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Published OnlineFirst August 23, 2017; DOI: 10.1158/1078-0432.CCR-16-2919

Cancer Therapy: Clinical

Clinical Cancer Research

Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34þ Cells in Healthy Volunteers

Michal Abraham1, Yaron Pereg2, Baruch Bulvik1, Shiri Klein3, Inbal Mishalian3, Hana Wald1, Orly Eizenberg1, Katia Beider4, Arnon Nagler4, Rottem Golan2, Abi Vainstein2, Arnon Aharon2, Eithan Galun3, Yoseph Caraco5, Reuven Or6, and Amnon Peled3,4

Abstract

Purpose: The potential of the high-affinity CXCR4 antagonist systemic reactions were mitigated by methylprednisolone, BL-8040 as a monotherapy-mobilizing agent and its derived paracetamol, and promethazine pretreatment. In the first part graft composition and quality were evaluated in a phase I clinical of the study, BL-8040 triggered rapid and substantial mobili-

  • study in healthy volunteers (NCT02073019).
  • zation of WBCs and CD34þ cells in all tested doses. Four hours

Experimental Design: The first part of the study was a ran- postdose, the count rose to a mean of 8, 37, 31, and 35 cells/mL domized, double-blind, placebo-controlled dose escalation (placebo, 0.5, 0.75, and 1 mg/kg, respectively). FACS analysis phase. The second part of the study was an open-label phase, in revealed substantial mobilization of immature dendritic, T, B, which 8 subjects received a single injection of BL-8040 (1 mg/kg) and NK cells. In the second part, the mean CD34þ cells/kg and approximately 4 hours later underwent a standard leukapher- collected were 11.6 Â 106 cells/kg. The graft composition was esis procedure. The engraftment potential of the purified mobi- rich in immune cells.

  • lized CD34þ cells was further evaluated by transplanting the cells
  • Conclusions: The current data demonstrate that BL-8040

  • into NSG immunodeficient mice.
  • is a safe and effective monotherapy strategy for the collection

Results: BL-8040 was found safe and well tolerated at all of large amounts of CD34þ cells and immune cells in a one-day doses tested (0.5–1 mg/kg). The main treatment-related adverse procedure for allogeneic HSPC transplantation. Clin Cancer Res; events were mild to moderate. Transient injection site and

23(22); 1–12. Ó2017 AACR.

interindividual variations in circulating progenitor and stem cell numbers (5), requiring 4–6 repeated dosing to collect a sufficient number of cells. In addition, although considered generally safe, G-CSF is frequently associated with a variety of side effects. Therefore, improved methods to mobilize and collect HSPCs for transplantation are required. It has been proposed that G-CSF induces the mobilization of HSPCs through an indirect mechanism by activating neutrophils to secrete a variety of proteolytic enzymes, including elastase, cathepsin G, MMP-2, and MMP-9 that can degrade the chemokine CXCL12 and its receptor CXCR4. Over recent years, it has become apparent that the interaction between CXCL12 and its receptor, CXCR4, plays a pivotal role in hematopoietic stem cell mobilization and engraftment (6–8). Consequently, disruption of CXCL12/CXCR4 interactions results in mobilization of hematopoietic stem and progenitor cells from the bone marrow to the peripheral blood system. Indeed, blockade of the CXCR4 receptor with the reversible CXCR4 antagonist AMD3100 (Plerixafor; Mozobil) results in rapid mobilization of HSPCs (9, 10). When AMD3100 as a single agent was compared with G-CSF as a mobilizer of CD34þ cells in healthy volunteers, AMD3100 was inferior to G-CSF (5). However, AMD3100 increased both G-CSF–stimulated mobilization and the leukapheresis yield of CD34þ cells. As such, Mozobil was approved in combination with G-CSF for the mobilization of CD34þ cells in patients with lymphoma and multiple myeloma that undergo stem cell mobilization (11, 12).

