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Drugs Jun 1989Muromonab CD3 (Orthoclone OKT3, Orthoclone, OKT3) is the first monoclonal antibody to become available for therapy in humans. In effect it blocks all cytotoxic T cell... (Review)
Review
Muromonab CD3 (Orthoclone OKT3, Orthoclone, OKT3) is the first monoclonal antibody to become available for therapy in humans. In effect it blocks all cytotoxic T cell function. Clinical trials show that muromonab CD3 is effective in reversing acute renal, hepatic, cardiac and combined kidney-pancreas transplant rejection episodes. It has also been shown to be effective in the treatment of rejections resistant to conventional treatment. As such it offers a significant alternative when no other therapeutic option remains open. Other clinical trials have shown that muromonab CD3 is more effective than high-dose corticosteroids in reversing first episodes of acute renal and hepatic rejection. Additionally, it appears effective as a prophylactic treatment against acute renal and cardiac rejection in the immediate post-transplantation period. Preliminary studies also indicate that it may be effective in preventing or reversing graft-versus-host disease in bone marrow transplant patients. The development of neutralising antibodies may limit the effectiveness of a second course of muromonab CD3 therapy in some patients. In conclusion, muromonab CD3 offers a significant new approach to immunosuppressive therapy and has provided a valuable therapeutic alternative for the treatment of acute solid organ transplant rejection.
Topics: Animals; Antibodies, Monoclonal; Graft Rejection; Humans; Muromonab-CD3
PubMed: 2503348
DOI: 10.2165/00003495-198937060-00004 -
Nihon Rinsho. Japanese Journal of... May 2005
Review
Topics: Acute Disease; Animals; Antibodies, Monoclonal; CD3 Complex; Cytomegalovirus Infections; Graft Rejection; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Transplantation; Muromonab-CD3; Pulmonary Edema; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 15954439
DOI: No ID Found -
Drugs May 1996The murine monoclonal antibody muromonab CD3 (OKT3) is directed against the CD3 antigen on peripheral human T cells and effectively blocks all T cell function.... (Review)
Review
The murine monoclonal antibody muromonab CD3 (OKT3) is directed against the CD3 antigen on peripheral human T cells and effectively blocks all T cell function. Prophylaxis with muromonab CD3 (5mg intravenously once daily for 10 to 14 days) as induction therapy together with corticosteroids, azathioprine and delayed cyclosporin (sequential therapy) optimises early graft function by delaying the potentially nephrotoxic and hepatotoxic effects of cyclosporin until graft function is established. Although clinical data are limited (by inconsistencies in trial design and trial size), prophylactic muromonab CD3-based sequential therapy is significantly more effective than standard triple therapy in the prophylaxis of allograft rejection in renal and hepatic, but not cardiac, transplant recipients. Benefits are particularly notable in patients with delayed graft function. No significant between-treatment differences in patient survival have been observed. The overall efficacy of muromonab CD3- and polyclonal-based prophylactic regimens appears to be similar, although results vary between investigators and confirmation is needed. An anti-interleukin-2 monoclonal antibody-based prophylactic regimen improved graft and patient survival compared with muromonab CD3-based prophylaxis in hepatic transplant recipients. Antimuromonab CD3 antibodies may develop; however, muromonab CD3 may be successfully reused in patients with low titres. Preliminary pharmacoeconomic data suggest that mean drug costs are greater with quadruple immunosuppressive regimens containing muromonab CD3, antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) than with triple therapy. Drug costs with prophylactic muromonab CD3-based regimens were similar or greater than those with polyclonal-based protocols. The first doses of muromonab CD3 are associated with the 'cytokine-release syndrome'. More severe first-dose events include aseptic meningitis, intragraft thromboses, seizures and potentially fatal pulmonary oedema. The incidence and/or severity of cytomegalovirus infection with prophylactic muromonab CD3 based immunosuppression is similar to or greater than that with triple therapy and ATG- or ALG-based regimens. However, the risk of infection and also the observed increase in lymphoproliferative disorders appears to be related to the degree of immunosuppression rather than to the drug itself Thus, sequential muromonab CD3-based therapy is more effective than standard triple therapy (in renal and hepatic transplant recipients) and appears to be similar to that of polyclonal-based regimens in the prophylaxis of transplant rejection. Although the routine use of prophylactic muromonab CD3 in low-risk patients with primary graft function does not appear to be justified, prophylactic muromonab CD3-based therapy has a role in patients at high risk of rejection.
