cells, various circulating lymphocytes, endothelial precursor cells, tissue macrophages and fibroblasts but the aberrant overexpression of CXCR4 is linked to various hematological malignancies, solid tumors and metastatic neoplasms. Moreover, CXCR4 overexpression is correlated with poor prognosis in many types of cancer, including breast, ovarian, colon, pancreatic, AML and glioblastomas. CXCR4 inhibition using siRNA, small-molecule and peptide inhibitors has demonstrated that it can inhibit tumor growth by blocking tumor cell survival/proliferation, metastasis, angiogenesis and tumor immune infiltrates. Here we describe a novel, fully human, antagonistic antibody to CXCR4, MEDI3185, which blocks SDF-1 binding to CXCR4. MEDI3185 has picomolar binding affinity to human CXCR4 and exhibits no significant binding to other chemokine receptors such as CCR4 or CXCR3. In vitro studies demonstrated that MEDI3185 inhibited tumor cell migration, blocked SDF-1 induced tumor cell signaling and induced apoptosis of tumor cells. In preclinical human tumor xenograft models in mouse, MEDI3185 showed single-agent tumor growth inhibition in multiple myeloma and B-cell Burkitt's lymphoma models and had combination activity in ovarian models. In addition, MEDI3185 extended survival as combination therapy in mouse models of CLL and also blocked lung tumor burden in a disseminated ovarian model. Combined, these data suggest that MEDI3185 is a potent CXCR4 antibody for the treatment of both hematological and solid tumors because it has pleiotropic effects on tumor biology that may enhance the efficacy of the current standard of care. Citation Format: Adeela Kamal, Youzhen Wang, Philipp Steiner, Anne-Marie Mazzola, Leslie Wetzel, Melissa Passino, Brenda McDermott, Keven Huang, Vahe Bedian, Norman Greenberg. MEDI3185, a potent anti-CXCR4 antibody, inhibits tumor cell migration, signaling and tumor growth in preclinical models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5462. doi:10.1158/1538-7445.AM2013-5462

The Chemokine Receptors CXCR4/CXCR7 and Their Primary Heterodimeric Ligands CXCL12 and CXCL12/High Mobility Group Box 1 in Pancreatic Cancer Growth and Development

“…Overexpression is associated with a range of malignancies including acute myelogenous leukemia, 15 pancreatic cancer, breast cancer, 16 colorectal cancer, 17 melanoma, 18 neuroblastoma, 19 renal cell carcinoma, 20 and prostate cancer. The CXCR4, which is also called fusin or cluster of differentiation 184, is normally expressed in bone marrow and progenitor cells, lymphocytes, endothelial precursor cells, tissue macrophages, and fibroblasts.…”

Molecular basis for the antagonistic activity of an anti-CXCR4 antibody

“… 20 We have also reported a fully human antagonistic anti-CXCR4 mAb, MEDI3185 (IgG1, κ). 21 MEDI3185 can inhibit tumor growth in hematologic tumors as a single-agent and shows combination activity in ovarian tumor models. While interest in developing anti-CXCR4 mAb therapy increases, so does understanding the molecular basis for the corresponding mechanism(s) of action.…”

Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways

“…In a phase I study in healthy volunteers (NCT01374503), ALX-0651 demonstrated appreciable CXCR4 targeting ability; however, the study and any subsequent investigations into ALX-0651 as an anti-cancer agent were halted due to an inability to outcompete other CXCR4 antibodies [209]. Other anti-CXCR4 antibodies include LY2624587, hz515H7 (F-50067), and MEDI3185, which exhibit anti-tumor activity in hematological malignancies in mice [210][211][212]. LY2624587 (NCT01139788) and hz515H7 have both been tested in Phase I clinical trials.…”