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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute myeloid leukemia is an attractive disease to treat with radiolabeled antibodies because it is radiosensitive and antibody has ready access to the marrow cavity. In order to evaluate potentially useful radiolabeled antibodies against human acute myeloid leukemia, we have developed a nude mouse xenograft model using the human acute leukemia cell line, HEL. Mice with s.c. xenografts of HEL cells received infusions of radioiodinated anti-CD33 antibody. Examination of the biodistribution of the antibody showed that uptake in the s.c. tumor was maximal [16.9% injected dose (ID)/g at 1 h after infusion] following infusion of 1-10 micrograms of antibody and decreased following infusion of 100 micrograms (6.5% ID/g at 1 h) presumably as a result of saturation of antigen sites. The radiolabel was poorly retained in tumor (4.5-8.2% ID/g at 24 h after infusion). These results were consistent with in vitro studies demonstrating rapid internalization and catabolism of the anti-CD33 antibody. Uptake in tumor could be improved by using either a radiolabel that is retained intracellularly, 111In-DTPA (18.5% ID/g at 24 h), or by targeting a surface antigen that does not internalize upon antibody binding, CD45 (20.5% ID/g at 24 h). These results indicate that this model system will be useful in evaluating the interaction of radiolabeled antibodies with human acute myeloid leukemia cells in an in vivo setting.
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PMID:Localization of radiolabeled antimyeloid antibodies in a human acute leukemia xenograft tumor model. 153 Jul 69

Leukemia is well suited for monoclonal antibody therapy due to the accessible, differentiation antigens that characterize stages of maturation. In this paper, we describe the use of radio-labeled M195, a murine IgG2a, anti-CD33 monoclonal antibody, that can be used to effectively cytoreduce AML cells in relapsed patients when tumor burden is high; or to eliminate minimal residual disease and lengthen disease-free survival in patients with APL in remission. To decrease the likelihood of immunogenicity, a humanized IgG1 version of M195 was constructed that demonstrated a higher avidity and improved effector function than the parent murine antibody. Preliminary results of the first trial in AML using a humanized antibody showed specific bone marrow targeting without an immunogenic response.
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PMID:Anti-CD33 monoclonal antibody M195 for the therapy of myeloid leukemia. 812 21

Individual patient response to radioimmunotherapy is influenced by each patient's tumor burden, antibody clearance kinetics and the antibody-antigen interaction. In hematologic malignancies, wherein antibody access to tumor-cell associated antigen is rapid, mathematical modeling may provide a quantitative basis for assessing the impact of patient variability on a particular therapeutic protocol. Compartmental modeling analysis of antibody pharmacokinetics from a Phase I trial of 131I-labeled monoclonal antibody, M195 (anti-CD33), was used to estimate tumor burden in cases of acute myelogenous leukemia and the absorbed dose in liver, spleen and red marrow. The suitability of a nonlinear, two-compartment model for simulating M195 distribution in leukemia patients was evaluated by comparing model predictions with patient measurements. The results demonstrate that for directly accessible, hematologically distributed tumor cells, a two-compartment model fits observed patient biodistribution data and may provide information regarding both total tumor burden and tumor burden in the liver, spleen and red marrow. The model also provides biodistribution information for absorbed dose calculations to tissues that are not directly sampled. Such information is important in determining the optimum therapeutic dose of radiolabeled antibody for a given patient.
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PMID:Modeling and dosimetry of monoclonal antibody M195 (anti-CD33) in acute myelogenous leukemia. 844 Oct 34

Disease recurrence following successful bone marrow transplantation remains a major impediment in the management of patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). A variety of monoclonal antibodies that deliver drugs or toxins to the site of activity, have been used in an attempt to augment marrow transplantation. Examples of three different monoclonal antibody techniques (naked antibody, drug antibody conjugations, and radiolabeled antibodies) are discussed. CD33 is an attractive antigen to use as a target for treating AML because it is present on most AML cells. Naked antibodies are limited in their ability to kill tumor cells, although studies to date suggest there may be a role in antileukemic therapy for unlabeled anti-CD33 humanized M195 antibody after the tumor burden has been reduced by chemotherapy. Calicheamicin, a novel and toxic drug moiety conjugated to anti-CD33 antibody, is currently under investigation in patients with refractory or relapsed AML. Results from a Phase I investigation were encouraging. Three different radiolabeled monoclonal antibodies have been evaluated in Phase I/II studies--131I-labeled anti-CD33 (p67) antibody, 213Bi-labeled humanized M195 antibody, and 131I-anti-CD45 antibody. CD45 is a cell-surface antigen broadly expressed by all circulating leukocytes and lymphocytes. Initial studies demonstrated that substantially greater doses of radiation could be delivered to targeted organs compared with nontargeted organs using 131I-anti-CD45 antibody. This approach offers the potential for augmenting leukemia therapy without increased risk of toxicity.
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PMID:Immunotherapy in acute myelogenous leukemia and myelodysplastic syndrome. 977 93