Topics: Animals; Graft Rejection; Humans; Immunosuppressive Agents; Muromonab-CD3
PubMed: 8861551
DOI: 10.2165/00003495-199651050-00010 -
The Annals of Pharmacotherapy Nov 1997To review the recently published medical literature for the practical and efficient use of muromonab-CD3 (OKT-3) and antithymocyte globulin (ATG) in renal... (Review)
Review
OBJECTIVE
To review the recently published medical literature for the practical and efficient use of muromonab-CD3 (OKT-3) and antithymocyte globulin (ATG) in renal transplantation.
DATA SOURCES
MEDLINE and EMBASE were searched (1985-February 1996). Key words used were antithymocyte globulin (ATG, Atgam), muromonab-CD3 (OKT-3, Orthoclone), and kidney transplantation. Thereafter, the search was restricted to English-language articles, clinical trials, and human studies.
STUDY SELECTION AND DATA EXTRACTION
The search was reviewed for articles of interest, and pertinent references from these articles were further reviewed to supplement the initial search. The review focused on antibody therapy as induction and/or rejection therapy in renal transplantation.
DATA SYNTHESIS
Although ATG and OKT-3 are effective in delaying and reducing the occurrence of acute rejection, their impact on long-term graft survival has not been established. Improved graft survival has, however, been demonstrated in patients at high risk for rejection. These risks are described in the review. As first-line or steroid-resistant rejection therapy, ATG and OKT-3 have proven efficacious. Some studies have shown improved graft survival with OKT-3. Although serious infections may occur, OKT-3 has been shown to be effective in reversing rejections resistant to both steroids and ATG. Therefore, reserving OKT-3 for steroid- or ATG-resistant rejections may be preferred over the first-line use of OKT-3, which is limited by the development of antimurine antibodies with subsequent uses. However, the benefits of first-line antibody therapy may outweigh the risks of developing these antibodies in patients for whom high-dose steroids may not be the most appropriate treatment. Other factors that need to be considered are adverse effects, which appear to be lower with ATG, cost, and total hospital charges. The accuracy of treatment outcomes analysis among these studies is limited by variations in the immunosuppressive regimens of the study centers, doses of concomitant therapies, use of prophylactic antibiotics, and time to follow-up.
CONCLUSIONS
While important benefits are realized from using antibody therapies in renal transplantation, their use is often associated with excess immunosuppression and increased treatment costs. Despite encouraging results from published trials, questions regarding the extent of their prophylactic use and impact on long-term outcomes need to be answered. The current literature contains no prospective, controlled, randomized comparisons of OKT-3 and ATG with standardized regimens of conventional immunosuppressive agents and antirejection protocols. The majority of studies use OKT-3 as part of the treatment protocol. Well-designed studies using ATG are lacking. Further research is needed to refine treatment protocols for ATG and OKT-3 to determine the optimal timing and dosing for these agents.
Topics: Antilymphocyte Serum; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Muromonab-CD3; T-Lymphocytes
PubMed: 9391693
DOI: 10.1177/106002809703101115 -
Journal of Transplant Coordination :... Sep 1996Many important advances in transplantation have been made during the last decade. The introduction of Orthoclone OKT3 into clinical trials and its subsequent approval by... (Review)
Review
Many important advances in transplantation have been made during the last decade. The introduction of Orthoclone OKT3 into clinical trials and its subsequent approval by the Food and Drug Administration in 1985 for use as an antirejection agent for renal transplantation were landmarks in the field of clinical transplantation of solid organs. In the decade since the approval of OKT3 for clinical use, much has been learned and written about OKT3. OKT3 now is considered a safe and effective agent for prophylaxis and first-line treatment of acute rejection of solid organ allografts. In this article, the development and use of OKT3 over the last 10 years, as well as the present status and future implications of immune therapy with OKT3, are reviewed.
Topics: Clinical Protocols; Drug Monitoring; Graft Rejection; Humans; Immunosuppressive Agents; Muromonab-CD3; Transplantation Immunology
PubMed: 9188368
DOI: 10.7182/prtr.1.6.3.8145l3u185493182 -
Toxicology Dec 1995Orthoclone OKT3 is a very powerful immunosuppressive drug marketed by Laboratory Cilag and the first monoclonal murine antibody to become available for therapy in... (Review)
Review
Orthoclone OKT3 is a very powerful immunosuppressive drug marketed by Laboratory Cilag and the first monoclonal murine antibody to become available for therapy in humans. It is indicated in acute allograft rejection treatment and its side-effects are strongly linked with its mechanism of action, ORT/OKT3 is an Ig2a immunoglobulin produced by hybridoma technique that recognizes, binds and blocks the CD3 complex of the T-cell receptor. Two types of side-effects may occur that are either the consequences of overimmunosuppression or activation of immune system, since ORT/OKT3 behaves as a foreign antigen. This report is a bibliographic review of the suspected side-effects of this product.
