Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia

Abstract

BackgroundThe 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.MethodsPatient-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.ResultsPF-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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0435-x) contains supplementary material, which is available to authorized users.

Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3

“…LY2624587 is another anti-CXCR4 IgG4 antibody with similar mode of action, which has also reached the clinical trial phase (Table 2) (Peng et al, 2016b). The combination of CXCR4 inhibition, induction of apoptosis, and ADCC and CDC effector functions is employed in an IgG1 from Pfizer, PF-06747143, and shows a strong effect in multiple hematologic tumor models (Table 2) (Kashyap et al, 2017;Liu et al, 2017;Zhang et al, 2017). Utilization of different antibody formats and Fc engineering strategies provides an attractive flexibility in pursuing specific therapeutic needs.…”

What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?

“…CVX15, a member of this series, was crystallized with CXCR4 in 2010 (142) demonstrating a much better fit with the binding pocket than can ever be achieved with a small molecule. Other biologic scaffolds used for antagonist development include engineered chemokines (10, 50, 121) as well as nanobodies and antibodies (47, 56, 57, 61, 81, 135). Mogamulizumab, a monoclonal antibody targeting CCR4, recently became the first biologic to be approved for cutaneous T-cell lymphoma (33).…”

A novel enediyne‐integrated antibody–drug conjugate shows promising antitumor efficacy against CD30+ lymphomas

“…Antibody‐dependent cellular cytotoxicity has been described as a major efficacy of action for immunotherapy with therapeutic antibodies relying on their constant region (Fc domain) ability (Kashyap et al ., ). To characterize the Fc‐mediated ADCC activity of anti‐CD30‐LDP or anti‐CD30 antibody, L540 or Karpas299 cells were incubated with the antibody in the presence of PBMCs.…”