High-dose therapy with iodine-131-labeled monoclonal antibody CC49 in patients with gastrointestinal cancers: a phase I trial.

1997 ◽  
Vol 15 (4) ◽  
pp. 1518-1528 ◽  
Author(s):  
M Tempero ◽  
P Leichner ◽  
G Dalrymple ◽  
K Harrison ◽  
S Augustine ◽  
...  
Keyword(s):  
Stem Cells ◽  
Monoclonal Antibody ◽  
Radiation Dose ◽  
Phase I ◽  
Hematopoietic Stem Cells ◽  
Phase I Trial ◽  
Gastrointestinal Cancers ◽  
Hematopoietic Stem ◽  
Iodine 131 ◽  
Absorbed Radiation Dose

PURPOSE A phase I trial that evaluated for extrahematopoietic toxicity was conducted with iodine-131 (131I) labeled monoclonal antibody (MAb) CC49. Correlative studies included pharmacokinetic and biodistribution analyses, estimates of absorbed radiation dose, and measurement of human antimonoclonal antibodies (HAMA). PATIENTS AND METHODS After collection and cryopreservation of hematopoietic stem cells, 15 patients with gastrointestinal cancers were administered a tracer dose of 131I-MAb CC49. Within 5 to 6 days, 14 patients (two to three per activity level) underwent a single treatment with 131I-MAb CC49 (50, 100, 150, 200, 250, and 300 mCi/m2). Biodistribution was determined using planar and single photon emission computer tomographic (SPECT) imaging. Pharmacokinetic studies were performed by measuring radioactivity in serial blood samples. In some patients, biopsies of metastases and related normal tissues were obtained for radioactivity measurements. Radiation dosimetry estimates were calculated using available biodistribution, pharmacokinetic, and tissue biopsy data. Toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria. RESULTS No dose-limiting extrahematopoietic toxicity was identified. Twelve patients experienced grade IV myelosuppression and met criteria for infusion of hematopoietic stem cells. Radioimmunolocalization was excellent. The T1/2 for 131I-MAb CC49 after diagnostic and therapeutic administration was 39.7 +/- 10.4 and 46.1 +/- 10.6 hours, respectively. The percent injected dose per killigram of tumor ranged from 0.2 to 2.1. Absorbed radiation dose in metastatic tumor sites ranged from 630 to 3300 cGy. CONCLUSION Although extrahematopoietic dose-limiting toxicity was neither observed or predicted, suboptimal absorbed dose estimates suggested that further escalation of 131I-MAb CC49 would not be useful. Future studies should focus on the use of radionuclides with high energy beta emissions, such as yttrium 90, and on strategies to optimize access of antibody to target antigens.

scholarly journals Resistance of human hematopoietic stem cells to a monoclonal antibody recognizing CD43

Stem Cells ◽  
1997 ◽  
Vol 15 (S2) ◽  
pp. 13-19 ◽  
Author(s):  
Vladimir Bazil ◽  
John E. Brandt ◽  
Ronald Hoffman
Keyword(s):  
Stem Cells ◽  
Monoclonal Antibody ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem

The Monoclonal Antibody W7C5 Defines a Novel Surface Antigen on Hematopoietic Stem Cells

2006 ◽  
Vol 938 (1) ◽  
pp. 175-183 ◽  
Author(s):  
CHRISTINA GIESERT ◽  
GRAÇA ALMEIDA-PORADA ◽  
ALEXANDER SCHEFFOLD ◽  
LOTHAR KANZ ◽  
ESMAIL D. ZANJANI ◽  
...  
Keyword(s):  
Stem Cells ◽  
Monoclonal Antibody ◽  
Hematopoietic Stem Cells ◽  
Surface Antigen ◽  
Hematopoietic Stem

