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• W2001367588 abstract "Defense against biothreat agents requires a broad-spectrum approach. Modulation of the innate immune system might fulfill this requirement. Hackett's previous review of innate immune activation as a broad-spectrum biodefense strategy identified several unresolved questions. The current article is a systematic approach to answering those questions with the focused participation of research groups developing this technology. Our team of academic and industry participants reviewed the promising agents and came to the following conclusions. It is feasible to construct a biodefense platform combining synergistic agents that activate the innate immune system against a broad range of pathogens on the basis of conserved microbial components by using a nasal spray for immune activation in the respiratory and gastrointestinal tracts because these are the most likely routes of attack. It might also be possible to include agents that inhibit molecular events leading to septic shock. Innate immune-activating agents designed to activate Toll-like and other receptors will probably provide protection against the biothreat pathogen spectrum for periods ranging from 2 to 14 days for IFNs up to 26 weeks for immunomodulatory oligonucleotides. Initial treatment is proposed on the first index case or biosensor alert. Boost doses would be required. Harmful inflammation is possible, but thus far, only transient fever has been observed. Autoimmune reaction and retroviral activation have not been seen thus far in preclinical and human trials of many of these compounds. Toll-like receptor agonists caused cytokine production in all subjects tested, but genetic polymorphism reduced the response to IFN in African American subjects. Defense against biothreat agents requires a broad-spectrum approach. Modulation of the innate immune system might fulfill this requirement. Hackett's previous review of innate immune activation as a broad-spectrum biodefense strategy identified several unresolved questions. The current article is a systematic approach to answering those questions with the focused participation of research groups developing this technology. Our team of academic and industry participants reviewed the promising agents and came to the following conclusions. It is feasible to construct a biodefense platform combining synergistic agents that activate the innate immune system against a broad range of pathogens on the basis of conserved microbial components by using a nasal spray for immune activation in the respiratory and gastrointestinal tracts because these are the most likely routes of attack. It might also be possible to include agents that inhibit molecular events leading to septic shock. Innate immune-activating agents designed to activate Toll-like and other receptors will probably provide protection against the biothreat pathogen spectrum for periods ranging from 2 to 14 days for IFNs up to 26 weeks for immunomodulatory oligonucleotides. Initial treatment is proposed on the first index case or biosensor alert. Boost doses would be required. Harmful inflammation is possible, but thus far, only transient fever has been observed. Autoimmune reaction and retroviral activation have not been seen thus far in preclinical and human trials of many of these compounds. Toll-like receptor agonists caused cytokine production in all subjects tested, but genetic polymorphism reduced the response to IFN in African American subjects. A bioterror attack requires an immediate and effective response. Vaccines are limited by the inability to predict the pathogen and resistance to prophylactic vaccination. The inherent delay in adaptive immune response renders it inadequate for protection from bioterror attack. Innate immunity is an underexplored option for biodefense. Recent therapeutic advances suggest that innate immunomodulation holds the potential for improved survival after a bioterror attack with an infectious agent. Numerous products targeting various processes in the innate immune response are either currently available and moving toward human trials or in the initial stages of development. In-depth investigation into opportunities offered by innate immunity for biodefense is currently lacking. Innate immune cells use pathogen recognition receptors to recognize pathogen macromolecules to provide an immediate