Gene Modulatory Effects, Pharmacokinetics, and Clinical Tolerance of Interferon-α1b: A Second Member of the Interferon-α Family

Abstract

Interferon-alpha1 (IFN-alpha1), which may have a primary role in innate immunity, differs significantly in amino-acid sequence from IFN-alpha2, the only recombinant IFN-alpha with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5-270 mug/m(2) of recombinant IFN-alpha1b. Gene modulation, pharmacokinetics, tolerability, and disease response were determined. Significant (P<0.01) dose and gene-dependent increases of 2-10 fold occurred in IFN-stimulated genes, including four (tumor necrosis factor-related apoptosis-inducing ligand, cig 5, p56, GEM) never previously identified as increased in patients; significant increases (P<0.01) resulted at the lowest dose (1.5 microg/m(2); 1.5 x 10(4) human antiviral units/m(2)). Increases (P<0.01) were sustainable for >4 weeks. Peak levels of IFN-alpha1b were at 3 h; an increase of approximately eightfold in both C(max) and AUC occurred between 15 microg/m(2) and 270 microg/m(2). Chronic toxicities of anorexia, weight loss, and fatigue were relatively uncommon. Eighteen patients were treated for >8 weeks; none experienced >grade 1 weight loss. Three patients at the highest dose developed grade 3 fatigue after > or =3 months, which required dose reduction or discontinuation. Patient acceptability of fatigue defined a dose for initiation of Phase II trials, 270 microg/m(2). Six patients (five with renal cell carcinoma) had progression-free survival for >1 year, including two who had partial responses. IFN-alpha1b resulted in potent stimulation of IFN-regulated genes and tumor regressions in renal cell carcinoma. Unique gene modulatory effects, when coupled with the moderate severity of side effects and a potentially central role in innate immunity, provide rationale for further clinical evaluation of IFN-alpha1 in virus infections and cancer.

Adjuvant activity of type I interferons

“…All type I IFNs induce comparable qualitative biological activities although quantitative differences in the activity of different subtypes has been reported (Masci et al, 2006). All type I IFNs bind to a common high-affinity cell surface receptor composed of two trans-membrane polypeptides, IFNAR1 and IFNAR2.…”

The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53- Independent Manner in Colon and Breast Cancer Cells

“…Interferons (IFN) type I are pleiotropic cytokines with antiviral and antitumor activities that are widely used in the clinic [8], [9]. In clinical trials and experimental settings the combination of IFNα with 5-FU has been demonstrated to be superior to 5-FU administered alone, although the mechanism of this synergistic effect is still poorly understood [10], [11], [12], [13].…”

Enhanced delivery efficiency and sustained release of biopharmaceuticals by complexation-based gel encapsulated coated microneedles: rhIFNα-1b example

“…The subtype IFNα1b is the first IFN recombined and commercialized in China (rhIFNα-1b), which cloned the gene from healthy Chinese cord blood leukocytes [2] . It was extensively studied for the antivirus treatment of RSV [3] , HBV [4] , [5] , [6] , and SARS-CoV [7] as well as antitumor treatment [8] , [9] , [10] . Considering that frequent injections cause a burden to patients during rhIFNα-1b treatment, it is essential to develop a non-invasive administration.…”