Interferons1

[CANCER RESEARCH 58. 2489-2499, June 15. 1998] Review

Biological Properties of Recombinant Â«-InterfÃ©rons:40thAnniversary of the Discovery of Interferons1

Lawrence M. Pfeffer,2 Charles A. Dinarello, Ronald B. Herberman, Bryan R. G. Williams, Ernest C. Borden, Ronald Bordens, Mark R. Walter, Tattanahalli L. Nagabhushan, Paul P. Trotta, and Sidney Pestka

Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38163 [L M. P.]; Department of Medicine, University of Colorado Health Science Center, Division of Infectious Diseases, Denver, Colorado 80262 1C. A. D.J; Departments of Medicine and Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 [R. B. H.]: Department of Cancer Biology, Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195 Â¡B.R. G. W.Â¡;University of Maryland School of Medicine Cancer Center, Baltimore. Maryland 21201 Â¡E.C. B.]; Schering-Plough Research Institute, Kenilworth, New Jersey 07033 [R. B.}; Department of Pharmacology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005 [M. R. W.]; Canji, Inc., San Diego, California 92121 IT. L. N.I: Applied Clinical Communications, Inc., Parsippany, New Jersey 07054 IP. P. TJ; and Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscalaway, New Jersey 08854-5635 [S. P.Â¡

Abstract whereas IFN-/3 is produced by fibroblasts. Another type I IFN, IFN-r, has been described only in ungulate species [see Pestka (3) for a IFNs were first described as potent antiviral agents 40 years ago, and review and specific references]. Type II IFN, which is acid labile, is recombinant IFN-a^ and IFN-a2h were approved for the treatment of referred to as IFN-7 or immune IFN and is a product principally of hairy cell leukemia just 11 years ago. Today, a-IFNs are approved world activated T cells and NK3 cells. Whether type I or II IFNs are wide for the treatment of a variety of malignancies and virologie diseases. Although the exact mechanism of action of IFN-a in the treatment of such produced depends on the stimulus and the nature of the cell that is diseases is not fully understood, many advances have been made in the being stimulated. The family of IFN-a genes is now known to consist characterization of the physicochemical and diverse biological properties of at least 14 distinct members, which encode 12 different proteins (3, of this highly pleiotropic cytokine. Here we review recent developments in 4). The IFN-a species are partially homologous in amino acid se our understanding of the antiviral and immunoregulatory properties of quence (about 75-80%) and generally display a high level of species IFN-a, the nature of the multisubunit IFN-a receptor, and the molecular specificity in their biological properties. mechanisms of signal transduction. Where available, we have included comparative data on recombinant a-IFNs derived from both naturally The IFNs act on the target cell (not on the virus) to confer a state of resistance to viral infectivity at one or more phases of the viral occurring and nonnaturally occurring synthetic genes. We also review clinical data and data on the side effects and antigenicity of different replication cycle. IFNs bind to specific cell surface receptors as the sources of recombinant a-IFNs in humans. These latter topics are of first obligatory step in the expression of their biological activity. clinical interest, because they may potentially affect the efficacy of these IFN-a and -j3 compete for binding to the same cell surface receptor, various products. Hopefully, what is already known about IFN will which is distinct from the IFN-y receptor. Two distinct receptor prompt further exploration into the mechanism(s) of action of IFN-a and subunits for IFN-a have been cloned and are referred to as IFN-aR 1 thus deliver new applications for this prototypic cytokine, whose full and IFN-aR2 (5-9). The IFN-aR2c polypeptide seems to be the major therapeutic potential is yet to be realized. ligand-binding component of the receptor complex, because it has an Introduction affinity for several IFN-a subtypes, as compared with IFN-aR 1, which plays an important role in signal transduction. Forty years have passed since the discovery of IFN by Isaacs and Based on numerous investigations with recombinant IFNs, it is Lindenmann (l), and 11 years have passed since the United States now well established that IFNs are highly pleiotropic cytokines, Food and Drug Administration approved recombinant IFN-a for the which demonstrate broad and potent immunoregulatory and anti- treatment of hairy cell leukemia. Isaacs and Lindenmann observed proliferative properties in addition to their antiviral effects against that chick chorioallantoic membranes incubated with a heat-inacti a variety of both RNA and DNA viruses (10-13). These various vated influenza virus produced a substance called IFN that conferred biological properties have suggested broad clinical applications. on fresh membranes a resistance to infection by live virus (2). IFNs The availability of multigram quantities of recombinant IFNs has were later shown to have the properties of a protein and to consist of permitted their evaluation as therapeutic agents in a variety of a family of distinct proteins, many of which are structurally related in cancers and virologie indications. Recombinant a-IFNs are now both amino acid sequence and three-dimensional structure. Type I approved worldwide in over 40 countries for the treatment of more IFNs have been categorized into IFN-a, -ÃŸ,and -o>, based on their than 14 malignancies and virologie diseases, including adjuvant immunogenic properties and amino acid sequences, and are generally therapy in metastatic melanoma, condyloma acuminata, Kaposi's acid stable. IFN-a species and IFN-io are products of leukocytes, sarcoma, and hepatitis B and C (14). Recently, a novel synthetic IFN-a termed IFN-conl has been tested in chronic hepatitis C Received 11/5/97; accepted 4/21/98. (15-17). This synthetic, nonnaturally occurring IFN was designed The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with by assigning each of the most frequently observed amino acids in 18 U.S.C. Section 1734 solely to indicate this fact. several IFN-a subtypes (18). Overall, IFN-conl has significant 1The contents of this article reflect data presented at a closed round table meeting entitled "Recombinant a-IFNs from Naturally Occurring Genes: The Gold Standard homology to IFN-o2 and IFN-a7. Continues," held in Tucson, Arizona from January 17-19, 1997. The meeting and The purpose of this review is to summarize the most recent devel- preparation of this article were supported by an unrestricted educational grant from Schering Oncology/Biotech, a division of Schering-Plough Corporation. A portion of the text represents work that was performed by C. A. D. and supported in part by NIH Grant 1 The abbreviations used are: NK, natural killer; IFN-conl, consensus IFN; ISRE, AI-15614. IFN-stimulated response element; ISO, IFN-stimulated gene; VSV, vesicular stomatitis 2 To whom requests for reprints should be addressed, at Department of Pathology, virus; IL, interleukin; TNF, tumor necrosis factor; JAK, Janus kina.se; STAT, signal University of Tennessee Health Science Center, 899 Madison Avenue, Memphis, TN transducers and activators of transcription; PGE2, prostaglandin E-,; COX, cyclooxygen- 38163. Phone: (901) 448-5362. ase; CML, chronic myelogenous leukemia. 2489

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1998 American Association for Cancer Research. a-IFNS: PROPERTIES AND APPLICATIONS opments in our current knowledge about the biochemical and biolog Table I Designations for type I human IFN of receptor components" ical properties of recombinant IFN-a species derived from naturally mRNAHu-IFN-aRl,Polypeptide chain or occurring and synthetic genes. Hu-IFN-aRaHu-IFN-aRls, (splicevariant Hu-IFN-aRb The IFN-a Receptor: A MultisubunU Structure V)Hu-IFN-aR2amissing exons IV,

A recent significant advance in understanding the mechanism of form)Hu-IFN-aR2b(short form)Hu-IFN-aR2c(soluble action of IFN-a has been the determination by high resolution X-ray form)aYAC (long crystallography of the three-dimensional structure of a zinc dimer of recombinant IFN-a2b (Fig. 1; Ref. 19). This topology was found to (FI36C5)Gene1FNARI1FNAR1IFNAR2IFNAR2IFNAK2IFNAKI,1FNAR2References52122776823 " Adapted with permission from Peslka (Ref. 24). resemble the motifs observed for other ligands of the class 1 and class 2 cytokine receptors (19). Based on structural comparisons with other cytokines as well as on the effects of mutations on biological activity, protein surfaces on the molecule were identified that might be in aRl is a 557-amino acid glycoprotein with a 21-amino acid trans- volved in interacting with the receptor and triggering a biological membrane segment and a 100-amino acid cytoplasmic domain. The response. This structure provides a basis for further research in elu requirement of the IFN-aR 1 component for type I IFN signaling was cidating receptor-ligand interactions. demonstrated directly by the observation that homozygous deletions The receptor subunits for IFN-a are members of the class II of IFN-aR 1 in mice caused a loss in antiproliferative activity of cytokine receptor family (5-8, 20) and are related to the fibronectin IFN-a and IFN-ÃŸas well as an enhanced sensitivity to viruses (25, type III structure, which in turn relates these structures to the immu- 26). Embryo fibroblasts from these mice also could not induce 2',5'- noglobulin superfamily. A critical step in receptor activation among oligoadenylate synthetase, which is an enzyme critical for the expres members of this receptor family, which also includes independent but sion of antiviral activity. similar receptors for IFN-y and IL-10, is the ligand-dependent oli- The major ligand-binding component of the type I IFN receptor is gomerization of receptor subunits. IFN-aR2, which exists in three distinct forms: (a) IFN-aR2a (short Two subunits of the IFN-a receptor have been identified to date; form); (b) IFN-aR2b (soluble form); and (c) IFN-aR2c (long form). both are located on human chromosome 21 (Table 1). Human IFN- All three chains are encoded by the same IFN-aR2 gene. The IFN-

Sol M-29

Fig. I. Molecular structure of human IFN-ct2b. A, structure of the human IFN-or2h monomer color coded by secondary structure: blue, a-helices; magenta, 3 ,â€žhelices; and yellow, loops. Although not observed in electron density maps, the connection between helices C and D is modeled for completeness. The start and stop points of the helices are shown. B, the human IFN-a2h dimer viewed approximately parallel to the 2-fold axis. The zinc ion is represented as a red sphere. C, view of the human IFN-a2h dimer perpendicular to the 2-fold symmetry axis. [Reprinted with permission from Radhakrishnan et al. (19).] 2490

aR2c gene has a large intracellular domain compared with the short domain of the IFN-aR2a polypeptide. IFN-aR2b is the soluble form of the receptor (6, 7). The longest form, IFN-aR2c (515 amino acids), acts as a functional receptor in type IIFN signaling (6, 8). Thus, the expression of this isoform restores the normal cell response to type I IFNs to a cell line defective in type I IFN binding and JAK-STAT activation (8). The protein tyrosine kinases Tyk2 and JAK1 are constitutively associated with IFN-oRl and IFN-aR2, respectively (7, 27-29). The various cytokines that use the JAK-STAT signal transduction pathway activate unique combinations of JAK and STAT proteins. Current evidence suggests that the JAKs do not contribute to the specificity of the JAK-STAT signal transduction pathway to the same extent as the STATs (3, 30). SH2, SH3, and DNA-binding domains are present in STAT proteins (31, 32). The choice of which STAT transcription factors are recruited to a specific receptor complex is determined by the specific interaction between the SH2 domains and the phosphotyrosine-containing recruitment sites on the intracellular domains of the cytokine receptors (33, 34). 0.1 1 10 100 1000 Affinity cross-linking of radiolabeled IFN-a2b to a variety of hu IFN concentration, nM man cells results in the formation of IFN receptor complexes of 120,000-150,000 dallons (35, 36), which can be resolved into discrete 120,000-, 130,000-, and 150,000-dalton cross-linked complexes (37). Whereas the IFN-aRl polypeptide chain seems to correspond to a B 110,000-135,000-dalton protein (33), the IFN-aR2c corresponds to a ~ 100,000-dalton protein (6, 8, 33). A number of studies also suggest other undefined receptor components (22, 38, 39). For further information on the properties of the IFN-a receptor and the history of its discovery and characterization, the interested reader is referred to several reviews (20, 24, 40-42).