response with broad specificity. The pathogen-associated molecular pattern system of Toll-like receptors (TLRs) comprises cell-surface and endosomic receptors that recognize broadly conserved ligands unique to microorganisms. Currently, one TLR agonist is licensed for use in human subjects for certain viral infections and skin cancers, and other agonists are in advanced stages of clinical development. TLRs might be exploited against bioterrorism agents on the basis of their mechanism of action; however, excessive activation of the innate immune system can result in autoimmune disease and septic shock.1Hackett C.J. Innate immune activation as a broad spectrum biodefense strategy: prospects and research challenges.J Allergy Clin Immunol. 2003; 112: 686-694Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar These issues are the focus of this investigation. In November 2004, a panel of invited experts met to consider the feasibility of innate immune modulation as biodefense, including the risks in stimulating innate immunity, current resources, the time needed to develop and produce effective agents, and interfacing with regulatory agencies. At the conclusion of the meeting, technical documents describing the application of a particular product or technology to biodefense were requested. In collaboration with independent reviewers, proposals were evaluated on compound–mechanism of action, potential activity, likelihood of product approval within 5 years, uniqueness, and overall grade. Criteria for evaluating this approach have been published by Hackett1Hackett C.J. Innate immune activation as a broad spectrum biodefense strategy: prospects and research challenges.J Allergy Clin Immunol. 2003; 112: 686-694Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar and were applied to submitted technologies. Questions raised by Hackett include the following:1.Which innate immune receptors stimulate effective prophylactic responses to the broadest range of bacterial and viral pathogens?2.How long does protection last?3.Could innate immune therapy trigger harmful inflammation?4.Will innate immune stimulation promote autoimmune reactions or retroviral activation?5.How important a factor is human genetic polymorphism within the innate immune system for innate immune therapy strategies? Innate immune cells use pathogen recognition receptors to recognize pathogen macromolecules and promote rapid response. As mentioned above, TLRs are type I transmembrane and endosomically expressed proteins that are evolutionarily conserved and have been identified as the key pathogen recognition receptors in innate immunity. TLRs 1 through 10 are present on human innate immune cells and act through cellular signal cascade to augment host immune response through inflammation. TLR agonists can modify host inflammatory responses, potentially offering increased protection from infection. Currently, TLR agonists are licensed and being used in human subjects in the setting of microbial infection and cancer. They can be tailored to specific diseases and administered through multiple routes. Microbial ligands recognized by TLRs are constitutively expressed and highly conserved structural molecules less prone to rapid genetic mutation, and thus TLR agonists are less likely to select for resistant strains (Fig 1). Specifically, certain TLRs might be exploited against bioterrorism agents on the basis of their mechanism of action. For example, TLR1 blocks TLR2 and TLR4 signaling. TLR2 recognizes bacterial proteoglycans. TLR3 recognizes viral double-stranded RNA. TLR4 recognizes bacterial LPS and lipoteichoic acids. TLR5 recognizes bacterial flagella. TLR6 is required for TLR2 signaling recognition of bacterial proteoglycans. TLR7 and TLR8 recognize viral single-stranded RNA. TLR9 recognizes bacterial CpG DNA. Studies on macrophages show that TLR stimulation can be sustained, and further amplification by other agonists might be possible. An understanding of naturally occurring cytokines and immune cells presents the possibility of using this knowledge to modulate the body's own defenses. IFN-α and IFN-β (type I IFNs) exhibit antiviral activity. IFN-γ (type II IFN) plays a role in bacterial infections. IFNs perform these roles through their receptors, which result in phosphorylation of kinases crucial to the cytokine cascade. CD4, expressed on macrophages and dendritic cells (DCs), activates and