Topics: Animals; Binding, Competitive; Blood Coagulation Disorders; Communicable Diseases; Cytokines; Graft Rejection; Humans; Immune System; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Neoplasms; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 8638282
DOI: 10.1016/0300-483x(95)03123-w -
Lancet (London, England) Aug 2011Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab.
METHODS
In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A(1c) (HbA(1C)) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697.
FINDINGS
763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group).
INTERPRETATION
Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children.
FUNDING
MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.
Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; C-Peptide; CD3 Complex; Canada; Child; Diabetes Mellitus, Type 1; Drug Administration Schedule; Drug Eruptions; Europe; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; India; Insulin; Insulin-Secreting Cells; Israel; Male; Mexico; Muromonab-CD3; Treatment Outcome; United States; Young Adult
PubMed: 21719095
DOI: 10.1016/S0140-6736(11)60931-8 -
Journal of Hepato-biliary-pancreatic... Nov 2010Refractory rejections still occur in the liver transplantation (LT) field. The aim of this study was to investigate significant factors for the introduction of therapy... (Comparative Study)
Comparative Study
BACKGROUND/PURPOSE
Refractory rejections still occur in the liver transplantation (LT) field. The aim of this study was to investigate significant factors for the introduction of therapy with muromonab-CD3 (MCD3) after LT.
METHODS
A total of 1415 LT patients were retrospectively evaluated, and 11 of the recipients received MCD3 therapy because of steroid-resistant rejections. The clinical factors before LT and before MCD3 therapy were investigated.
RESULTS
The recipients were retrospectively divided into two groups based on responses to MCD3 therapy, including their clinical courses after MCD3 therapy and their outcomes. The MCD3 therapy had positive effects in LT recipients with the following four factors: low score of model for end-stage liver disease or pediatric end-stage liver disease; earlier time point of the first incidence of rejection; more frequent steroid pulse therapy (SPT) within 2 weeks after LT; and the expression of CD3 in the peripheral blood before MCD3 introduction.
CONCLUSION
Optimal induction of MCD3 triggered recovery from refractory rejections, especially in LT recipients in a stable condition, but not in those in a critical or compromised condition.
Topics: Adolescent; Adult; Biopsy, Needle; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Flow Cytometry; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infant; Japan; Liver Diseases; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Muromonab-CD3; Retrospective Studies; Time Factors; Treatment Outcome; Young Adult
PubMed: 20458505
DOI: 10.1007/s00534-010-0288-y -
DICP : the Annals of Pharmacotherapy Feb 1991
Review
Topics: Antibodies, Monoclonal; Humans; Immunosuppression Therapy; Meningitis, Aseptic; Muromonab-CD3
PubMed: 1905440
DOI: No ID Found -
Journal of Child Neurology Nov 2001Muromonab-CD3 is widely used for immunosuppression in patients undergoing solid organ transplant. We report two siblings with oligomeganephronia and end-stage renal...
Muromonab-CD3 is widely used for immunosuppression in patients undergoing solid organ transplant. We report two siblings with oligomeganephronia and end-stage renal disease who developed encephalopathy and seizures from muromonab-CD3 following renal transplant. The first case is a 13-year-old girl who developed encephalopathy, seizure, and triparesis following renal transplant while muromonab-CD3 was used for immunosuppression. The second case was the 6-year-old sister of the first case, who also developed recurrent focal seizures while she was on muromonab-CD3 for renal transplant immunosuppression. In both cases, a sequential brain magnetic resonance image (MRI) showed progression of abnormalities from the cerebral cortex to the white matter. In the first case, the MRI normalized after muromonab-CD3 was discontinued. In the second case, the patient developed a leukoencephalopathy following cyclosporin administration. The pathophysiology of muromonab-CD3 encephalopathy is believed to be a disturbance to the blood-brain barrier mediated by cytokine release from lymphocyte stimulation by muromonab-CD3. Because the major histocompatibility complex genes are known to regulate cytokine responses, it is possible that the excessive production of cytokines that causes encephalopathy may occur in patients who share close major histocompatibility complex genes. Muromonab-CD3 in a patient whose sibling has developed cerebral complications from its use should be administered with caution. The second case suggests that muromonab-CD3 encephalopathy predisposes patients to develop cyclosporin neurotoxicity. Because the pathogenesis of muromonab-CD3 encephalopathy and cyclosporin-related cerebral complications are both potentially mediated through a disturbance of the blood-brain barrier, it is possible that one agent may predispose a patient to the complication of the other.
Topics: Adolescent; Child; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnetic Resonance Imaging; Muromonab-CD3; Neurotoxicity Syndromes; Nuclear Family; Time Factors
PubMed: 11732768
DOI: 10.1177/08830738010160110801