Competition between IFN-a Species for Binding to the Cell Surface Receptors Studies with iodinated type I IFNs have demonstrated that there are 500-5000 high-affinity binding sites per human cell (Kd = 50 pM: Refs. 33 and 43). The Daudi cell line, a B lymphoblastoid cell line, and the CaKi cell line, which is derived from a renal cell carcinoma, were chosen for the binding studies summarized here because they are highly sensitive to the antiviral, antiproliferative, and gene-inducing effects of type I IFNs (44-46). Competitive binding studies have 0.1 1 10 100 1000 indicated that IFN-conl, IFN-a8, and IFN-a2h bind with similar IFN concentration, nM affinity to the type I IFN-a receptor on human cells, whereas IFN-a7 Fig. 2. Competitive binding experiments with '"l-labeled IFN were conducted in the has different receptor binding properties. With either the Daudi cell Daudi and CaKi cell lines for IFN-a2b, -a7, -aÂ«,-ÃŸ.and -coni. A. results of experiments in the Daudi cell line. IFN-conl was iodinated lo a specific activity of ~75 Ci/g. Daudi line (Fig. 2A) or the CaKi cell line (Fig. 2fl), competitive binding cells were incubated at 2 X IO6 cells/ml binding medium (RPMI 1640 containing 5% experiments with I25l-labeled IFN-conl demonstrated that IFN-conl bovine calf serum and 20 mm HEPES (pH 7.4)] with 50 pM I25l-labeled IFN-conl in the and IFN-a2b as well as IFN-jBcould compete well for the receptor presence of increasing concentrations of unlabeled IFN for 2 h at 15Â°C.The cells were binding sites recognized by 125I-labeled IFN-conl. In contrast, centrifuged through dibutyl-phthalate oil for 1 min at 10.000 X g. The tip of the microcentrifuge tube that contained the IFN bound to cells was cutoff and counted in a IFN-a8 competed poorly for binding, followed by IFN-a7, which was gamma counter. The data represent the ratio of the radioactivity bound to cells in the the weakest competitor (Fig. 2). Similarly, when 125I-labeledIFN- presence of unlabeled IFN:radioactivity bound in the absence of unlabeled IFN X 100%. The results of three separate experiments were averaged. B, results of experiments in the conl or I25I-labeled IFN-o8 was used in competitive binding studies CaKi cell line. CaKi cells (10* cells/2.1 cm2 well) were incubated wilh 50 pM '-''[-labeled with the CaKi cell line, IFN-a2h and IFN-conl competed well for IFN-conl in the presence of increasing concentrations of unlabeled type I IFNs for 4 h at ligand binding, followed by IFN-/3 and IFN-a7, which was a poor 4Â°C.The cells were washed three times with PBS and lysed in 0.5% SDS. and lysates were counted in a gamma counter. The results of four separate experiments were averaged. competitor. It is notable that IFN-a7 competed poorly for binding to [Reprinted with permission from Pfeffer (58).) CaKi cells, although it did demonstrate detectable biological activity on these cells. These results indicate that IFN-conl, IFN-a8, and IFN-a2b have similar affinities for the type I receptor, whereas IFN-a7 competes less used in these studies. This result raises the possibility that different effectively. The relative binding affinities for IFN-a subtypes are as type I IFNs have different binding sites, and IFN-con 1 can bind with follows: in Daudi cells, IFN-a2b = IFN-conl = IFN-a8 Â» IFN-a7; high efficiency to these different sites. However, the implications of and in CaKi cells, IFN-a2b = IFN-conl > IFN-a8 y> IFN-a7. this result for the biological activity profile, therapeutic efficacy, or Interestingly, the number of binding sites recognized by IFN-con 1 toxicity in the clinic of IFN-conl or other IFNs are yet to be estab was consistently higher than those recognized by the other a-IFNs lished. 2491

IFNAR1 ^ ^ IFNAR2-2

Fig. 3. Early events in IFN-a signaling. IFNARI, IFN-a receptor 1; /FNAR2-2, IFN-a re TYK2 CPLA2 ceptor 2c; C-PLA2,cytoplasmic phospholipase A2. STAT2 O

STATI

Mechanisms of IFN-a Signal Transduction by one or two nucleotides (31, 48, 56). The ISRE is a necessary and sufficient component of the induction of genes by IFN-a. The binding of IFN-a to the cell surface receptor initiates signals Further information on signal transduction mechanisms and tran- that are transmitted from the cell surface to the nucleus. IFN-receptor scriptional factors that regulate gene expression by IFN-a may be interaction results in oligomerization of the receptor chains (i.e., the found in recent reviews (24, 57). IFN-a-occupied IFN-aR2 associates with the IFN-aRl chain), which triggers a tyrosine phosphorylation cascade. IFN-a receptors lack Antiviral Activity intrinsic protein kinase activity but are associated with JAKs, which are activated by receptor binding. The receptor-associated JAKs Various recombinant type I IFNs from naturally occurring genes and the synthetic IFN-conl have been tested for their ability to induce transphosphorylate each other, and the activated kinases, in turn, may phosphorylate tyrosine residues on the associated receptor chains. The an antiviral effect on human cells (58). Cells were treated overnight early events in IFN-a signaling are depicted in Fig. 3. with varying concentrations of a-IFNs, followed by infection with VSV at a multiplicity of infection of 0.1 plaque-forming units/cell. The phosphorylated residues on the receptor chains become dock ing stations for the cytoplasmic STAT proteins (i.e., signal transducers The Vero cell line was used as an indicator cell line to titer the virus and activators of transcription), which themselves are phosphorylated by receptor-associated JAKs. STAT proteins contain a unique tyrosine residue near the carboxyl terminus (i.e., Y701, Y690, and Y705 in CELL STATI, STAT2, and STAT3, respectively) that is phosphorylated by SURFACE JAKs in response to IFN-a and other cytokines (47). It was reported that Tyk2-mediated phosphorylation of tyrosine 466 of IFN-aRl P- serves as a docking station for STAT2, which is phosphorylated by TYK2 JAK.2 -P Tyk2 at tyrosine 690 (29). STATI then docks to the receptor-bound -P P- J' JAKP-1 phosphorylated STAT2, which is phosphorylated at tyrosine 701. However, other reports have suggested that the IFN-aR2c chain constitutively binds STAT2. As a consequence of this phosphorylation cascade, the formation of a STAT1-STAT2 heterodimer and a STATI-STATI homodimer oc CYTOPLASM curs (Fig. 4). The activated, phosphorylated dimeric STATs translo cate to the nucleus, where they interact with their cognate enhancer elements upstream of the ISGs. The STAT1-STAT2 heterodimer binds to the p48 protein to form a trimeric complex ISO factor 3, which activates the ISRE sequences on the cognate genes (Refs. 31, 47, and 48; Fig. 4). IFN-a-inducible genes that do not contain the ISRE sequence are also activated by dimers of STAT proteins (49, 50). Cytoplasmic phospholipase A2 has been implicated in the trans- activation of the ISRE-containing genes (51, 52). The result of this complex pathway is the expression of a set of genes that mediate the multiple biological activities characteristic of a-IFNs. Fig. 4 also contains, for comparison, the signal transduction mechanisms for IFN-y. The ISGs that are induced by IFN-a are normally either quiescent or are expressed at low levels. Their expression is regulated at the level of transcription in a rapid, transient process that lasts only for several hours (53). This effect is mediated through an enhancer termed NUCLEUS the ISRE, which is characterized by a conserved 15-bp element (54, 55). This conserved element has a consensus sequence GAAAN(N)GAAA (where N is any nucleotide), which is character Fig. 4. Mechanisms of gene activation by IFNs. GAP, IFN--y-activated factor; IR, ized by a direct repeat of the nucleotide sequence GAAA spaced apart inverted repeat; IRBF, IR binding factor; ISCF3, ISC factor 3; X and Y. unknown factors. 2492

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1998 American Association for Cancer Research. a-IFNS: PROPERTIES AND APPLICATIONS released into the medium. Significant differences were observed be Table 3 Effects of IFN-a on the activity of NK cells" tween the IFN-a subtypes with respect to their ability to induce Effector phase antiviral activity; the dose dependence for this effect is shown in Fig. Increase in binders (seen with only some targets) 5. IFN-conl and IFN-a2b demonstrated similar ability to induce an Nonlytic binders activated to lytic activity Accelerated kinetics antiviral state, which was significantly greater than that induced by Recycling (lysis of multiple targets) either IFN-a7 or IFN-ag. The antiviral activities of the latter two Effects on target cells Decreased susceptibility to NK cells (seen with only some targets) subtypes were nearly equivalent. IL-2-dependent growth These results are, in general, consistent with the results of compet Increased response to IL-2 itive-binding experiments cited previously. However, it is notable that Induction of T cell-dependent growth inhibition IFN-a7 competed very poorly for ligand binding, despite having " Adapted with permission from Herberman (Ref. 59). significant antiviral activity. It is important to recognize that the relative binding affinities and antiviral activities for the various IFN-a subtypes are also a function of the experimental conditions in the adhesion molecules. The availability of recombinant natural and syn respective assays (e.g., the cell line chosen, the conditions of its thetic IFNs has permitted a systematic study of the relative potency in growth, and the virus). Thus, caution must be exercised in comparing affecting immune function. This information has also provided in sights into structure-function relationships. binding affinities and antiviral titers that were obtained under different experimental conditions. The augmentation of the cytotoxic activity of NK cells has been the most extensively studied effect of IFN-a on immunological effector Immunoregulation cells, with exposure times as low as 1-2 h resulting in a significant effect (60-64). The complex variety of mechanisms potentially re IFN-a can affect the growth, differentiation, and function of vari sponsible for the augmentation of NK activity by IFN-a are summa ous types of cells in the immune system (Table 2). In addition to rized in Table 3. Interestingly, certain target cells incubated with having these pleiotropic effects, IFN-a can also modulate the ability IFN-a show a diminished susceptibility to lysis by NK cells, an effect of various immunological effector cells to interact with malignant most likely mediated by enhanced expression of class I MHCs (65). cells or virus-infected cells. The latter is mediated, at least in part, IFN-a can also affect other functions of NK cells, including antibody- through enhanced expression of class I MHC antigen and cellular dependent cellular cytotoxicity against antibody-coated NK-resistant target cells (66). IFN-a can also broaden its immunomodulatory effects by enhancing the production and/or release of various cyto- 100000000 kines from NK cells (67). h 10000000 Purified recombinant IFN-a subtypes differ significantly in their

