A phase I trial of monoclonal antibody M195 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide.

Ten patients with myeloid leukemias were treated in a phase I trial with escalating doses of mouse monoclonal antibody (mAb) M195, reactive with CD33, a glycoprotein found on myeloid leukemia blasts and early hematopoietic progenitor cells but not on normal stem cells. M195 was trace-labeled with iodine-131 (131I) to allow detailed pharmacokinetic and dosimetric studies by serial sampling of blood and bone marrow and whole-body gamma-camera imaging. Total doses up to 76 mg were administered safely without immediate adverse effects. Absorption of M195 onto targets in vivo was demonstrated by biopsy, pharmacology, flow cytometry, and imaging; saturation of available sites occurred at doses greater than or equal to 5 mg/m2. The entire bone marrow was specifically and clearly imaged beginning within hours after injection; optimal imaging occurred at the lowest dose. Bone marrow biopsies demonstrated significant dose-related uptake of M195 as early as 1 hour after infusion in all patients, with the majority of the dose found in the marrow. Tumor regressions were not observed. An estimated 0.33 to 1.0 rad/mCi 131I was delivered to the whole body, 1.1 to 6.1 rad/mCi was delivered to the plasma, and up to 34 rad/mCi was delivered to the red marrow compartment. 131I-M195 was rapidly modulated, with a majority of the bound immunoglobulin G (IgG) being internalized into target cells in vivo. These data indicate that whole bone marrow ablative doses of 131I-M195 can be expected. The rapid, specific, and quantitative delivery to the bone marrow and the efficient internalization of M195 into target cells in vivo also suggest that the delivery of other isotopes such as auger or alpha emitters, toxins, or other biologically important molecules into either leukemia cells or normal hematopoietic progenitor cells may be feasible.

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141 Phase I Trial of Genetically Modified Hematopoietic Progenitor Cells Facilitate Bone Marrow Chemoprotection and Enabling TMZ/O6BG Dose Escalation Resulting in Improved Survival

Neurosurgery ◽

10.1227/01.neu.0000489711.06584.23 ◽

2016 ◽

Vol 63 ◽

pp. 157 ◽

Cited By ~ 2

Author(s):

Andrew E. Sloan ◽

Hua Fung ◽

Jane Reese ◽

Lisa R. Rogers ◽

Christopher Murphay ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Progenitor Cells ◽

Dose Escalation ◽

Phase I Trial ◽

Genetically Modified ◽

Hematopoietic Progenitor Cells ◽

Hematopoietic Progenitor

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Orderly Process of Sequential Cytokine Stimulation Is Required for Activation and Maximal Proliferation of Primitive Human Bone Marrow CD34+ Hematopoietic Progenitor Cells Residing in G0

Blood ◽

10.1182/blood.v90.2.658 ◽

1997 ◽

Vol 90 (2) ◽

pp. 658-668 ◽

Cited By ~ 63

Author(s):

Amy C. Ladd ◽

Robert Pyatt ◽

Andre Gothot ◽

Susan Rice ◽

Jon McMahel ◽

...

Keyword(s):