scholarly journals Self-Renewal Pathways in Acute Myeloid Leukemia Stem Cells

2020 ◽  
Author(s):  
Jonason Yang ◽  
Nunki Hassan ◽  
Sheng Xiang Franklin Chen ◽  
Jayvee Datuin ◽  
Jenny Y. Wang
Keyword(s):  
Stem Cells ◽  
Monoclonal Antibody ◽  
Acute Myeloid Leukemia ◽  
Hematopoietic Stem Cells ◽  
Myeloid Leukemia ◽  
Leukemia Stem Cells ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Clinical Potential ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a difficult-to-treat blood cancer. A major challenge in treating patients with AML is relapse, which is caused by the persistence of leukemia stem cells (LSCs). Self-renewal is a defining property of LSCs and its deregulation is crucial for re-initiating a new leukemia after chemotherapy. Emerging therapeutic agents inhibiting aberrant self-renewal pathways, such as anti-RSPO3 monoclonal antibody discovered in our recent study, present significant clinical potential that may extend beyond the scope of leukemogenesis. In this chapter, we provide an overview of normal and malignant hematopoietic stem cells, discuss current treatments and limitations, and review key self-renewal pathways and potential therapeutic opportunities in AML.

scholarly journals Delayed activation of quiescent donor hematopoietic stem cells in the host marrow cavity by anti-host monoclonal antibody

Blood ◽  
1989 ◽  
Vol 74 (7) ◽  
pp. 2325-2329
Author(s):  
MW Sadelain ◽  
TG Wegmann
Keyword(s):  
Stem Cells ◽  
Monoclonal Antibody ◽  
Hematopoietic Stem Cells ◽  
Graft Failure ◽  
Cellular Proliferation ◽  
Conditioning Regimen ◽  
Host Cells ◽  
Hematopoietic Stem ◽  
F1 Hybrid ◽  
Marrow Cavity

To understand the mechanisms controlling hematopoietic engraftment in untreated, normal recipients, we investigated the fate of parental, donor hematopoietic stem cells after apparent graft failures in unconditioned F1 hybrid recipient mice. By administering an anti-host H- 2K monoclonal antibody, which targets host cells but spares the donor, we found that chimerism could be induced by delayed conditioning in animals with apparent graft failure. Engraftment kinetics in the host were followed by typing individual colony forming unit-- granulocyte/macrophage (CFU-GM) colonies for their origin and showed that parental cells, which were otherwise virtually absent, become promptly detectable within the marrow cavity after antibody administration. Marrow transfers to secondary hosts suggested that parental stem cells were present in the marrow of the untreated recipients. These findings establish that the elimination of all parental cells cannot account for the absence of peripheral blood chimerism in the unconditioned F1 hybrid recipient. Thus, viable and functional donor stem cells, which remain quiescent in the host marrow, can be activated by a selective conditioning regimen and can rescue an apparent graft failure. The selective activation in vivo of marked stem cells in an unirradiated microenvironment may be a useful system to study the regulation of cellular proliferation within the marrow cavity.

EB10, an Anti-FLT3 Monoclonal Antibody, Prolongs Survival and Reduces NOD/SCID Engraftment of AML Cell Lines and Primary Blasts.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2534-2534
Author(s):  
Obdulio Piloto ◽  
Mark Levis ◽  
Li Li ◽  
Bao Nguyen ◽  
Kyu-Tae Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Hematopoietic Stem Cells ◽  
Cell Lines ◽  
Leukemic Cells ◽  
Clinical Activity ◽  
Hematopoietic Stem ◽  
Juxtamembrane Region

