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PubMed1988

The long-term stability of recombinant (serine-17) human interferon-beta.

Escherichia coli-derived (Serine 17) human interferon-beta (HuIFN-beta SER) was formulated with SDS and placed at multiple isothermal temperatures (-70 degrees C to 37 degrees C). Three stability-indicating test methods (bioassay, SDS-PAGE, RP-HPLC) were used to evaluate the long-term stability of this preparation. No change was observed when stored for nearly a year at either -70 degrees C or 4 degrees C. At the elevated temperatures, proteolytic cleavage, noncovalent oligomer formation, and loss of antiviral activity were observed. The absence of a carrier protein makes this stable IFN-beta frozen reference preparation useful as a standard in both biological assays and protein chemical methods of analysis.

Biological Assay↗

PubMed1988

Phase II trial of a combination of interferon-beta ser and interferon-gamma in patients with advanced malignant melanoma.

Based upon the in vitro synergistic activity of interferon-beta (IFN-beta) and interferon-gamma (IFN-gamma) observed in melanoma cells, we initiated a Phase II trial using the combination to determine the clinical antitumor efficacy in patients with advanced disease. Fifteen patients with metastatic malignant melanoma were given 2,000 micrograms of recombinant IFN-gamma (rIFN-gamma) (Biogen) intravenously (i.v.) over 10 min, followed by a 10 min i.v. injection of 30 million units of recombinant IFN-beta (rIFN-beta ser) (Triton) 3 x/week. Six patients had skin, soft tissue, nodal, or subcutaneous metastases, 6 had visceral disease only, and 3 had both. Seven patients had received prior treatment, including chemotherapy (6), radiotherapy (3), and/or immunotherapy (3). Side effects included typical IFN constitutional symptoms such as anorexia, fatigue, nausea, and myalgias, but were not dose limiting. The mean drop in the white blood cell count (WBC) following 1 month of therapy, compared to baseline, was 3.3 x 10(3)/mm2 (p = 0.002); the mean increase in SGOT was 24.1 U/l (p less than 0.001). One patient had a dose reduction for Grade III anorexia and fatigue which did not resolve with repeated treatment. One patient with liver metastases had radiographical and clinical stabilization of his disease for 1 year. No responses were seen. The median time to progression was 6 weeks. Two patients' tumors were evaluable in the human tumor colony forming assay (HTCFA) and were markedly sensitive to the antiproliferative effects of IFN combinations. Both patients, however, failed to respond clinically.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

Effect of recombinant interferon-beta ser on primary human tumor colony-forming units.

A capillary cloning system for primary human tumor colony-forming units was applied to a total of 286 tumors, and 226 (79%) provided satisfactory cultures. These were used to study the in vitro anti-proliferative effects of a recombinant DNA human interferon-beta (rIFN-beta ser). Growth inhibition was somewhat greater when relatively high IFN concentrations were used, but continuous exposure to the IFN was not more effective than exposure for only 1 h. The tumors inhibited included breast, kidney, lung (non-small-cell), head and neck cancers, melanoma, and, especially, mesothelioma. This spectrum of activity differs from that of the IFNs-alpha so far examined. The IFN-beta ser did not differ significantly in activity from native IFN-beta. When tested in combination with five cytotoxic anticancer agents, it did not increase their effects. Future correlation of these in vitro data with clinical results will show whether this capillary cell cloning method is a useful predictor of antitumor activity in patients.

Dose-Response Relationship, Drug↗

PubMed1989

Enhancement of indoleamine 2,3-dioxygenase activity in cancer patients receiving interferon-beta Ser.

