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What drug discoverers should know about interferon and its future
Over the last several decades, interferon (IFN)-based therapeutics have come to represent hope, survival and quality-of-life improvements for countless individuals suffering from multiple sclerosis, cancer or severe infectious diseases. Yet, continuing research on the many functions of IFNs leads us to believe that we have only scratched the surface of these molecules' therapeutic potentials.
The biomedical community continues to build on the clinical success of the alpha interferons Roferon-A and IntronA (IFN-α2a and IFN-α2b, respectively), the first FDA-approved biotherapeutics for treating hairy cell leukemia, and subsequently, hepatitis B and C infections. For example, the effectiveness of IFN-α2 in combating HCV has been dramatically improved through combination with the nucleoside analog Ribavirin. Longer serum half-life IFNs such as Pegasys and PegIntron (pegylated IFN-α2a and IFN-α2b, respectively) have also been approved, allowing less frequent dosing, thereby substantially reducing side effects associated with peak circulating levels of the non-pegylated IFNs.
In addition to enhancing the biophysical nature of IFN molecules and determining better drug combinations for approved indications, researchers and clinicians are actively examining new clinical indications where IFNs may improve patient outcomes. In particular, oncology is a rapidly expanding area of interest for IFN researchers because of the potent antiproliferative and immunomodulatory effects of IFNs. Many laboratory and clinical investigations have revealed the in vitro and in vivo potencies and efficacy of IFN-α2 in treating a wide variety of cancers, including malignant melanoma, several leukemias and AIDS-related Kaposi's sarcoma, though many additional oncology indications are addressed with IFN-α2 only through off-label use.
Historically, treatment of cancer patients with IFN-α2 has required the protein to be maintained for extended periods of time at substantial concentration at the tumor site. However, because IFN-α2 is typically cleared quickly from the circulation, frequent IFN administration generally is required to foster any resolution of solid tumors. Yet frequent, high-dose administration of IFNs often triggers serious side effects such as depression, flu-like symptoms, and hematological sequelae.
With the development of pegylated IFNs yielding increased half-life and more stable IFN levels in the circulation, patients can receive lower and less frequent IFN doses typically accompanied by less severe side effects than those of the standard IFNs. Still, although pegylated IFNs have greatly improved the clinical outcomes of patients with viral infections such as hepatitis C, the utility of these modified IFNs in treating patients with solid tumors has remained extremely limited.
In an attempt to improve the understanding of the structure-function differences between the different IFN-α subtypes, and in some cases, to design improved IFN-α therapeutics, several laboratories and companies have pursued limited or aggressive IFN mutagenesis or hybrid approaches. In addition to giving rise to one further approved IFN-α-based therapeutic, Infergen (Alphacon-1), approved for treatment of chronic hepatitis C, these research programs as a whole have shaped our understanding of contact regions between IFN and the type I IFN receptor, and have delineated select amino acid residues within the IFN-α proteins that are crucial to high affinity binding or highly effective signal transduction.
Despite all the excitement and progress in recent years in the clinical use of IFNs, much remains to be done. For example, though the human IFN-αs comprise 13 individual protein subtypes, only a single native subtype, IFN-α2 (i.e., the IFN-α2a and -α2b allelic variants), is available for use in the clinical setting. While the 13 IFN-α subtypes share approximately 75 to 85 percent amino acid sequence identity, an extensive body of literature reveals that these molecules display substantially different pleiotropic activity profiles. Given that, a single, strategically located amino acid change can yield in vitro potency enhancements of well over an order of magnitude, the different IFN-α family members are highly likely to exert physiological effects that are not entirely overlapping even though they each signal through the type I IFN receptor (IFNAR). In addition, the evolutionarily conserved redundancy of the IFN-αs points not only to their essential value in higher eukaryotes, but also to the dramatic potential of these molecules to fine-tune immune system responses against specific pathological threats. Discovery of the therapeutic advantages of any one of the 12 remaining members of this family for use in the clinic is an enormous opportunity in itself. As a whole, these 12 proteins form a striking repository of clinical potential waiting to be unraveled.