Cell Cycle ◽

Bone Marrow ◽

Phase I ◽

Progenitor Cells ◽

Phase Ii ◽

Hematopoietic Progenitor Cells ◽

Hematopoietic Progenitor ◽

Cd34 Cells ◽

Cytokine Stimulation ◽

Phase Iv

Abstract Bone marrow (BM) CD34+ cells residing in the G0 phase of cell cycle may be the most suited candidates for the examination of cell cycle activation and proliferation of primitive hematopoietic progenitor cells (HPCs). We designed a double simultaneous labeling technique using both DNA and RNA staining with Hoechst 33342 and Pyronin Y, respectively, to isolate CD34+ cells residing in G0(G0CD34+ ). Using long-term BM cultures and limiting dilution analysis, G0CD34+ cells were found to be enriched for primitive HPCs. In vitro proliferation of G0CD34+ cells in response to sequential cytokine stimulation was examined in a two-step assay. In the first step, cells received a primary stimulation consisting of either stem cell factor (SCF), Flt3-ligand (FL), interleukin-3 (IL-3), or IL-6 for 7 days. In the second step, cells from each group were washed and split into four or more groups, each of which was cultured again for another week with one of the four primary cytokines individually, or in combination. Tracking of progeny cells was accomplished by staining cells with PKH2 on day 0 and with PKH26 on day 7. Overall examination of proliferation patterns over 2 weeks showed that cells could progress into four phases of proliferation. Phase I contained cytokine nonresponsive cells that failed to proliferate. Phase II contained cells dividing up to three times within the first 7 days. Phases III and IV consisted of cells dividing up to five divisions and greater than six divisions, respectively, by the end of the 14-day period. Regardless of the cytokine used for primary stimulation, G0CD34+ cells moved only to phase II by day 7, whereas a substantial percentage of cells incubated with SCF or FL remained in phase I. Cells cultured in SCF or FL for the entire 14-day period did not progress beyond phase III but proliferated into phase IV (with <20% of cells remaining in phases I and II) if IL-3, but not IL-6, was substituted for either cytokine on day 7. G0CD34+ cells incubated with IL-3 for 14 days proliferated the most and progressed into phase IV; however, when SCF was substituted on day 7, cells failed to proliferate into phase IV. Most intriguing was a group of cells, many of which were CD34+, detected in cultures initially stimulated with IL-3, which remained as a distinct population, mostly in G0 /G1 , unable to progress out of phase II regardless of the nature of the second stimulus received on day 7. A small percentage of these cells expressed cyclin E, suggesting that their proliferation arrest may have been mediated by a cyclin-related disruption in cell cycle. These results suggest that a programmed response to sequential cytokine stimulation may be part of a control mechanism required for maintenance of proliferation of primitive HPCs and that unscheduled stimulation of CD34+ cells residing in G0 may result in disruption of cell-cycle regulation.

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Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.6.2169 ◽

1998 ◽

Vol 16 (6) ◽

pp. 2169-2180 ◽

Cited By ~ 171

Author(s):

A L Yu ◽

M M Uttenreuther-Fischer ◽

C S Huang ◽

C C Tsui ◽

S D Gillies ◽

...

Keyword(s):

Monoclonal Antibody ◽

Phase I ◽

Dose Escalation ◽

Phase I Trial ◽

Dose Schedule ◽

Maximum Tolerated Dose ◽

Target Cells ◽

Complement Dependent Cytotoxicity ◽

Clinical Responses

PURPOSE To evaluate the toxicity, immunogenicity, and pharmacokinetics of a human-mouse chimeric monoclonal antibody (mAb) ch 14.18 directed against disialoganglioside (GD2) and to obtain preliminary information on its clinical efficacy, we conducted a phase I trial in 10 patients with refractory neuroblastoma and one patient with osteosarcoma. PATIENTS AND METHODS Eleven patients were entered onto this phase I trial. They received 20 courses of mAb ch 14.18 at dose levels of 10, 20, 50, 100, and 200 mg/m2. Dose escalation was performed in cohorts of three patients; intrapatient dose escalation was also permitted. RESULTS The most prevalent toxicities were pain, tachycardia, hypertension, fever, and urticaria. Most of these toxicities were dose-dependent and rarely noted at dosages of 20 mg/m2 and less. Although the maximum-tolerated dose was not reached in this study, clinical responses were observed. These included one partial (PR) and four mixed responses (MRs) and one stable disease (SD) among 10 assessable patients. Biologic activity of ch 14.18 in vivo was shown by binding of ch 14.18 to tumor cells and complement-dependent cytotoxicity of posttreatment sera against tumor target cells. An anti-ch 14.18 immune response was detectable in seven of 10 patients studied. CONCLUSION In summary, with the dose schedule used, ch 14.18 appears to be clinically safe and effective, and repeated mAb administration was not associated with increased toxicities. Further clinical trials of mAb ch 14.18 in patients with neuroblastoma are warranted.

