Toxicity of OKT3 increases with dosage: a controlled study in renal transplant recipients

Parlevliet, K. J.; Bemelman, Fréderike J.; Yong, S. L.; Hack, C. E.; Surachno, J.; Wilmink, J. M.; Berge, Ineke J. M. ten; Schellekens, P. T. A.

doi:10.1111/j.1432-2277.1995.tb01489.x

Cited by 3 publications

(3 citation statements)

References 21 publications

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“…Side effects were evaluated semiquantitatively, as described [16]. In short, patients were observed and questioned for the presence of (1) fever above 38·5 ∞ C, (2) chills, (3) dyspnoea with increased breathing frequency, (4) nausea or vomiting, (5) diarrhoea and (6) headache, in the time intervals ranging from 0 to 3 h, 3-6 h, 6-12 h, 12-24 h, 24-48 h and 48-72 h after the first administration.…”

Section: Clinical Assessment and Control Groupmentioning

confidence: 99%

Treatment of acute kidney allograft rejection with a non-mitogenic CD3 antibody

Meijer

Surachno

Yong

et al. 2003

Clinical and Experimental Immunology

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SUMMARYT3/4.A is a non-mitogenic murine IgA mAb to human CD3 that was selected for clinical studies to provide an alternative for the mitogenic, T cell-activating, therapeutic mAb OKT3. Previously, we reported that T3/4.A is better tolerated in humans than the IgG2a-CD3 mAb T3/4.2a. Here we report the results of a phase II clinical trial to assess the immunosuppressive potential of T3/4.A. Eighteen first kidney transplant recipients with a first rejection episode were included. Baseline immunosuppression consisted of cyclosporin and prednisolone. Rejection treatment consisted of 5 mg mAb per day during 10 days. Fourteen patients responded, of whom four experienced a second rejection within 2 weeks, one experienced chronic rejection after 2·5 years, whereas the others remained rejection-free after treatment (median duration of follow-up 42 months). Four patients did not respond and eventually lost their graft. These results are similar to treatment results with OKT3, as reported in the literature. Following the first dose of T3/4.A, side effects were limited, and reduced compared to OKT3-treated controls. On the second day, 15 patients developed transient vomiting and/or diarrhoea, which coincided with elevated serum levels of proinflammatory cytokines. Minimal or even no side effects occurred during the remaining days, which is in sharp contrast to that seen generally during OKT3 treatment. Both T cell numbers and TCR expression were reduced during the therapy. We conclude that T3/4.A is a good alternative for OKT3 to treat rejection episodes in renal transplant recipients.

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Section: Clinical Assessment and Control Groupmentioning

confidence: 99%

Treatment of acute kidney allograft rejection with a non-mitogenic CD3 antibody

Meijer

Surachno

Yong

et al. 2003

Clinical and Experimental Immunology

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“…The most common and important adverse effect associated with muromonab‐CD3 is cytokine release syndrome, a condition in which activated T‐cells release their cytokines resulting in a systemic inflammatory response (hypotension, pyrexia and rigors) similar to that found in severe infection. Muromonab‐induced toxicity is dose‐dependent and is mediated not only by cytokine release but also by activation of complement and neutrophils (Parlevliet et al ., 1995). Other toxicities of muromonab therapy include aseptic meningitis, seizures, acute respiratory distress, reactivation of CMV infection and post‐transplant lymphoproliferative disorders (Thistlethwaite et al ., 1988; Hibberd et al ., 1992; Macdonald et al ., 1993; Wasson et al ., 2006; Orthoclone OKT3 USPI, 2011).…”

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confidence: 99%

Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targets

Bugelski

Martin

2012

British J Pharmacology

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Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 15 currently approved mAbs and fusion proteins targeted to the cell surface. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency 'Scientific Discussions'; and the US Food and Drug Administration 'Pharmacology/Toxicology Reviews' and package inserts (United States Prescribing Information). Data on the 15 approved biopharmaceuticals were included: abatacept; abciximab; alefacept; alemtuzumab; basiliximab; cetuximab; daclizumab; efalizumab; ipilimumab; muromonab; natalizumab; panitumumab; rituximab; tocilizumab; and trastuzumab. For statistical analysis of concordance, data from these 15 were combined with data on the approved mAbs and fusion proteins directed towards soluble targets. Good concordance with human pharmacodynamics was found for mice receiving surrogates or non-human primates (NHPs) receiving the human pharmaceutical. In contrast, there was poor concordance for human pharmacodynamics in genetically deficient mice and for human adverse effects in all three test systems. No evidence that NHPs have superior predictive value was found. AbbreviationsADCC, antibody-dependent cellular cytotoxicity; CD, cluster of differentiation; CDC, complement-dependent cytotoxicity; CTL, cytotoxic T lymphocyte; CTLA4, cytotoxic T lymphocyte antigen 4; CMV, cytomegalovirus; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FDA, Food and Drug Administration; ICAM-1, intercellular adhesion molecule-1; LFA, lymphocyte function associated antigen; JCV, human polyoma JC virus; mAb, monoclonal antibody; NHP, non-human primate; NK, natural killer; PML, progressive multifocal leukoencephalopathy; RBC, red blood cell; SCID, severe combined immunodeficiency; SIV, simian immunodeficiency virus; SLE, systemic lupus erythematosus; TCR, T-cell receptor; USPI, United States Prescribing Information; VLA-4, very late antigen-4; WBC, white blood cell IntroductionMonoclonal antibodies (mAb) and soluble receptors (fusion proteins) make an important contribution to the treatment of a variety of diseases. Over 30 mAb or fusion proteins have been approved for clinical use and more than 200 more are in various stages of clinical development (Dimitrov and Marks, 2009). Because species cross-reactivity is usually highly BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 British Journal of Pharmacology (2012) restricted to humans and non-human primates (NHPs), mAbs directed towards human targets are usually pharmacologically inactive in rodents (Cavagnaro, 2008). As a consequence, preclinical studies with many of the mAbs or mAb-like molecules need to be conducted in NHPs (ICH, 2011). However, there are some notable exceptions, for example abatacept (...

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“…Muronmonab-CD3 (OKT3) achieves immunosuppression by inactivating CD3 lymphocytes, and is most often combined with corticosteroids, azathioprine, and cyclosporine. The most common neurologic symptom of OKT3 is headache but, rarely, neurotoxicity has been reported to produce aseptic meningitis, seizures, cerebral edema, and vision loss (33)(34)(35).…”

Section: Muromonab-cd3 (Okt3)mentioning

confidence: 99%

Seizures in Organ Transplant Recipients

Worrell

Wijdicks

Seizures in Critical Care

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Seizures are a nonspecific neurological manifestation of cerebral dysfunction and are not indicative of any particular disease processes or pathology. Thus, the evaluation and treatment of seizures in transplant patients generally follows the same clinical approach used for other patients. A seizure in a transplant patient is commonly unanticipated and entirely unexplained. The effects can be substantial, with aspiration, loss of vascular catheters, and tissue trauma. Patients undergoing organ transplantation are at risk for seizures for multiple reasons, and although much of the neurological and transplantation literature reports on the incidence of seizures according to the particular organ transplanted (Table 1), there are many similarities (e.g., immunosuppression drugs). This chapter concentrates on organ transplantation as a whole.

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Toxicity of OKT3 increases with dosage: a controlled study in renal transplant recipients

Cited by 3 publications

References 21 publications

Treatment of acute kidney allograft rejection with a non-mitogenic CD3 antibody

Treatment of acute kidney allograft rejection with a non-mitogenic CD3 antibody

Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targets

Seizures in Organ Transplant Recipients

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