Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Leukemic blast cells express the CD33 antigen in most patients with acute myeloid leukemia (AML), but this antigen is not expressed by hematopoietic stem cells. We conducted a study to determine whether normal hematopoiesis could be restored in patients with AML by selective ablation of cells expressing the CD33 antigen. In a dose escalation study, 40 patients with relapsed or refractory CD33(+) AML were treated with an immunoconjugate (CMA-676) consisting of humanized anti-CD33 antibody linked to the potent antitumor antibiotic calicheamicin. The capacity of leukemic cells to efflux 3, 3'-diethyloxacarbocyanine iodide (DiOC2) was used to estimate pretreatment functional drug resistance. Leukemia was eliminated from the blood and marrow of 8 (20%) of the 40 patients; blood counts returned to normal in three (8%) patients. A high rate of clinical response was observed in leukemias characterized by low dye efflux in vitro. Infusions of CMA-676 were generally well tolerated, and a postinfusion syndrome of fever and chills was the most common toxic effect. Two patients who were treated at the highest dose level (9 mg/m2) were neutropenic >5 weeks after the last dose of CMA-676. These results show that an immunoconjugate targeted to CD33 can selectively ablate malignant hematopoiesis in some patients with AML.
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PMID:Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. 1033 74

The availability of antibodies reactive with antigens expressed only by hematopoietic cells has provided clinical investigators with new tools for use in developing therapies for acute myeloid leukemia (AML). Studies performed to date have investigated the use of such antibodies in an unmodified state, combined with potent chemicals to form immunotoxins or combined with various radionuclides. Encouraging results have been obtained in all three settings. The CD33 antigen is expressed by most early myeloid cells and by more than 90% of cases of AML but is not present on the hematopoietic stem cell. Initial in vivo studies with an unmodified murine anti-CD33 antibody in patients with AML demonstrated that the antibody quickly bound to leukemia cells and that the antigen-antibody complex rapidly internalized following cell binding. However, when administered to patients with overt leukemia, unmodified antibody resulted in only brief decreases in peripheral blast counts, not in sustained response. A number of CD33-based immunotoxins have also been studied, including a calicheamicin conjugate, CMA-676. In a phase I dose-escalation study of patients with refractory AML, CMA-676 was well tolerated with the only consistent toxicities being the development of fevers and chills several hours after administration and the subsequent development of temporary pancytopenia. A phase III study has been performed involving patients with AML in first relapse. An interim analysis of the first 23 patients found that in 10, treatment with CMA-676 resulted in elimination of blasts from peripheral blood and marrow. This was achieved with far less toxicity than seen with standard chemotherapy. Radiolabeled antibodies have been explored as a stand-alone treatment or in the context of bone marrow transplantation. In an effort to avoid toxicities to normal stem cells residing alongside leukemic cells in the marrow, studies have been performed to explore the use of 231Bi conjugated to an anti-CD33 monoclonal antibody. The short path length of this alpha-emitter could theoretically allow killing of the targeted leukemic cell without damage to normal neighbors. Of 12 patients with recurrent AML who received this drug, eight had reductions in marrow and peripheral blast counts. Complete remissions (CRs) have not been observed to date. Another set of studies focused on the use of radiolabeled antibodies to deliver radiation specifically to sites of leukemia as part of a transplant preparative regimen. In a phase I clinical trial, 131I-labeled anti-CD45 antibody delivered at least threefold more radiotherapy to spleen and marrow than any other organ. In a phase II trial, among 25 AML patients in first remission, 22 are alive and in remission for periods up to 6 years.
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PMID:Antibody-targeted therapy for myeloid leukemia. 1053 Jul 10

There are several competing models of stem cell involvement in acute myeloid leukemia (AML). At issue is whether the disease origin is in the pluripotent stem cell or whether it arises later in a more mature progenitor cell. The observation that the CD33 antigen is present on AML cells, and on normal and leukemic progenitors, suggested that one might be able to target these cells while sparing the normal stem cells. Response rates of acute myelogenous leukemia patients treated with the newly developed anti-CD33 antibody-calicheamicin conjugate suggest that at least for a proportion of patients early precursors responsible for re-establishing hematopoiesis are likely to be predominantly normal in origin.
Leukemia 2000 Mar
PMID:Monoclonal antibodies to the myeloid stem cells: therapeutic implications of CMA-676, a humanized anti-CD33 antibody calicheamicin conjugate. 1072 Jan 44

Calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, CMA-676, has recently been introduced to clinics as a promising drug to treat patients with acute myeloid leukemia (AML) in relapse. However, the mechanism of action of CMA-676 has not been well elucidated. The cytotoxic effect of CMA-676 on HL60, NOMO-1, NB4, NKM-1, K562, Daudi, and the multidrug-resistant sublines, NOMO-1/ADR and NB4/MDR, was investigated by cell cycle distribution and morphology. These studies were done by a video-microscopic system, DNA fragmentation, dye exclusion and 3H-thymidine uptake after analysis of CD33, CD34, P-glycoprotein (P-gp), multidrug resistance (MDR)-associated protein and lung-related protein on these cells. A dose-dependent, selective cytotoxic effect of CMA-676 was observed in cell lines that expressed CD33, and was dependent on the amount of CD33 and the proliferative speed of the cells. Sensitive cells were temporally arrested at the G2/M phase before undergoing morphological changes. CMA-676 is not effective on P-gp-expressing multidrug-resistant sublines compared with parental cell lines. MDR modifiers, MS209 and PSC833, restored the cytotoxic effect of CMA-676 in P-gp-expressing sublines. CMA-676 is a promising agent in the treatment of patients with AML that expresses CD33. The combined use of CMA-676 and MDR modifiers may increase the selective cytotoxic effect in multidrug-resistant AML.
Leukemia 2000 Aug
PMID:Calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (gemtuzumab zogamicin, CMA-676) shows cytocidal effect on CD33-positive leukemia cell lines, but is inactive on P-glycoprotein-expressing sublines. 1094 40

Although the standard approach to myeloid leukaemias remains chemotherapy, the agents currently available rarely result in cure. Recent advances in understanding the biology of these disorders have lead to the development of targeted treatment strategies. In acute promyelocytic leukaemia (APL), all-trans retinoic acid (ATRA), sodium phenylbutyrate and arsenic trioxide are agents which either induce differentiation or apoptosis and have been used to successfully achieve remission. The tyrosine kinase inhibitor, STI-571, antisense oligonucleotides, and bcr-abl vaccines are strategies which focus on the oncogenic events in chronic myelogenous leukaemia (CML). Two anti-CD33 monoclonal antibody conjugates, Y90-HuM195 and CMA-676, have been used in acute myelogenous leukaemia (AML) and have shown some efficacy. Although the preliminary results with these targeted therapies are promising, further studies are needed to establish them as effective, less toxic alternatives to the current standard of care.
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PMID:Targeted therapies for the myeloid leukaemias. 1106 Jul 36

A promising new development in cancer treatment is antibody-targeted chemotherapy (ATC), a strategy that allows antineoplastic drugs to be delivered to malignant cells but not most normal ones, possibly resulting in fewer side effects. A new drug, gemtuzumab ozogamicin (Mylotarg), employs the ATC strategy and has been approved by the Food and Drug Administration for the treatment of CD33+ acute myeloid leukemia (AML) in patients who are 60 years of age and older, are in their first relapse, and are not considered candidates for cytotoxic chemotherapy. AML is the second most frequent type of leukemia in adults and is associated with a poor prognosis. If untreated, death usually occurs within a few months of diagnosis.
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PMID:Antibody-targeted chemotherapy for the treatment of relapsed acute myeloid leukemia. 1118 67

Curative therapy for acute myeloid leukemia (AML) remains unsatisfactory. However, three recent advances may play an important role in determining how AML is treated in the near future. First, the development of targeted antibody therapy using the anti-CD33-calicheamicin conjugate (gemtuzumab ozogamicin, Mylotarg) represents a novel targeted approach to the killing of leukemia cells. Second, modern molecular methods have improved our ability to identify minimal residual disease (MRD) in patients who appear to be in remission. These methods will allow physicians to tailor therapy, offering, for example, more intensive therapy to patients who harbor MRD. Lastly, the development of microarray gene expression technology allows for the simultaneous study of thousands of genes. With this technology, we may determine the genes responsible for the biological properties of treatment response and relapse in leukemia patients.
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PMID:New developments in the treatment of acute myeloid leukemia. 1119 6

Conventional cytotoxic management of leukemia has less than optimal results, while it is associated with life-threatening toxic effects due to lack of specificity for hematopoietic cells. Therefore, novel therapeutic strategies with monoclonal antibodies (MAbs) are being explored for delivering chemotherapy or radiation directly to malignant cells. Recently, anti-CD33 antibodies have been engineered to target malignant myeloid and immature normal cells and have been used to deliver cytotoxic agents or radiation to leukemic cells. 131I-labeled anti-CD45 antibodies are used in combination with conventional chemotherapy in leukemic patients receiving marrow transplantation. Additionally, the emergence of Rituximab (against CD20) and Campath-1H (against CD52) for chronic lymphocytic leukemia (CLL) has provided encouraging clinical results for the prognosis of this disease. In conclusion, there has been ongoing research indicating that the approach of patients with leukemia through the application of MAbs might be safer and more effective than current treatment. Considering the preliminary data, MAb therapy appears to be a new, promising weapon in the oncologist's armentarium.
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PMID:The development of monoclonal antibody therapy in leukemias. 1146 62

Bispecific anti-CD33 x anti-CD64 antibody (BsAb) directly inhibited proliferation and colony formation of human acute myeloid leukemia cell lines, without affecting the function of normal monocytes. Addition of BsAb to normal monocytes induced tyrosine phosphorylation of Cbl and Vav, association of these molecules with CD33, and downstream signaling. In leukemia cells that were insensitive to BsAb treatment, Vav and Cbl were constitutively phosphorylated and, therefore, constitutively associated with CD33. Direct growth inhibition is an additional mechanism by which BsAb may be useful in the therapy of AML.
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PMID:Direct effect of bispecific anti-CD33 x anti-CD64 antibody on proliferation and signaling in myeloid cells. 1168 86


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