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Flt3 Ligand Negatively Regulates In Vitro Migration, Intracellular Signaling Activated by SDF-1α/CXCR4 and In Vivo Homing of Hematopoietic Progenitor Cells.

Blood ◽

10.1182/blood.v104.11.2674.2674 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2674-2674

Author(s):

Seiji Fukuda ◽

Hal E. Broxmeyer ◽

Louis M. Pelus

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Hematopoietic Progenitor Cells ◽

Leukemia Cells ◽

Flt3 Ligand ◽

Hematopoietic Progenitor ◽

Short Term ◽

Hematopoietic Stem

Abstract The Flt3 receptor tyrosine kinase (Flt3) is expressed on primitive normal and transformed hematopoietic cells and Flt3 ligand (FL) facilitates hematopoietic stem cell mobilization in vivo. The CXC chemokine SDF-1α(CXCL12) attracts primitive hematopoietic cells to the bone marrow microenvironment while disruption of interaction between SDF-1α and its receptor CXCR4 within bone marrow may facilitate their mobilization to the peripheral circulation. We have previously shown that Flt3 ligand has chemokinetic activity and synergistically increases migration of CD34+ cells and Ba/F3-Flt3 cells to SDF-1α in short-term migration assays; this was associated with synergistic phosphorylation of MAPKp42/p44, CREB and Akt. Consistent with these findings, over-expression of constitutively active ITD (internal tandem duplication) Flt3 found in patients with AML dramatically increased migration to SDF-1α in Ba/F3 cells. Since FL can induce mobilization of hematopoietic stem cells, we examined if FL could antagonize SDF-1α/CXCR4 function and evaluated the effect of FL on in vivo homing of normal hematopoietic progenitor cells. FL synergistically increased migration of human RS4;11 acute leukemia cells, which co-express wild-type Flt3 and CXCR4, to SDF-1α in short term migration assay. Exogenous FL had no effect on SDF-1α induced migration of MV4-11 cells that express ITD-Flt3 and CXCR4 however migration to SDF-1α was partially blocked by treatment with the tyrosine kinase inhibitor AG1296, which inhibits Flt3 kinase activity. These results suggest that FL/Flt3 signaling positively regulates SDF-1α mediated chemotaxis of human acute leukemia cells in short-term assays in vitro, similar to that seen with normal CD34+ cells. In contrast to the enhancing effect of FL on SDF-1α, prolonged incubation of RS4;11 and THP-1 acute myeloid leukemia cells, which also express Flt3 and CXCR4, with FL for 48hr, significantly inhibited migration to SDF-1α, coincident with reduction of cell surface CXCR4. Similarly, prolonged exposure of CD34+ or Ba/F3-Flt3 cells to FL down-regulates CXCR4 expression, inhibits SDF-1α-mediated phosphorylation of MAPKp42/p44, CREB and Akt and impairs migration to SDF-1α. Despite reduction of surface CXCR4, CXCR4 mRNA and intracellular CXCR4 in Ba/F3-Flt3 cells were equivalent in cells incubated with or without FL, determined by RT-PCR and flow cytometry after cell permeabilization, suggesting that the reduction of cell surface CXCR4 expression is due to accelerated internalization of CXCR4. Furthermore, incubation of Ba/F3-Flt3 cells with FL for 48hr or over-expression of ITD-Flt3 in Ba/F3 cells significantly reduced adhesion to VCAM1. Consistent with the negative effect of FL on in vitro migration and adhesion to VCAM1, pretreatment of mouse bone marrow cells with 100ng/ml of FL decreased in vivo homing of CFU-GM to recipient marrow by 36±7% (P<0.01), indicating that FL can negatively regulate in vivo homing of hematopoietic progenitor cells. These findings indicate that short term effect of FL can provide stimulatory signals whereas prolonged exposure has negative effects on SDF-1α/CXCR4-mediated signaling and migration and suggest that the FL/Flt3 axis regulates hematopoietic cell trafficking in vivo. Manipulation of SDF-1α/CXCR4 and FL/Flt3 interaction could be clinically useful for hematopoietic cell transplantation and for treatment of hematopoietic malignancies in which both Flt3 and CXCR4 are expressed.