^.:-r.GCt>3ai-aÂ£1000000100000100001000100A ability to augment NK activity (60). The most unexpected result was noted with the species IFN-a7. Pretreatment, even with high concen trations, failed to induce significant augmentation of NK activity, although IFN-a7 still possessed antiviral and antiproliferative activi ties (61). Competitive binding analysis and direct binding studies with radiolabeled IFN-a7 demonstrated that this lack of NK-boosting activity was not due to a failure of IFN-a7 to interact with its receptor (68). Additional studies revealed that substitutions at residues 116 and 132 could significantly enhance the NK-stimulating activity of this species (62). One study has compared IFN-conl with IFN-a2h and 100 1000 10000 IFN-a2a with respect to their ability to enhance NK activity and IFN concentration, U/ml mediate other biological functions (69). NK augmentation was meas Fig. 5. Antiviral activity induced by type I IFNs in CaKi cells after infection with VSV. ured at the same protein concentration of each species, and under CaKi cells (IO5 cells/30-mm well) were preincubated overnight with type I IFNs at these conditions, IFN-conl demonstrated a superior ability to boost varying concentrations and infected with VSV (Indiana strain) for 1.5 h at O.I plaque- forming units/cell. At 24 h postinfection, the virus yield in the medium was assayed by NK activity per unit mass. Another study has compared IFN-a 1 to plaque formation on Vero cells. The results of four separate experiments were averaged IFN-a2a and demonstrated equivalent activity in vitro and in vivo and expressed as the -fold reduction in VSV titer. D, tÂ»2;Ãˆ, al; O, Â«8;Ãœ,coni. (Reprinted with permission from Pfeffer (58).] (70, 71). Regulation of Proinflammatory Mediators Table 2 Pleiotropic effects of IFN-a on the immune system" PGE2. IFN-a therapy has been associated with fever and flu-like Increases in membrane antigens, especially class I MHC antigens and cellular adhesion molecules, on tumor cells and effector cells symptoms, not unlike those reported with low doses of IL-1 or TNF. Promotion of differentiation of various lymphoid cells As with IL-1 and TNF, these symptoms are ameliorated by coadmin- Activation of effector cells Augmentation of NK cell activity istration of COX inhibitors. Given the release of arachidonic acid Activation of macrophages induced by IFN-a-mediated activation of phospholipase A2 in vitro, it Stimulation of generation of immune T cells (weak relative to IFN-y) is not surprising that IFN-a induces PGE2, which may account for Effects on multiple functions of lymphoid cells Cytotoxicity these IFN-associated symptoms. In a rabbit model of fever, IFN-a Cytokine production induces an endogenous pyrogen-like fever, which is not due to con Possible alteration of homing patterns in vivo taminating endotoxins. In rabbit brain homogenates, IFN-a triggers Effects on proliferation of lymphoid cells Inhibition of proliferation of activated lymphocytes in vitro the production of PGE2 during a short incubation (72). This induction Increases in number of NK cells in vivo explains, in part, the fever due to IFN. Similar to IFN-a, IL-1 also Effects on endothelial cells Antiangiogenesis induces brain PGE2 synthesis (72, 73). Thus, the observation that Increase in cellular adhesion molecules COX inhibitors reduce fever and the generalized symptoms is con " Adapted with permission from Herberman (Ref. 59). sistent with the rapid release of arachidonic acid by IFN-a and the 2493

Side Effects and Antigenicity of IFN-a Inflammatory processes, nonbacterial infection, Side effects and antigenicity are unwanted extensions of clinical hepatitis, other viral infections, use. Side effects of IFNs, which almost certainly reflect an extension melanoma of gene modulatory and physiological actions, can be considered in IFN two groups: (a) those that commonly limit dosage; and (/?) those that do not (87). The most troublesome of the former are chronic consti tutional effects that begin a few weeks after the initiation of IFN-a therapy. These include fatigue, anorexia, weight loss, depression, IFN impaired cognitive function, and diminished sexual interest and po tency (88, 89). Although of marked variability from patient to patient, side effects may substantially influence the quality of life. In addition, antigenicity of IFNs may influence the development of resistance without causing any side effects. Studies of pathophysiological mechanisms underlying these chronic toxicities have begun in preclinical models (90). IFN-a- Fig. 6. Effects of inflammatory processes, nonbucterial infections, hepatitis, other viral infections, and melanoma on the induction of blood monocytes and tissue macrophages to induced hypothalamic dysfunction resulting in early satiety has been produce proinflammatory cytokines such as IL-1. TNF, and IL-8. These in turn stimulate correlated with patient reports. Weight loss may result from early bystander cells via the specific cell receptors for each cytokine. In hepatitis, this bystander cell is a hepalocyte. an endothelial cell, or a Kupffer cell. In melanoma, the bystander cell satiety or anorexia or may be related directly to hypothulamic dys is an endothelial cell. These bystander cells can induce more inflammatory cells to function. Fatigue may be related to endocrinological, neurotransmit- emigrate into the tissue or produce growth factors for fibrosis or tumor growth. When the primary macrophage stimulant is IL-1 or TNF, IFN acts to inhibit the production of IL-1. ter, hypothalamic, or endocrinological dysfunction (91, 92). No con TNF. and IL-8, thus providing a negative signal ( â€”).IFN also stimulates macrophages to trolled studies suggest how this might be alleviated. Among the produce IL-IRa and release soluble TNF receptors, thus providing a positive signal {+ ). psychological disturbances due to IFN therapy, depression has These actions, in turn, block the ability of either IL-1 or TNF to exert its respective biological effects on the bystander cells. emerged as a clinically important manifestation (93, 94). The depres sion may be nothing more than minor mood alteration or may progress to meeting psychiatric criteria for major depression. Acute toxicities occur on the first day or two of administration and ability of constitutive COX (also called COX-1) to oxidize this include fever, chills, malaise, and arthralgias. Although unpleasant, substrate into PGE2. In contrast, there is little information about the these are rarely dose limiting, can be partially alleviated with acet ability of IFN to induce COX-2. IL-1 is a very potent inducer of aminophen, and spontaneously dissipate after no more than a few COX-2 and accounts for the dramatic systemic changes after i.v. days. They probably reflect PGE2 synthesis and/or other cytokines injection of IL-1 into humans (74). (72, 73, 95). Myelosuppression and occasionally thrombocytopenia Proinflammatory Cytokines and Cytokine Antagonists. The occur universally but usually reach a nadir plateau despite continued production of the proinflammatory cytokines IL-1 and TNF and the administration. Bone marrow suppression reverses within a few days various chemokines from human blood monocytes is often used to of stopping therapy and rarely causes clinical complications. Hepatic indicate the presence of disease (Fig. 6). Some investigators proposed toxicity, manifested as transaminase elevations, may be more serious that the symptoms associated with IFN-a therapy were due to IFN- and. if not detected, may lead to death. dependent IL-1 and TNF production. This hypothesis was supported Certain patients treated with IFN-a for either viral or malignant by reports that IFN. particularly IFN-y. induced IL-1 and TNF from diseases may develop antibodies to the administered protein human blood monocytes in vitro [reviewed by Schindler et al. (75)]. [reviewed by Antonelli (96, 97), Vial and Descotes (98). and McK- However, this finding could not be confirmed using the blood mono enna and Oberg (99)]. The extent and nature of such antibody pro cytes from over 30 human donors (76, 77). Thus, the presence of small duction, which has been observed with both recombinant and natu amounts of endotoxins introduced into the monocyte cultures seemed rally occurring preparations, depend on the patient population, the to explain why some investigators reported that IFN induced the type of IFN-a administered (e.g.. synthetic versus naturally occurring production of IL-1 and TNF. In an attempt to remove all exogenous IFN-a), and the dosage and scheduling of administration. Antibody cytokine-inducing agents that might be present in commercially avail production may even be naturally occurring (100). The detection of able culture media, ultrafiltration with highly hydrophobic hollow- antibodies to administered proteins like IFN-a and their quantitation fiber membranes was used (78-80) that resulted in no spontaneous will also be related to the type of assay methodology used for IL-IÃŸor TNF gene expression or synthesis (75-77, 81 ). The addition detection; standardization is essential (101). Because the formation of of IFN-y or IFN-a to human blood monocytes cultured in ultrafiltered such antibodies may have clinical consequences for the therapeutic tissue culture media did not induce IL-1 or TNF (75-77, 81). As potential of IFN-a, the state of current knowledge on the incidence of expected, the addition of IFN-y enhanced endotoxin-induced IL-1 and antibody formation to IFN-a in man are reviewed below. TNF production (75-77, 81). In virologie and oncologie diseases, the highest incidence of bind The effects of IFN-y and IFN-a on IL-1-induced IL-1 were exam ing antibodies has been observed for lymphoblastoid IFN in patients ined. Previous studies have reported that IL-1 induced its own pro with papillomatosis (66.0%); 6.6% of these were neutralizing (Table duction (82, 83). IL-1 also induced TNF in vitro and in vivo (84). 4). The highest incidence of neutralizing antibody production occurs Either IFN-y or IFN-a suppresses IL-1-induced IL-1 (75-77). Others in patients receiving IFN-a-,a (26.2%). IFN-a-,c has shown the lowest have reported that IFNs suppress the production of the inflammatory incidence of neutralizing antibodies (1.1% of 371 samples). chemokine IL-8 (85). This suppression of IL-8 production took place A comprehensive summary of the literature describing antibodies to at the level of nuclear factor KB, which is a transcription factor IFN-a developed in patients treated with various IFN-a preparations involved in the regulation of many inflammatory response genes (85). for virologie and oncologie indications has also been recently com Other investigators have reported that IFN-a down-regulates nuclear piled by McKenna and Oberg (99). These authors also found a factor KB activity (86). different level of neutralizing and nonneutralizing antibodies with the 2494

Table 4 Summary of recent literature reports of antibodies lo IFN-afor virologie and ments for both low- and intermediate-grade non-Hodgkin's lympho oncologÃ¬eindications" mas (146-148). IFN-a2, 50 X IO6 units/3 X m2/week, was effective samplesBindingof assayed in 45% of patients with advanced cutaneous T-cell lymphomas (149).