Degradation of tryptophan to kynurenine, catalyzed by indoleamine 2,3-dioxygenase (IDO), has been shown previously to be augmented in human peripheral blood mononuclear cells (PBMCs) treated in vitro with interferons-alpha, -beta, and -gamma (IFNs), and in human epithelial cells treated with IFN-gamma. To determine whether administration of IFN in vivo also induced IDO activity, tryptophan degradation by PBMCs purified from patients was measured. PBMCs, obtained prior to and 24 h after i.v. bolus injection of 90 X 10(6) units or 180 X 10(6) units of IFN-beta Ser, were cultivated in medium containing [3H]tryptophan. After 48 h incubation, culture supernatants were harvested, and the amount of tryptophan degraded was measured by fractionation with high-performance liquid chromatography and quantification of radioactivity in resultant fractions. Significantly enhanced IDO activity was observed after IFN-beta Ser treatment, with a mean paired increase of 43% of maximum inducible activity. Thus, measurement of in vivo induction of IDO activity may be a useful indicator in optimizing therapeutic use of IFNs in neoplastic, infectious, and other clinical disorders.

Drug Administration Schedule↗

PubMed1989

Comparative susceptibility of respiratory viruses to recombinant interferons-alpha 2b and -beta.

Intranasal recombinant interferon-alpha 2b (rIFN-alpha 2b) protects against natural colds due to rhinoviruses, but apparently not against those caused by viruses. Because rIFN-beta serine17 (rIFN-beta ser) appears less active than rIFN-alpha 2b in preventing natural rhinovirus colds, we compared the two IFNs in two in vitro assays against selected respiratory viruses. In a yield reduction assay, both IFNs had comparable activity against rhinovirus types 39 and 1A and coronavirus 229E, which were inhibited by 90% or more at IFN concentrations of 10(-11) to 10(-10) gram of protein/ml (approximately 2-20 IU/ml). Similar activities were observed with rIFN-beta ser against rhinoviruses isolated from clinical specimens. At concentrations of 10(-9) gram protein/ml, both IFNs inhibited the growth of influenza A and parainfluenza viruses, but not of adenovirus or respiratory syncytial virus in the cell culture systems tested. Thus, the different clinical protection conferred by rIFN-alpha 2b and rIFN-beta ser in studies of natural rhinovirus colds are not accounted for by differences in their in vitro activity against these viruses, and other explanations must be found.

Biological Assay↗

PubMed1989

Recombinant human interferon-beta suppresses the replication of HIV and acts synergistically with AZT.

The in vitro effects of recombinant human interferon-beta ser (rIFN-beta ser) and 3'-azido-3'-deoxythymidine (AZT) alone and in combination on human immunodeficiency virus (HIV) replication were examined. rIFN-beta ser inhibited HIV progeny virus synthesis in cell cultures chronically infected with HIV. When used in combination, suboptimally effective concentrations of rIFN-beta ser and AZT synergistically inhibited HIV-mediated syncytium formation in HeLa T4 cell cultures. Whereas AZT alone reduced HIV replication in human MT-2 cells, addition of low concentrations of rIFN-beta ser reduced by 4- to 1,000-fold the amount of AZT required to maximally block HIV p24 antigen synthesis and HIV-mediated cell lysis. No drug-related cytoxicity was observed when the two agents were used together at and above maximally effective concentrations. These results suggest that a safer, yet effective, therapy for HIV infections may be achieved with reduced doses of AZT in combination with rIFN-beta ser.

Cells, Cultured↗

PubMed1990

Growth inhibitory effects of interferon-beta but not interferon-alpha on human glioma cells: correlation of receptor binding, 2',5'-oligoadenylate synthetase and protein kinase activity.