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Orderly Process of Sequential Cytokine Stimulation Is Required for Activation and Maximal Proliferation of Primitive Human Bone Marrow CD34+ Hematopoietic Progenitor Cells Residing in G0

Blood ◽

10.1182/blood.v90.2.658.658_658_668 ◽

1997 ◽

Vol 90 (2) ◽

pp. 658-668 ◽

Cited By ~ 8

Author(s):

Amy C. Ladd ◽

Robert Pyatt ◽

Andre Gothot ◽

Susan Rice ◽

Jon McMahel ◽

...

Keyword(s):

Cell Cycle ◽

Bone Marrow ◽

Phase I ◽

Progenitor Cells ◽

Phase Ii ◽

Hematopoietic Progenitor Cells ◽

Hematopoietic Progenitor ◽

Cd34 Cells ◽

Cytokine Stimulation ◽

Phase Iv

Bone marrow (BM) CD34+ cells residing in the G0 phase of cell cycle may be the most suited candidates for the examination of cell cycle activation and proliferation of primitive hematopoietic progenitor cells (HPCs). We designed a double simultaneous labeling technique using both DNA and RNA staining with Hoechst 33342 and Pyronin Y, respectively, to isolate CD34+ cells residing in G0(G0CD34+ ). Using long-term BM cultures and limiting dilution analysis, G0CD34+ cells were found to be enriched for primitive HPCs. In vitro proliferation of G0CD34+ cells in response to sequential cytokine stimulation was examined in a two-step assay. In the first step, cells received a primary stimulation consisting of either stem cell factor (SCF), Flt3-ligand (FL), interleukin-3 (IL-3), or IL-6 for 7 days. In the second step, cells from each group were washed and split into four or more groups, each of which was cultured again for another week with one of the four primary cytokines individually, or in combination. Tracking of progeny cells was accomplished by staining cells with PKH2 on day 0 and with PKH26 on day 7. Overall examination of proliferation patterns over 2 weeks showed that cells could progress into four phases of proliferation. Phase I contained cytokine nonresponsive cells that failed to proliferate. Phase II contained cells dividing up to three times within the first 7 days. Phases III and IV consisted of cells dividing up to five divisions and greater than six divisions, respectively, by the end of the 14-day period. Regardless of the cytokine used for primary stimulation, G0CD34+ cells moved only to phase II by day 7, whereas a substantial percentage of cells incubated with SCF or FL remained in phase I. Cells cultured in SCF or FL for the entire 14-day period did not progress beyond phase III but proliferated into phase IV (with <20% of cells remaining in phases I and II) if IL-3, but not IL-6, was substituted for either cytokine on day 7. G0CD34+ cells incubated with IL-3 for 14 days proliferated the most and progressed into phase IV; however, when SCF was substituted on day 7, cells failed to proliferate into phase IV. Most intriguing was a group of cells, many of which were CD34+, detected in cultures initially stimulated with IL-3, which remained as a distinct population, mostly in G0 /G1 , unable to progress out of phase II regardless of the nature of the second stimulus received on day 7. A small percentage of these cells expressed cyclin E, suggesting that their proliferation arrest may have been mediated by a cyclin-related disruption in cell cycle. These results suggest that a programmed response to sequential cytokine stimulation may be part of a control mechanism required for maintenance of proliferation of primitive HPCs and that unscheduled stimulation of CD34+ cells residing in G0 may result in disruption of cell-cycle regulation.

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Therapeutic Targeting of CD163 on Hematopoietic Progenitor Cells By Novel Monoclonal Antibody TBI 304H Demonstrates an Increase in Erythropoiesis in Humanized Mice

Blood ◽

10.1182/blood.v126.23.1163.1163 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1163-1163

Author(s):

Kathryn Matthews ◽

Irina Eberle-Ayres ◽

Katherine Lu ◽

Nishi Singh ◽

Murray J Cutler ◽

...