Recent work in the elucidation of the innate immune response through unique cellular receptors including toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) has shown that multiple IFNs are expressed in a stimuli- and cell type-dependent manner suggesting that responses to certain pathogens involve complex regulation of expression of far more than a single IFN subtype. These studies further suggest that IFN proteins other than IFN-α2 or combinations of IFNs may be effective in the control and elimination of certain viruses or cancers.
It has also been shown that individuals with certain autoimmune disorders, such as systemic lupus erythematosus (SLE), exhibit elevated levels of IFN-αs. Several clinical trials are currently underway to determine the efficacies of IFN-neutralizing antibodies in mitigating the symptoms and progression of this chronic autoimmune disease. SLE is but one of over 100 autoimmune disorders, the majority of which are rare and poorly understood. Further studies are warranted to determine if the use of IFNs, such as IFN-β, or IFN-neutralizing antibodies would benefit additional subsets of patients with autoimmune disorders.
As already mentioned, the key to realizing IFNs' full potentials as 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 basic research into IFNs opened the door for their use in the treatment of several diseases, recent development research (and funding) has leaned more heavily toward expanding the clinical applications of the very few approved IFN molecular entities rather than pursuing additional members of the family with regard to their clinical utilities. The impact of this shift has had both positive and negative consequences.
On one hand, several seminal papers have engendered heightened interest in the potential for IFN-α2 to treat specific cancers. On the other hand, many important questions on the molecular, genetic, and mechanistic levels have been deferred or left unanswered perhaps further encouraging the misperception that all IFN-α proteins behave similarly. This latter impression has persisted for decades.
Several decades later, there has been a resurgence of interest in IFN research, particularly in their signal transduction pathways, often geared toward better understanding the delicate balance between innate immunity (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 factors controlling the expression of IFNs; and many others. Such groundbreaking work has and will help define the means by which IFNs tune the innate immune response to clear infections and establish memory cells without inducing undesired autoimmune responses.
Returning to SLE as an example, research into IFN signal pathway functionality appears to be an avenue that could lead to encouraging results. Circulating cellular debris including antibodies and nucleic acids are known to activate innate immune response pathways. It is also clear that high circulating levels of IFN-α proteins in serum comprise a heritable risk factor for SLE. Furthermore, it has been suggested that viral infections, which generally result in the endogenous production of IFNs as well as IFN activation of downstream signaling, may be potential environmental triggers for SLE. As mentioned above, clinical trials of at least two anti-IFN alpha neutralizing monoclonal antibodies are underway. Newer research tools such as multiplex cytokine arrays will be imperative in determining the manner in which anti-IFN-α antibodies interrupt the cascade of immunological mediators and events leading to flares in SLE, and will better illustrate the complex interplay of multiple IFNs and other cytokines reflected in subclinical and flare states.
The members of the biomedical community have been able to overcome many challenges in developing effective new ways to prevent and better treat disease. Through the drive of this community and the willingness to take on projects with substantial risk, several IFN molecules become central to improving quality of life of millions of patients worldwide. Nearly 1,000 clinical trials currently mention IFN alpha, beta and gamma, with more than 600 clinical trials mentioning IFN alpha alone. With the 2008 worldwide market for IFN-based therapeutics estimated at approximately $8 billion, it is remarkable and surprising how much remains unclear regarding the many functions and effects of these proteins. Fortunately, we are in the midst of an exciting resurgence of interest in the IFN field. In order to expedite the discovery of new and effective IFN therapeutics and therapeutics that induce or inhibit IFN expression and/or function, we must strive toward a deeper understanding of each IFN's signaling pathways in various cell types, each IFN's functional impact on immune and cancer cells and each IFN's unique physiological sequelae in 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 the founder and chief scientific officer at PBL InterferonSource.