Monoclonal antibody cytokine release

Priliximab (cM-T412) is an anti-CD4 chimeric monoclonal antibody that was evaluated in the clinic for the treatment of autoimmune diseases. Priliximab binds to CD4 on the surface of T cells and leads to a profound and sustained decrease in circulating CD4+ T cells decreased counts have been reported to be below normal levels at 18 and 30 months following single- and multiple-infusions.81 Similar findings were observed in preclinical studies in chimpanzees.82 The administration of priliximab was also associated with a cytokine-release syndrome that caused transient fever, myalgia, chills, headache, nausea, and/or hypotension that was accompanied by an increase in serum IL-6. Although evidence of efficacy was observed in clinical trials for CD, the... 

Alegre, M.L., Vandenabeele, P., Depierreux, M., Florquin, S., Deschodt-Lanckman, M., Flamand, V., Moser, M., Leo, 0 Urbain, J. and Fiers, W. (1991) Cytokine release syndrome induced by the 145-lCll anti-CD3 monoclonal antibody in mice prevention by high doses of methylprednisolone. Journal of Immunology (Baltimore, MD, 1950), 146, 1184-1191. 

Muromonab is a mouse monoclonal antibody against the CD3 receptor of T-lymphocytes. Its activity is based on inhibition of interactions between antigen-presenting cells and T-cells. By preventing antigen presentation it suppresses T-cell activation and proliferation. The indication for muromonab is the treatment of acute graft rejection after kidney, liver and hart transplantations. Its adverse effects consist of those symptoms that are initiated by the release of cytokines and lymphokines as a result of the reaction of muromonab with CD3 positive T-lymphocytes. These symptoms may vary from a mild flu-like syndrome to serious cardiac, pulmonale and neurological reactions. 

The adverse effects of ALG are mostly those associated with injection of a foreign protein. Local pain and erythema often occur at the injection site (type III hypersensitivity). Since the humoral antibody mechanism remains active, skin-reactive and precipitating antibodies may be formed against the foreign IgG. Similar reactions occur with monoclonal antibodies of murine origin, and reactions thought to be caused by the release of cytokines by T cells and monocytes have also been described. 

Th3 lymphocytes are mainly found in mucous membranes, they release TGFp and cytokines IL 4 and IL 10. They are sometimes referred to as CD4+ CD25-since they do not demonstrate CD25 expression. They can be obtained after oral administration of myelin to mice. Their presence has been observed in mesenterial lymph nodes. Th3 lymphocytes may inhibit the development of allergic encephalitis in mice, if they are administered peritoneally. Administering anti-TGFp monoclonal antibodies to mice reversed the immunosuppression effect (Chen et al., 1994). 

Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999 94(7) 2217-24. 

Several humanized CD3 antibodies have been produced and tested, with the aim of reducing the adverse effects associated with the murine orthoclone antibody. The first results in renal transplant patients were encouraging, with promising clinical results, no evidence of antiglobulin response, and no or very few and minimal adverse effects attributable to various humanized monoclonal CD3 antibodies (16,17). In particular, careful patient monitoring failed to identify any significant cytokine release syndrome. 

Chatenoud L. OKT3-induced cytokine-release syndrome prevention effect of anti-tumor necrosis factor monoclonal antibody. Transplant Proc 1993 25(2 Suppl 1) 47-51. 

Infnsion reactions with rituximab are generally well tolerated, as with most monoclonal antibodies. Most reactions are limited to the first infusion, including nansea, chills, and fever. They occur in over 90% of patients. More serious is the cytokine-release syndrome, which occnrs within 60-90 minutes and is characterized by fever, chills, rigors, bronchospasm, hypoxia, hypotension, nrticaria, and angioedema. Infusion must be discontinued, and the patient carefully monitored with chest radiography and fluid and electrolyte assessment and treated with oxygen and bronchodUators. 

In general, complement-binding monoclonal antibodies are more likely to cause a first dose response and cytokine release and potentially renal failure. 

OKT3, an immunosuppressive monoclonal antibody, can induce systemic vascular changes (leaky syndrome) and prerenal azotemia, presumably by stimulating the release of cytokines (e.g., tumor necrosis factor). These effects are seen more often in poorly hydrated patients. There is also evidence that OKT3 may induce a direct tubular toxicity, since significant numbers of patients developing renal insufficiency also exhibit enzymuria. 

This chapter will examine the nephrotoxic potential of the cytokines or monoclonal antibodies at the doses being used in the treatment of cancer, autoimmune diseases, and transplantation. Non-specific inununomodulators and highly specific monoclonal antibodies are being used singly or in various combinations to treat cancer, autoimmune disease, and solid organ transplants. Many of these therapies achieve their effect by stimulahng the release of cytokines or release cytokines as a by-product of therapy. 

Monoclonal antibodies that are associated with systemic response consistent with cytokine release include ... 

Anti-CD4 (humanized hIgGl-CD4 modulating, non-depleting monoclonal antibody). Anti-CD4 monoclonal antibodies have been used in the treatment of rheumatoid arthritis, psoriasis, systemic lupus erythematosus, and multiple sclerosis. First dose reactions were observed (dyspnea, chills, hypotension [32]. Of note, the anti-IL-2 Receptor (a chain) antibodies dadi-zumab (Zenapax) and basiliximab (Simulect), widely studied in renal transplant recipients, do not induce cytokine release or first dose reactions [33]. 

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