Drugs June 1989, Volume 37, Issue 6, pp 871-899

Muromonab CD3
Peter A. Todd, Rex N. Brogden

Summary
Synopsis
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.

Pharmacology
Muromonab CD3 is a purified murine monoclonal antibody directed against the CD3 antigen, which is found on all mature human T cells. It reacts only with human T cells and those from higher primates such as chimpanzee but not with other human tissues. It is an IgG2a immunoglobulin which binds to one of the subunits of the CD3 complex, a part of the T cell receptor, thereby blocking function of the adjacent Ti complex involved in recognition of foreign antigens by the T cell. Within minutes of intravenous muromonab CD3 administration there is a rapid clearance of CD3 +cells from circulation which is complete within 1 hour. The T cells are believed to be, at least in part, opsonised and removed from circulation by the reticuloendothelial system. In addition, the CD3 antigen is modulated from the surface of some T cells. The various mediators released after binding of muromonab CD3 to peripheral T cells is thought to contribute to the side effects frequently observed in patients after the first dose. In effect, muromonab CD3 blocks all T cell function including both the induction and effector phases of cell-mediated lympholysis and T cell proliferative responses to both class I and II major histocompatibility complex antigens. During repeated administration of muromonab CD3 once daily, CD3 + cells remain undetectable although increasing numbers may be seen in some patients during the second week of administration, possibly as a result of the development of neutralising antibodies. CD3+ cells return rapidly to normal levels after withdrawal of the drug. Concomitant with the initial depletion of CD3 +cells, there is a consequent depletion of CD4+, CD8+ and CD11+ cells, but after a few days treatment increasing numbers of CD3 CD4+ and CD3 CD8+ cells appear. These cells have had the CD3 antigen modulated and are thus non-functional. Before the concomitant administration of cyclosporin, the majority of patients developed anti-muromonab CD3 antibodies following therapy. Two types of antibody may develop: an anti-mouse isotype and an anti-idiotype. The anti-mouse isotype develops less often and apparently does not affect the ability to readminister the drug. Unfortunately, anti-idiotypic antibodies can develop more frequently and may neutralise the effect of muromonab CD3. The ability to administer a second course of treatment may be limited in some patients, although there are reports of patients successfully receiving a second course of muromonab CD3. Mean trough steady-state plasma concentrations of muromonab CD3 are about 0.9 mg/L after about 2 or 3 oncedaily intravenous doses of muromonab CD3 5mg. This plasma concentration is generally believed to be adequate to block cytotoxic T cell function based on in vitro studies.

Therapeutic Studies
Clinical studies have shown that muromonab CD3 administered for 10 to 14 days reverses acute renal, hepatic, combined kidney-pancreas and cardiac transplant cellular rejection episodes resistant to conventional treatment with high-dose steroids and/or antithymocyte globulin in about 80, 75, 85 and 95% of cases, respectively. As such it offers a significant therapeutic alternative when no option other than retransplantation remains open in these patients. Comparative multicentre clinical trials have shown that higher rates of rejection reversal are achieved when muromonab CD3 is used for the first-line treatment of first episodes of renal or hepatic allograft rejection than when used as rescue therapy; up to 94% for renal rejection. In addition, these comparative trials demonstrated that such first-line treatment with muromonab CD3 is significantly more effective than conventional treatment with high-dose steroids. Muromonab CD3 has also been shown effective in prophylactic treatment in conjunction with azathioprine and/or cyclosporin and low-dose steroids against acute renal, hepatic and cardiac rejection in the immediate post-transplantation period. Preliminary studies indicate that muromonab CD3 may be effective in preventing or reversing graft-versus-host disease in bone marrow transplant patients. More clinical research and experience is needed with muromonab CD3 to further refine treatment protocols and to determine when it is best to intervene with the drug. Current clinical practice uses cyclosporin in prophylactic and maintenance immunosuppressive regimens following transplantation. Evidence suggests that many acute renal and hepatic rejection episodes developing despite maintenance cyclosporin immunosuppression are rapidly reversed by a course of high-dose steroid pulses. Furthermore, most of the small proportion of total patients who do not respond to this short course of corticosteroids rapidly respond to muromonab CD3. This overall therapeutic approach offers the advantage of reserving muromonab CD3 for rescue therapy, and may additionally permit less aggressive immunosuppressive therapy and consequently a lower than usually encountered rate of post-treatment infectious complications. However, prophylactic use of muromonab reduces the need for cyclosporin and improves renal function. Further clinical study is required to determine optimum regimens to minimise rerejection and infection post-treatment.