Introduction

Allogenic hematopoietic stem and progenitor cell (HSPC) transplantation (ALSPCT) has emerged as the preferred strategy in the treatment of a variety of hematologic malignancies (1, 2). Mobilization of stem cells using granulocyte colony-stimulating factor (G-CSF) from healthy donors is the common clinical practice. G-CSF–mobilized peripheral blood mononuclear cells (PBMC) are routinely used as a source of hematopoietic stem cells (HSC) for transplantation (3, 4). Despite the potency of G-CSF in mobilizing stem cells, it ultimately results in broad

1Biokine Therapeutics Ltd, Ness Ziona, Israel. 2BioLineRx LTD, Modi'in, Israel. 3Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem, Israel. 4Hematology Division, Chaim Sheba Medical Center and Tel Aviv University, Tel-Hashomer, Israel. 5Clinical Pharmacology Unit, Hadassah University Hospital, Jerusalem, Israel. 6Cancer Immunotherapy and Immunobiology Research Center, Hadassah University Hospital, Jerusalem, Israel.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

M. Abraham and Y. Pereg contributed equally to this article. Corresponding Author: Amnon Peled, Hadassah University Hospital, P.O Box 12000, Jerusalem, Israel. Phone: 972-2677-8780; Fax: 972-26430982; E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-16-2919 Ó2017 American Association for Cancer Research.

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Abraham et al.

two consecutive days). Part 1 of the study served to select the optimal safe and efficacious dose of BL-8040 to be used in part 2. Part 2 (dose expansion) was an open-label study, exploring the safety, tolerability, and pharmacodynamic effect of BL-8040 in a single cohort of healthy subjects who received the selected dose regimen of BL-8040 (1 mg/kg) based on the data collected from part 1 (numbered 5001–5008). In addition, subjects underwent leukapheresis to examine the yield and characteristics of the mobilized cells. Each cohort in part 1 consisted of 8 subjects; 6 subjects in each cohort randomly allocated to receive BL-8040 and 2 subjects to receive placebo. Part 2 involved a single cohort of 8 subjects, who received BL-8040 at the selected optimal dose level.

Translational Relevance

Allogeneic hematopoietic stem and progenitor cell (HSPC) transplantation (ALSPCT) has emerged as the preferred strategy in the treatment of a variety of hematologic malignancies. Improved methods to mobilize and collect leukapheresis (LP) products with shortened time to engraftment, immune reconstitution, and antitumor effects are essential. In the final LP products mobilized and collected after BL-8040, there were much higher number of CD34þ HPCs compared with CD34þ HPCs collected after mobilization with granulocyte colonystimulating factor (G-CSF). Furthermore, in the LP products mobilized and collected after BL-8040, there were much higher number of CD4þCD8þ T, NKT, NK, and dendritic cells, compared with LP collected after mobilization with G-CSF. This new graft composition may have a different effect on the engraftment ability, antitumor effect, and immune reconstitution potential of the LP product.

Eligibility criteria

As this was a dose escalation study in healthy volunteers, men only selection was for safety reasons to exclude exposure of childbearing potential subjects. The main criteria for inclusion for this study were: healthy male subjects aged between 18 and 45 years, with body mass index (BMI) between 18 and 30 kg/m2 and weight ꢀ 60 kg. In addition, subjects had to be either surgically sterilized (vasectomy), or if their partner was of childbearing potential, had to use two methods of contraception, one of which had to be a barrier method, from the first dose until 3 months after the last dose. All the subjects were Caucasian males.

  • BL-8040 (BKT140) demonstrates
  • a
  • higher affinity and

longer receptor occupancy for CXCR4 and provides a greater effect on the retention–mobilization balance of bone marrow SCs when compared with AMD3100 in both in vitro and in vivo mice studies (13–15). This study investigated the capacity of BL-8040 to mobilize and retain CD34þ cells in healthy volunteers, hypothesizing that a single day procedure of BL-8040 monotherapy administration (single injection) followed by one apheresis session will provide sufficient amounts of CD34þ HSPCs for transplantation.
After providing an informed consent, adult male subjects ages 18–45 years old were screened for study eligibility by assessment of inclusion and exclusion criteria. Inclusion criteria consisted of a BMI measure between 18 and 30 kg/m2 and weight ꢀ 60 kg. The subjects were healthy as indicated by their medical history, physical examination, 12-lead electrocardiogram (ECG), and laboratory safety tests. Screening procedures included the collection of demographic data, medical history, physical examination [including height, weight and body mass index (BMI)], vital signs (blood pressure, pulse rate, respiration rate and oral temperature), 12-lead electrocardiogram (ECG), and safety laboratory evaluations [hematology, biochemistry, coagulation (PT/INR and aPTT)] and urinalysis.