Abstract The FLT3 receptor is a potential target in AML due to its role in leukemogenesis and its high degree of expression on blasts from approximately 90% of acute myeloid leukemia (AML) patients. In addition, mutant forms of FLT3, including internal tandem duplications (ITD) in the juxtamembrane region and point mutations in the kinase domain, constitutively activate FLT3 signaling. ITD mutations in particular are also associated with poor prognosis. A number of small molecule tyrosine kinase inhibitors (TKI) against FLT3 are currently in clinical trials and have shown some clinical activity. However, TKIs have various limitations, including their lack of specificity, which may produce toxicities, and can select for drug resistant cells. In an attempt to overcome some of these limitations and to generate new agents which might cooperate in targeting FLT3, we generated a fully humanized phage display monoclonal antibody (EB10). This antibody is capable of inhibiting both ligand-activated wild-type and, to a lesser degree, ligand-independent mutant FLT3 signaling. When EB10 is used to treat cells expressing activated FLT3, inhibition of downstream pathways including STAT5, AKT and MAPK are also frequently seen. EB10 treatment of cells expressing FLT3 in the presence of NK cells leads to antibody-dependent cell-mediated cytotoxicity (ADCC). EB10 treatment of NOD/SCID mice injected with FLT3 expressing AML cell lines or with primary AML blasts significantly prolongs survival and/or reduces engraftment of leukemic cells. EB10 proved efficacious in vivo against cells even when in vitro EB10 treatment did not significantly reduce FLT3 signaling. This indicates that ADCC may be the primary mechanism mediating cytotoxicity as opposed to direct FLT3 inhibition. In contrast to the effects on AML cell lines and primary samples, EB10 treatment did not significantly reduce NOD/SCID engraftment of normal human CD34+ hematopoietic stem cells. Anti-FLT3 antibodies, like EB10, may be a promising therapeutic agent that can specifically target malignant cells with limited toxicities against normal hematopoietic stem cells and should be considered for clinical trials.

Development of an anti-porcine CD34 monoclonal antibody that identifies hematopoietic stem cells

2007 ◽  
Vol 35 (1) ◽  
pp. 171-178 ◽  
Author(s):  
Daniel S. Layton ◽  
A. David G. Strom ◽  
Terri E. O'Neil ◽  
Mary M. Broadway ◽  
Garth L. Stephenson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Monoclonal Antibody ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem

57R2A, a newly established monoclonal antibody against mouse GPR56, marks long-term repopulating hematopoietic stem cells

2018 ◽  
Vol 59 ◽  
pp. 51-59.e1 ◽  
Author(s):  
Yusuke Tokoro ◽  
Yoko Yamada ◽  
Shin-ichiro Takayanagi ◽  
Tetsuya Hagiwara
Keyword(s):  
Stem Cells ◽  
Monoclonal Antibody ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem

Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results.

1998 ◽  
Vol 16 (6) ◽  
pp. 2202-2212 ◽  
Author(s):  
D D Bigner ◽  
M T Brown ◽  
A H Friedman ◽  
R E Coleman ◽  
G Akabani ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Phase I ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
Metastatic Brain Tumors ◽  
Tumor Patients ◽  
Iodine 131 ◽  
Dose Limiting Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD) of iodine 131 (131I)-labeled 81C6 monoclonal antibody (mAb) in brain tumor patients with surgically created resection cavities (SCRCs) and to identify any objective responses to this treatment. METHODS In this phase I trial, eligible patients were treated with a single injection of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating dosages of 131I (starting dose of 20 mCi with a 20-mCi escalation in subsequent cohorts) administered through an Ommaya reservoir in the SCRC. Patients were followed up for toxicity and response until death or for a minimum of 1 year after treatment. The SCRC patients, who were previously irradiated, were followed up without additional treatment unless progressive disease was identified. RESULTS We administered 36 treatments of 131I doses up to 120 mCi to 34 previously irradiated patients with recurrent or metastatic brain tumors. Dose-limiting toxicity was reached at 120 mCi and was limited to neurologic or hematologic toxicity. None of the patients treated with less than 120 mCi developed significant neurologic toxicity; one patient developed major hematologic toxicity (MHT). The estimated median survival for patients with glioblastoma multiforme (GBM) and for all patients was 56 and 60 weeks, respectively. CONCLUSION The MTD for administration of 131I-labeled 81C6 into the SCRCs of previously irradiated patients with recurrent primary or metastatic brain tumors was 100 mCi. The dose-limiting toxicity was neurologic toxicity. We are encouraged by the minimal toxicity and survival in this phase I trial. Radiolabeled mAbs may improve the current therapy for brain tumor patients.

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