The antiproliferative effects of human recombinant interferon-alpha (rIFN-alpha A) and interferon-beta (rIFN-beta ser) were assessed in vitro against seven human glioma cell lines. Further analysis of one of these lines (EFC-2) in response to rIFN-alpha A demonstrated a minimum growth inhibition by day 6 of treatment, whereas a 50% inhibition of cell growth was observed with a dose of 50 U/ml of IFN-beta ser. No significant growth inhibition was seen by rIFN-alpha A at doses up to 500 U/ml. Addition of rIFN-alpha A to rIFN-beta ser-treated EFC-2 cells neither suppressed nor augmented the antiproliferative response to IFN-beta ser. The binding of 125I-labeled rIFN-alpha A or 125I-labeled rIFN-beta ser to EFC-2 cells was inhibited competitively by increasing concentrations of either unlabeled rIFN-alpha A or rIFN-beta ser. This suggests that the cellular receptors for both rIFN-alpha A and rIFN-beta ser appear to be intact and appear to bind both agents equally. Furthermore, incubation of EFC-2 cells for 72 h with either rIFN-alpha A or rIFN-beta ser resulted in an increase in 2',5'-oligoadenylate (2-5A) synthetase activity 5-fold with rIFN-alpha A and 50-fold with rIFN-beta ser. Similarly, the 68-kD IFN-induced protein kinase was induced substantially with rIFN-beta ser but only slightly induced with rIFN-alpha A treatment. These results suggest that EFC-2 human glioma cells demonstrate a differential sensitivity in terms of growth inhibition to rIFN-beta ser and to rIFN-alpha A which appears to correlate with a differential induction of both intracellular 2-5A synthetase and protein kinase activity. These results cannot be explained solely on the basis of surface receptor binding of rIFN-alpha A and rIFN-beta ser. These data do suggest that, for human glioma cells in culture, type I IFN receptors may display a subtle architectural variation that allows equivalent binding of both IFN-alpha and IFN-beta ser, but allows an enhanced signal transduction and biological effect only after binding a specific IFN subtype.

2',5'-Oligoadenylate Synthetase↗

PubMed1990

Basal and interferon-induced 2',5'-oligoadenylate synthetase in human monocytes, lymphocytes, and peritoneal macrophages.

2',5'-Oligoadenylate (2-5A) synthetase is an intracellular enzyme induced during viral diseases and after clinical administration of interferons (IFN). Because monocytes and T and B lymphocytes in peripheral blood are targets of viral infection, we compared the basal levels and induction of 2-5A synthetase activity in these three cell types. IFN-beta induced significant, three- to eightfold increases in 2-5A synthetase activity in monocytes and T and B lymphocytes, both in vitro and in vivo. IFN-gamma was less effective in inducing 2-5A synthetase than IFN-beta, yielding up to 2.6-fold increases in monocytes and slight increases in lymphocytes in vitro. IFN-beta also had greater 2-5A synthetase-inducing activity than IFN-gamma in HL-60 and U937 monocytic cell lines and in human peritoneal macrophages. Baseline levels of 2-5A synthetase in untreated peripheral blood monocytes separated by adherence or density gradients were three- to fivefold higher than in lymphocytes. 2-5A synthetase levels were twofold higher in B than in T lymphocytes separated by fluorescence-activated cell sorting. Tumor necrosis factor-alpha (TNF-alpha) did not induce this enzyme in peripheral blood mononuclear cells (PBMCs) or peritoneal macrophages. Thus, monocytes had greater basal and induced levels of 2-5A synthetase activity than did lymphocytes and contributed disproportionately to total 2-5A synthetase activity in peripheral blood.

2',5'-Oligoadenylate Synthetase↗

PubMed1990

Phase II evaluation of recombinant interferon-beta (IFN-beta ser) in patients with diffuse mesothelioma: a Southwest Oncology Group study.

Fourteen evaluable patients with diffuse malignant mesothelioma were treated with a once-a-day for 5 days out of 7 for 6 weeks regimen of recombinant interferon-beta (IFN-beta ser). No responses were noted. The major toxicities included fever, chills, nausea, vomiting, and anorexia. IFN-beta ser at this dose and schedule does not appear to be an active single agent for patients with refractory malignant mesothelioma.

Drug Evaluation↗

PubMed1990

Biological and clinical effects of interferon-beta ser at two doses.