Materials and Methods

Clinical study

A phase I, two-part study exploring the safety, tolerability, pharmacodynamic, and pharmacokinetic effects of ascending doses of BL-8040 in healthy subjects (study BL-8040.02) after informed consent was obtained. The study was conducted at the Hadassah Clinical Research Center (HCRC), Hadassah Medical Center, Jerusalem, Israel and approved by the Human Subjects Committee Institutional Review Boards of Hadassah Medical Center, Jerusalem, Israel. All subjects gave informed consent to participate in the study, which was approved by local Institutional Review Boards and conducted in accordance with the ethical principles of the Declaration of Helsinki.

Determination of blood counts and FACS analysis

WBCs and differential counts, immunophenotyping for neutrophils, T, B, NK cells, CD34þ cell counts, and expression of CXCR4 using the 12G5 mAb were assessed for part 1 and 2 by FACS analysis. Immunophenotyping of peripheral blood and of cells collected by the leukapheresis (exploratory endpoint) were assessed by FACS analysis for the following surface markers: CD34, CD16, CD56, CD3, CD4, CD8, CD19, CD11c, CD83,

Patients and methods

The study had two parts: part 1 (dose escalation) was a CD25, Foxp3, CXCR4 (part 2). Yields of hematopoietic progenrandomized, double-blind, placebo-controlled study exploring itor cells were tested by a methylcellulose medium with recomthe safety, tolerability, and the pharmacodynamic and phar- binant cytokines and EPO for human cells (MethoCult H4435; macokinetic profiles of BL-8040 injected subcutaneously at StemCell Technologies Inc.)

  • doses of 0.5, 0.75, and 1 mg/kg. Individuals who received the
  • The expression of CXCR4 on mobilized CD34þ from BL-8040–

dose of 0.5 mg/kg (n ¼ 6) and their placebo (n ¼ 2) were mobilized cells and from G-CSF–mobilized cells was done folnumbered 1001–1008. Individuals who received the dose of lowing staining with two different CXCR4 antibody clones: 12G5 0.75 mg/kg (n ¼ 6) and their placebo (n ¼ 2) were numbered (binds to the second extracellular loops) or 1D9 (binds to the 2001–2008 and individuals who received the dose of 1 mg/kg N-terminal portion). Controls were incubated with appropriate (n ¼ 6) and their placebo (n ¼ 2) were numbered 3001–3008. isotype controls.

  • WBCs and CD34þ cell mobilization were measured in healthy
  • BL-8040–mobilized-CD34þ cells (n ¼ 4) and G-CSF–mobi-

subjects following administration of BL-8040 (once daily on lized-CD34þ cells (n ¼ 4) were stained with mAbs against CD34,

OF2 Clin Cancer Res; 23(22) November 15, 2017

Clinical Cancer Research

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Published OnlineFirst August 23, 2017; DOI: 10.1158/1078-0432.CCR-16-2919

Rapid and Robust Mobilization of HSPCs in Healthy Volunteers

  • CD38, CD45RA, Thy1 (CD90), and CD49f antigens and the
  • Eight weeks following transplantation second transplanta-

different hematopoietic stem and progenitors population was tion was performed. A total of 2 Â 105 bone marrow cells/

  • analyzed with BD LSR II flow cytometer (Becton Dickinson).
  • mouse were transplanted as described. The engraftment of cells

in the second transplantation was allowed for 14 weeks after transplantation.

Leukapheresis

For all 8 subjects in part 2 (5001–5008), a leukapheresis procedure was performed approximately 4 hours after a single BL-8040 injection was administered. All mobilized products were collected using a Cobe Spectra apheresis device (Gambro BCT). Five subjects of G-CSF–mobilized peripheral blood cells were collected by apheresis from healthy donor (Chaim Sheba Medical Center, Hematology Division, Tel-Hashomer, Israel) under informed consent and Helsinki approval. Healthy donors received G-CSF (Neupogen; Amgen), in a standard dose of 10 mg/kg body weight subcutaneously for 4 days. On the morning of the fifth day, they underwent conventional leukapheresis. Stem cell harvesting was performed using Cobe Spectra Apheresis System (Caridian BCT, version 6.1 or 7). A 4-fold estimated blood volume was processed daily in 4 to 5 hours. Volume and processing of apheresis products were done according to standardized procedures. If 1 leukapheresis was insufficient, an additional dose of G-CSF was administrated and a second leukapheresis was performed.
Following engraftment mice were sacrificed and blood, bone marrow and spleen were taken for analysis. Cells were isolated from those organs, stained with anti-human CD45, and antihuman CD34þ antibodies and percentage of cells evaluated by FACS. For further analysis of transplanted cells, different staining was done using specific anti-human fluorescence antibodies: CD34/CD38, CD3/CD4/CD8, CD14/CD16, and CD19/CD56/ CD3. FACS analysis was done using a FACSCalibur Flow Cytometer (BD Biosciences). The data were analyzed using software from CellQuest (version 3.3; BD Biosciences). To evaluate the number of human progenitor cells following transplantation of human CD34þ cells, a colony-forming cell (CFC) assay was performed. The colonies were assayed by plating 1 Â 105 of cells collected from the mice bone marrow, following lysis of RBC, in a methylcellulose medium with recombinant cytokines and EPO for human cells (MethoCult H4435; StemCell Technologies Inc.). The cultures were incubated at 37ꢁC in a humidified atmosphere containing 5% CO2. The colonies that developed 10 days later were visually scored using a light microscope (employing morphologic criteria).