Neutralizing In nodular, poorly differentiated B-cell lymphomas, a greater then IFN subtypeNo. antibodies antibodiesReferences 45% response frequency has occurred with IFN-a-, alone, even in Lymphoblastoid 35/53(66.0%) 14/212(6.6%) 102-106 patients previously treated with combination chemotherapy (146, 150, a,. 145/267(54.3%) 141/538(26.2%) 102,103.107-124 151). Combination of IFN-a2 with doxorubicin-based regimens has O2b 7/101 (6.9%) 32/615(5.2%) 102, 103. 112, 114, 125-131 a2c No published data 4/371(1.1%) 132,133 been identified as prolonging both disease-free survival and overall " Adapted with permission from Schering-Plough Research Institute. survival. Despite careful design to ensure that effective chemotherapy doses would not be compromised, total cytotoxic chemotherapy doses were reduced by participating investigators in the chemotherapy-alone various IFNs. Although controlled comparisons were not possible arm on one of these Phase III trials (147). Despite this, a positive because of differences in the treatment protocols, storage of IFNs, and therapeutic impact of IFN-a2 was evident (147). In the other trial, diseases treated, the IFN-a->a preparations produced higher levels of although 11% of patients had to discontinue IFN-a2 due to toxicity, antibodies than did the IFN-a2h and IFN-a2c preparations. However, significant gains were made in event-free survival (P < 0.001) and more recent formulations of IFN-a,., may have reduced the antige- overall survival (P = 0.02) for follicular lymphoma (P = 0.02; Ref. nicity of IFN-a2a(134, 135). 148). Therapeutic Effects of IFN-o In CML, sustained therapeutic responses occur in a majority (>75%) of patients (152-155). A higher dose (5 X IO'1units/m2) than IFNs have achieved a substantial role in clinical medicine, well that required for hairy cell leukemia is needed to achieve the best beyond that of the selective antiviral activity envisioned by Alick therapeutic control. Frequency of administration for optimal clinical Isaacs from his discovery (1). Clinically beneficial therapeutic activity effect has not been critically examined in controlled trials, but higher of IFN-os as a single agent has been demonstrated in hairy cell response rates have been reported with a daily administration rather leukemia, Kaposi's sarcoma, CML. B- and T-cell lymphomas, mela than a 3 times/week s.c. administration. For survival, the superiority nomas, myelomas, and renal cell carcinoma (136, 137). These find of IFN-a2 to busulfan and hydroxyurea. previous therapeutic stand ings have led to regulatory approvals around the world, with IFN ards, has been demonstrated (156,157). In addition to reducing leu- representing the first human protein to increase survival of cancer kemic cell mass, a gradual reduction has occurred in the frequency of patients. Increasing therapeutic effectiveness could lead to wider cells bearing the underlying 9-22 chromosomal translocation. The adoption (brother malignancies such as ovarian, breast, bronchogenic, median survival for responding patients who have any evidence bladder, and gastrointestinal carcinomas and acute leukemias, in (although incomplete) of cytogenetic response is approximately 6 which Phase I or Phase II clinical trials have suggested potential years. Further increase in major cytogenetic response frequency and benefit ( 136). survival has resulted from the addition of l-ÃŸ-o-arabinofuranosylcy- In hairy cell leukemia, IFN-a-, resulted in a gradual decrease in tosine to IFN-a2 (158). bone marrow infiltration with malignant cells as well as a normaliza tion of peripheral hematological parameters. This resulted in reduced Summary and Future Directions morbidity from the disease process and improved quality of life: a reduction in RBC and platelet transfusion requirements; and a de IFNs are effective therapy for malignancies. During the decade creased frequency of infection ( 138). Responses occurred at doses as after the 1986 approval of IFN-a-,h and IFN-a-,., for treatment of hairy low as 0.2 X IO6 units/m2 but were slower than the responses cell leukemia, recombinant IFNs have demonstrated broad applica observed at the more conventional dose of 2 x IO6 units/m2 (139). tions in cancer as well as virologie diseases. Clinically beneficial Although now supplanted in clinical use by other even more effective therapeutic activity of IFN-a has now been demonstrated in nonmeta- static melanoma. CML, B- and T-cell lymphomas. and Kaposi's drugs, approval in hairy cell leukemia opened the way for expanded clinical trials of IFN-a2 in other disease states. From these studies, sarcoma. Phase II data with IFN-a2a or IFN-a2h have suggested three human malignancies of established clinical sensitivity to IFN-a, therapeutic effects in superficial bladder cancer, renal cell carcinoma, as a single agent provide paradigms for augmented clinical activity. ovarian cancer, metastatic melanoma, and multiple myeloma (10, 14, These include melanoma (tumor bulk reduction), lymphomas (com 159). bination with cytotoxic chemotherapies), and CML (modulation of The unique molecular and cellular effects of IFNs complement the oncogene expression). mechanisms of actions of other therapies ( 160). Combinations of IFNs Greater effectiveness of IFNs with tumor cell burden first reduced with other modalities thus seem likely to result in new and most by surgery or chemotherapy has been demonstrated for established effective clinical applications. When combined with other therapies in murine tumors (140). Immunomodulatory effects may be greater preclinical models, IFNs have augmented effectiveness for malignan when tumor cell mass is reduced (141). The pioneering studies of cies of diverse histologies. The reduction in cell number or tumor size IFNs in osteosarcoma involved patients who were at risk for recur and prolongation of survival have in most cases been additive and rence after surgery for osteosarcoma (142). The cumulative response often synergistic. Therapeutic applications of IFNs will probably rate in metastatic melanoma to IFN-a was 15% ( 10% partial response continue to increase. Evidence also exists that IFNs may have either and 5% complete response), a level comparable to results with cyto synergistic or additive effects with other biological response modifiers toxic agents (143, 144). These results, coupled with the preclinical (e.g., combinations of IFN-a and IFN-y) or cytotoxic drugs (e.g., work, led to a study that demonstrated prolongation of disease-free 5-fluorouracil) and can be potent inhibitors of angiogenesis (161, survival and overall survival for patients receiving IFN-a2h (145). 162). lFN-a2h is the only adjuvant to surgery for high-risk patients that has The design of combination therapy regimens does not differ from demonstrated improved outcome in a randomized trial. principles used in the development of other combination chemother For B-cell lymphomas, the significant single-agent activity of apies and modalities that have been previously used in malignancies. IFN-a2 has been integrated into effective combined modality treat Cellular proteins, such as thymidine phosphorylase, protein kinase R. 2495