Keyword(s):

Monoclonal Antibody ◽

Bone Marrow ◽

Single Dose ◽

Fold Increase ◽

Hematopoietic Progenitor Cells ◽

Hematopoietic Progenitor ◽

Human Cd34 ◽

Cd34 Cells ◽

Dose Dependent

Abstract Hemoglobin (Hb) is known to stimulate erythropoiesis, a process that may be mediated by CD163. CD163 is a receptor for the hemoglobin-haptoglobin (Hb-Hp) complex expressed on monocyte/macrophages as well as a subpopulation of human CD34+ hematopoietic progenitor cells (HPCs). We have demonstrated that administration of ligands to the CD163 receptor can measurably stimulate erythropoiesis in human CD34+ cell-engrafted severe-combined immunodeficiency (SCID) mice. To better elucidate the role of CD163 in hematopoiesis, we investigated the effects of the natural ligand to CD163 (Hb-Hp) as well as a stimulatory antibody, TBI 304H, on HPCs in vivo. SCID mice engrafted with human CD34+ cells were used as a model system were used to investigate the effect of Hb and anti-CD163 monoclonal antibodies (TBI 304 and TBI 304H) on human hematopoiesis in vivo. In an initial study, NOD-SCID IL2R gammanull (NSG) mice were engrafted with human CD34+ cells and animals with < 30% human CD45+ cells in the peripheral blood were administered 2 mg Hb/mouse, or 100 or 500 µg/mouse TBI 304 every 4 days for a total of four doses. At study termination on day 14, bone marrow cells (BMCs) were examined by flow cytometry and CD34+ cells were recovered from the BMCs for enumeration in colony-forming assays. Hemoglobin administration resulted in an increase of human CD34+ cells ranging from 4% to 7% of BMCs and a corresponding 57% increase in colony-forming cells (CFCs) over control animals. In contrast, the monoclonal antibody (mAb), TBI 304, produced a dose-dependent decrease in CD34+ and colonies, possibly reflecting a depletion of CD34+/CD163+ cells as a result of overstimulation due to the much longer circulating half-life of the mAb compared to Hb.. To confirm this hypothesis, human CD34+ cell engrafted animals were given only a single dose of 10 or 100 µg/mouse of TBI 304 and BMCs were examined earlier on day 7. TBI 304 provided a 3.5-fold increase in human CD34+ cells as well as a 1.8 to 6.7-fold increase in bone marrow erythroid lineage engraftment (huGlyA+, huCD36+ and huCD71+) and a 2-fold increase in colony-forming cells. The ability of TBI 304 to stimulate erythropoiesis in preclinical models led to the creation of an anti-CD163 mAb suitable for human clinical use. TBI 304H was generated by grafting the complementarity-determining regions derived from TBI 304 onto a humanized IgG4 framework without altering antigen specificity. An IgG4 framework, as an antibody without Fc effector function, was deemed the most suitable for an agonistic mAb. In the single dose, 7 day Hu-SCID model human CD34+ cells were mobilized from the mouse bone marrow by TBI 304H, as reflected by dose dependent decreases in huCD34+, huCD71+, and huGlyA+ cells in the mouse marrow. At the highest dose tested (500 µg/mouse) the decrease in human HPCs was similar to that found in animals administered Hb (2 mg/mouse). In this model, human hematopoiesis derived from the engrafted human CD34+ cells is not sustained and these date may reflect a mobilization of human HPCs through stimulation by an anti-CD163 antibody. Therapure has received U.S. FDA approval to conduct a Phase I trial of the novel therapeutic antibody TBI 304H. The Phase I clinical trial is a single-center, open-label, intra-subject escalating dose study, which will evaluate the safety, tolerability and pharmacokinetics of TBI 304H following administration to subjects experiencing chemotherapy-induced anemia. Disclosures Matthews: Therapure Biopharma: Employment. Eberle-Ayres:Therapure Biopharma: Employment. Lu:Therapure Biopharma: Employment. Singh:Therapure Biopharma: Employment. Cutler:Therapure Biopharma: Employment. Bell:Therapure Biopharma: Employment.

