Practical problems with IFN biotherapies

Variable levels of (naturally occurring) IFN-alpha and IFN-beta prior to therapy
Both healthy individuals and patients have type 1 IFN's in the circulation, particularly in connection with infectious (viral) diseases (7). Furthermore, up to 10% of normal individuals may have neutralising autoantibodies (aAb) to IFN-alpha (natural aAb to IFN-beta are rarely seen, at least in healthy individuals)(2). Individuals with prexisting type 1 IFN or with aAb to IFN-alpha may not benefit from a standard dose regime of IFN-alpha or IFN-beta. It is therefore clinically relevant to measure the levels of type 1 IFN's and, particularly important for therapeutic efficacy, IFN-alpha aAb before therapy with IFN biopharmaceuticals.
Despite this, these naturally occurring type 1 IFN- and anti-IFN-alpha molecules are not monitored as a routine in patients considered for treatment with IFN biopharmaceuticals.

Variable bioavailibility
Bioavailibility of many biopharmaceuticals varies considerably from patient to patient, particularly when given by the subcutaneous route (8). This means that a standard dosage of IFN-alpha or IFN-beta in some patients may not yield sufficient blood concentration for therapeutic efficacy. And, in contrast, efficacy may be maintained in other patients even after dose reductions.
The only possibility to take this into consideration clinically is to measure the concentrations of the IFN species in the blood or in other relevant tissue fluids.

Immunogenicity
Prolonged therapies with many biopharmaceuticals, including IFN-alpha and IFN-beta, often lead to development of neutralising antibodies (NAb)(8-10). It is readily understandable that IFN constructs may be immunogenic if the amino acid sequence deviates from that of the native IFN species. However, even 100% human peptide constructs are potentially immunogenic (2, 3, 5). For example, differences in glycosylation of otherwise 100% human biopharmaceuticals may contribute to antibody development and therapeutic failure, and 'unnatural' routes of delivery; e.g. subcutaneous administration of human IFN-alpha/IFN-beta, may trigger T- and B-lymphocyte activation and, hence, antibody production. This is a problem which if not recognized may jeopardize therapeutic efficacy and cause side effects from local and/or circulating immune complexes (11, 12).
Despite this, it is difficult or impossible for clinicians to have patients monitored for development of antibodies under IFN therapies.

Costs
Treatment with the above mentioned biopharmaceuticals is costly (about US$15,000 per patient per year; December 2003). One would not expect society to accept therapies with drugs that expensive if they are not administered optimally, or if doubt arises during therapy concerning efficacy.
Monitoring patients for bioavailibility and antibody development is therefore both rational and cost-effective.

Cited litterature:
1. Bendtzen K, Hansen MB, Ross C, Svenson M. High-avidity autoantibodies to cytokines. Immunol Today 1998;19:209-11.
2. Bendtzen K, Ross C, Hansen MB, Svenson M. Natural and induced anti-cytokine antibodies. In: Ciliberto G, Savino R, editors. Cytokine inhibitors. New York: Marcel Dekker; 2000. p. 53-95.
3. Schellekens H. Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther 2002;24:1720-40.
4. Bendtzen K. Anti-IFN BAb and NAb antibodies: A minireview. Neurology 2003;61, Suppl. 5:S6-S10.
5. Bendtzen K. Immunogenicity of biopharmaceuticals. Experience with interferon-beta, EPO and anti-TNF (in Danish: Immunogenicitet af biologiske lægemidler. Erfaringer med betainterferon, EPO og anti-TNF). Ugeskr Laeger 2003;48:4629-32.
6. Herzyk DJ. The immunogenicity of therapeutic cytokines. Curr Opin Mol Ther 2003;5:167-71.
7. Basler CF, Garcia-Sastre A. Viruses and the type I interferon antiviral system: induction and evasion. Int Rev Immunol 2002;21:305-37.
8. Ross C, Clemmesen KM, Svenson M, Sorensen PS, Koch-Henriksen N, Skovgaard GL, Bendtzen K. Immunogenicity of interferon-b in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Danish Multiple Sclerosis Study Group. Ann Neurology 2000;48:706-12.
9. von Wussow P, Freund M, Block B, Diedrich H, Poliwoda H, Deicher H. Clinical significance of anti-IFN-alpha antibody titres during interferon therapy. Lancet 1987;2:635-6.
10. Itri LM, Sherman MI, Palleroni AV, Evans LM, Tran LL, Campion M, Chizzonite R. Incidence and clinical significance of neutralising antibodies in patients receiving recombinant interferon-a2a. J Interferon Res 1989;9, Suppl. 1:S9-15.
11. Vial T, Descotes J. Immune-mediated side-effects of cytokines in humans. Toxicology 1995;105:31-57.
12. Sorensen PS, Ross C, Clemmesen KM, Bendtzen K, Frederiksen JL et al. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet 2003;362:1184-91.

KB 2003