RNase L, IFN regulatory factor transcription family proteins, and 11. Pestka, S., Langer. J. A., Zoon, K. C., and Samuel. C. E. Interferons and their p2jWAFi/cip wnjc|1 aj-g rnodulated in expression by IFNs, have the actions. Annu. Rev. Biochem.. 56: 727-777, 1987. 12. Sen, G. C., and Lengyel, P. The interferon system: a bird's eye view of its potential to influence the cell cycle and the response to chemothera- biochemistry. J. Biol. Chem., 267: 5017-5020, 1992. peutic agents. Other IFN-induced genes such as MHC class I antigen, 13. Trotta, P. P., and Siegel. R. J. Interferon: current concepts of mechanisms of action. In: F. M. Muggia (ed.). Concepts. Clinical Developments and Therapeutic Advances GTP cyclohydrolase I, ISO 15, and carcinoembryonic antigen may in Cancer Chemotherapy, pp. 141-159. Boston: Martinus-Nijhoff, 1987. influence the immunological response: thus, the sequencing, timing, 14. Nagabhushan. T. L., and Giaquinto. A. Interferon or2b: an overview from a regula dose ratios, and duration of administration become important consid tory perspective. In: A. S. Lubiniecki and S. A. Vargo (eds.). Regulatory Practice for Biopharmaceutical Production, pp. 221-234. New York: Wiley-Liss, 1994. erations. For clinical trial design, better definition of these molecular 15. Jensen, D. M.. Blatt, L. M., Tong. M. J., Lee, W. M., Mullen, K.. Joefs, J. C., Keeffe, interactions will be increasingly critical. E., Hollinger. F. B., Heathcote, E. J. L.. White, H.. Rouse. R. T.. Krawitt, E. L., The side effects with chronic administration are not trivial but do Fromm. H.. Black. M., Albert. D., Gerrard. T., and the Consensus Interferon Study Group. Treatment of high viral titer chronic HCV patients with consensus interferon reverse within weeks of discontinuation. However, when difficulty results in a significantly greater number of sustained HCV RNA responders as tolerating a drug is an issue, it becomes important to define both compared to treatment with Interferon a-2b. Presented at the 47th annual meeting of quality of life and cost-effectiveness. Quantitative analyses of these the American Association for the Study of Liver Diseases; November 11, 1996; Chicago, 111.Abstract 593. parameters in patients with CML or melanoma suggest IFN-a2 is 16. Keeffe, E., Blatt, L. M.. Dusheiko. G., Tong, M. J.. Hollinger, F. B.. James, S., cost-effective even when quality of life and expense are considered MÃ¼llen.K.. Everson, G.. Pimstone. N., Healhcote, E. J. L.. Donovan, J.. Conrad, A.. (163-166). Identification of effective interventions to decrease the Schmid. P., Alben, D., Gerrard. T.. and the Consensus Interferon Study Group. Differential response to treatment with consensus interferon (C1FN) and IFN a-2b chronic side effects would further improve quality of life. Controlled in chronic HCV patients infected with different HCV serotypes. Presented at the clinical research studies to identify such interventions need to be more 47th annual meeting of the American Association for the Study of Liver Diseases; November 11, 1996; Chicago. 111.Abstract 594. actively pursued. 17. Pockros, P. J., Tong, M. J., Lee, W. M., van Leeuwen, D. J., Keeffe, E., Bala, K., There are at least 12 naturally occurring IFN-a subtypes as well as Killenberg, P. G., Foust, R. T., Rosenblate, H. J., Payne, K. M., Fromm, H., Lesesne. H. R.. Black. M.. Snyder, R.. Gerrard. T., Conrad, A., Blatt. L. M., and the synthetic IFN species. These IFNs may well demonstrate a different Consensus Inlerferon Study Group. Relationship between biochemical and virolog- clinical activity or toxicity profile. Although all of the IFN-a subtypes ical response to lype 1 inlerferon therapy of chronic HCV infection. Presented at the compete for binding to a common cell surface receptor, each seems to 47th annual meeting of the American Association for ihe Study of Liver Diseases; November 9. 1996; Chicago, III. Abstract 113. possess discrete biological activities when assayed on the same cell 18. Alton, K. Y., Stabinsky. R., Richards, R., Ferguson, B., Goldstein, L., Altrock, B.. culture system, potentially leading to different clinical effects. The Miller. L.. and Stebbing. N. Production, characterization and biological effects of data reviewed herein suggest variations in the in vitro biological recombinant DNA derived human IFN-a and IFN-y analogs. In: E. DeMaeyer and H. Schellekens (eds.). The Biology of the Interferon System, pp. 119-128. Amster activities of IFN-a species, depending on the cells and experimental dam: Elsevier. 1983. conditions used for end point assay. 19. Radhakrishnan. R., Walter, L. J., Hruza, A., Reichen. P.. Troua, P. P., Nagabhushan, T. L., and Walter, M. R. Zinc mediated dimer of human interfcron-a2b revealed by With influence on STAT transcription factors, MHC class I antigen, X-ray crystallography. Structure (Lond.), 4: 1453-1463. 19%. NK cells, and T cells, the immunomodulatory effects of IFN-a are 20. UzÃ©.G..Lutfalla. G., and Mogensen, K. E. a and ÃŸinterferons and their receptor and substantial. Effects on host resistance may contribute to the therapeu their friends and relatives. J. Interferon Cytokine Res., 15: 3-26, 1995. tic activity of IFN-a in cancer and virologie diseases. Further preclin- 21. Cleary. C. M.. Donnelly. R. J.. Son, J.. Mariano, T. M., and Pestka. S. Knockout and reconstitution of a functional human type I interferon receptor complex. J. Biol. ical and clinical research is needed to dissect the mechanisms of Chern.. 269: 18747-18749. 1994. action of IFN-a in achieving a therapeutic benefit in humans: the role 22. Cook, J. R., Cleary. C. M.. Mariano. T. M.. [/.otova. L., and Peslka, S. Differential responsiveness of a splice variant of the human type I interferon receptor to of immunoaugmentation: direct anticellular effects; oncogene sup interfÃ©rons.J. Biol. Chem.. 271: 13448-13453. 1996. pression; or angiogenesis inhibition. Defining the underlying mecha- 23. Soh, J.. Mariano. T. M.. Lim, J-K., l/.otova, L., Mirochnitchenko. ()., SchwÃ¤rt/, B.. nism(s) for the clinical antitumor action of IFNs remains a critical Langer, J. A., and Pestka, S. Expression of a functional human type I interferon receptor in hamster cells: application of functional yeast anificia! chromosome challenge, the resolution of which would aid clinical trial design and (YAC) screening. J. Biol. Chem.. 269: 18102-18110, 1994. therapeutic outcomes. 24. Pestka. S. The interferon receptors. Semin. Oncol.. 24 (Suppl. 9): S9-18-S9-40. 1997. References 25. MÃ¼ller.U.. Steinhoff, U., Reis, L. F.. Hemmi, S., Pavlovic. J., Zinkernagel, R. M., and Aguet, M. Functional role of type I and type II interfÃ©ronsin antiviral defense. 1. Isaacs, A., and Lindenmann, 1. Virus interference. I. The inlerferon. Proc. R. Soc. Science (Washington DC), 264: 1918-1921. 1994. Lond. Ser. B.. 147: 258-267, 1957. 26. Hwang, S. Y.. Hertzog, P. J., Holland, K. A.. Sumarsono. S. H.. Tymms. M. J., 2. Lindenmann. 1. Induction of chick interferon: procedures of the original experi Hamilton. J. A.. Whitty, G.. Bertoncello, I., and Kola, I. A null mutation in the gene ments. Methods Enzymol.. 7H: 181-188. 1981. encoding a type I interferon receptor component eliminates antiproliferative and 3. Pestka, S. The human interferon-a species and hybrid proteins. Semin. Oncol.. 24 antiviral responses to interferons a and ÃŸand alters macrophage responses. Proc. (Suppl. 9)/ S9-4-S9-17, 1997. Nati. Acad. Sci. USA, 92: 11284-11288. 1995. 4. Zoon, K. C.. Bckisz. Â¡.,and Miller. D. Human interferon a family: protein structure 27. Colamonici, O., Yan, H.. Domanski. P.. Handa. R.. Smalley, D.. Mullersman, J.. and function. In: S. Baron. D. H. Coopenhaver. F. Dian/ani. W. R. Fleishmann, Witte, M.. Krishnan. K., and Krolewski. J. Direct binding to and tyrosine phospho- T. K. Hughes. Jr.. G. R. Kimpel. Jr.. D. W. Niesel. G. J. Stanlon, and S. K. Tyring rylalion of the a subunit of Ihe type I inlerferon receptor by p 135lyk2tyrosine kinase. (eds.), Inlerferon: Principles and Medical Applications, pp. 95-105. Galveston. TX: Mol. Cell. Biol.. 14: 8133-8142. 1994. The University of Texas Medical Branch at Galveston. 1992. 28. Colamonici. O. R.. Uyttendaele. H.. Domanski. P.. Yan. H., and Krolewski, J. J. pl35lyk2. an interferon-or-aclivated lyrosine kinase, is physically associated with an 5. Uze. G., Lutfalla, G., and Grosser, 1. Genetic transfer of a functional human interferon a receptor into mouse cells: cloning and expression of its cDNA. Cell, 60: interferon-a receptor. J. Biol. Chem., 269: 3518-3522, 1994. 225-234. 1990. 29. Yan, H., Krishnan, K., Lim, J. T.. Contillo, L. G., and Krolewski. J. J. Molecular 6. Domanski. P.. Witte, M.. Kellum. M.. Rubinstein. M.. Hacken. R.. Pitha, P., and characterization of an a-interferon receptor I subunit (IFNaR I) domain required for Colamonici. O. R. Cloning and expression of a long form of the ÃŸ-subunitof the TYK2 binding and signal transduction. Mol. Cell. Biol., 16: 2074-2082, 1996. interferon aÃŸreceptor that is required for signaling. J. Biol. Chem., 270.- 21606- 30. Kolenko, S. V., Izolova, L. S., Pollack, B. P., Mulhukumaran, G.. Silvennoinen, O.. 21611, 1995. Paukku, K.. Ihle. J. N., and Peslka. S. Jak kinases can substitute for Jak2 in the 7. Novick. D., Cohen, B., and Rubinstein. M. The human interieron o/ÃŸreceptor: IFN-y signal transduction. J. Biol. Chem., 271: 17174-17182. 1996. characterisation and molecular cloning. Cell, 77: 391-400, 1994. 31. Darnell, J. E., Jr., Kerr, 1. M.. and Stark. G. R. Jak-STAT pathways and transcrip- 8. Lutfalla, G.. Holland, S. J., Cinato, E., Monneron. D., Reboul. J., Rogers. N. C., tional activation in response to IFNs and other exiracellular signaling proleins. Smith, J. M.. Stark, G. R., Gardiner, K.. Mogensen, K. E., Kerr, I. M., and UzÃ©,G. Science (Washinglon DC), 264: 1415-1421, 1994. Mutant U5A cells are complemented by an interferon-orÃŸreceptor subunit generated 32. Fu, X-Y. A direcl signaling pathway through tyrosine kinase activation of SH2 by alternative processing of a new member of a cytokine receptor gene cluster. domain-containing transcription factors. J. Leukoc. Biol., 57: 529-535, 1995. EMBO J.. 14: 5100-5108, 1995. 33. Constantinescu, S. N., Croze, E.. Wang, C., Murti, A., Basu, L., Mullersman. J. E., 9. Domanski. P.. and Colamonici, O. R. The lype-I interferon receptor. The long and and Pfeffer, L. M. Role of interferon aJÃŸreceplor chain 1 in ihe structure and short of it. Cylokine Growth Factor Rev., 7: 143-151. 1996. transmembrane signaling of the interferon a/ÃŸreceptor complex. Proc. Nail. Acad. 10. Nagabhushan, T. L.. and Trotta, P. P. Interferons. In: Ullmann's Encyclopedia of Sci. USA. 91: 9602-9606. 1994. Industrial Chemistry, 5th ed.. Vol. A14, pp. 365-380. Weinheim. Germany: VCH 34. Yang. C. H.. Shi. W.. Basu, L., Murti, A.. Constantinescu, S. N.. Blall, L.. Croze, E., Verlagsgesellschaft mbH. 1989. Mullersman, J. E.. and Pfeffer. L. M. Direct association of STATS with the 2496