In vitro and in vivo studies in mice

Isolation of CD34þ and CD3þ cells. Isolation of cells was done

using the Human MicroBeads Isolation Kit from Miltenyi Biotec. Isolation of mobilized CD34þ cells was done from all collected grafts and from G-CSF–mobilized cells. Isolation of CD3þ T cells was done from the BL-8040 collected grafts (mobilized CD3þ cells) and from the blood of healthy donors who have not experienced mobilization with BL-8040 (normal CD3þ cells). Purity of isolated cells was determined by FACS.

Statistical methods

All measured variables and derived parameters are listed individually and, where appropriate, presented using descriptive statistics. The safety parameters and changes from baseline were examined and summarized for descriptive purposes. Adverse events (AE) were coded according to the MedDRA (version 17.1) system organ class and preferred term. The individual study drug pharmacokinetic parameters and the mean, SD, and 95% confidence interval (CI) values were calculated for each dose group, for all subjects. Pharmacodynamic analyses included the values, changes from predose, and fold increases of WBCs (neutrophils, lymphocytes, monocytes, and platelets), CD34þ and CD138þ counts, red blood cells (RBC), and the number of stem cell collections. The individual measurements and changes from baseline by time point are presented in addition to summary tables by dose group. A P value of less than 0.05 was considered significant, and the significance of the differences between the groups for the stem cell collection was performed using Student t test. A paired two-tailed Student t test was used to evaluate the significant differences between the groups.

In vitro migration of mobilized cells. A migration assay was

performed using transmigration plates of 6.5 mm/diameter and 5 mm/pore (Costar). Purified CD34þ cells (from BL- 8040–mobilized cells and from G-CSF–mobilized cells) were suspended in RPMI medium containing 1% FCS. Cells (2 Â 105 cells/well) were added to the top chambers in a total volume of 100 mL, and 600 mL RPMI supplemented with 100 ng/mL CXCL12 (PeproTech) was added to the bottom chambers. The same amount of isolated mobilized CD3þ cells from the collected grafts and normal CD3þ cells were added to the Transwell. The cells migrating to the bottom chamber of the Transwell within 4 hours were counted using a FACSCalibur Flow Cytometer (BD Biosciences). The data were analyzed using software from CellQuest (version 3.3; BD Biosciences).

Results

Mice. Female NOD SCID gamma (NSG) mice (8–9 weeks old) were maintained under specific pathogen-free conditions at the Hebrew University Animal Facility (Jerusalem, Israel). All experiments were approved by the Animal Care and Use Committee of the Hebrew University.

Demographics and baseline characteristics

Twenty-five subjects were enrolled into part 1 of the study; however, one subject did not receive the study drug and two subjects received only one dose of the study drug. A total of 40 potential subjects were screened for part 1 of the study. Twenty-eight subjects met all inclusion and exclusion criteria
Engraftment of mobilized human CD34þ cells in mice. NSG mice and were eligible to participate in the study. Of these, 24 were were first irradiated with 300 cGy and 24 hours later mobilized initially included in the study. One subject, initially randomhuman CD34þ cells were intravenously injected (2 Â 105 cells/ ized to the BL-8040 1 mg/kg group, was withdrawn from the mouse) into the mouse via the dorsal tail vein in a final volume study due to the investigator's decision (the subject fainted of 200 mL. Engraftment of cells was allowed for 4, 8, and 22 weeks before BL-8040/placebo administration). An additional subject

  • after transplantation.
  • was therefore added to that group to replace this early dropout.

