[Selective serotonin reuptake inhibitors (SSRI's) are not indicated for children and adolescents with depression].
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Antidepressive Agents, Second-Generation↗
Biomedical subjects
H Schellekens
Publications and source records attributed to H Schellekens.
Significance of neutralizing antibodies to interferon beta during treatment of multiple sclerosis: expert opinions based on the Proceedings of an International Consensus Conference.
On August 30, 2002, an international panel of neurologists who specialize in the treatment of multiple sclerosis (MS) was convened in Paris (France) to discuss the issue of neutralizing antibodies (NAb) to interferon beta (IFN-beta) therapy in patients with MS. The goals of this meeting were to: (i) review the most recent clinical information on NAb, (ii) come to a consensus on the clinical relevance of NAb in the management of patients with MS receiving IFN-beta therapy, and (iii) establish a framework for the development of patient management guidelines based on scientific consensus. The meeting was chaired by Hans-Peter Hartung (Heinrich-Heine University, Düsseldorf, Germany) and Huub Schellekens (Utrecht University, Utrecht, the Netherlands). This article summarizes the opinions of the expert panel on a number of key issues raised at the meeting.
Animals↗
When biotech proteins go off-patent.
The patents of the first generation of biopharmaceuticals derived from recombinant DNA such as interferons, growth hormone and epoietins are expiring, opening up the possibility for competitors to introduce biosimilar products. The concept of generics that applies to classical drugs and allows market admission on limited documentation cannot be extrapolated to these "off-patent biologics". Physicochemical characterization, bioassays and animals studies do not predict completely the efficacy and safety of therapeutic proteins. Clinical studies will nearly always be necessary to obtain marketing authorization for off-patent biologics. Immunogenicity is considered to be the main problem with therapeutic proteins. The recent upsurge of pure red cell aplasia (PRCA), a severe form of anemia associated with the use of epoietin-alpha, highlights both the unpredictability and the severe consequences of immunogenicity. A risk-based approach can be used to evaluate the potential induction of antibodies by off-patent biologics.
Animals↗
Biosimilar therapeutic agents: issues with bioequivalence and immunogenicity.
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Drugs, Generic↗
Immunogenicity of biopharmaceuticals. The European perspective.
In 1993 a Concerted EU Action was started to coordinate research concerning the immunogenicity of biopharmaceuticals bringing together researchers from academia and industry. The main topic of this concerted action has been interferon alpha. The factors influencing its immunogenicity were studied. Blind panel testing of patients' sera showed large differences in reported titres as an important variable in different studies. The EMEA has requested the three marketing authorization holders of interferon beta to develop a common assay for antibodies to this product. The status of this project will be discussed. The occurrence of about 30 cases of pure red cell aplasia related to antibodies induced by erythropoietin treatment will also be reported.
Biological Factors↗
The immunogenicity of biopharmaceuticals. Lessons learned and consequences for protein drug development.
Most biopharmaceuticals, including those proteins that are more or less identical to native human proteins, induce antibodies in a significant fraction of patients. The main factors contributing to immunogenicity are impurities and the presence of aggregates. Sequence divergence from the native proteins only plays a minor role except in proteins from microbial, plant or distant vertebrate origin. In the majority of cases the antibodies have no biological or clinical effects. The most common clinical effect is the loss of efficacy of the biopharmaceutical. Serious complications of immunogenicity are rare. The best method to prevent immunogenicity is optimizing production, purification and formulation of the biopharmaceutical protein to generate soluble, non-aggregated, native protein free of contaminating adjuvants. The best way to predict immunogenicity in humans is evaluation in immune tolerant transgenic mice.
Animals↗
[Genetic modification of animals].
Genetic modificated animals are an essential part of modern biotechnology since the years of the seventies of last century. In the past selective crossbreeding of plants and animals took place in order to obtain the desired characteristics but nowadays this is done with the aid of biotechnology i.e. through transgenese, knock-out animals and cloning. A number of fields of application of genetic modification of animals are listed. In order to limit the risks that genetic modificated animals may carry with them the necessary legislation is formulated. A number of risks and the main rules are mentioned.