IFNAR-1 chain of the human type I Interferon receptor. J. Biol. Chem., 271: 66. Ortaldo. J. R.. Pestka, S.. Slease. R. B., Rubinstein. M.. and Herberman, R. B. 8057-8061, 1996. Augmentation of human K cell activity with interferon. Scand. J. Immunol.. 12: 35. Faltynek. C. R.. Branca, A. A., McCandless, S., and Baglioni. C. Characterization of 365-369, 1980. an Interferon receptor on human lymphoblastoid cells. Proc. Nati. Acad. Sci. USA, 67. Jewell. A., and Bonavida. B. Interferon-a actÃvalescytotoxic function but inhibits 80: 3269-3273. 1983. interleukin-2-medialed proliferalion and Iunior necrosis factor-a secretion by im 36. Joshi. A. R.. Sarkar, F. H.. and Gupta. S. L. Interferon receptors: cross linking of mature human natural killer cells. J. Clin. Immunol., 15: 35-44. 1995. human leukocyte interferon a-2 to its receptor on human cells. J. Biol. Chem.. 257: 68. Langer, J. A.. Ortaldo. J. R., and Peslka. S. Binding of human a-inlerferons lo 13884-13887. 1982. natural killer cells. J. Interferon Res.. 6: 97-105, 1986. 37. Vanden Broecke, C.. and Pfeffer, L. M. Characterization of interferon-a hinding 69. Ozes. O. N.. Reiler. Z.. and Klein, S. A comparison of interferon-Conl wilh nalural sites on human cell lines. J. Interferon Res.. 8: 803-811. 1988. recombinanl intcrferons-a: anliviral. anliproliferative. and natural killer-inducing 38. Hertzog, P. !.. Hwang. S. Y.. Holland, K. A., Tymms. M. J.. lannello. R.. and Kila. activities. J. Interferon Res.. 12: 55-59. 1992. I. A gene on human chromosome 21 located in the region 21q22.2 to 21q22.3 70. Hawkins, M. J.. Borden, E. C., Merrill, J. A.. Edwards. B. S., Ball. L. A., Grossbard. encodes a factor necessary for signal transduction and antiviral response to type I E., and Simon. K. J. Comparison of Ihe biologic effects of two recombinant human interferons. J. Biol. Chem., 269: 14088-14093. 1994. interferons a (rA and rD) in humans. J. Clin. Oncol., 2: 221-226, 1984. 39. Abramovich. C.. Chebath, J., and Revel, M. The human interferon a-receptor protein 71. Edwards, B. S., Hawkins, M. J., and Borden. E. C. Comparalive in vivo and in vitro confers differential responses to human interferon-ÃŸversus interferon-a subtypes in aclivalion of human nalural killer cells by Iwo recombinanl a inlerferons differing mouse and hamster cell transfectants. Cytokine, 6: 414-424. 1994. in anliviral aclivily. Cancer Res.. 44: 3135-3139. 1984. 40. Aguet, A. Molecular-cloning of interferon receptors: a short review. Br. J. Haema- 72. Dinarello. C. A.. Bernheim. H. A.. Duff. G. W.. Lc. H. V.. Nagabhushan. T. L.. tol., 79 (Suppl. 1): 6-8, 1991. Hamilton. N. C.. and Coceani. F. Mechanisms of fever induced by recombinant 41. Langer, J. A., and Pestka. S. Interferon receptors. Immunol. Today. 9: 393-400, human interferon. J. Clin. Invest.. 74: 906-913. 1984. 1988. 73. Dinarello. C. A., and Bernheim. H. A. Ability of human leukocytic pyrogen lo 42. Mogensen, K. E., UzÃ©.G.,and Eid. P. The cellular receptor of the a-ÃŸinterferons. slimulale brain proslaglandin synlhesis in vitro. J. Neurochem.. 37: 702-708. 1981. Experientia (Basel). 45: 500-508. 1989. 74. Dinarello. C. A. Biologic basis for inlerleukin-1 in disease. Blood. 87: 2095-2147. 43. Pfeffer. L. M.. Stebbing. N., and Donner. D. B. Cytoskeletal association of human 1996. a-interferon-receptor complexes in interferon-sensitive and -resistant lymphoblas 75. Schindler. R., Ghezzi. P.. and Dinarello, C. A. Interferons as inhibitors of interleukin toid cells. Proc. Nati. Acad. Sci. USA. 84: 3249-3253. 1987. I-induced interleukin 1 synthesis. Lymphokine Res.. 8: 275-280, 1989. 44. Nanus. D. M.. Pfeffer, L. M.. Bander. N. H.. Bahn. S., and Albino, A. P. Anlipro- 76. Ghezzi, P.. and Dinarello, C. A. IL-I induces IL-I. III. Specific inhibition of IL-1 liferative and antitumor effects of cr-interferon in renal cell carcinomas: correlation production by IFN--y. J. Immunol.. 140: 4238-4244. 1988. with the expression of a kidney-associated differentiation glycoprotein. Cancer Res.. 77. Schindler. R.. Ghezzi. P.. and Dinarello. C. A. IL-1 induces IL-1. IV. IFN-y 50: 4190-4194. 1990. suppresses IL-I but noi lipopolysaccharide-induced Iranscriplion of IL-1. J. Immu 45. Pfeffer. L. M., and Donner, D. B. The down-regulation of a-interferon receptors in nol., 144: 2216-2222. 1990. human lymphoblastoid cells: relation to cellular responsiveness to the anliprolifera- 78. Schindler, R., and Dinarello. C. A. A method for removing interleukin-1- and tumor tive action of a-interferon. Cancer Res., 50: 2654-2657, 1990. necrosis factor-inducing substances from baclerial cullures by ultrafiltration with 46. Pfeffer, L. M., and Tamrn, I. Comparison of the effects of a and ÃŸinterferons on the polysulfone. J. Immunol. Melhods. 116: 159-165. 1989. proliferation and volume of human tumor cells (HeLa-S3, Daudi, P3HR-1). J. In terferon Res.. 3: 395-408. 1983. 79. Schindler, R., and Dinarello. C. A. Ultrafiltration to remove endoloxins and olher cylokine-inducing materials from tissue culture media und parenteral fluids. Bio- 47. Schindler. C., and Darnell. J. E.. Jr. Transcriptional responses to polypeptide ligands: techniques. 8: 408-413, 1990. the JAK-STAT pathway. Annu. Rev. Biochem.. 64: 621-651. 1995. 48. Williams, B. R. G. Transcriptional regulation of interferon-stimulated genes. Eur. 80. Dinarello, C. A., Ikejima. T.. Warner. S. J.. Orencole. S. F.. Lonnemann, G., Cannon. J. G., and Libby. P. Interleukin 1 induces interleukin 1. I. Induction of J. Biochem., 200: 1-11, 1991. circulaling inlerleukin 1 in rabbils in vivo and in human mononuclear cells I'Mvitro. 49. Haque, S. J.. and Williams, B. R. G. Identification and characterization of an I. Immunol., 139: 1902-1910. 1987. interferon (IFN)-stimulated response element-IFN-stimulated gene factor 3-inde- 81. Schindler, R., Clark, B.D.. and Dinarello. C. A. Dissociation between inlerleukin-1 ÃŸ pendent signaling pathway for IFN-a. J. Biol. Chem.. 269: 19523-19529. 1994. 50. Sims. S. H., Cha, Y.. Romine, M. F., Gao, P-Q., Gottlieb, K.. and Deisseroth, A. B. mRNA and prolein synlhesis in human peripheral blood mononuclear cells. J. Biol. A novel interferon-inducible domain: structural and functional analysis of the human Chem., 265: 10232-10237. 1990. interferon regulatory factor I gene promoter. Mol. Cell. Biol., 13: 690-702. 1993. 82. Warner, S. J. C.. Auger, K. R.. and Libby. P. Inlerleukin-1 induces interleukin-1. II. 51. Flati, V.. Haque. S. J., and Williams. B. R. G. Interferon-a-induccd phosphorylation Interleukin-1 induces production of interleukin-1 by adult human vascular endothelial cells in vitro. J. Immunol.. 139: 1911-1917. 1987. and activation of cytosolic phospholipase A> is required for the formation of interferon-slimulated gene factor 3. EMBO J.. /5: 1566-1571. 19%. 83. Dinarello. C. A.. Lonnemann, G., Maxwell. R.. and Shaldon. S. Ultrafillralion lo 52. Hannigan, G. E., and Williams, B. R. G. Signal transduction by inlerferon-a through rejecl human interleukin-1-inducing substances derived from bacterial cultures. arachidonic acid metabolism. Science (Washington DC), 25/: 204-207. 1991. J. Clin. Microbiol.. 25: 1233-1238, 1987. 53. Sen, G. C.. and Ransohoff. R. M. Interferon-induced antiviral actions and their 84. Ikejima. T.. Okusawa. S., Ghezzi. P.. van der Meer. J. W. M., and Dinarello, C. A. regulation. Adv. Virus Res.. 42: 57-101. 1993. Interleukin-1 induces tumor necrosis factor (TNF) in human peripheral blood mono- 54. Reich, N. C.. Evans. B.. Levy, D., Fahey. D.. Knight. E.. Jr.. and Darnell. J. E., Jr. nuclear cells in vitro and a circulating TNF-like activity in rabbils. J. Infect. Dis., Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an /62: 215-223. 1990. upstream enhancer element. Proc. Nati. Acad. Sci. USA, 84: 6394-6398, 1987. 85. Oliveira. I. C.. Mukaida. N.. Matsushima. K.. and Vilcek. J. Transcriptional inhibi tion of the interleukin-8 gene by inlerferon is mediated by the NF-xB sile. Mol. Cell. 55. Reid. L.. Brasnett. A.. Gilbert. C. S.. Porter. A. C.. Gewert, D. R., Stark, G. R.. and Kerr, I. M. A single DNA response element can confer inducibility by both a- and Biol., 14: 5300-5308, 1994. â€¢y-inlerferons.Proc. Nail. Acad. Sci. USA, 86: 840-844. 1989. 86. Gribaudo, G.. Ravaglia. S.. Gaboli, M., Gariglio, M., Cavallo, R.. and Landolfo. S. 56. Kishimoto, T., Taga, T., and Akira, S. Cytokine signal transduction. Cell, 76: lnlerferon-a inhibils the murine cytomegalovirus immediate-early gene expression 253-262, 1994. by down-regulating NF-KB aclivity. Virology. 211: 251-260. 1995. 57. Kalvakolanu. D. V., and Borden, E. C. An overview of the interferon system: signal 87. Borden. E. C., and Parkinson. D. A perspective on Ihe clinical effecliveness and transduction and mechanisms of action. Cancer Investig.. 14: 25-53, 1996. tolerance of interferon-a. Semin. Oncol.. 25: 3-8. 1998. 58. Pfeffer, L. M. Biologic activities of natural and synthetic type I interferons. Semin. 88. Quesada, J. R.. Talpaz. M.. Rios. A., Kurzrock. R., and Gullerman. J. U. Clinical Oncol., 24 (Suppl. 9): S9-63-S9-69, 1997. toxicity of inlerferon in cancer palients: a review. J. Clin. Oncol.. 4: 234-243. 1986. 59. Herberman, R. B. Effect of Â«-interfÃ©ronsonimmune function. Semin. Oncol., 24 89. Weiss, K. Safely profile of inlerferon-a Iherapy. Semin. Oncol.. 25: 9-13, 1998. (Suppl. 9): S9-78-S9-80, 1997. 90. Plala-Salaman. C. R. Cylokines and anorexia: a brief overview. Semin. Oncol.. 25: 60. Ortaldo. J. R.. Mantovani. A.. Hobbs. D.. Rubinstein. M.. Pestka. S.. and Herberman. 64-72, 1998. R. B. Effects of several species of human leukocyte interferon on cytotoxic activity 91. Dalakas. M. C.. Mock, V., and Hawkins. M. J. Fatigue: definitions, mechanisms, and of NK cells and monocytes. Int. J. Cancer. 31: 285-289. 1983. paradigms for study. Semin. Oncol.. 25: 48-53. 1998. 61. Ortaldo, J. R., Mason, A., Rehberg, E.. Moschera, J.. Kelder. B., Pestka, S.. and 92. Jones, T. H., Wadler, S., and Hupart, K. H. Endocrine-mediated mechanisms of Herberman, R. B. Effects of recombinant and hybrid recombinant human leukocyte fatigue during Irealmenl wilh inlerferon-a. Semin. Oncol., 25: 54-63, 1998. interferons on cytotoxic activity of natural killer cells. J. Biol. Chem., 24: 15001- 93. Licinio, J.. Kling. M. A., and Hauser, P. Cylokines and brain function: relevance to 15015. 1983. interferon-a-induced mood and cognilive changes. Semin. Oncol., 25: 30-38, 1998. 62. Ortaldo. J. R.. Herberman, R. B., Harvey, C., Osheroff, P., Pan, Y-C. E., Kelder, B., 94. Valentine, A. D., Meyers, C. A., Kling, M. A.. Richelson. E.. and Hauser. P. Mood and Pestka, S. A species of human a interferon that lacks the ability to boost human and cognitive side effects of interferon-a therapy. Semin. Oncol.. 25: 39-47. 1998. natural killer activity. Proc. Nati. Acad. Sci. USA, 81: 4926-4929. 1984. 95. Taylor. J. L.. and Grossberg. S. E. The effects of inlerferon-a on Ihe production and 63. Li, B-L., Zhao, X-Y.. Liu. X-Y., Kim, H. S.. Raska, K., Jr., Ortaldo, J., Schwartz, action of other cytokines. Semin. Oncol., 25: 23-29. 1998. B., and Pestka, S. a-Interferon structure and natural killer cell stimulatory activity. 96. Anionelli. G. Developmenl of neulralizing and binding anybodies lo inlerferon Cancer Res.. 50: 5328-5332. 1990. (IFN) in palients undergoing 1FN therapy. Antiviral Res.. 24: 235-244. 1994. 64. Pestka, S. Interferon from 1981 to 1986. In: S. Pestka (ed.). Methods in Enzymol- 97. Antonelli, G. In vivo developmenl of anlibody lo inlerferons: an updale lo 1996. ogy. Vol. 119. pp. 3-14. New York: Academic Press. 1986. J. Inlerferon Cylokine Res.. 17 (Suppl. I): S39-S46, 1997. 65. Fellous, M.. Nir. U.. Wallach. D.. Merlin, G.. Rubinstein. M., and Revel, M. 98. Vial, T., and Descoles. J. Immune-medialed side effecls of cylokines in humans. Interferon-dependent induction of mRNA for the major histocompatibility antigens Toxicology, /05: 31-57. 1995. in human fibroblasts and lymphoblastoid cells. Proc. Nati. Acad. Sci. USA. 79: 99. McKenna. R. M.. and Oberg. K. E. Antibodies to interferon-a in trealed cancer 3082-3086. 1982. palienls: incidence and significance. J. Interferon Cytokine Res.. 17: 141-143. 1997. 2497