modulates their maturation and activity against pathogens. An enemy bioterror attack is likely to target either the respiratory or gastrointestinal tracts because they are the most easily accessible from the external environment. However, chronic or systemic activation of the innate immune system as prophylaxis could have harmful or fatal consequences. Activating these receptors for limited time periods through localized delivery (eg, intranasal or oral) might minimize toxicity, with the potential for retreatment as necessary to maintain short-term innate sensitization against bioterror agents. There are, however, concerns that TLR agonists that activate plasmacytoid DCs (TLR7 and TLR9 agonists) are more likely to induce autoimmune disease. This has been shown in a number of preclinical trials and human topical studies. Furthermore, some studies have suggested a relationship between IFN levels and autoimmune disease. Further studies must demonstrate not only the efficacy but also the safety in the case of TLRs and those products that increase IFN levels. 3M Pharmaceuticals has developed a class of immune response modifiers (IRMs) that act by stimulating TLR7 and TLR8 and have exhibited antiviral and antineoplastic activity in human subjects. Aldara has been shown to be of benefit in human clinical studies against human papillomavirus (HPV),2Cox J.T. Petry K.U. Rylander E. Roy M. Using imiquimod for genital warts in female patients.J Womens Health (Larchmt). 2004; 133: 265-271Crossref Scopus (18) Google Scholar molluscum contagiosum,3Theos A.U. Cummins R. Silverberg N.B. Paller A.S. Effectiveness of imiquimod cream 5% for treating childhood molluscum contagiosum in a double-blind, randomized pilot trial.Cutis. 2004; 74 (141-2): 134-138PubMed Google Scholar and leishmaniasis.4Arevalo I. Ward B. Miller R. Meng T.C. Nagar E. Alvarez E. et al.Successful treatment of drug-resistant cutaneous leishmaniasis in humans by use of imiquimod, an immunomodulator.Clin Infect Dis. 2001; 33: 1847-1851Crossref PubMed Scopus (173) Google Scholar Aldara is US Food and Drug Administration (FDA) approved for use in the treatment of actinic keratoses, basal cell carcinoma, and genital warts. 3M Pharmaceuticals plans to use compounds selective for activation of TLR7, TLR8, or both by using an influenza virus challenge with cytokine response and immunity as outcome measures. Similar experiments and goals are planned for select agents (eg, Hantavirus) in collaboration with the US Army Medical Research Institute of Infectious Diseases. Nasal and pulmonary delivery protection against influenza, as well as pharmacokinetics and pharmacodynamics of systemic treatment, will also be explored. 3M has addressed the questions from Hackett's article as follows: TLR7 and TLR8 should have broad activity against numerous pathogens. Potent antiviral activity in mouse and primate models against herpes simplex virus (HSV) 1 and 2, cytomegalovirus, Banzivirus, Rift Valley fever, influenza, and West Nile has been demonstrated. Their IRM models also suggest utility against Leishmania, Listeria, and Mycobacterium species. Imiquimod is currently applied 2 to 3 times per week with active immunomodulatory effects between treatments. IRM models suggest administration 3 to 4 days before exposure provides adequate anti-infective protection. Rare inflammatory side effects have been reported, specifically in those with T cell–mediated autoimmune disorders that subside after therapy is discontinued. Potential systemic side effects, such as fever, are possible in conjunction with cytokine toxicity. Genetic polymorphisms might play a role in response variability. 3M screened blood from more than 100 individuals and demonstrated variable IRM response, but cytokine production was observed in all subjects. Fatigue and influenza-like symptoms have been reported with use. There is concern about the relationship between TLR7 agonists and autoimmune disease; however, in extensive preclinical and clinical trials with IRMs, autoimmunity has not been observed. Aldara (imiquimod 5% cream) has gone through phase III clinical trials and is approved for the treatment of external genital warts, actinic keratosis, and basal cell carcinoma. Other TLR7/TLR8 agonists are in preclinical and clinical development for multiple indications, including cervical HPV infection. Coley Pharmaceutical Group has developed a TLR9 agonist, CPG 7909, which activates both innate and adaptive immune systems. Three different classes of CpG oligodeoxynucleotides (ODNs) are distinguished by their structure and immune effects. A-class (also known as type D) CpG ODNs stimulate plasmacytoid DCs to secrete high levels of IFN-α and natural killer (NK) cells to secrete IFN-γ,5Krug A. Rothenfusser S. Hornung V. Jahrsdorfer B. Blackwell S. Ballas Z.K. et al.Identification of CpG oligonucleotide sequences with high induction of IFN-alpha/beta in plasmacytoid dendritic cells.Eur J Immunol. 