Recent advances on the use of the CXCR4 antagonist plerixafor (AMD3100, Mozobil™) and potential of other CXCR4 antagonists as stem cell mobilizers
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Plerixafor
CXCR4 antagonist
The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation.We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis.Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls.Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted.ClinicalTrials.gov NCT01280955.
Plerixafor
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Hematology
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Background: Hematopoietic stem cell (HSC) transplantation is a treatment option for hematological malignancies. Current mobilization regimes frequently result in inadequate numbers of HSC for transplant therefore alternative methods of mobilization are required. Objective: The chemokine receptor CXCR4 and ligand SDF-1 are integrally involved in HSC homing and mobilization. Disruption of the SDF-1/CXCR4 axis by the CXCR4 anatagonist, plerixafor, is shown to improve HSC mobilization. Methods: The molecular and in vivo pharmacology of plerixafor and subsequent clinical development is reviewed. Results/conclusion: Preclinical studies demonstrate that plerixafor is a selective antagonist of CXCR4 and can rapidly mobilize HSC. Clinical trials demonstrated improved HSC mobilization when plerixafor was included in the mobilization regimen. These data suggest the potential for a significant role for plerixafor in hematological disease.
Plerixafor
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Previous chemotherapy and radiation exposure can make adequate stem cell mobilisation prior to autologous transplant extremely difficult in paediatrics. Plerixafor, a selective reversible CXCR4 antagonist interferes with CXCR4 interaction with Stromal cell‐derived factor 1 alpha (SDF‐1). Combination with granulocyte‐colony stimulating factor (G‐CSF) amplifies G‐CSF affects in mobilising haematopoietic stem cells. Whilst licensed for use with G‐CSF for enhancement of mobilisation of haematopoietic stem cells in adults, paediatric data for use of plerixafor remain limited. We present a retrospective review of outcomes seen with plerixafor and G‐CSF to mobilise stem cells heavily pre‐treated paediatric patients with cancer. Pediatr Blood Cancer 2015;62:1477–1480. © 2015 Wiley Periodicals, Inc.
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Abstract Disruption of the SDF-1α/CXCR4 axis by CXCR4 inhibitors has been proven to be an attractive investigational therapeutic approach for acute myeloid leukemia (AML). Moreover, the addition of CXCR4 inhibitor plerixafor to cytotoxic chemotherapy in a phase 1/2 study was associated with increased response rates in relapsed AML (Blood 2012:119;3917). However, plerixafor as a single agent induces only 2- to 4-fold mobilization of leukemic blasts, and this is thought to be due to incomplete inhibition of the SDF-1α/CXCR4 axis and short half-life. LY2510924 is a selective peptidic CXCR4 antagonist that blocks SDF-1α from binding to the receptor. Flow cytometry using OCI-AML3 cells showed that LY2510924 inhibited binding of anti-CXCR4 antibody 12G5 to surface CXCR4 in a concentration-dependent fashion. LY2510924 was 100 times more potent compared to plerixafor (normalized surface expression, LY2510924 at 1 nM, 10.7±0.27%; plerixafor at 1 nM and 100 nM, 74.6±1.23% and 11.0±0.29%, respectively). The action of LY2510924 started as early as 1 minute and continued up to 72 hours at 10 nM. SDF-1α induced migration of OCI-AML3 and primary AML cells, which was abolished by 1 nM LY2510924 but not suppressed by 1 nM plerixafor. LY2510924 inhibited SDF-1α-induced AKT and/or ERK phosphorylation in AML cell lines (OCI-AML3 and U937) and primary AML cells as shown by immunoblotting and multi-parameter phospho-flow cytometry. To test the efficacy of LY2510924 in vivo, we injected OCI-AML3/luc/mCherry cells into sub-lethally irradiated NSG mice. Twelve days after cell injection, mice were randomized into 4 groups: control, cytarabine, LY2510924, and LY2510924 plus cytarabine. On day 21 after cell injection, we observed a 3.4±1.4-fold increase of circulating leukemic cells at 3 hours and a 24.1±15.4-fold mobilization at 24 hours after LY2510924 injection. Bioluminescence imaging demonstrated that mice treated with LY2510924 had lower leukemia burden than cytarabine-treated and control mice. On day 39, the combination group showed less luciferase activity than the LY2510924 group (P=0.034). Hematoxylin-eosin and immunohistochemical staining with human CD45 antibody demonstrated that the LY2510924-treated groups had a significant decrease in leukemic infiltration of bone marrow, spleen, liver, and lung. This anti-leukemia effect translated into a significant prolongation of survival in LY2510924-treated mice (40 days vs. 26 days, P<0.001). In summary, in vitro data showed that a novel peptidic CXCR4 antagonist, LY2510924, could effectively disrupt the SDF-1α/CXCR4 axis in AML cells and was more potent than plerixafor. In vivo data showed anti-leukemia effects of LY2510924 as a single agent. LY2510924's stronger potency than plerixafor, rapidity of action, and prolonged CXCR4-inhibitory effects will likely translate into a higher anti-leukemia potency than that of plerixafor in future clinical applications. Citation Format: Byung Sik Cho, Zhihong Zeng, Hong Mu, Teresa McQueen, Marina Protopopova, Jorge Cortes, Joe Marszalek, Sheng-Bin Peng, Donald E. Thornton, Michael Andreeff, Marina Konopleva. Novel peptidic CXCR4 antagonist LY2510924 disrupts the SDF-1α/CXCR4 axis resulting in anti-AML efficacy in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4768. doi:10.1158/1538-7445.AM2014-4768
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Autologous hematopoietic stem cell (HSC) transplantation is an important therapeutic option for patients with non-Hodgkin's lymphoma and multiple myeloma. The primary source of HSC is from the peripheral blood which requires mobilization from the bone marrow. Current mobilization regimens include cytokines such as G-CSF and/or chemotherapy. However not all patients mobilize enough HSC to proceed to transplant. The chemokine receptor CXCR4 and its ligand CXCL12 are an integral part of the mechanism of HSC retention in the bone marrow niche. The discovery of plerixafor, a selective inhibitor of CXCR4, has provided a new additional means of mobilizing HSC for autologous transplantation. Plerixafor consists of two cyclam rings with a phenylenebis(methylene) linker. It inhibits CXCL12 binding to CXCR4 and subsequent downstream events including chemotaxis. The molecular interactions of plerixafor have been defined indicating a unique binding mode to CXCR4. Plerixafor rapidly mobilizes HSC within hours compared with the multi-day treatment required by G-CSF in mouse, dog and non-human primate. The mobilized cells once transplanted are capable of timely and endurable engraftment. Additionally CXCR4 has been implicated in the pathology of HIV, inflammatory disease and cancer and the pharmacology of plerixafor in various disease models is described.
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Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be corroborated in humans.
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Stem cells harvested from peripheral blood are the most commonly used graft source in hematopoietic stem cell transplantation. While G-CSF is the most frequently used agent for stem cell mobilization, the use of G-CSF alone results in suboptimal stem cell yields in a significant proportion of patients undergoing autologous transplantation. Plerixafor (AMD3100, Genzyme Corporation) is a bicyclam molecule that antagonizes the binding of the chemokine stromal cell-derived factor-1 (SDF-1) to its cognate receptor CXCR4. Plerixafor results in the rapid and reversible mobilization of hematopoietic stem cells into the peripheral circulation and is synergistic when combined with G-CSF. In clinical studies of autologous stem cell transplantation, the combination of plerixafor and G-CSF allows the collection of large numbers of stem cells in fewer apheresis sessions and can salvage those who fail G-CSF mobilization alone.
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