100. Meager, A. Natural auloanlihodics to interferons. J. Interferon Cytokine Res.. 125. Bell. J. B.. Barfoot. R.. Iveson. T.. Powles. R. L.. and Millar. B. C. Neutralising /7(Suppl. 1): S51-S53, 1997. antibodies in patients with multiple myeloma receiving maintenance therapy with 101. Schellekens. H., Ryff, I. C.. and van der Meide. P. H. Assays for antibodies to interferon a 2b. Br. J. Cancer, 70: 646-651, 1994. human interferon-a: the need for siandardizaiion. J. Interferon Cytokine Res., 126. Davis, G. L., Balan. L. A.. Schiff, E. R., Lindsay. K.. Bodenheimer. H. C.. Jr.. //(Suppl. I): S5-S8, 1997. Perrillo. R. P.. Carey. W., Jacobson. I. M.. Payne, J.. Dienstag. J. L.. VanThiel. 102. Antonelli, G.. Currenli. M.. Turriziani, O., and Dianzani, F. Neutrali/ing antibodies D. H., Tamburro, C.. Lefkowitch, J.. Albrecht, J., Meschievitz. C.. Ortego, T. J., and to inlerferon-a: relative frequency in patients treated with different interferon Gibas, A., for the Hepatitis Interventional Therapy Group. Treatment of chronic preparations. J. Infect. Dis., 163: 882-885, 1991. hepatitis C with recombinanl Â¡nterferon a. A multicenter randomized, controlled 103. Antonelli, G.. Currenti, M., Turri/iani, O.. Riva. E., and Dian/ani, F. Relative trial. N. Engl. J. Med.. 321: 1501-1506. 1989. frequency of nonneutrali/ing antibodies to interferon (IFN) in hepatitis patients 127. Dianzani. F.. Antonelli. G.. Amicucci. P.. Cefaro, A., and Pintus, C. Low incidence of neutralizing antibody formation to intert'eron-a 2b in human recipients. J. Inter treated with different IFN-u preparations. J. Infect. Dis.. 165: 593-594. 1992. 104. Camps, J.. Garcia-Granero, M., Riezu-Boj, J. I., Larrea, E., de Alava. E.. Civeira, feron Res., 9 (Suppl. I): S33-S36. 1989. M. P., Castilla. A., and Prieto, J. Prediction of sustained remission of chronic 128. Golomb. H. M., Ratain, M. J., Fefer, A.. Thompson, J., Golde, D. W., Ozer, H., hepatitis C after a 12-month course of a-interferon. J. Hepatol. (Amst.). 21: 4-11, Portlock. C.. Silber. R.. Rappeport. J., Bonnern. E.. Spiegel, R.. Tensen, L., Burke. 1994. J. S., and Vardiman. J. W. Randomized study of the duration of treatment with 105. Galton, J. E.. Bedford. P., Scott. J. E.. Brand. C. M.. and Nethersell. A. B. Antibodies interferon a-2b in patients with hairy cell leukemia. J. Nati. Cancer Inst., 80: to lymphoblastoid interferon. Lancet. 11:572-573. 1989. 369-373, 1988. 106. Thurmond. L. M.. Brand. C. M., Leventhal, B. G.. Finter, N. B., and Johnston. J. M. 129. Jacobs. S. J.. Sullivan, L. M.. Salfi. M., Grossberg. H., Spiegel. R. J.. Leibowitz, Antibodies in patients with recurrent respiratory papillomatosis treated with lym P. J.. Oden, E. M.. Kelsey D. K., and TreuhatÃ¬.M. W. Minimal antigenicity of intron phoblastoid interferon. J. Lab. Clin. Med., 118: 232-240. 1991. A in human recipients demonstrated by three analytical methods. J. Biol. Response 107. Berman. E.. Heller. G.. Kempin. S.. Gee. T., Tran, L. L., and Clarkson. B. Incidence Modif.. 7: 447-456. 1988. of response and long-term follow-up in patients with hairy cell leukemia treated with 130. Muller. R.. Baumgarten. R.. Markus. R.. Schult/., M.. Wittenberg. H., Hintsche- recombinanl interferon a-2a. Blood. 75: 839-845. 1990. Kilger. B.. Fengler. J-D.. von Wussow. P., Meisel. H.. Klein. H.. Malmus. K.. and Schmidt, F. W. Treatment of chronic hepatitis B with interferon a-2b. J. Hepatol. 108. Bonetti. P.. Diodati. G.. Drago. C.. Casarin. C.. Scaccabarozzi. S.. Realdi. G.. Ruol. (Amst.), // (Suppl. I). S137-S140. 1990. A., and Alberti, A. Interferon antibodies in patients with chronic hcpatitic C virus infection treated with recombinant interferon a-2a. J. Hepatol. (Amst.), 20: 416- 131 Perrillo. R. P.. Schiff, E. R., Davis. G. L., Bodenheimer. H. C.. Jr., Lindsay, K., Payne. J.. Dienstag. J. L.. O'Brien. C.. Tamburro. C.. Jacobson. I. M.. Sampliner. R.. 420. 1994. 109. Brand, C. M., Leadbealer, L., Bellati. G., Maretta. F.. and Ideo, G. Antibodies Feit, D.. Lefkowitch. J., Kuhns. M.. Meschievitz. C.. Sanghvi, B., Albrecht. J., and developing against a single recombinant interferon protein may neutralise many Gibas. A., for the Hepatitis Interventional Therapy Group. A randomized, controlled other interteron-a subtypes. J. Interferon Res.. 13: 121-125, 1993. trial of interferon a-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N. Engl. J. Med., 323: 295-300, 1990. 110. Douglas. D. D.. Rakela, J.. Lin, H. J.. Hollinger. F. B., Taswell, H. F.. Czaja. A. J., Gross. J. B.. Anderson. M. L.. Parent. K.. Fleming. C. R.. Canjemi. J. R.. O'Brien, 132. Gisslinger. H.. Ludwig. H.. Linkesch. W., Chott. A.. Fritz. E.. and Radaszkiewicz. P. C., and Powis. P. E. Randomi/ed controlled trial of recombinant a-2a-imerferon T. Long-term interferon therapy for thrombocytosis in myeloproliferative diseases. Lancet, i: 634-637. 1989. for chronic hepatitis C. Comparison of alanine aminotransferase normalization versus loss of HCV RNA and anti-HCV IgM. Dig. Dis. Sci.. 38: 601-607. 1993. 133. Steinmann. G. G.. God. B.. Rosenkaimer. F., Adolf. G.. Bidlingmaier, G., Fruhheis, B.. Lamche, H.. Lindner. J.. Patzelt. E., SchmÃ¤hung. C.. and Schneider. F-J. Low 111. Figlin. R. A., deKemion, J. B.. Mukamel. E.. Palleroni. A. V.. Itri, L. M.. and Sarna. incidence of antibody formation due to long-term interferon-oc^. treatment of cancer G. P. Recombinant interferon u-2a in metastalic renal cell carcinoma: assessment of patients. Clin. Investig., 70: 136-141, 1992. antilumor activity and anti-intcrferon antibody formation. J. Clin. Oncol.. 6. 1604- 134. Hochuli. E. Interferon immunogenicity: technical evaluation of interferon-a2a. 1610. 1988. J. Interferon Cytokine Res., 17 (Suppl. 1).-S15-S21. 1997. 112. Grander, D.. Oberg. K.. Lundqvist. M. L.. Janson, E. T., Eriksson, B., and Einhorn. S. Interferon-induced enhancement of 2',5'-oligoadenylate synthetasc in mid-gut 135. Ryff, J. C. Clinical investigation of the immunogenicity of interferon-a2a. J. Inter feron Cytokine Res.. 17 (Suppl. 1): S29-S33. 1997. carcinoid tumours. Lancet, 336: 337-340. 1990. 136. Borden. E. C. Interferons. In: J. F. Holland, E. Frei 111.J. R. Bast, D. W. Kufe, D. L. 113. Itri. L. M.. Campion, M.. Dennin. R. A.. Palleroni. A. V.. Guttcrman. J. U.. Morton, and R. R. Weichselbaum (eds.). Cancer Medicine, pp. 1199-1212. Balti Groopman. J. E.. and Trown. P. W. Incidence and clinical significance of neutral izing antibodies in patients receiving recombinant inlerteron a-2a by intra-muscular more, MD: Williams & Wilkins. 1997. injection. Cancer (Phila.t. 59. 668-674, 1987. 137. Gutterman. J. U. Cytokine therapeutics: lessons form interferon a. Proc. Nati. Acad. Sci. USA. 91: 1198-1205. 1994. 114. Lok. A. S. F., and Lai. C. L. Incidence, neutralizing activity, and clinical significance Golomb. H. M.. Jacobs. A.. Fefer, A., Ozer, H., Thompson. J.. Portlock. C.. Ratain. of interferon antibodies in chronic hepatitis B patients receiving recombinant a-in- 138. M., Golde, E., Vardiman, J.. Burke. J. S., Brady. J.. Bonnern. E., and Spiegel. R. a-2 terferons. In: F. B. Hollinger, S. M. Lemon, and H. Margolis (eds.). Viral Hepatitis IFN therapy of hairy-cell leukemia: a multicenter study of 64 patients. J. Clin. and Liver Disease, 7th ed.. pp. 643-644. Baltimore. MD: Williams & Wilkins. 1991. Oncol., 4: 900-905. 1986. 115. Lok, A. S. F.. Lai, C. L., and Leung. E. K. Interferon antibodies may negate the 139. Smalley, R. V.. Anderson, S. A.. Tuttle. R. L.. Connors. J.. Thurmond. L. M.. Huang, antiviral effects of recombinanl a-interferon treatment in patients with chronic A., Castle, K.. Magers, C., and Whisnant, J. K. A randomized comparison of two hepatitis B virus infection. Hepatology. 12: 1266-1270, 1990. doses of human lymphoblastoid interferon-a in hairy cell leukemia. Wellcome HCL 116. Milella, M.. Anlonelli. G.. Santantonio. T.. Currenti. M.. Monno. L.. Mariano. N.. Study Group. Blood, 78: 3133-3141. 1991. Angarano, G.. Dianzani. F.. and Pastore, G. Neutralizing antibodies to recombinant 140. Gresser. I.. Maury, C., and Belardelli. F. Anti-tumor effects of interferon in mice a-inlerferon and response to therapy in chronic hepatitis C virus infection. Liver. 13: injected with interferon-sensitive and interferon-resistant Friend leukemia cells. VI. 146-150, 1993. Adjuvant therapy after surgery in the inhibition of liver and spleen mÃ©tastases.Int. 117. Porres, J. C., Carreno, V.. Ruiz, M., Marron, J. A., and BartolomÃ©,J. Interferon J. Cancer, 39: 789-792, 1987. antibodies in patients with chronic HBV infection treated with recomhinanl inter 141. Jaffe. H. S.. and Herberman, R. B. Rationale for recombinant human interferon--y feron. J. Hepatol. (Amst.). 8: 351-357. 1989. adjuvant immunotherapy for cancer. J. Nati. Cancer Inst., 8Ãœ:616-618. 1988. 118. Prummer. O. Interferon-a antibodies in patients with renal cell carcinoma treated 142. Strander. H.. Adamson. U.. Aparisi, T.. Brostrom. L. A., Cantell. K.. Einhorn. S.. with recomhinant interferon-a-2a in an adjuvant multicenter trial. The Delta-P Study Hall. K.. Ingimarsson. S.. Nilsonne. U., and Sodcrberg, G. Adjuvant interferon Group. Cancer (Phila.). 71: 1828-1834. 1993. treatment of human osteosarcoma. Recent Results Cancer Res.. 68: 40-44. 119. Quesada. J. R., Rios. A.. Swanson. D.. Trown. P.. and Gutterman. J. U. Antitumor 1978. activity of recombinant-derived interferon a in metastatic renal cell carcinoma. 143. Robinson, W. A.. Mughal. T. I., Thomas. M. R., Johnson. M.. and Spiegel. R. J. J. Clin. Oncol., 3: 1522-1528, 1985. Treatment of metastalic malignant melanoma with recombinant interferon a 2. 120. Ronnblom. L. E.. Janson. E. T., Perers, A.. Oberg. K. E.. and Aim. G. V. Charac Immunobiology, 172: 275-282, 1986. terization of anti-interferon-a antibodies appearing during recombinant inlerferon- 144. Kirkwood. J. M. Interferons. Melanoma. In: V. T. DeVita, Jr.. S. Hellman. and S. A. a-2a treatment. Clin. Exp. Immunol.. 89: 330-335. 1992. Rosenberg (eds.). Biologic Therapy of Cancer. 2nd Ã©d..pp.388-411. Philadelphia. 121. Russo. D., Candoni. A.. Zuffa. E.. Minisini, R.. Silvestri, F., Fanin. R., Zaja, F.. PA: J. B. Lippincott Co., 1995. Martinclli. G.. Tura, S.. Botta. G., and Baccarani. M. Neutralizing anti-interferon-a 145. Kirkwood. J. M., Strawderman. M. H.. Ernstoff. M. S.. Smith. T. J.. Borden, E. C., antibodies and response to treatment in patients with Ph+ chronic myeloid leukae and Blum, R. H. Interferon a-2b adjuvant therapy of high risk resected cutaneous mia sequentially treated with recombinant (a 2a) and lymphoblastoid interferon-a. melanoma: the Eastern Cooperative Oncology Group trial est. 1684. J. Clin. Oncol., Br. J. Haematol.. 94: 300-305. 1996. 14: 7-17, 1996. 122. Shtalrid. M.. Lugassy, G., Rosensaft, J., and Berrebi. A. Treatment of chronic 146. Borden, E. C. Innovative treatment strategies for non-Hodgkin's lymphoma and myeloid leukemia with inlerferon a (Roferon): results of the Israeli Study Group on multiple myeloma. Semin. Oncol.. 21 (Suppl. 14): 14-22, 1994. Smalley. R. V.. Anderson. J. W.. Hawkins. M. J.. Bhide. V.. O'Connell, M. J., CML. Leuk. Lymphoma. // (Suppl. 1): 193-197, 1993. 147. 123. Steis, R. G., Smith, J. W.. II. Urba. W. J.. Clark. J. W.. Itri. L. M.. Evans. L. M., Oken, M. M.. and Borden, E. C. Interferon a combined with cytotoxic chemo Schoenberger, C., and Longo, D. L. Resistance to recombinant interferon ct-2a in therapy for patients with non-Hodgkin's lymphoma. N. Engl. J. Med., 327: hairy-cell leukemia associated with neutralizing anti-interferon antibodies. N. Engl. 1336-1341, 1992. J. Med., 318: 1409-1413. 1988. 148. Solal-Celigny. P., Lepage. E.. Brousse. N., Reyes, F., Haioun. C.. Leporrier. M., 124. von Wussow. P.. Pralle. H., Hochkeppel. H-K.. Jakschies. D.. Sonnen. S., Schmidt. Peuchmaur. M.. Bosly, A., Parlier, Y., Brice. P.. Coiffier, B., and Gisselbrecht, C.. H., Muller-Rosenau. D.. Franke, M.. Haferlach, T.. Zwingers. T., Rapp. U., and for the Groupe d'Etude des Lymphomes de L'Adulte. Recombinanl inlerferon or-2b Deicher. H. Effective natural interferon-a therapy in recombinant interferon-a- combined with a regimen containing doxorubicin in patients with advanced follic- resistant patients with hairy cell leukemia. Blood. 78: 38-43. 1991. ular lymphoma. N. Engl. J. Med.. 329: 1608-1614. 1993. 2498

