What drug discoverers should know about interferon and its future

A deeper understanding of interferons’ varied functions within the immune system may lead to discovery of more effective therapies

Dr. Sidney Pestka
Over the last several decades, interferon (IFN)-basedtherapeutics have come to represent hope, survival and quality-of-lifeimprovements for countless individuals suffering from multiple sclerosis,cancer or severe infectious diseases. Yet, continuing research on the manyfunctions of IFNs leads us to believe that we have only scratched the surfaceof these molecules' therapeutic potentials.
The biomedical community continues to build on the clinicalsuccess of the alpha interferons Roferon-A and IntronA (IFN-α2a and IFN-α2b,respectively), the first FDA-approved biotherapeutics for treating hairy cellleukemia, and subsequently, hepatitis B and C infections. For example, theeffectiveness of IFN-α2 in combating HCV has been dramatically improved throughcombination with the nucleoside analog Ribavirin. Longer serum half-life IFNssuch as Pegasys and PegIntron (pegylated IFN-α2a and IFN-α2b, respectively)have also been approved, allowing less frequent dosing, thereby substantiallyreducing side effects associated with peak circulating levels of thenon-pegylated IFNs.
In addition to enhancing the biophysical nature of IFNmolecules and determining better drug combinations for approved indications,researchers and clinicians are actively examining new clinical indicationswhere IFNs may improve patient outcomes. In particular, oncology is a rapidlyexpanding area of interest for IFN researchers because of the potentantiproliferative and immunomodulatory effects of IFNs. Many laboratory and clinicalinvestigations have revealed the in vitroand in vivo potencies andefficacy of IFN-α2 in treating a wide variety of cancers, including malignantmelanoma, several leukemias and AIDS-related Kaposi's sarcoma, though manyadditional oncology indications are addressed with IFN-α2 only throughoff-label use.
Historically, treatment of cancer patients with IFN-α2 hasrequired the protein to be maintained for extended periods of time atsubstantial concentration at the tumor site. However, because IFN-α2 istypically cleared quickly from the circulation, frequent IFN administrationgenerally is required to foster any resolution of solid tumors. Yet frequent,high-dose administration of IFNs often triggers serious side effects such asdepression, flu-like symptoms, and hematological sequelae.
With the developmentof pegylated IFNs yielding increased half-life and more stable IFN levels inthe circulation, patients can receive lower and less frequent IFN dosestypically accompanied by less severe side effects than those of the standardIFNs. Still, although pegylated IFNs have greatly improved the clinicaloutcomes of patients with viral infections such as hepatitis C, the utility ofthese modified IFNs in treating patients with solid tumors has remained extremelylimited. 
In an attempt to improve the understanding of thestructure-function differences between the different IFN-α subtypes, and insome cases, to design improved IFN-α therapeutics, several laboratories andcompanies have pursued limited or aggressive IFN mutagenesis or hybridapproaches. In addition to giving rise to one further approved IFN-α-basedtherapeutic, Infergen (Alphacon-1), approved for treatment of chronic hepatitisC, these research programs as a whole have shaped our understanding of contactregions between IFN and the type I IFN receptor, and have delineated selectamino acid residues within the IFN-α proteins that are crucial to high affinitybinding or highly effective signal transduction.  
Despite all the excitement and progress in recent years inthe clinical use of IFNs, much remains to be done. For example, though thehuman IFN-αs comprise 13 individual protein subtypes, only a single nativesubtype, IFN-α2 (i.e., the IFN-α2a and -α2b allelic variants), is available foruse in the clinical setting. While the 13 IFN-α subtypes share approximately 75to 85 percent amino acid sequence identity, an extensive body of literaturereveals that these molecules display substantially different pleiotropicactivity profiles. Given that, a single, strategically located amino acidchange can yield in vitro potencyenhancements of well over an order of magnitude, the different IFN-α familymembers are highly likely to exert physiological effects that are not entirelyoverlapping even though they each signal through the type I IFN receptor(IFNAR). In addition, the evolutionarily conserved redundancy of the IFN-αspoints not only to their essential value in higher eukaryotes, but also to thedramatic potential of these molecules to fine-tune immune system responsesagainst specific pathological threats. Discovery of the therapeutic advantagesof any one of the 12 remaining members of this family for use in the clinic isan enormous opportunity in itself. As a whole, these 12 proteins form a strikingrepository of clinical potential waiting to be unraveled.
Recent work in the elucidation of the innate immune responsethrough unique cellular receptors including toll-like receptors (TLRs) andRIG-I-like receptors (RLRs) has shown that multiple IFNs are expressed in astimuli- and cell type-dependent manner suggesting that responses to certainpathogens involve complex regulation of expression of far more than a singleIFN subtype. These studies further suggest that IFN proteins other than IFN-α2or combinations of IFNs may be effective in the control and elimination ofcertain viruses or cancers.
