Patent Application: US-29185105-A

Abstract:
an improved understanding and method for the clinical adjuvant and immunomodulatory use of dsrnas and ply - iclc in particular , alone or in conjunction with other drugs and various vaccines designed to prevent or treat various microbial , viral , neoplastic , autoimmune diseases , and or degenerative diseases .

Description:
the complex interaction of the interferons and dsrna - activated systems can be manipulated to therapeutic advantage , particularly in the case of those certain microbial and neoplastic diseases that thrive by circumventing certain host defense mechanisms involving both innate immunity ( eg oas and the pkr ) and adaptive immunity . poly - iclc should be administered intramuscularly or subcutaneously locally in the same limb as vaccine , in order to stimulate local dendritic cell trafficking . administration in a remote site will be much less effective or ineffective . poly - iclc can also be administered orally or mucosally including nasally at about the time of vaccine administration or mixed with vaccine in order to achieve the desired adjuvant effect . clinical data will be presented to support this claim . clinical trials of poly - iclc to date have utilized the intravenous ( iv ) or intramuscular ( im ) routes of administration . wong and others have demonstrated that intranasal poly - iclc can protect from nasal viral challenge in anesthetized mice . we have now have demonstrated that intranasal treatment of non - human primates ( rhesus monkeys ) with poly - iclc will also result in a robust systemic response as measured by plasma interferon at 24 hours , but not 8 hours from administration , as shown in fig1 . this unexpected result opens the possibility of using intranasal , sublingual , or topical poly - iclc for treatment of systemic diseases . this may be especially advantageous in long term treatment of cancer or autoimmune diseases , treatment of large number of individuals exposed to hiv or a bioterror threat such as smallpox ; or for veterinary use , as in containment of an outbreak of foot and mouth disease in cattle , management of the bovine respiratory complex , avian influenza , or respiratory syncytial virus infection . however , as noted above , one consideration is the duration of exposure of the nasal and bronchial mucosa to poly - iclc . the animals treated in the experiment illustrated in fig1 were anesthetized prior to nasal administration , ensuring exposure of the full dose for at least 30 minutes to mucosal surfaces . this implies that for clinical use in humans or for veterinary applications , a practical aerosol or spray formulation that ensures such prolonged mucosal exposure may be necessary for adequate protection of the respiratory portal . similarly , based on the experience with oral interferon use , it is also hypothesized that orally or sublingually administered poly - iclc may be sufficient to yield a clinical therapeutic response . oral administration in a suitable formulation could also be especially advantageous in large - scale human or veterinary uses . finally , older rabbit studies demonstrated protection from vaccinia by topically administered poly - iclc . this suggests that topical administration of poly - iclc in a dermatologic preparation or dermal patch may also be efficacious for certain applications in humans . ( levy and lvovsky 1978 ) further data will be presented to support these claims . an improved method for the clinical and veterinary immunomodulatory or adjuvant use of poly - iclc it is expected that poly - iclc would have application to the treatment of a variety of diseases including certain neoplastic , infectious , and autoimmune disorders . the following examples are illustrations , but not limitations , of the approach . given these examples , one of ordinary skill in the art could apply the same approach to other diseases . a ) example of clinical treatment of a retroviral disease : treatment of aids with poly - iclc . in an open pilot trial , low dose ( 0 . 2 - 2 mg ) poly - iclc was administered intramuscularly ( im ) 1 - 3 times per week with or without zidovudine over up to 30 months to 22 patients with hiv infection or aids . ( salazar , morales et al . 1990 ) poly - iclc was well tolerated , with no significant clinical or laboratory toxicity . side effects consisted of a mild 12 - 24 hour flu - like syndrome with low - grade fever and malaise at the higher doses , but usually disappeared after the first half - dozen treatments . 12 / 20 patients showed at times dramatic initial rises in t4 cell counts along with symptomatic improvement , although this was not uniformly maintained . plasma p - 24 titers ( a measure of viral load ), which were positive in 8 / 16 patients before biweekly treatment , either became undetectable or remained so in all but one patient , whose titers were markedly elevated at onset and dropped by 75 % with treatment . in a separate dosing study of poly - iclc in 8 aids patients , neuropsychological testing has shown a marked improvement in choice reaction time and the purdue pegboard test at 16 weeks of treatment , with a deterioration back to baseline when poly - iclc was discontinued . this contrasts with a gradual , statistically significant deterioration in choice reaction time seen in an untreated hiv + cohort ( n = 41 ) over six months . as suggested above , it is expected that even better responses than those seen to date may be achievable utilizing the new double - dosing technique described in section b , above , and shown in fig5 . this and other considerations led us to an open trial of high dose ( 100 mcg / kg ) intravenous poly - iclc showed moderately severe acute toxicity in 15 patients with chronic ms ; several patients improved or stabilized , but deteriorated when drug was stopped , as reported by bever , salazar , et al ., 1986 . ( bever , salazar et al . 1986 ) subsequently , salazar continued to treat some of these and other ms patients with a completely new extended regimen using much lower doses of poly - iclc intramuscularly over a longer period of time . results of this follow - up study are unpublished , and are disclosed below . methods : thirty one patients with either chronic progressive ( cp ) or exacerbating progressive ( ep ) multiple sclerosis received 5 - 100 mcgm / kg piclc im q 3 - 14 days for up to 15 years ; most received a median dose of 10 mcg / kg weekly . toxicity was markedly reduced to an inconstant , mild , transient malaise . the kurtzke expanded disability status score ( edss , which varies between 0 ( normal ) and 9 ( totally bedridden and dependent ) was used to evaluate outcome . as shown in fig6 , the edss remained stable or improved in 15 / 31 patients ( dramatically in 5 ). six patients deteriorated when poly - iclc was stopped . the 19 cp patients showed a median edss change of 0 . 09 points per year over a median of 60 months ; while the 12 ep patients showed a slight improvement (− 0 . 1 edss per year ) over a median of 28 months . these rates compare very favorably with the expected rates of progression in untreated multiple sclerosis patients . ( note that a lower kurtzke score is better ). therefore , im low dose poly - iclc may be a valuable alternative to the more expensive and toxic beta - interferons for long - term management of ms . as suggested above , it is expected that even better response rates than those seen to date may be achievable utilizing the new double - dosing technique described above . c ) example of reversal of viral and tumor induced inhibition of dendritic cells with poly - iclc and other pamps additional data will be presented to demonstrate the prevention as well as reversal of tumor - induced inhibition of dendritic cells either in vivo or in vitro by treatment of cell cultures and / or cancer patients with poly - iclc and certain other dsrnas . in vitro studies will demonstrate preemption / reversal of dc inhibition by prostate specific antigen . clinical trials in patients with advanced prostatic cancer will demonstrate in - vivo reversal of dc inhibition and enhanced ctl response to a prostatic cancer antigen based vaccine in response to poly - iclc priming and treatment as described herein . aalamian , m ., i . tourkova , et al . 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