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Therefore, a total of 25 subjects were randomized to participate placebo group were all below the limit of quantitation, as in part 1 of the study and 24 subjects received at least one dose expected, and were not considered in the pharmacokinetic analand were included in the safety analysis. A total of 22 subjects ysis. Likewise, predose plasma concentrations were below the (22/24, 91.7%) completed the study. Two subjects (8.3%) limit of quantitation in all subjects randomized to receive BL- withdrew prematurely: one subject in the BL-8040 0.5 mg/kg 8040. After subcutaneous administration of BL-8040 on day 1, the treatment group withdrew his consent for participation in the appearance of the compound in the plasma was rapid, with a study, and one subject in the BL-8040 1 mg/kg withdrew from median Tmax ranging between 0.25 and 0.5 hour. Thereafter, the study due to injection site pain, tension headaches, nausea, plasma concentrations declined monoexponentially with a short

  • vomiting, and abdominal discomfort.
  • half-life of approximately 1 hour. For that reason, plasma levels of

All subjects were male and Caucasian. The data below is BL-8040 were below the limit of detection in the majority of presented only for the 24 subjects who received the study drug. subjects by 8 hours and in all subjects at 23 hours after dosing. Summary tables for baseline demographic data are presented in Summary statistics of pharmacokinetic parameters of BL-8040 Supplementary Table S1A. The baseline characteristics were after day 1 (first dose and second dose) can be found in Supplesimilar across groups, and no subject reported any history of mentary Table S2A.

  • alcohol and/or drug abuse or addiction and/or active/past (up
  • Increases in the dose of BL-8040 led to overall approximate

to 2 years before screening) nicotine consumption. No subject proportional increases in plasma exposure, as measured by reported a clinically significant medical history (Supplementary Cmax, AUC0–t, AUC0–24, and AUC0–¥ (Fig. 1). Dose-normalized

  • Table S1A).
  • Cmax and AUC0–24 and t1/2 values were comparable across the

Eight subjects were enrolled into part 2 of the study. All subjects 3 dose groups suggesting dose proportionality across the 0.5 to were male and Caucasian. All subjects received BL-8040. Sum- 1 mg/kg dose range.

  • mary tables for baseline demographic data are presented in
  • The plasma concentration–time profile on day 2 was con-

Supplementary Table S1B. No subject reported any history of sistent with day 1 and characterized by the rapid absorption alcohol and/or drug of abuse addiction and/or active/past (up and elimination of BL-8040 from the circulation. Consistent to 2 years before screening) nicotine consumption. No subject with its short half-life, accumulation of BL-8040 upon once reported clinically significant medical history (Supplementary daily repeated administration for two days was minimal.

  • Table S1B).
  • The pharmacokinetic parameters on day 2 (Supplementary

Table SS2B; Fig. 1) were similar to those of day 1.

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    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2017/223229 Al 28 December 2017 (28.12.2017) W !P O PCT (51) International Patent Classification: (74) Agent: RED), Andrea L.C. et al; One International A61K 31/445 (2006.01) C07D 221/00 (2006.01) Place, 40th Floor, 100 Oliver Street, Boston, Massachusetts A61K 31/451 (2006.01) C07D 227/04 (2006.01) 021 10-2605 (US). A61K 31/4523 (2006.01) C07D 235/06 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US2017/038590 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, 2 1 June 2017 (21 .06.2017) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (25) Filing Language: English KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (26) Publication Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (30) Priority Data: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, 62/352,816 2 1 June 2016 (21 .06.2016) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
  • A Phase I Trial of LY2510924, a CXCR4 Peptide Antagonist, in Patients with Advanced

    A Phase I Trial of LY2510924, a CXCR4 Peptide Antagonist, in Patients with Advanced