Animals↗
Efficacy and safety of orally/sublingually, intranasally, and intraperitoneally administered recombinant murine interferon in the treatment of murine encephalomyocarditis virus.
Interferons (IFN) have been shown to be effective in protecting animals against lethal viral infections when administered systemically in relatively high doses. Intraperitoneal (i.p.) injection of mice with encephalomyocarditis virus (EMCV) gives rise to a rapidly progressive fatal disease characterized by central nervous system involvement and encephalitis. IFN-alpha has been shown to be effective in protecting mice against lethal EMCV infection when given via parenteral and oral/sublingual routes. The current study was designed to explore the ability of orally/sublingually and intranasally (i.n.) administered IFN-alpha to treat mice infected with EMCV in support of a planned clinical trial to evaluate efficacy of oral IFN-alpha in human viral infections. The primary objective of the study was to determine the efficacy of recombinant murine IFN-alpha (rMuIFN-alpha) in the treatment of mice infected with 100 LD(50) EMCV following oral, i.n., and i.p. administration at doses of 20,000 and 100,000 IU. The results of the current experiment did not indicate protection from infection with EMCV in mice that received IFN by the i.n. or oral/sublingual routes. The negative controls, infection of mice with 100 LD(50) of EMCV followed by treatment with excipient via all three routes, resulted in death of nearly all mice, as expected. The positive control, treatment of EMCV-infected (100 LD(50)) mice with rMuIFN-alpha via the i.p. route, was successful in protecting a significant number of mice from death compared with matched controls. This study points out the need to determine the optimum conditions for administration of oral/sublingual or i.n. IFN to insure maximum efficacy against viral infections.
Administration, Intranasal↗
Oromucosal interferon therapy: relationship between antiviral activity and viral load.
Intraperitoneal (i.p.) administration of 20,000 IU recombinant murine IFN-alpha (rMuIFN-alpha) was highly effective in protecting mice challenged i.p. with doses of encephalomyocarditis virus (EMCV) ranging from 44 to 440 LD(50) (p<0.001). Oromucosal (o.m.) IFN therapy was also found to be effective in protecting mice challenged with a lethal dose of EMCV. Thus, 40% of animals infected with 44 LD(50) of EMCV and treated o.m. with 20,000 IU rMuIFN-alpha survived infection with a mean survival time of 12.0 +/- 2.46 days relative to a mean of 6.11 +/- 0.38 days in the control group (p<0.05). Oromucosal IFN therapy was found to be ineffective, however, in animals infected with higher doses of EMCV (88-440 LD(50)), even though intraperitoneal administration of the same dose of rMuIFN-alpha resulted in the survival of 90%, 50%, and 60% of animals infected with 88, 220, and 440 LD(50) of EMCV, respectively. These results suggest that oromucosal IFN therapy is effective at relatively low viral load only and that the mechanism of action of oromucosal IFN therapy may be different from that of parenterally administered IFN. Our results suggest that oromucosal IFN therapy may be most effective in chronic viral infections as an alternative to parenterally administered IFN, which is clinically effective but poorly tolerated.
Administration, Intranasal↗
Health risks of genetically modified foods.
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Agriculture↗
Tolerance and antiviral effects of high-dose interferon-alpha B/D in patients with chronic hepatitis B.
A novel recombinant interferon-alpha B/D hybrid was applied to assess tolerability, antiviral effect, and biological activity in chronic hepatitis B. The study was designed as an open nonrandomized trial. Treatment comprised a two-week run-in phase with 16 MU three times a week followed by 14 weeks with 64 MU three times a week (or 48 MU if toxicity occurred with 64 MU). Total follow-up was 36 weeks. Nineteen patients were included; three discontinued treatment during the run-in with 16 MU. Fourteen of 16 patients had 14 weeks of treatment with > or = 32 MU three times a week. Fourteen dose reductions were necessary in nine patients. The adverse experience profile was similar to other interferon-alphas. HBV-DNA decreased using all doses studied. HBV-DNA became undetectable in five patients, two of whom had HBeAg seroconversion. No HBsAg seroconversion was observed. It is concluded that interferon-alpha B/D is well tolerated in high doses. The anti-viral effect starts at at least 16 MU three times a week.
Adult↗
Anti-cytokine autoantibodies: epiphenomenon or critical modulators of cytokine action.