To assess biological response, therapeutic activity, and side effects, a randomized, double-blind trial of two doses of interferon-beta ser (IFN-beta ser), differing by 20-fold 4.5 and 90 x 10(6) units), was undertaken in 64 patients with metastatic renal carcinoma. Patients were treated intravenously with injections daily for 10 days with an 11-day rest before treatment was reinitiated. The trial confirmed the relatively good toleration of IFN-beta ser; in the first cycle only 4/63 patients had anorexia of moderate or greater severity. Median weight change over the duration on study was -1.5 kg; in the first cycle only 7% of patients had performance status decline greater than 1 level. Statistically significant changes (p less than 0.05) occurred in granulocytes, lymphocytes, calcium, cholesterol, alkaline phosphatase, and aspartate transferase (AST); however, except for AST, overall clinical differences in the two doses were not great. Of 60 patients evaluated, 1 developed neutralizing antibody. When assessed 24 h after IFN-beta ser at 4.5 x 10(6) units, significant (p less than 0.05) augmentation had occurred in beta 2-microglobulin, HLA-DR, and HLA-DQ expression on monocytes, 2',5'-oligoadenylate (2-5A) synthetase in peripheral mononuclear cells, and natural killer (NK) and K cells functional activity. Although the 90 x 10(6) unit dose also resulted in stimulation of these responses, little additional augmentation of biological response occurred at the higher dose. Except for a decline in monocyte HLA-DR expression, biological responses remained increased at both doses over the 10-day period of treatment. However, no objective regressions of metastatic disease occurred. In view of objective responses in metastatic renal carcinoma in other trials with IFN-beta ser, consideration should be given to alternative schedules.

2',5'-Oligoadenylate Synthetase↗

PubMed1992

Absence of biological effects of orally administered interferon-beta ser.

To assess biological effectiveness of interferon (IFN) administered orally, we measured serum IFN and several proteins and metabolites induced by IFN after oral administration of 2.5 mg or 7.5 mg of recombinant IFN-beta ser to 6 healthy volunteers. These IFN-induced metabolites, beta 2-microglobulin, and neopterin in serum, and 2',5'-oligoadenylate (2-5A) synthetase in peripheral blood mononuclear cells, are more sensitive to the presence of IFN than bioassay of IFN in serum. Up to 48 h after oral IFN was administered, serum IFN, beta 2-microglobulin, neopterin, or 2-5A synthetase were not generally increased compared to pretreatment levels, indicating that oral IFN had no significant biological effects.

Adenine Nucleotides↗

PubMed1992

Phase II trials of interferons-alpha and -beta in advanced sarcomas.

Interferons (IFNs)-alpha and -beta were administered to patients with metastatic sarcomas in two different Eastern Cooperative Oncology Group studies. In one study, patients received IFN-alpha 2b, 20 million units/m2 i.v. 5 days/week x 4, then 10 million units s.c.t.i.w. In the second study, patients received IFN-beta ser 180 million units t.i.w. Of 87 patients evaluable for response, there were three responses in 64 patients (5%) treated with IFN-alpha-2b and no responses in 23 patients treated with IFN-beta ser. Severe or life-threatening fatigue with decline in performance status complicated treatment of 37% of patients receiving IFN-alpha 2b and 17% of patients receiving IFN-beta ser. Further investigation of IFNs in sarcomas should depend on evidence from preclinical studies demonstrating synergistic effects of IFNs combined with a cytoreductive modality which has proven activity in these malignancies.

Adult↗

PubMed1988

Tolerance and efficacy of intranasal administration of recombinant beta serine interferon in healthy adults.

We performed two studies to determine the dose-related tolerance and the efficacy of recombinant beta serine interferon (rIFN-beta ser) in experimental rhinovirus infection. In the tolerance study, 120 healthy adults received intranasal sprays of rIFN-beta ser or placebo daily for 25 d. No differences in nasal symptoms were found. Rhinoscopy detected more mucosal bleeding sites in high-dose (38%) versus low-dose (12.5%) or placebo (12.5%) recipients. There were more subepithelial lymphocytes in nasal biopsy specimens in the high-dose (54%) than the low-dose (17%) or placebo (17%) groups. In the efficacy study, 34 volunteers received daily nasal drops of IFN, beginning 36 h before challenge and for three days afterwards. The numbers of infections and days of shedding of virus were not reduced, but colds occurred less often in the high-dose (25%) than in the low-dose (55%) or placebo (64%) recipients. Nasal mucus weights were lower in the high-dose (mean +/- SD g per five days; 5 +/- 4) than placebo (31 +/- 37) recipients. Thus, rIFN-beta ser may have a more favorable therapeutic ratio than do previously tested alpha interferons.