2001; 31: 2154-2163Crossref PubMed Scopus (776) Google Scholar as well as monocyte maturation into functional DCs,6Gursel M. Verthelyi D. Klinman D.M. CpG oligodeoxynucleotides induce human monocytes to mature into functional dendritic cells.Eur J Immunol. 2002; 32: 2617-2622Crossref PubMed Scopus (76) Google Scholar with little IL-6 or B-cell stimulation. Conversely, B-class (type K) CpG ODNs induce modest IFN-α production, weak NK cell activation, and profound B-cell and monocyte activation, with secretion of IgM, IL-10, and IL-6.7Vollmer J. Weeratna R. Payette P. Jurk M. Schetter C. Laucht M. et al.Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities.Eur J Immunol. 2004; 34: 251-262Crossref PubMed Scopus (510) Google Scholar C-class CpG ODNs have intermediate immune effects7Vollmer J. Weeratna R. Payette P. Jurk M. Schetter C. Laucht M. et al.Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities.Eur J Immunol. 2004; 34: 251-262Crossref PubMed Scopus (510) Google Scholar and are very stable in vivo, with easy formulation. CPG 7909, a B-class ODN, was the first ODN to enter clinical trials in 1999. CPG 10101, a C-class ODN, recently entered clinical trials as monotherapy for chronic HCV infection. A recently developed type of CpG ODN (fma CpG ODN) by Daniela Verthelyi and Serge Beaucage at the FDA has an altered chemistry that will allow for CpG ODNs to be prepared as prodrugs, thereby easing their production (Beaucage and Verthelyi, unpublished data). Some studies suggest that intranasal or pulmonary delivery might be superior for protection against inhaled pathogens. There is also some evidence suggesting synergy with antibiotic treatment to infection (Mycobacterium avium and clarithromycin) and the possibility of postexposure efficacy. Class CPG 7909 has been tolerated locally and systemically in more than 700 subjects thus far, with flu-like symptoms and transient injection site reactions commonly seen in patients receiving more than 1 mg. C-class CPG 10101 has shown a similar safety profile in clinical trials with more than 80 healthy volunteers or HCV-infected subjects. Possible proinflammatory activity through the intranasal route and autoimmune disease has been described in mice.8Obermeier F. Dunger N. Deml L. Herfarth H. Scholmerich J. Falk W. CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice.Eur J Immunol. 2002; 32: 2084-2092Crossref PubMed Scopus (118) Google Scholar The use of CpG ODNs in most models requires that they be administered 3 to 6 days before infection. Newly developed fma CpG ODNs have backbones with thermolytic protective moieties that prolong the ODN activity. At 37°C, the ODNs become spontaneously deprotected, ultimately allowing ODNs to act as prodrugs.9Grajkowski A. Pedras-Vasconcelos J. Wang V. Ausin C. Hess S. Verthelyi D. et al.Thermolytic CpG-containing DNA oligonucleotides as potential immunotherapeutic prodrugs.Nucleic Acids Res. 2005; 33: 3550-3560Crossref PubMed Scopus (27) Google Scholar Studies in rodents have shown that CpG ODNs have immunoprotective effects against the following pathogens: bacteria (Bacillus anthracis, Francisella tularensis, Listeria monocytogenes, Klebsiella pneumoniae, Mycobacterium species, Brucella abortus, Burkholderia mallei, Burkholderia pseudomallei, Salmonella typhi, Pseudomonas aeruginosa, and Orientia tsutsugamushi), viruses (vaccinia and other orthopox viruses, arena, Ebola, Venezuelan equine encephalitis, Friend leukemia, HSV papillomavirus, cytomegalovirus, respiratory syncytial virus, murine acquired immunodeficiency virus complex, and influenza), fungus (Cryptococcus neoformans), and parasites (malaria, Leishmania major, and toxoplasmosis). CpG DNA innate protection was evident for a period of from approximately 2 days after treatment up to 2 weeks later, with possible repeated administration for extended protection.10Klinman D.M. Immunotherapeutic uses of CpG oligodeoxynucleotides.Nat Rev Immunol. 