Immunotherapy using bispecific antibodies (BsAb) to direct immune effector cells toward target tumor cells has been shown to be effective in a number of studies. Several immune trigger molecules have been characterized. Among them, FcgammaRI appears to play an important role in antibody-dependent cellular cytotoxicity. It is expressed mainly on monocytes, macrophages, and neutrophils under certain clinical situations. The expression of FcgammaRI can be regulated by a variety of cytokines, primarily by IFN-gamma. Recent studies have shown that granulocyte-colony-stimulating factor (G-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) can increase the number of the FcgammaRI-positive monocytes, increase the expression of FcgammaRI on circulating neutrophils after in vivo infusion, and greatly enhance the cytotoxic activity of circulating neutrophils. CD33 is a glycoprotein expressed on the cell surface of mature monocytes, myeloid progenitor cells, and myeloid leukemic blasts, but not on the earliest hematopoietic progenitor cells and other normal tissues. Herein, we report the construction of a BsAb, 251 x 22, by conjugating an anti-CD33 mAb (mAb 251) to an anti-FcgammaRI mAb (mAb 22). The BsAb 251 x 22 is capable of enhancing the cytotoxicity of several leukemia cell lines by cytokine-activated monocytes. Our data also show that G-CSF- and GM-CSF-stimulated monocytes can mediate cytotoxicity of target leukemia cells comparable to that of IFN-gamma-stimulated monocytes. The expression of FcgammaRI on monocytes after 24-h in vitro incubation with G-CSF and GM-CSF was increased, although not significantly. Prolonged incubation of monocytes with G-CSF for 48 h significantly increased the FcgammaRI expression. Because humanized anti-CD33 and anti-FcgammaRI mAb are available, and because GM-CSF and G-CSF have been used widely for patients after chemotherapy to stimulate the recovery of myeloid hematopoiesis, additional clinical development of this project is feasible. A BsAb comprised of humanized anti-CD33 and anti-FcgammaRI could have clinical application in the treatment of myeloid leukemia, especially in the management of minimal residual disease.
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PMID:Monocyte-mediated lysis of acute myeloid leukemia cells in the presence of the bispecific antibody 251 x 22 (anti-CD33 x anti-CD64). 981 27

Monoclonal antibody-based therapeutics are beginning to realize the promise that was predicted with the advent of the core technology more than 20 years ago. Antibody-based therapeutics targeting tumor cell surface antigens such as B-cell idiotypes, CD20 on malignant B cells, CD33 on leukemic blasts, and HER2/neu on breast cancer cells have shown efficacy in clinical trials. Multiple antibody-based strategies have shown promising efficacy in recent clinical trials. Unconjugated immunoglobulins directed against CD20 induce partial and complete responses in up to 50% of patients with advanced, indolent non-Hodgkin's lymphoma When such antibodies are conjugated to appropriate radionuclides and administered in therapeutic doses, the proportions of complete and overall responses increase considerably. Conjugates composed of anti-CD33 antibodies and the chemotherapy agent, calicheamicin, show promising activity in patients with relapsed or refractory acute myelogenous leukemia. Treatment of patients with advanced breast cancer using the anti-HER2/neu antibody trastuzumab (Herceptin; Genentech, San Francisco) leads to objective responses in some patients whose tumors overexpress the HER2/neu oncoprotein. These exciting results justify recent enthusiasm for continued efforts to refine existing approaches and to develop new antibody-based strategies to treat human malignancy.
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PMID:An overview of monoclonal antibody therapy of cancer. 1048 93