Administration, Intranasal↗

PubMed1989

Liposomal interferon-beta: sustained release treatment of simian varicella virus infection in monkeys.

Liposomal formulations (distearoylphosphatidylcholine:dipalmitoylphosphatidylglycerol, 9:1) of recombinant human interferon-beta ser17 (IFN-beta), administered im to African green monkeys at doses of 10(7) units/kg on days 1 and 6 after infection with simian varicella virus, resulted in partial protection of the monkeys from viral infection. Aqueous interferon administered under the same dosing regimen was ineffective. When given at 10(6) units/kg per dose twice daily for 10 d, however, it was highly effective in reducing viremia and rash. The antiviral efficacy obtained with the liposomal IFN-beta formulation given in two injections 5 d apart was thus significantly more efficacious than aqueous IFN-beta given in the same dosing regimen. However, it was not as efficacious as repeated, twice-daily injections of aqueous IFN-beta. Thus, im-injected liposomal IFN-beta, which results in sustained release of the IFN-beta from the injection site, exerts antiviral efficacy in a primate model superior to that obtained with the identical dosing regimen of aqueous IFN-beta.

Animals↗

PubMed1989

Ineffectiveness of recombinant interferon-beta serine nasal drops for prophylaxis of natural colds.

Two randomized, double-blind, placebo-controlled trials during early autumn of 1986 and 1987 evaluated the efficacy and tolerance of recombinant interferon-beta serine (rIFN-beta ser) nasal drops for prevention of natural rhinovirus colds. In 1986, 9 X 10(6) units of rIFN-beta ser (139 subjects) or placebo (157) were administered once daily except Sundays for 4 w. Rhinovirus colds occurred in 2.8% of rIFN-beta ser recipients and 6.0% of placebo recipients during the treatment period (52% reduction, P = .3). In 1987, 24 X 10(6) units of rIFN-beta ser (186) or placebo (197) were given daily for 25 consecutive days. Rhinovirus colds developed in 6.3% of rIFN-beta ser recipients and 5.3% of placebo recipients. In each study, illness frequency and number of days with subjective colds did not differ between the groups. Recipients of nasal drops of rIFN-beta ser at either dosage did not differ in tolerance from placebo recipients. The lack of both prophylactic efficacy and nasal toxicity are in contrast to prior observations with nasal sprays of rIFN-alpha 2b.

Administration, Intranasal↗

PubMed1989

Human biologic response modification by interferon in the absence of measurable serum concentrations: a comparative trial of subcutaneous and intravenous interferon-beta serine.

The effect on a range of biologic responses of interferon-beta serine (IFN-beta ser), administered by either the sc or the iv route, was examined in 16 patients. Despite the absence of IFN in the serum of 13 of 16 patients after sc administration, biologic changes associated with IFN administration occurred. Significant increases in peripheral mononuclear cell surface proteins were evident. Monocyte human leukocyte antigen-DR (HLA-DR) showed a 23% increase in mean fluorescent intensity (P = .04) and a 9% increase in percentage of positive cells (P = .02); lymphocyte OKT10 had an 11% increase in percentage of positive cells (P less than .0001) and a 26% increase in mean fluorescent intensity (P = .002). Natural killer cell activity against the Change target increased by 125% (P = .004). Intracellular activity of 2',5'-oligoadenylate synthetase increased 297% at 24 hours and 226% at 48 hours (P less than .0001). Significant increases in serum concentrations of beta 2 microglobulin (24% at 24 hr and 27% at 48 hr, P less than .0001) and neopterin (85%, P = .0001 and 165%, P = .00001) were observed. These alterations after sc administration were similar quantitatively to those resulting from the same dose of IFN-beta ser given iv. Thus, serum IFN concentrations did not have to be measurable for IFN-beta ser to exert biologic activity. The different effects of two dose levels, 45 X 10(6) IU and 180 X 10(6) IU, also were compared independent of route. The higher dose resulted in greater increases over baseline of 2',5'-oligoadenylate synthetase activity (344% vs. 145% at 24 hr; 231% vs. 83% at 48 hr) and serum neopterin concentrations (185% vs. 99% at 24 hr; 271% vs. 153% at 48 hr). For all the other parameters, there was no significant difference between the two doses.