2004; 4: 249-259Crossref PubMed Scopus (852) Google Scholar The experience in primates is more restricted. Protection was only demonstrated thus far when CpG ODNs of type D were administered to macaques infected with L major.11Verthelyi D. Gursel M. Kenney R.T. Lifson J.D. Liu S. Mican J. et al.CpG oligodeoxynucleotides protect normal and SIV-infected macaques from Leishmania infection.J Immunol. 2003; 170: 4717-4723PubMed Google Scholar Although theoretic concerns remain regarding the possibility that TLR9 agonist therapy could trigger harmful inflammation, this has not been seen in initial clinical trials in human subjects. Other concerns include genetic polymorphism.12Leifer C.A. Verthelyi D. Klinman D.M. Heterogeneity in the human response to immunostimulatory CpG oligodeoxynucleotides.J Immunother. 2003; 26: 313-319Crossref PubMed Scopus (34) Google Scholar Lederer, at Harvard, is working with Coley Pharmaceutical Group on a synergistic platform, combining their CpG ODNs with a double-stranded RNA, Ampligen (see later), which stimulates immune reactions through TLR3. CPG 7909 has shown some positive results in several human clinical trials involving a total of more than 900 subjects as an adjuvant for hepatitis B, flu, and cancer vaccines and in the treatment of melanoma, renal cell carcinoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and lung cancer. A C-class CpG ODN, CPG 10101, has induced greater than 1 log reductions in viral load among patients with chronic hepatitis C virus (HCV) infection. Hybridon has developed second-generation immunomodulatory oligonucleotides (IMOs) containing synthetic stimulatory motifs, CpR, YpG, and R′pG, as TLR9 agonists.13Wang D. Kandimalla E.R. Yu D. Tang J.X. Agrawal S. Oral administration of second generation immunomodulatory oligonucleotides induces mucosal Th1 immune responses and adjuvant activity.Vaccine. 2005; 23: 2614-2622Crossref PubMed Scopus (33) Google Scholar In addition to synthetic motifs, IMO is composed of a novel DNA structure with 3′-3′ attached structure that has higher stability against 3′-exonuclease digestion and is a candidate for oral administration.13Wang D. Kandimalla E.R. Yu D. Tang J.X. Agrawal S. Oral administration of second generation immunomodulatory oligonucleotides induces mucosal Th1 immune responses and adjuvant activity.Vaccine. 2005; 23: 2614-2622Crossref PubMed Scopus (33) Google Scholar The two 5′ ends facilitate increased TLR9 activation. IMO induces cytokine secretion profiles distinct from CpG dinucleotide. On the basis of immune profiles in various cell-based and in vivo studies, including in nonhuman primates, IMOs are broadly classified into 3 distinct groups.14Kandimalla E.R. Bhagat B. Li Y. Yu D. Wang D. Cong Y.P. et al.Immunomodulatory oligonucleotides containing a cytosine-phosphate-2′-deoxy-7-deazaguanosine motif as potent Toll-like receptor 9 agonists.Proc Natl Acad Sci U S A. 2005; 102: 6925-6930Crossref PubMed Scopus (93) Google Scholar Phase I clinical trials in human subjects have shown increased levels of cytokine secretion (including IFN-γ/α). Subcutaneous trials in human subjects have used weekly dosing up to 3 to 4 weeks, with no dose-limiting toxicity observed and no evidence of adverse reactions. IMOs offer potential for innate immune responses, including localized delivery after exposure. Hybridon has addressed Hackett's questions as follows: On the basis of animal models, TLR9 agonists provide broad protection against bacteria and viruses through TH1 immune responses. TLR9 agonists have produced strong antigen-specific IgG2a antibody responses lasting up to 26 weeks, with successful antigen challenge at week 24 in animals. IMO use could potentially address B anthracis, Yersinia species, variola, dengue, Ebola, Salmonella species, Listeria species, hepatitis A, West Nile Virus (WNV), influenza, rickettsia, rabies, and Severe Acute Respiratory Syndrome (SARS) infections. Humoral responses last up to 26 weeks. IMOs have been shown to be safe when given once a week for up to a year in patients with cancer and have been designed to induce a defined cytokine profile to avoid harmful inflammatory responses. On the basis of transgenic and knockout mouse models, autoimmune reactions might occur in susceptible individuals but are not observed in clinical trials with any CpG-containing