Low amounts of high-affinity autoantibodies to various cytokines have been detected in sera from healthy donors. Their levels, although highly variable, are increased in the circulation of patients subjected to cytokine therapy or suffering from a variety of immunoinflammatory diseases. It has been suggested that these autoantibodies play a regulatory role in the intensity and duration of an immune response. The antibodies may prevent the binding of a cytokine to its specific cell surface receptor thereby neutralizing its biological activity in vivo. They may also act as carrier proteins preventing the rapid elimination of a cytokine from the circulation and thus increase its bioactivity. Additionally or alternatively, autoantibodies may modulate cytokine-induced intracellular signal transduction pathways or trigger complement-mediated cytotoxicity towards cells carrying membrane-bound cytokines. The autoantibodies may exert their regulatory role in compliance with the other factors that control cytokine activity, including soluble cytokine receptors, cell surface decoy receptors, and receptor antagonists. Although not favored by many investigators, a less sophisticated role for naturally occurring anti-cytokine autoantibodies should be considered as well. Recent evidence has shown that autoantibodies are generated at a high frequency as part of a response to foreign antigens. These antibodies are produced by B cells arising from the process of somatic mutation. Thus anti-cytokine autoantibodies may be the result of a "leaky" B cell response triggered by immunoinflammatory processes. High-titered autoantibodies induced by cytokine therapy are of clinical concern since their occurrence is often associated with the loss of response to treatment. Moreover, they may also neutralize endogenously produced cytokines with possible pathological consequences. In this paper we have reviewed the available information on the biological and clinical significance of both naturally occurring and therapeutically induced anti-cytokine autoantibodies in animals and man with the emphasis on antibodies directed to interferons.
Autoantibodies↗
Assays for antibodies to human interferon-alpha: the need for standardization.
Since the first reported occurrence of anti-interferon (IFN) antibodies in 1981, the reported incidence of antibody production has differed enormously. In some clinical trials of human IFN preparations, no patients developed antibodies, whereas other studies reported an incidence of more than 80%. In patients with hepatitis C, the reported incidence varies from 7% to 61%. One of the factors contributing to the variability of the results is the lack of a standard assay system to measure antibodies to IFNs. In 1994, a Concerted Action funded by the European Commission started to coordinate studies into the immunogenicity of recombinant DNA-derived pharmaceuticals. These studies aimed to examine whether antibodies could interfere with the efficacy of treatment and also studied the long-term effects on cytokines produced by the patients themselves. Only when a well-calibrated and standardized assay is available, however, will it be possible to define the biologically relevant titer of antibody. Assays for both binding and neutralizing antibodies are discussed here.
Antigen-Antibody Reactions↗
[Pulmonary infection with Coccidioides immitis].
A man aged 42 who was referred to the outpatient department for Pulmonary Diseases because of a cough of two weeks' standing and fever up to 40 degrees C, had recently spent 10 days in the desert (San Joaquin Valley, California). Physical examination revealed no distinct abnormalities. Radiologically, an infiltrative lesion in the left upper lobe of the lung was established, as well as swollen lymph nodes near the pulmonary hilus. Blood testing revealed leukocytosis and eosinophilia. Possibilities considered were tuberculosis and, because the patient had been in California, coccidioidomycosis. The Mantoux test and several Ziehl-Neelsen preparations were negative. However, the immunodiffusion test for Coccidioides immitis antibodies was positive. Also, C. immitis was cultured from the sputum. The diagnosis read ¿pulmonary coccidioidomycosis with eosinophilia'. Because of aggravation of the pulmonary lesions and eosinophilia, treatment with ketoconazole was instituted. This was the first time in the Netherlands that a human infection with the fungus C. immitis could be confirmed serologically as well.
Antibodies, Fungal↗
Factors inhibiting IFN activity.