2',5'-Oligoadenylate Synthetase↗

PubMed1989

Selective interferon-induced enhancement of tumor-associated antigens on a spectrum of freshly isolated human adenocarcinoma cells.

Freshly isolated cells from patients with pleural or peritoneal effusions cytologically diagnosed as adenocarcinoma (n = 43), malignant nonepithelial neoplasms (n = 10), and benign (n = 8) were analyzed for expression of constitutive levels of the tumor antigens TAG-72 [recognized by monoclonal antibody (MAb) B72.3] and carcinoembryonic antigen (CEA) (recognized by MAb COL-4) as well as the class I and class II major histocompatibility (MHC) antigens, and the ability of human interferons (Hu-IFNs) to enhance cell surface expression of those antigens as measured by MAb binding. Both type I and type II IFNs enhanced the expression of TAG-72 and CEA and altered the level of expression of the MHC antigens. Comparative studies of three different Hu-IFNs (IFN-alpha A, IFN-beta ser, and IFN-gamma) revealed that IFN-gamma was the most potent in augmenting either B72.3 or COL-4 binding. Unlike the IFN-gamma -mediated induction of the class II human leukocyte antigens, the change in tumor antigen expression consisted of enhanced constitutive antigen expression; de novo induction of either TAG-72 or CEA could not be achieved by either type I or type II IFN. Of 43 effusions isolated from different adenocarcinoma patients, 42 (97.7%) expressed either CEA or TAG-72, and treatment with Hu-IFN increased the level of expression of either antigen in 36 of 42 samples (85.7%). These studies demonstrate the augmentation of tumor-associated antigens on human carcinoma cells isolated from serous effusions by Hu-IFNs which may be used to enhance the targeting of conjugated MAbs to human carcinoma lesions.

Adenocarcinoma↗

PubMed1987

Growth of astrocytomas in the human tumor clonogenic assay and sensitivity to mismatched dsRNA and interferons.

Nine astrocytoma specimens were received from seven patients and processed for testing in the human tumor clonogenic assay (HTCA). Cells derived from these specimens were challenged with human natural alpha-interferon (alpha-IFN) and beta interferon (beta-IFN), recombinant beta interferon (beta ser-IFN), and mismatched double-stranded (ds) RNA (Ampligen). Six of the astrocytoma specimens formed adequate colonies for drug sensitivity testing (greater than or equal to 30 colonies/plate), and all were high-grade (III-IV) tumors. Sensitivity was defined as a greater than or equal to 50% decrease in tumor colony formation following drug exposure and was observed with alpha-IFN (2/4), beta-IFN (3/4), and mismatched dsRNA (4/5) exposure. No decrease in colony growth was observed after recombinant beta ser-IFN exposure, and in 2 of 3 cases, colony formation was stimulated. The sensitivity of 75 non-CNS solid tumors to mismatched dsRNA was compared to the high-grade astrocytomas in the HTCA. Of the 10 additional histologic tumor types studied, carcinoid and renal cell carcinomas exhibited the greatest sensitivity to mismatched dsRNA: 63% and 52%, respectively. However, in comparison, 80% of the high-grade astrocytomas were sensitive, demonstrating that these gliomas are among the most sensitive of human tumors to mismatched dsRNA in vitro. Clinical trials of interferons and mismatched dsRNA, coupled with in vitro sensitivity studies, should further define their therapeutic potential.

Astrocytoma↗