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CIRCULATING HEMATOPOIETIC PROGENITOR CELLS IN PATIENTS AFFECTED BY CHORNOBYL ACCIDENT

Experimental Oncology ◽

10.31768/2312-8852.2016.38(4):242-244 ◽

2016 ◽

Vol 38 (4) ◽

pp. 242-244 ◽

Cited By ~ 1

Author(s):

N M Bilko ◽

I S Dyagil ◽

I S Russu ◽

D I Bilko

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Peripheral Blood ◽

Functional Activity ◽

Mononuclear Cells ◽

Hematopoietic Progenitor Cells ◽

Hematopoietic Progenitor ◽

Scientific Center ◽

Cleanup Workers

High radiation sensitivity of stem cells and their ability to accumulate sublethal radiation damage provides the basis for investigation of hematopoietic progenitors using in vivo culture methodology. Unique samples of peripheral blood and bone marrow were derived from the patients affected by Chornobyl accident during liquidation campaign. Aim: To investigate functional activity of circulating hematopoietic progenitor cells from peripheral blood and bone marrow of cleanup workers in early and remote periods after the accident at Chornobyl nuclear power plant (CNPP). Materials and Methods: The assessment of the functional activity of circulating hematopoietic progenitor cells was performed in samples of peripheral blood and bone marrow of 46 cleanup workers, who were treated in the National Scientific Center for Radiation Medicine of the Academy of Medical Sciences of Ukraine alongside with 35 non radiated patients, who served as a control. Work was performed by culturing peripheral blood and bone marrow mononuclear cells in the original gel diffusion capsules, implanted into the peritoneal cavity of CBA mice. Results: It was shown that hematopoietic progenitor cells could be identified in the peripheral blood of liquidators of CNPP accident. At the same time the number of functionally active progenitor cells of the bone marrow was significantly decreased and during the next 10 years after the accident, counts of circulating progenitor cells in the peripheral blood as well as functionally active hematopoietic cells in bone marrow returned to normal levels. Conclusion: It was shown that hematopoietic progenitor cells are detected not only in the bone marrow but also in the peripheral blood of liquidators as a consequence of radiation exposure associated with CNPP accident. This article is a part of a Special Issue entitled “The Chornobyl Nuclear Accident: Thirty Years After”.

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A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity

Blood ◽

10.1182/blood.v83.7.1760.bloodjournal8371760 ◽

1994 ◽

Vol 83 (7) ◽

pp. 1760-1768 ◽

Cited By ~ 1

Author(s):

PC Caron ◽

JG Jurcic ◽

AM Scott ◽

RD Finn ◽

CR Divgi ◽

...

Keyword(s):

