The expiry of the first patents for recombinant-DNA-derived biopharmaceuticals will open the possibility of marketing generics, if they can be shown to be essentially similar to the innovator product. However, as shown by the problem of immunogenicity, the properties of biopharmaceuticals are dependent on many factors, including downstream processing and formulation. Products from different sources cannot be assumed to be bioequivalent, even if identical genes are expressed in the same host cells and similar production methods are used. Some of the influencing factors are still unknown, which makes it impossible to completely predict biological behaviour, such as immunogenicity, which can sometimes lead to serious side effects.

Bioequivalence and the immunogenicity of biopharmaceuticals

Breast is best

With the explosion in interest in cytokines and an increasing understanding of their possible involvement in the pathogenesis of many diseases, the number of studies measuring cytokines in body fluids has increased markedly over the last 5 to 10 years. However, it is readily apparent from the literature that the level of awareness of the many factors that can potentially influence the results obtained is very low. Such factors are likely to contribute considerably to the disparities seen among similar types of study. These include assay properties such as standardization and specificity, type of sample and sample handling, and many biological influences such as age, sex, ethnic background, and diurnal rhythmicity. Clearly, it is not possible to control for all these factors, but a minimum evaluation of assays should be carried out as described, including recovery and parallelity studies using relevant samples and the establishment of reproducibility and normal healthy population levels. An awareness of these factors, which is the purpose of this review, may hopefully lead to an improvement in the quality of studies incorporating the measurement of cytokines in clinical samples and should aid in the interpretation of the data.

Measurement of Cytokines in Clinical Samples Using Immunoassays: Problems and Pitfalls

The incidence and clinical significance of therapy-induced neutralizing interferon β (IFNs) antibodies was studied in a group of 21 melanoma patients treated with natural IFNs and 7 patients treated with recombinant IFNs. They were treated subcutaneously with 3×106 IU three times per week in an adjuvant open trial for 24 weeks after surgical removal of all detectable metastases. Of the 21 patients treated with natural IFNs, 95% developed significant levels of neutralizing antibodies after 24 weeks. In comparison, 28% of the 7 patients treated with recombinant IFNs developed neutralizing IFNs antibodies. Cross-reactivity of the antibodies could be demonstrated. Persistence of antibody titers was seen in 80% of the patients 24 weeks after cessation of treatment with natural IFNs. No correlation between the maximum antibody titers and the antibody persistence after cessation of therapy could be established. We detected a clear correlation between the formation of neutralizing antibodies and the decrease in β2-microglobulin and 2′,5′-oligoadenylate synthease and therefore the drop in biological activity. In this adjuvant trial there was no difference in relapse rate and time until relapse between antibody-positive and antibody-negative patients. No difference in clinical outcome could be established between the patients treated with natural IFNs and recombinant IFNs.

Neutralizing interferon β antibodies in melanoma patients treated with recombinant and natural interferon β

Characterization and potential clinical applications of autoantibodies against cytokines.

In an adjuvant clinical trial, 34 high-risk malignant melanoma patients were treated with natural interferon (IFN)-beta and recombinant IFN-gamma. Patients with tumor location on head, neck, and trunk received 3 million IU IFN-beta intravenously (IV) three times weekly for 24 weeks. Patients with tumor location on the extremities received subcutaneous (SC) injection of 2 million IU of IFN-beta distal the locoregional lymph nodes instead. All patients were given 50 micrograms IFN-gamma SC on 3 consecutive days every 4 weeks. Antibody formation was detected by coincubation of IFN and patients' serum and assessment of the inhibition of the cytopathic effect by a virus suspension. Soluble interleukin-2 receptors (sIL-2R) were determined by enzyme-linked immunosorbent assay (ELISA) technique. No antibodies against IFN-gamma were observed. The overall incidence of antibody formation to IFN-beta was 55.8% (19/34). Ninety-two percent of the SC-treated patients (13/14) and 30% (six of 20) of the IV-treated patients developed antibodies. Soluble interleukin-2 receptors were found to be significantly lower in antibody-positive patients than in antibody-negative patients. The authors conclude that IFN-beta antibody formation is frequent and might influence IFN induced sIL-2R elevation in vivo.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819910501%2967%3A9%3C2300%3A%3AAID-CNCR2820670916%3E3.0.CO%3B2-A

Formation of neutralizing antibodies against natural interferon‐β, but not against recombinant interferon‐γ during adjuvant therapy for high‐risk malignant melanoma patients

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Formation of neutralizing antibodies against natural interferon‐β, but not against recombinant interferon‐γ during adjuvant therapy for high‐risk malignant melanoma patients