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(12) Patent Application Publication (10) Pub. No.: US 2013/0315952 A1 Turner Et Al US 2013 0315952A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0315952 A1 Turner et al. (43) Pub. Date: Nov. 28, 2013 (54) ADMINISTRATION OF INTERFERON FOR Publication Classification PROPHYLAXIS AGAINST OR TREATMENT OF PATHOGENIC INFECTION (51) Int. C. A638/2I (2006.01) Applicant: Defyrus, Inc., Toronto (CA) A639/2 (2006.01) (71) A6M I5/00 (2006.01) A6M 16/14 (2006.01) (72) Inventors: Jeffrey D. Turner, Toronto (CA); Jane A6M II/02 (2006.01) E. Ennis, Toronto (CA) CI2N 5/86 (2006.01) A619/00 (2006.01) (52) U.S. C. (73) Assignee: Defyrus, Inc., Toronto (CA) CPC .............. A61 K38/212 (2013.01): CI2N 15/86 (2013.01); A61 K39/12 (2013.01); A61 K 9/0073 (2013.01); A61M 16/14 (2013.01); (21) Appl. No.: 13/675,897 A61M II/02 (2013.01); A61M 15/00 (2013.01) USPC ... 424/204.1: 435/320.1: 514/44 R; 424/93.2: 128/203.12; 128/200.21; 128/203.15 (22) Filed: Nov. 13, 2012 (57) ABSTRACT The invention provides compositions and methods for the prophylaxis or treatment of diseases or disorders in a subject Related U.S. Application Data (e.g., a mammal. Such as a human) including, e.g., diseases or (63) Continuation of application No. 12/797.575, filed on disorders caused by biological agents, autoimmune diseases, Jun. 9, 2010, now Pat. No. 8,309,531. and cancer. The compositions include a delivery vector (e.g., a viral vector, Such as an Ad5 vector) encoding an interferon (60) Provisional application No. 61/185.261, filed on Jun. (e.g., IFN-O.), and are provided to the Subject by, e.g., intra 9, 2009. nasal or pulmonary administration. Patent Application Publication Nov. 28, 2013 Sheet 1 of 12 US 2013/0315952 A1 Figure 1 girlap. Stitt *?,*;***$.§ . T : s , . ; F s . -kai is ... 8 IF - 18, 5. $8, F : . E. E. F . f : . 5 (4) : , 8 S. | M. R. S. f : . S. , , ; ; ; ; ; , , , , . R. S. F. S. L & E R I, E. Patent Application Publication Nov. 28, 2013 Sheet 2 of 12 US 2013/0315952 A1 Figure 2 conINF-0. Patent Application Publication Nov. 28, 2013 Sheet 3 of 12 US 2013/0315952 A1 Figure 3 FN Gene Ad5 Vector IFN polypeptide / 0 / / Air of Nasal Cavity Epithelial Cells BOOdstream D Patent Application Publication Nov. 28, 2013 Sheet 4 of 12 US 2013/0315952 A1 Figure 4 Patent Application Publication Nov. 28, 2013 Sheet 5 of 12 US 2013/0315952 A1 Figure 5 Viral Family Virus No. Groups; Formulation(s); Treatment Challenge Significant Number/Group Dilution levels) Route; Route; Findings Volume; Level; Schedule Schedule Arenavirus Pichinde 10; Liquid DEF201; IN; IP; 100%. Survival Syrian Hamsters 10, 10, 10 100ul; LD95; Prophylaxis Single dose; Single dose -4.hr (d0) Bunyavirus Punta 10; Liquid DEF201; IN; IN; 100% Toro Syrian hamsters 10, 10, or 10 10Oul; LD95; Survival PFU/animal Single dose; Single dose Prophylaxis -4.hr (d0) Bunyavirus Punta 10; Liquid mDEF201; IN; IN; Significant Toro 10 Balb/c/group 5 x 10 PFU/animal 5Oul LD95; reduction in Single dose; Single dose viraltiters & -21, -14, -7, or - (d0) Serum ALT 1d Coronavirus SARS 4; Liquid mDEF201; IN; IN; 100% 10 Balb/c/group 10° or 10 5Oul, LD95; Survival PFU/animal Single dose; Single dose Prophylaxis -24hr dO) Coronavirus SARS 5, Liquid mDEF201; IN; IN; 90% 10 Balb/c/group 10 or 10 50ul; LD95; Treatment PFU/animal Single dose; Single dose Survival +6, 12, or 24hr dO Flavivirus Yellow 15-2O Liquid DEF201; IN; IP; 100% Survival Fewer Syrian Hamsters 108,5x10, 5x10, 100ul; 10 CCIDso; Prophylaxis 5x10 Single dose; Single dose PFU/animal -4.hr dO) Flavivirus Yellow 15-20 Liquid DEF201; IN; IP; 100% Fewer Syrian Hamsters 5x10' PFU/animal 100ul; 10 CCIDso Treatment Single dose; Single dose Survival +1d, +2d or +3d dO) Filovirus Ebola -- 3; Liquid mDEF201; IN or IM; IP; 100% aire 10B10.BR/group 10'PFU/animal 5Oul; 1000LD50; Treatert Single dose; Single dose Survival +3Omir dO) Filovirus Ebola - 5, Liquid mDEF201; IN or IM; IP; 100% Zaire 3 Hartley Guinea 2x10 PFU/animal 25Cul; 1OOLD50; Treatment pigs/group Single dose; Single dose Survival +3Omir dO) Togavirus WEE 5; Liquid mDEF201; IN; IN; 100% 10 Balb/c/group 10' PFU/animal 5Oul; 43LD50 Survival Single dose; Single dose Prophylaxis d -21, -14, -A, or - dO) 1. Togavirus WEE 3; Liquid mDEF201; IN; IN; 100% 10 Balb/c/group 10' PFU/animal 5Oul 43LD50 Treatment Single dose; +6h Single dose Survival (d0) Togavirus WEE 3; Liquid mDEF201; M; Sub O; 100% 8 Balb/c/group 10' PFU/animal 50ul 10 LD50; Survival Single dose; Single dose Prophylaxis -24hr (d0) Patent Application Publication Nov. 28, 2013 Sheet 6 of 12 US 2013/0315952 A1 Figure 6 - DEF201108 pfu -- DEF2011 07 pfu - - - DEF201106 pfu - EV 108 pfu - Ribavirin 50 mg/kg/day •oe Placebo 1. 