Monoclonal Antibody ◽

Bone Marrow ◽

Myeloid Leukemia ◽

Myelogenous Leukemia ◽

Whole Body ◽

Leukemia Cells ◽

Target Cells ◽

Humanized Monoclonal Antibody ◽

Myeloid Leukemias

This trial studied the biodistribution, pharmacology, toxicity, immunogenicity, and biologic characteristics of a trace-labeled, anti- CD33, humanized monoclonal antibody M195 (Hu-M195) in patients with relapsed and refractory myeloid leukemia. Hu-M195 is a computer- modeled, “complementarity-determining region-grafted,” IgG1, humanized version of M195. M195 is a murine monoclonal antibody that reacts with CD33, a 67-kD glycoprotein expressed on early myeloid progenitor cells and myeloid leukemia (acute myelogenous leukemia and chronic myelogenous leukemia) cells, but not normal stem cells. 131I-murine- M195 has already shown significant ability to cytoreduce patients with relapsed or refractory myeloid leukemias. Hu-M195 has higher avidity than the original mouse monoclonal antibody and, unlike murine M195, has the capability to mediate antibody-dependent cellular cytotoxicity against leukemia targets. Thirteen patients with relapsed or refractory myelogenous leukemia were treated with Hu-M195 at 4 levels of 0.5, 1.0, 3.0, and 10.0 mg/m2 in a phase I trial. Patients received a total of 6 doses per patient over 18 days. Two patients were retreated for a total of 12 doses. The first dose of Hu-M195 was trace-labeled with 131I to allow detailed pharmacokinetic and biodistribution studies by serial sampling of blood, radioimmunoassays of cells, and whole-body gamma- camera imaging. Cumulative total doses of up to 216 mg of Hu-M195 were administered safely. Reversible fever and rigors were observed after infusion at the highest dose levels. The entire bone marrow was specifically and clearly imaged within hours after infusion, with optimal biodistribution occurring at the 3 mg/m2 level. Adsorption of Hu-M195 onto targets in vivo was demonstrated by flow cytometry; near saturation of available sites occurred at the 3 mg/m2 dose level. Plasma and whole body half lives were 38 and 51 hours, respectively, which may reflect continual replenishment of target sites on new leukemia cells. 131I-Hu-M195 was rapidly internalized into the target cells in vivo within 1 hour. Human antihuman antibody responses were not observed. In conclusion, Hu-M195 can be administered safely in multiple doses, without significant toxicity or any evidence of immunogenicity, and can localize rapidly and efficiently to the bone marrow in patients with myeloid leukemias. Additional phase II trials with this agent alone or in combination with cytokines or isotopes are warranted at the optimal biologic dose.

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Lack of the Transcription Factor NFAT (Nuclear Factor of Activated T cells) c2 in Hematopoietic Progenitor Cells Results in Profound Hematological Abnormalities in Mice

Blood ◽

10.1182/blood.v118.21.1296.1296 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1296-1296

Author(s):

Laleh S. Arabanian ◽

Michael Haase ◽

Ivonne Habermann ◽

Malte von Bonin ◽

Claudia Waskow ◽

...

Keyword(s):

Bone Marrow ◽

Transcription Factor ◽

Progenitor Cells ◽

Conflicts Of Interest ◽

Extramedullary Hematopoiesis ◽

Hematopoietic Progenitor Cells ◽

Hematopoietic Progenitor ◽

Hematopoietic Stem ◽

Hematological Abnormalities

Abstract Abstract 1296 Understanding the transcriptional mechanisms that control hematopoiesis and the interaction between hematopoietic stem cells and the bone marrow microenvironment in vivo is of considerable interest. We have previously shown that aged mice lacking the transcription factor NFATc2 develop bone marrow hypoplasia, anemia, and extramedullary hematopoiesis in spleen and liver. The proliferation and differentiation of NFATc2-deficient hematopoietic progenitor cells (HPC) ex vivo, however, was found to be intact. It remained therefore unclear whether the disturbed hematopoiesis in NFATc2-deficient mice was caused by the hematopoietic or the stroma component of the bone marrow hematopoietic niche. In the current study we dissected the relative contribution of hematopoietic and stroma cells to the phenotype of the NFATc2-deficent mice by transplanting immunomagnetically purified NFATc2-deficient (ko) HPCs to lethally irradiated wildtype (wt) mice, and vice versa. After a posttransplantation period of 6–8 months, peripheral blood, bone marrow as well as spleen and liver of the transplanted animals were analyzed and compared to wt and ko mice transplanted with control cells. Transplantation of NFATc2-deficient HPCs into wt recipients (ko → wt) induced similar hematological abnormalities as those occurring in non-transplanted ko mice or in ko mice transplanted with ko cells (ko → ko). Compared to wt mice transplanted with wt cells (wt → wt), ko → wt mice showed evidence of anemia, thrombocytopenia and a significantly reduced number of hematopoietic cells in their bone marrow. Likewise, ko → wt mice developped clear signs of extramedullary hematopoiesis in spleen and liver, which was not the case in wt → wt control animals. Our data demonstrate for the first time, that NFAT transcription factors directly regulate the intrinsic function of hematopoietic progenitor cells in vivo. The transcriptional targets for NFAT in these cells are yet unknown and are the focus of further investigations. Disclosures: No relevant conflicts of interest to declare.

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