Monoclonal antibody therapy is beginning to realize its promise. Efficacy has been seen in clinical trials using antibodies that target tumor cell surface antigens such as B-cell idiotypes, CD20 on malignant B cells, CD33 on leukemic blasts, and HER2/neu on breast cancer. Unconjugated immunoglobulins directed against CD20 induce partial and complete responses in up to 50% of patients with advanced, indolent non-Hodgkin's lymphoma. When such antibodies are conjugated to radionuclides, complete and overall response rates increase. Conjugates composed of anti-CD33 antibodies and the chemotherapy agent, calicheamicin, show promising activity in patients with relapsed or refractory acute myelogenous leukemia Treatment of patients with advanced breast cancer using the anti-HER2/neu antibody, trastuzumab (Herceptin; Genentech, San Francisco, CA) leads to objective responses in some patients with overexpression of the HER2/neu oncoprotein. These exciting results provide a basis for further refinement of the existing approaches to develop new antibody-based cancer therapy strategies.
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PMID:Monoclonal antibody therapy of cancer. 1056 Oct 17

Monoclonal antibodies (mAbs) have become an important modality for cancer therapy. A genetically engineered, humanized anti-CD33 antibody HuM195 has demonstrated activity against over relapsed acute myelogenous leukemia (AML) and against minimal residual disease in acute promyelocytic leukemia (APL). Radioimmunotherapy with beta (beta) particle-emitting isotopes has produced significant responses while minimizing radiation exposure to normal tissues in both nonmyeloablative and myeloablative regimens. Targeted alpha (alpha) particle therapy with 213Bi-labeled HuM195 offers the possibility of more selective tumor cell kill. Additionally, directed chemotherapy using an anti-CD33-calicheamicin conjugate (CMA-676) has produced remissions in patients with relapsed AML.
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PMID:Antibody therapy of acute myelogenous leukemia. 1104 Oct 16

The purpose of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin (Mylotarg; Wyeth-Ayerst Laboratories, St. Davids, PA) in patients with acute myeloid leukemia (AML) in first relapse. Gemtuzumab ozogamicin is an antibody-chemotherapeutic conjugate characterized as antibody-targeted chemotherapy, consisting of an engineered human anti-CD33 antibody (hP67.6) linked to a potent cytotoxic agent, N-acetyl-gamma calicheamicin DMH. The pharmacokinetics of gemtuzumab ozogamicin was evaluated in 59 adult AML patients in first relapse, enrolled in a phase II study. Plasma was collected following each dose at specified times, and the pharmacokinetics was characterized by measures of hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. After administration of the first 9 mg/m2 dose of gemtuzumab ozogamicin, the pharmacokinetic parameters (mean +/- SD) of hP67.6 following the first dose were as follows: peak plasma concentration, 2.86 +/- 1.35 mg/L; AUC, 123 +/- 105 mg x h/L; t 1/2, 72.4 +/- 42.0 hours; and clearance, 0.265 +/- 0.229L/h. Increased concentrations were observed after the second dose and are believed to be due to a decrease in clearance by CD33-positive blast cells, a result of the reduced tumor burden following the first dose. The concentration profiles of calicheamicin followed the same time course as hP67.6, evidence that calicheamicin remained conjugated to the antibody and delivered to leukemic cells. No relationship was found between plasma concentration and response at the recommended dose. The pharmacokinetics of gemtuzumab ozogamicin has been characterized in AML patients receiving doses at the proposed therapeutic level.
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PMID:Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted chemotherapy agent for the treatment of patients with acute myeloid leukemia in first relapse. 1169 53

The approval of monoclonal antibodies for therapy of hematologic malignacies (Rituxan, Mylotarg, Campath) renewed the interest in antibodies as potential new treatment options for cancer patients. Antibodies are effective in inhibiting tumor cell growth , inducing apoptosis, and activating host effector mechanisms for tumor cell killing. Monoclonal antibodies can be clinically effective as monotherapy, as targeting agents delivering either potent cytotoxic drugs or radionuclides as well as in combination with conventional chemotherapies. Advances in antibody engineering provided new capabilities to reduce immunogenicity, alter half life, increase effector functions, and increase tumor targeting for optimal therapeutic modalities requiring chronic dosing regimens. During the next decade, as new tumor-specific surface antigens are discovered and the linkage between genes and function is better understood, new targets will be identified for regulating tumor cell growth by engineered antibodies with agonist or antagonist activity. Additionally, antibody engineering will allow for more efficient radionuclide or cytotoxic drug targeting or lead to more selective activation of relevant host effector mechanisms, leading to a safe and effective therapy of cancer.
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PMID:Future approaches for treating hematologic disease. 1176 18


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