Side Effects
The first doses of muromonab CD3 are associated with a number of side effects which can be frequent and inconvenient or, more rarely, severe and life-threatening. The first few doses are therefore administered under close hospital supervision, while remaining doses can be administered on an outpatient basis. Most side effects occur within 45 to 60 minutes of administration and last several hours: they are believed to be related to the presence of mediators released as a result of T cell activation and/or depletion during the first doses. The severity and incidence of these side effects has diminished with time as appropriate symptomatic or supplemental therapy has been developed and contraindications recognised. The most frequent effect is a flu-like complex consisting of fever and chills in most patients (> 50%) followed by dyspnoea, tremor, chest pain and tightness, wheezing, diarrhoea, nausea and vomiting in about 10 to 20% of patients, and infrequently tachycardia, hypertension, hypotension, joint pain, pruritus and rash. More severe first-dose effects are aseptic meningitis and pulmonary oedema. A consequence of all immunosuppressive therapy is an increase in the occurrence of infectious, particularly viral and bacterial, complications. There is conflicting evidence as to whether muromonab CD3 increases the rate and severity of post-treatment infectious complications compared with conventional antirejection therapy with high-dose steroids and/or antilymphocyte globulin.

Dosage and Administration

The recommended adult dose of muromonab CD3 is 5mg administered by intravenous bolus injection once daily for 10 to 14 days. Some patients require as much as 10mg to achieve T cell depletion. A dose of 2.5mg is usually used in children weighing 30kg or less. Before treatment patients with temperature exceeding 37.8C should receive antipyretics. The most serious, but infrequent, first-dose adverse reaction, potentially fatal severe pulmonary oedema, has occurred in patients with fluid overload. Patients should therefore be evaluated for fluid overload by chest x-ray and monitoring of weight gain. Weight should be brought to a value of less than or equal to 3% above the minimum usual weight in the week before muromonab CD3 treatment is initiated. Intravenous methylprednisolone sodium succinate 1.0 mg/kg given just before muromonab CD3 administration and intravenous hydrocortisone sodium succinate 100mg 30 minutes after muromonab CD3 administration decreases the incidence and severity of first-dose reactions. Paracetamol (acetaminophen) and antihistamines can be given concomitantly with muromonab CD3 to reduce early reactions. Dosages of conventional concomitant immunosuppressive therapy should be lowered during muromonab CD3 administration to a daily dose of prednisone 0.5 mg/kg and azathioprine 25mg. Preliminary studies indicate that

the use of cyclosporin should be temporarily discontinued during muromonab CD3 treatment. Maintenance immunosuppression should be resumed about 3 days before stopping muromonab CD3 therapy. Various sections of the manuscript reviewed by: L. Chatenoud, Immunology Clinic, Necker Hospital, Paris, France; A.B. Cosimi, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA; H. Kreis, Transplantation Unit, Necker Hospital, Paris, France; K. Onoue, Institute for Medical Immunology, Kumamoto University Medical School, Kumamoto, Japan; C. Ponticelli, Division of Nephrology, Ospedale Maggiore, Milano, Italy; P.A. Rowe, Nottingham Health Authority, City Hospital, Nottingham, England; Y. Yoshikai, Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.