149. Bunn, P. A.. Jr. Recombinam imerferon a-2a, an active agent in advanced cutaneous 158. Guilhot, F.. Chastang, C., Michaile!, M.. Guerci, A.. Harousseau. J-L.. Maloisel, F., T-cell lymphomas. Int. J. Cancer, / (Suppl.): 9-13, 1987. Bouabdallah, R., Guyotat, D., Chron, N., Nicholini, F., Abgrall, J-F., and Tanzer, 150. Wagstaff, J., Scarffe, J. H., and Crowther. D. Interferon in the treatment of multiple J. Imerferon a-2b combined with cytarabine versus imerferon alone in chronic myeloma and the non-Hodgkin's lymphomas. Cancer Treat. Rev., 12B: 39-44. 1985. myelogenous leukemia. For the French Chronic Myeloid Leukemia Study Group. 151. Foon, K. A., Sherwin, S. A., Abrams, P. G., Longo, D. L., Fer, M. F., Stevenson, N. Engl. J. Med., 337: 223-229, 1997. H. C.. Ocho, J. J., Bottino, G. C., Schoenberger, C. S., Zeffren, J., Jaffe. E. S., and Oldham, R. K. Treatment of advanced non-Hodgkin's lymphoma with recombinant 159. Lindner, D. J., Kalvakolanu, D. V., and Borden. E. C. Increasing effectiveness of Interferon-a for malignancies. Semin. Oncol.. 24 (Suppl. 9): S9-99-S9-104. 1997. leukocyte A imerferon. N. Engl. J. Med., 311: 1148-1152. 1984. 160. Wadler, S., and Schwartz, E. L. Antineoplastic activity of the combination of 152. Alimena, G., MorrÃ , E., Lazzarino, M., Liberati, A. M.. Montefusco. E.. Inverardi. interferon and cytotoxic agents against experimental and human malignancies: a D., Bemasconi, P., Mancini, M., Donti, E., Grignani, F., Bernasconi. C., Dianzani, review. Cancer Res.. 50: 3473-3486, 1990. F., and Mandelli. F. Interferon a-2b as therapy for Ph-positive chronic myelogenous 161. Dinney, C. P., Bielenberg. D. R.. Perrotte. P.. Reigh, R.. Eve. B. Y.. Bucana, C. D., leukemia: a study of 82 patients treated with intermittent or daily administration. and Fidler, I. J. Inhibition of basic fibroblast growth factor expression, angiogenesis, Blood, 72: 642-647, 1988. and growth of human bladder carcinoma in mice by systemic interferon-a admin 153. Kantarjian, H. M.. Deisseroth, A.. Kurzrock, R., Estrov, Z., and Talpaz, M. Chronic istration. Cancer Res., 58: 808-814, 1998. myelogenous leukemia: a concise update. Blood. 82: 691-703, 1993. 162. Sidky. Y. A., and Borden, E. C. Inhibition of angiogenesis by interfÃ©rons:effects on 154. Ozer. H. Biolherapy of chronic myelogenous leukemia with IFN. Semin. Oncol., 15 tumor- and lymphocyte-induced vascular responses. Cancer Res., 47: 5155-5161, (Suppl. 5); 14-20, 1988. 1987. 155. Talpaz. M. Use of interferons in the treatment of chronic myelogenous leukemia. Semin. Oncol., 21 (Suppl. 14). 3-7, 1994. 163. Kattan, M. W., Inoue, Y., Giles, F. J., Talpaz, M., Ozer, H.. Guilhot. F., Zuffa, E., Huber, S. L., and Beck, J. R. Cost-effectiveness of interferon-a and conventional 156. Hehlmann, R., Heimpel, H., Hasford, J.. Kolb, H. J., Pralle, H., Hossfeld, D. K., chemotherapy in chronic myelogenous leukemia. Ann. Intern. Med., 125: 541-548, Queisser, W., Loffler, H., Hochhaus, A., Heinze, B., Georgii, A., Bartram, C. R., Griesshammer, M., Bergmann, L., Essers, U., Falge, C., Queisser, U., Meyer, P., 1996. Schmilz, N.. Eimermacher, H., Walther, F., Fett, W., Kleeberg, U. R., Kabisch. A., 164. Cole, B. F., Gelber, R. D.. Kirkwood, J. M., Goldhirsch, A., Barylak. E., and Borden, E. Quality-of-life-adjusted survival analysis of interferon a-2b adjuvant treatment of Neri, C., Zimmermann, R., Meuret, G., Tichelli, A.. Kanz, L., Tigges. F. J.. Schmid. L., Brockhaus, W., Tobler, A.. Reiter, A., Perker, M.. Emmerich, B., Verpoort, K.. high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group Zankovich, R., Von Wussow, P.. Prummer, O.. Thiele. J.. Buhr, T.. Carbonell, F., Study. J. Clin. Oncol., 14: 2666-2673, 1996. and Ansari, H. Randomized comparison of interferon-a with busulfan and hy- 165. Hillner. B. E., Kirkwood, J. M., Atkins, M. B., Johnson. E. R., and Smith, T. J. droxyurea in chronic myelogenous leukemia. The German CML Study Group. Economic analysis of adjuvant imerferon a-2b in high-risk melanoma based on Blood, 84: 4064-4077, 1994. projections from Eastern Cooperative Oncology Group 1684. J. Clin. Oncol., 15: 157. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Imerferon 2351-2358. 1997. a-2a as compared with conventional chemotherapy for the treatment of chronic 166. Liberato, N. L., Quaglini. S.. and Barasi, G. Cost-effectiveness of Â¡nlerferona in myeloid leukemia. N. Engl. J. Med.. 330: 820-825. 1994. chronic myelogenous leukemia. J. Clin. Oncol.. 15: 2673-2682, 1997.

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