3 5. 7 9 11 13 1517, 1921 Days post infection Patent Application Publication Nov. 28, 2013 Sheet 7 of 12 US 2013/0315952 A1 Figure 7 A DEF201 against WEEV Calif. H Group 1 c -- Group 2 -v- Group 3 -- Group 4 E -O Group 5 9 - Group 6 : - A Group 7 O 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time to death (Days) DEF201 against WEEV CBA87 B g H Group 1 80 -- Group 2 70 A Group 3 60 -o- Group 4 E 50 -v- Group 5 s - Group 6 20 -O Group 7 10 O O 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time to Death (Days) Patent Application Publication Nov. 28, 2013 Sheet 8 of 12 US 2013/0315952 A1 Figure 8 1. :::::: - ar 2. s reorr r , or error son's rero - or rr ; r. s r. s r. s r. s r. r * r * r s - : s sm o t roamy Fo s Time 2 s 8 8. 22 Post Virus Exposure -- PSS (-14 days PWE) -- mDEF201 (-14 days PWE) -- PSS (-7 days PWE) or mDEF201 (-7 Days PWE) - a PSS (-5 days PWE) -- mdeF201 (-5 Days PWE) -v- PSS (-3 days PWE) -- mDEF201 (-3 Days PWE) w Poly CLC (1 mg/kg/day B 0 58: s 8. 50 o 3 14 Post virus exposure wn. PSS (+6 h) -- moF201 (106 PFU, +6 h) *** PC0.001 vs. Pss (+6h) -- PSS (+12 h) - moeF201 (106 PFU, +12 h) re PSS (24 h) -- moeF201 (106 PFU, +24 h) -- meF201 (1 OPFU, +6 h) * P-0.05 vs. PSS (+6h) -- moF201 (105PFU, +12h) - moeF201 (105PFU, +24 h) -- Poly ICLC (1 mg/kg/day; -24h, +8h) * PK0.001 vs. all PSS Patent Application Publication Nov. 28, 2013 Sheet 9 of 12 US 2013/0315952 A1 Figure 9 e E. day of death ... i 8. is of dest Patent Application Publication Nov. 28, 2013 Sheet 10 of 12 US 2013/0315952 A1 Figure 10 O SO O8. O3, O O. 3O8. O8. O. 9 13 5 Days Post-Exsie A. ---- -- Control memFM-0 Protein --DEF2O - - - - ---- 6 - 8 1 C 11 12 13, 14 15, 16 Days Post-Exposure Patent Application Publication Nov. 28, 2013 Sheet 11 of 12 US 2013/0315952 A1 Figure 11 : s: . SS - SS - . s «Sixswoxsw8wixos. : S & 3 a & 3 3. ay Patent Application Publication Nov. 28, 2013 Sheet 12 of 12 US 2013/0315952 A1 Figure 12 isis &. x3x sists 73: x83 is Li's: its - 3 x is3 is ::iii. 3. 63: sis g: is W X. is . iss3six iii$x'8't ;88 is& 33m. s: 33s... 8 & 3:3 E33. 3. i. 2 : 3 x s 3 s : 3 2 is is Tirisays Post-infection US 2013/03 15952 A1 Nov. 28, 2013 ADMINISTRATION OF INTERFERON FOR response. It is directly responsible for NK and T cell respon PROPHYLAXIS AGAINST OR TREATMENT siveness, which drives the Subsequent immune response. OF PATHOGENIC INFECTION Because of the early response of IFN-C. in the immune cas cade, its primary role is suggested to be to induce a priming CROSS REFERENCE TO RELATED state during the initial response to infection, and it has been APPLICATIONS shown that low dose IFN-O. results in increased protection from a viral challenge. 0001. This application is a continuation of U.S. Ser. No. 0007 IFN-O, as a recombinant human therapeutic agent, 12/797.575, filed on Jun. 9, 2010, now U.S. Pat. No. 8,309, is expensive to manufacture by c0MP is hindered by its short 531, which claims priority to U.S. Provisional Application half-life in Vivo, and is produced in a non-glycosylated form. No. 61/185,261, filed on Jun. 9, 2009. IFN-O. has an initial distributive half-life of 7 minutes and a beta half-life of 2 to 5 hours. This rapid decay requires mul FIELD OF THE INVENTION tiple injections, usually three times weekly, to maintain thera 0002 The invention is directed to the treatment of or pro peutic levels. Thus, at $2,500 per dose retail, the cost of using phylaxis against diseases or disorders caused by biological or recombinant human IFN-O. as a broad-spectrum antiviral in chemical agents in a subject (e.g., a mammal. Such as a counter bioterrorism or military operations is prohibitive. human). 0008. In order to mitigate this rapid in vivo degradation, PEGylated forms of IFN-O. have been developed that have BACKGROUND OF THE INVENTION half-lives that are on the order of days instead of hours, thus 0003. There is a suite of emerging viruses that are reducing the number of injections to once per week.
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