It has also been shown that individuals with certainautoimmune disorders, such as systemic lupus erythematosus (SLE), exhibitelevated levels of IFN-αs. Several clinical trials are currently underway todetermine the efficacies of IFN-neutralizing antibodies in mitigating thesymptoms and progression of this chronic autoimmune disease. SLE is but one ofover 100 autoimmune disorders, the majority of which are rare and poorlyunderstood. Further studies are warranted to determine if the use of IFNs, suchas IFN-β, or IFN-neutralizing antibodies would benefit additional subsets ofpatients with autoimmune disorders.
As already mentioned, the key to realizing IFNs' full potentialsas therapeutic agents lies in understanding their diverse mechanisms of action,particularly the immunological pathways that are activated, inhibited,modulated, or otherwise engaged by these molecules. While extensive basicresearch into IFNs opened the door for their use in the treatment of severaldiseases, recent development research (and funding) has leaned more heavilytoward expanding the clinical applications of the very few approved IFNmolecular entities rather than pursuing additional members of the family withregard to their clinical utilities. The impact of this shift has had bothpositive and negative consequences. 
On one hand, several seminal papers have engendered heightened interestin the potential for IFN-α2 to treat specific cancers. On the other hand, manyimportant questions on the molecular, genetic, and mechanistic levels have beendeferred or left unanswered perhaps further encouraging the misperception thatall IFN-α proteins behave similarly. This latter impression has persisted fordecades. 
Several decades later, there has been a resurgence ofinterest in IFN research, particularly in their signal transduction pathways,often geared toward better understanding the delicate balance between innateimmunity (beneficial) and autoimmunity (destructive). During the past decade,many new discoveries have come to light: The TLRs and their pathways;mechanisms of IFN mRNA and protein regulation; the cellular and viral factorscontrolling the expression of IFNs; and many others. Such groundbreaking workhas and will help define the means by which IFNs tune the innate immuneresponse to clear infections and establish memory cells without inducingundesired autoimmune responses.
Returning to SLE as an example, research into IFN signalpathway functionality appears to be an avenue that could lead to encouragingresults. Circulating cellular debris including antibodies and nucleic acids areknown to activate innate immune response pathways. It is also clear that highcirculating levels of IFN-α proteins in serum comprise a heritable risk factorfor SLE. Furthermore, it has been suggested that viral infections, whichgenerally result in the endogenous production of IFNs as well as IFN activationof downstream signaling, may be potential environmental triggers for SLE. Asmentioned above, clinical trials of at least two anti-IFN alpha neutralizingmonoclonal antibodies are underway. Newer research tools such as multiplexcytokine arrays will be imperative in determining the manner in which anti-IFN-αantibodies interrupt the cascade of immunological mediators and events leadingto flares in SLE, and will better illustrate the complex interplay of multipleIFNs and other cytokines reflected in subclinical and flare states.
The members of the biomedical community have been able toovercome many challenges in developing effective new ways to prevent and bettertreat disease. Through the drive of this community and the willingness to takeon projects with substantial risk, several IFN molecules become central toimproving quality of life of millions of patients worldwide. Nearly 1,000clinical trials currently mention IFN alpha, beta and gamma, with more than 600clinical trials mentioning IFN alpha alone. With the 2008 worldwide market forIFN-based therapeutics estimated at approximately $8 billion, it is remarkableand surprising how much remains unclear regarding the many functions andeffects of these proteins. Fortunately, we are in the midst of an excitingresurgence of interest in the IFN field. In order to expedite the discovery ofnew and effective IFN therapeutics and therapeutics that induce or inhibit IFNexpression and/or function, we must strive toward a deeper understanding ofeach IFN's signaling pathways in various cell types, each IFN's functionalimpact on immune and cancer cells and each IFN's unique physiological sequelaein patients.
Dr. Sidney Pestka is known as the "father of interferon" for his early,groundbreaking work leading up to the beginnings of the biotechnology industry,including the first recombinant interferons for the treatment of cancers,leukemias, viral diseases such as hepatitis B and C and multiple sclerosis.Pestka is currently chairman and professor of the Department of Microbiology,Molecular Genetics and Immunology at UMDNJ Robert Wood Johnson Medical, and thefounder and chief scientific officer at PBL InterferonSource.

Dr. Sidney Pestka

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