    Author Manuscript Published OnlineFirst on April 11, 2014; DOI: 10.1158/1078-0432.CCR-13-2686 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. A Phase I Trial of LY2510924, a CXCR4 Peptide Antagonist, in Patients with Advanced Cancer Matthew D. Galsky1*, Nicholas J. Vogelzang1, Paul Conkling2, Eyas Raddad3, John Polzer3, Stephanie Roberson3, John R. Stille3, Mansoor Saleh4, Donald Thornton5 1US Oncology Research/Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA 2 US Oncology Research/Virginia Oncology Associates, Norfolk, Virginia, USA 3The Chorus Group, Eli Lilly and Company, Indianapolis, IN, USA 4Georgia Cancer Specialists, PC, Atlanta, Georgia, USA 5Eli Lilly and Company, Indianapolis, IN, USA *Corresponding Author: Matthew D. Galsky, MD Mount Sinai School of Medicine 10 East 102nd Street Tower Building, Second Floor Box 1128 New York, NY 10029 Phone: 212-824-8583 Fax: 646-537-9639 [email protected] Running header: LY2510924 in patients with advanced cancer Keywords: CXCR4, LY2510924, cancer, CD34+ Word Count Abstract- 245 (Clinical Cancer Research limit = 250) Word Count Text- 4030 (CCR limit = 5000) Tables/Figures-6 (CCR limit = 6) Research support: The study was sponsored by Eli Lilly and Company. 1 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 11, 2014; DOI: 10.1158/1078-0432.CCR-13-2686 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Statement of clinical relevance (required for submission to journal): This manuscript reports the results of a phase I study designed to evaluate the safety and tolerability of the C-X-C motif receptor 4 (CXCR4) inhibitor LY2510924 in patients with advanced cancer.
  • Enhanced Unique Pattern of Hematopoietic Cell Mobilization Induced by the CXCR4 Antagonist 4F-Benzoyl-TN14003

    Enhanced Unique Pattern of Hematopoietic Cell Mobilization Induced by the CXCR4 Antagonist 4F-Benzoyl-TN14003

    CANCER STEM CELLS Enhanced Unique Pattern of Hematopoietic Cell Mobilization Induced by the CXCR4 Antagonist 4F-Benzoyl-TN14003 MICHAL ABRAHAM,a KATIA BIYDER,a MICHAL BEGIN,a HANNA WALD,a IDO D. WEISS,a EITHAN GALUN,a Downloaded from ARNON NAGLER,b AMNON PELEDa aGoldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel; bBone Marrow Transplantation Department, Chaim Sheba Medical Center, Tel-Hashomer, Israel Key Words. CXCR4 • Mobilization • Hematopoietic stem cells • Hematopoietic progenitors www.StemCells.com ABSTRACT An increase in the number of stem cells in blood following cells (WBC) in blood, including monocytes, B cells, and T mobilization is required to enhance engraftment after high- cells, it had no effect on mobilizing natural killer cells. dose chemotherapy and improve transplantation outcome. T-140 was found to efficiently synergize with granulocyte Therefore, an approach that improves stem cell mobilization colony-stimulating factor (G-CSF) in its ability to mobi- is essential. The interaction between CXCL12 and its recep- lize WBC and progenitors, as well as to induce a 660-fold tor, CXCR4, is involved in the retention of stem cells in the increase in the number of erythroblasts in peripheral at Bernman National Medical Library, Hebrew University of Jerusalem on April 18, 2009 bone marrow. Therefore, blocking CXCR4 may result in blood. Comparison between the CXCR4 antagonists mobilization of hematopoietic progenitor and stem cells. We T-140 and AMD3100 showed that T-140 with or without have found that the CXCR4 antagonist known as 4F-benzo- G-CSF was significantly more potent in its ability to yl-TN14003 (T-140) can induce mobilization of hematopoi- mobilize hematopoietic stem cells and progenitors into etic stem cells and progenitors within a few hours post- blood.
  • Interplay Between SARS-Cov-2 and the Type I Interferon Response Margarida Sa Ribero, Nolwenn Jouvenet, Marlène Dreux, Sébastien Nisole

    Interplay Between SARS-Cov-2 and the Type I Interferon Response Margarida Sa Ribero, Nolwenn Jouvenet, Marlène Dreux, Sébastien Nisole

