A Novel CXCR4 Antagonist IgG1 Antibody (PF-06747143) for the Treatment of Hematological Malignancies (2014)

Abstract CXCR4 is a chemokine receptor that belongs to the G-coupled protein receptor (GPCR) family. It is over-expressed in various cancers, including solid tumors and hematological malignancies, and correlates with poor prognosis. CXCR4 expressing cells actively respond to CXCL12 (SDF-1), a chemokine constitutively secreted by stromal cells in bone marrow. Activation of CXCR4 induces cell trafficking and homing to the marrow microenvironment, where CXCL12 retains these cells in close contact with marrow stromal cells that provide growth signals, promote self-renewal, and contribute to drug resistance, leading to poor prognosis and relapse. Here we describe the generation of a highly potent and selective anti-CXCR4 humanized IgG1 antagonist Ab (PF-06747143) that binds to human CXCR4 with high affinity and blocks SDF-1-induced Calcium flux and cAMP signaling. We have also characterized the ability of PF-06747143 to induce cell death through three different mechanisms: a) mobilization of cells from CXCL12-rich niches, making them more sensitive to chemotherapy b) direct cell-death through a mechanism dependent on the antibody’s bivalency; c) ADCC- and CDC-dependent cell death through the Fc-region in IgG1 backbone, when in the presence of effector cells or serum proteins. Weekly administration of PF-06747143 at 10 mg/kg, as a monotherapy, significantly improved survival, induced sustained regression and reduced bone marrow tumor burden in various patient population relevant murine disseminated tumor models of Acute Myeloid Leukemia (MV4-11, PDXs), Non Hodgkin Lymphoma (Raji and Ramos), Chronic Lymphocytic Leukemia (JVM-13) and Multiple Myeloma (OPM-2). The CXCR4 IgG1 antibody was also shown to be similar or more efficacious than approved standards of care agents currently employed for treatment of hematological malignancies. The safety and PK/PD profile of PF-06747143 were evaluated in a Non-Human Primate (NHP) exploratory toxicology study. Results from this study indicate that the CXCR4 IgG1 Ab was well tolerated in a two-week exploratory study at pharmacologically relevant doses. Upon treatment with PF-06747143, egression of white blood cells (WBC) from bone marrow (leukocytosis) was noted, which is consistent with target (CXCR4) modulation. Following the peak of leukocytosis between 1-6 hours post antibody administration, the number of circulating WBCs rapidly decreased back to baseline levels at 24 hrs. These results are likely explained by the direct cell killing through the effector function of this IgG1 CXCR4 antibody. Altogether, the promising preclinical efficacy and safety data support clinical evaluation of PF-06747143 in hematological malignacies. Disclosures Pernasetti: Pfizer: Employment. Liu:Pfizer: Employment. Hallin:Pfizer: Employment. Gu:Pfizer: Employment. Ho:Pfizer: Employment. Zhang:Pfizer: Employment. Pascual:Pfizer: Employment. Simmons:Pfizer: Employment. Yan:Pfizer: Employment. Huser:Pfizer: Employment. Wang:Pfizer: Employment. Lam:Pfizer: Employment. Spilker:Pfizer: Employment. Blasi:Pfizer: Employment. Tran:Pfizer: Employment. Kudaravalli:Pfizer: Employment. Ma:Pfizer: Employment. Chin:Pfizer: Employment. Shelton:Pfizer: Employment. Smeal:Pfizer: Employment. Fantin:Pfizer: Employment.