RRC ID 68564
著者 Kashyap MK, Amaya-Chanaga CI, Kumar D, Simmons B, Huser N, Gu Y, Hallin M, Lindquist K, Yafawi R, Choi MY, Amine AA, Rassenti LZ, Zhang C, Liu SH, Smeal T, Fantin VR, Kipps TJ, Pernasetti F, Castro JE.
タイトル Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia.
ジャーナル J Hematol Oncol
Abstract BACKGROUND:The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL.
METHODS:Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model.
RESULTS:PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine.
CONCLUSIONS:We show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients.
巻・号 10(1)
ページ 112
公開日 2017-5-19
DOI 10.1186/s13045-017-0435-x
PII 10.1186/s13045-017-0435-x
PMID 28526063
PMC PMC5438492
MeSH Animals Antineoplastic Agents, Immunological / immunology Antineoplastic Agents, Immunological / therapeutic use* B-Lymphocytes / drug effects B-Lymphocytes / immunology B-Lymphocytes / pathology CHO Cells Cell Death / drug effects Cricetulus Female Humans Immunoglobulin G / immunology Immunoglobulin G / therapeutic use* Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy* Leukemia, Lymphocytic, Chronic, B-Cell / immunology Leukemia, Lymphocytic, Chronic, B-Cell / pathology Mice, Inbred BALB C Mice, SCID Reactive Oxygen Species / immunology Receptors, CXCR4 / analysis Receptors, CXCR4 / antagonists & inhibitors* Receptors, CXCR4 / immunology Signal Transduction / drug effects T-Lymphocytes / drug effects T-Lymphocytes / immunology T-Lymphocytes / pathology Tumor Cells, Cultured
IF 11.059
リソース情報
ヒト・動物細胞 StromaNKtert(RCB2350)