oligonucleotides to date. There is no evidence that TLR9 single-nucleotide polymorphisms affect CpG responses or TLR9 signaling. One exception might be polymorphisms in IL-1 receptor–associated kinase 4, leading to decreased responsiveness to innate immunotherapy. CpG DNA and IMO share similar mechanisms of TLR9 activation. Lead IMO is in phase II trials for renal carcinoma and in phase I trials with Remune (HIV-1 whole killed virus) as an adjuvant. Several other IMOs with different immunostimulatory properties are at various stages of development and preclinical studies for a number of disease indications, including infectious diseases. Thymalfasin (thymosin α1), manufactured by SciClone Pharmaceuticals, is a synthetic analog of a thymic peptide.15Billich A. Thymosin alpha1. SciClone Pharmaceuticals.Curr Opin Investig Drugs. 2002; 3: 698-707PubMed Google Scholar It has been shown to have broad immunostimulatory activities both in vitro and in vivo, resulting in enhancement of adaptive and innate immune responses as evidenced by TH1 cell stimulation and increases in NK cell activity and DC activation. Current indications include hepatitis B virus (HBV) and HCV.15Billich A. Thymosin alpha1. SciClone Pharmaceuticals.Curr Opin Investig Drugs. 2002; 3: 698-707PubMed Google Scholar Mouse models suggest innate stimulation in the setting of Aspergillus species infection, leading to increased survival.16Romani L. Bistoni F. Gaziano R. Bozza S. Montagnoli C. Perruccio K. et al.Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling.Blood. 2004; 103: 4232-4239Crossref PubMed Scopus (182) Google Scholar SciClone has addressed Hackett's questions as follows: Thymalfasin might be effective for a range of infections, including viruses (HCV, HBV, influenza, HIV, and herpes), fungi (Candida and Aspergillus species), and bacteria (Listeria species, Pseudomonas species, and Serratia marcescens). Biweekly treatment of human patients up to 1 year has been safe, with no cases of harmful inflammation or autoimmune activation seen in the thousands of human subjects treated with thymalfasin to date. The effect of genetic polymorphism is unknown. Thymalfasin has been approved in more than 30 countries and is in phase III testing in the United States (to be completed by year end 2005). Recent evidence suggests that among TLRs in airway epithelial cells, TLR3 activation resulted in the greatest increase of innate immune response.17Sha Q. Truong-Tran A.Q. Plitt J.R. Beck L.A. Schleimer R.P. Activation of airway epithelial cells by toll-like receptor agonists.Am J Respir Cell Mol Biol. 2004; 31: 358-364Crossref PubMed Scopus (413) Google Scholar Hemispherx Biopharma produces Ampligen (poly I: polyC12U, a synthetic double-stranded RNA), a TLR3 agonist that induces IFN cascade and activates critical enzymes (p68 kinase and 2′-5′ adenylate synthetase) normally induced by IFNs by mimicking double-stranded long cytoplasmic RNAs produced during viral infection. Synergistic immune activation is observed when Ampligen is given in conjunction with IFN-α. Ampligen has already been tested against more than 25 viruses and will be used in Advanced Biosystem's proposal for inhaled IFN (in conjunction with Alferon, see later). Ampligen has been demonstrated recently to mediate protective antiviral responses as long as 2 days after experimental infection with Coxsackie B3 virus in a murine model.18Padalko E. Nuyens D. De Palma A. Verbeken E. Aerts J.L. De Clercq E. et al.The interferon inducer ampligen [Poly(I)-Poly (C12U)] markedly protects mice against coxsackie B3 virus-induced myocarditis.Antimicrob Agents Chemother. 2004; 48: 267-274Crossref PubMed Scopus (49) Google Scholar Phase II/III trials of Ampligen have been completed successfully in human subjects with chronic fatigue syndrome and HIV infection. Ampligen therapy was generally well tolerated. Corixa Corporation is developing TLR4 innate immunomodulators for airway delivery, including CRX-527 and CRX-527. A single-dose, dose-escalation, phase I clinical trial with intranasally delivered CRX-675 (a moderate-strength TLR4 agonist) is currently underway for the treatment of allergic rhinitis. CRX-527 is a highly active synthetic TLR4 agonist that induces innate resistance to airway challenge by viral and bacterial pathogens. Studies in mice have demonstrated that CRX-527 enhances protective immunity in the airways to L monocytogenes, influenza virus, respiratory syncytial virus, and Haemophilus influenzae, with resistance to infection persisting between 4 and 7 days accompanied by induction of cytokines, chemokines, defensins, and type 1 IFNs. Animal models suggest response within hours of administration and lasting up to a week. Weekly or biweekly administration can extend protection without inducing tolerance. Protective doses of CRX-527 are significantly lower than toxic doses, suggesting a safe therapeutic index.19Cluff C.W. Baldridge J.R. Stöver A.G. Evans J.T. Johnson D.A. Lacy M.J. et al.Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge.Infect Immun. 2005; 73: 3044-3052Crossref PubMed Scopus (100) Google Scholar, 20Stöver A.G. Da Silva Correia J. Evans J.T. Cluff C.W. Elliott M.W. Jeffery E.W. et al.Structure-activity relationship of synthetic toll-like receptor 4 agonists.J Biol Chem. 2004; 279: 4440-4449Crossref PubMed Scopus (137) Google Scholar A phase I, multidose, dose-escalation trial with CRX-527 (a high-activity TLR4 agonist) is scheduled for early 2006. It is expected that CRX-527's effects will last between 3 and 7 days, with biweekly dosing extending the duration for 6 to 12 weeks. Redosing might avoid prolonged innate stimulation and potential autoimmune reactions. Biweekly intranasal delivery has not been associated with systemic inflammation. Corixa does not anticipate that genetic polymorphism will significantly affect TLR4 agonist responses; however, a recent study suggests phylogenetic and individual diversity in TLR4 responses, suggesting possible variability in efficacy for TLR4 agonists. A phase I clinical trial with CRX675 was recently completed, with no serious or severe adverse events reported. Additional clinical trials with CRX527 (phase I safety study) and CRX675 (phase II) are planned for 2006. IFN-α plays a significant role in innate immunity to viral infections. There is also some evidence of viral decoy mechanisms, whereby some viruses have developed mechanisms to evade innate immunity.21Hahm B. Trifilo M.J. Zuniga E.I. Oldstone M.B. Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling.Immunity. 2005; 22: 247-257Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar A multicomponent approach to IFN treatment could possibly overcome this potential form of innate resistance. Activating the innate immune system through IFNs raises safety issues regarding possible adverse reactions, including microbial reactions (as seen in sarcoid-like disease in mice)22Nishiwaki T. Yoneyama H. Eishi Y. Matsuo N. Tatsumi K. Kimura H. et al.Indigenous pulmonary propionibacterium acnes primes the host in the development of sarcoid-like pulmonary granulomatosis in mice.Am J Pathol. 2004; 165: 631-639Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar and those seen in current treatment of hepatitis infection with pegylated IFNs.23Matthews S.J. McCoy C. Peginterferon alfa-2a: a review of approved and investigational uses.Clin Ther. 2004; 26: 991-1025Abstract Full Text PDF PubMed Scopus (67) Google Scholar Hemispherx Biopharma also produces Alferon, a natural IFN-α. Alferon-N injection might soon b" @default.
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• W2001367588 cites W1990784698 @default.
• W2001367588 cites W1994215252 @default.
• W2001367588 cites W1999587028 @default.
• W2001367588 cites W2003937801 @default.
• W2001367588 cites W2010837851 @default.
• W2001367588 cites W2013821847 @default.
• W2001367588 cites W2031558790 @default.
• W2001367588 cites W2041111263 @default.
• W2001367588 cites W2047445859 @default.
• W2001367588 cites W2049399563 @default.
• W2001367588 cites W2074403536 @default.
• W2001367588 cites W2087144130 @default.
• W2001367588 cites W2098905001 @default.
• W2001367588 cites W2101173190 @default.
• W2001367588 cites W2109485753 @default.
• W2001367588 cites W2111819461 @default.
• W2001367588 cites W2135876044 @default.
• W2001367588 cites W2139437304 @default.
• W2001367588 cites W2141550596 @default.
• W2001367588 cites W2141862597 @default.
• W2001367588 cites W2143127434 @default.
• W2001367588 cites W2160369507 @default.
• W2001367588 cites W2164094601 @default.
• W2001367588 cites W2183162582 @default.
• W2001367588 cites W2328010767 @default.
• W2001367588 cites W2402541676 @default.
• W2001367588 cites W2416709236 @default.
• W2001367588 cites W39083769 @default.
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