    Interplay between SARS-CoV-2 and the type I interferon response Margarida Sa Ribero, Nolwenn Jouvenet, Marlène Dreux, Sébastien Nisole To cite this version: Margarida Sa Ribero, Nolwenn Jouvenet, Marlène Dreux, Sébastien Nisole. Interplay between SARS- CoV-2 and the type I interferon response. PLoS Pathogens, Public Library of Science, 2020, 16 (7), pp.e1008737. 10.1371/journal.ppat.1008737. inserm-02965704 HAL Id: inserm-02965704 https://www.hal.inserm.fr/inserm-02965704 Submitted on 13 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License PLOS PATHOGENS REVIEW Interplay between SARS-CoV-2 and the type I interferon response 1 2 1 3 Margarida Sa RiberoID , Nolwenn Jouvenet *, Marlène DreuxID *, SeÂbastien NisoleID * 1 CIRI, Inserm, U1111, Universite Claude Bernard Lyon 1, CNRS, E cole Normale SupeÂrieure de Lyon, Univ Lyon, Lyon, France, 2 Institut Pasteur, CNRS UMR3569, Paris, France, 3 IRIM, CNRS UMR9004, Universite de Montpellier, Montpellier, France * [email protected] (NJ); [email protected] (MD); [email protected] (SN) a1111111111 a1111111111 a1111111111 Abstract a1111111111 a1111111111 The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic.
  • A Highly Selective and Potent CXCR4 Antagonist for Hepatocellular Carcinoma Treatment

    A Highly Selective and Potent CXCR4 Antagonist for Hepatocellular Carcinoma Treatment

    A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment Jen-Shin Songa,1, Chih-Chun Changb,1, Chien-Huang Wua,1, Trinh Kieu Dinhb, Jiing-Jyh Jana, Kuan-Wei Huangb, Ming-Chen Choua, Ting-Yun Shiueb, Kai-Chia Yeha, Yi-Yu Kea, Teng-Kuang Yeha, Yen-Nhi Ngoc Tab, Chia-Jui Leea, Jing-Kai Huanga, Yun-Chieh Sungb, Kak-Shan Shiaa,2, and Yunching Chenb,2 aInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, Republic of China; and bInstitute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, 30013 Hsinchu, Taiwan, Republic of China Edited by Michael Karin, University of California San Diego, La Jolla, CA, and approved February 4, 2021 (received for review July 23, 2020) The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, advanced HCC (9, 17), the concept of which has been experimentally CXCL12, are overexpressed in various cancers and mediate tumor validated by the discovery of a CXCR4 antagonist, BPRCX807. progression and hypoxia-mediated resistance to cancer therapy. AMD3100 was the first Food and Drug Administration (FDA)- While CXCR4 antagonists have potential anticancer effects when approved CXCR4 antagonist used for peripheral blood stem cell combined with conventional anticancer drugs, their poor potency transplantation (PBSCT) (18); however, its application to solid against CXCL12/CXCR4 downstream signaling pathways and sys- tumors is limited by its poor pharmacokinetics and toxic adverse temic toxicity had precluded clinical application. Herein, BPRCX807, effects after long-term administration (19, 20). Thus, a CXCR4 known as a safe, selective, and potent CXCR4 antagonist, has been antagonist with higher safety and better pharmacological and designed and experimentally realized.
  • Current Insights Into Immunology and Novel Therapeutics of Atopic Dermatitis

    Current Insights Into Immunology and Novel Therapeutics of Atopic Dermatitis

    cells Review Current Insights into Immunology and Novel Therapeutics of Atopic Dermatitis Hidaya A. Kader 1,†, Muhammad Azeem 2,†, Suhib A. Jwayed 1, Aaesha Al-Shehhi 1 , Attia Tabassum 3, Mohammed Akli Ayoub 1 , Helal F. Hetta 4 , Yasir Waheed 5 , Rabah Iratni 1 , Ahmed Al-Dhaheri 6 and Khalid Muhammad 1,* 1 Department of Biology, College of Science, UAE University, Al Ain 15551, United Arab Emirates; [email protected] (H.A.K.); [email protected] (S.A.J.); [email protected] (A.A.-S.); [email protected] (M.A.A.); [email protected] (R.I.) 2 Department of Pathology, University of Würzburg, 97080 Würzburg, Germany; [email protected] 3 Department of Dermatology, Mayo Hospital, Lahore 54000, Pakistan; [email protected] 4 Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt; [email protected] 5 Foundation University Medical College, Foundation University Islamabad, Islamabad 44000, Pakistan; [email protected] 6 Department of Dermatology, Tawam Hospital, Al Ain 15551, United Arab Emirates; [email protected] * Correspondence: [email protected] † Authors contributed equally to this work. Abstract: Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon Citation: Kader, H.A.; Azeem, M.; of atopic march, during which infant AD patients are predisposed to progressive secondary allergies Jwayed, S.A.; Al-Shehhi, A.; such as allergic rhinitis, asthma, and food allergies.