Several factors may inhibit the activity of IFNs. Some of these occur naturally, others are therapy-induced or artificial. Naturally occurring antibodies appear to have a much broader reactivity than therapy-induced antibodies. Naturally induced antibodies are reported in patients suffering from chronic graft-versus-host disease after bone marrow transplantation. Differences in the reported immunogenicity between interferons may not be due to the minor variation in amino acid sequence. The clinical significance of therapy-induced antibodies has been unclear. In patients treated for chronic hepatitis C, antibody formation is closely related to relapse. In animal studies the efficacy of treatments targeting the IFN receptor interaction has been shown. Soluble IFN-gamma receptor inhibits the development of autoimmune diseases in mice. Monoclonal antibodies to the IFN-alpha receptor protects against allograft rejections in monkeys. Two naturally occurring inhibitors of IFN action were reported. The clinical significance and structure of these inhibitors remain elusive.
Animals↗
Cytokines and the immune response.
Cytokines participate in many physiological processes including the regulation of immune and inflammatory responses. These effector molecules are produced transiently and locally controlling the amplitude and duration of the response. A variety of experiments has shown that excessive or insufficient production may significantly contribute to the pathophysiology of a range of diseases. Particularly cytokines released by CD4+ T cells at the onset of an immune response are thought to be decisive for pathological or physiological consequences. The meeting in Budapest was focussed on cytokines known to contribute to the pathophysiology of autoimmune diseases, infectious diseases and allograft rejection (e.g., IL-1, IL-4, IL-6, IL-10, IL-12, TNF-alpha and IFN-alpha, -beta, -gamma). A central role for IFN-gamma in autoimmunity was suggested by blocking experiments in vivo using monoclonal antibodies and soluble forms of the IFN-gamma receptor (IFN-gamma SR). These agents ameliorated disease development in a variety of experimental autoimmune diseases in rodents. In a mouse model for the human disease Myasthenia gravis, IFN-alpha was found to reduce both the incidence and progression of the disease. Treatment of R. aurantiacus-infected mice with anti-IL-4 monoclonal antibodies (mAbs) was reported to interfere with the regression of granulomas in spleen and liver, most likely through inadequate IL-4-mediated suppression of IFN-gamma production. In addition, it was shown that mice with disrupted IFN-gamma R genes died rapidly after infection with the BCG strain of M. bovis, whereas normal mice survived the infection. IL-12 was found to be the main inductor of IFN-gamma during the lethal Shwartzman reaction. TNF-alpha was identified as the principal cause of mortality after the second injection with LPS. In a variety of studies examining the role of cytokines in the pathogenesis of AIDS, much attention was given to the in vitro effects of HIV-1 and/or the HIV-1 viral membrane protein gp120 on triggering cytokine production by peripheral blood leukocytes (PBLs) and purified monocytes/macrophages (Mø) originating from healthy donors. Gp120 as a sole agent significantly suppressed IFN-gamma production by mitogen-stimulated PBLs and induced the production of IFN-alpha in cultures of normal human peripheral blood mononuclear cells (PBMCs). In a human macrophage cell line, TNF-alpha exerted a stimulatory effect on viral replication and programmed cell death induced by HIV-1 which was potentiated by the simultaneous incubation with IFN-gamma. Upon transfection of human PBLs and CD4+ T cells with a retroviral vector encoding human IFN-beta, a notable reduction in reverse transcriptase activity after HIV-1 challenge was observed. Gp120 was also found to induce both IL-6 and TNF-alpha expression and to induce morphological changes reminiscent for apoptosis in primary astrocytes and in a re-aggregated human brain cell model, suggesting a role for these cytokines in the neuropathology of AIDS dementia. Moreover, data were presented indicating that cytokine-induced expression of cell adhesion molecules (e.g., ICAM-1) in HIV-1 infected U 937 cells leads to high level incorporation of this molecule in the membrane of the viral progeny which may play a role in the attachment of such virions to CD4-negative cells.
Animals↗
The effect of recombinant human interferon alpha B/D compared to interferon alpha 2b on SIV infection in rhesus macaques.
The model of simian immunodeficiency virus (SIV) infection in rhesus macaques was used to evaluate the effects of recombinant human interferon alpha, Hu IFN-alpha 2b and Hu IFN-gamma B,D, at two doses. Administration began 1 day prior to infection and was continued for 90 days postinfection. Both interferons suppressed SIV antigenemia during the treatment period. Following treatment animals were monitored for 4 years for rate of disease progression. Neither IFN prolonged the asymptomatic period or survival.
Animals↗