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(12) Patent Application Publication (10) Pub. No.: US 2010/0166780 A1 Debelak Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0166780 A1 Debelak Et Al US 20100166780A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0166780 A1 Debelak et al. (43) Pub. Date: Jul. 1, 2010 (54) CPG OLGONUCLEOTDE ANALOGS Related U.S. Application Data CONTAINING HYDROPHOBC TANALOGS WITHENHANCED IMMUNOSTIMULATORY (60) Provisional application No. 60/847,811, filed on Sep. ACTIVITY 27, 2006. (75) Inventors: Harald Debelak, Hilden (DE); Publication Classification Eugen Uhlmann, Glashuetten (51) Int. Cl. (DE); Marion Jurk, Dormagen A6139/00 (2006.01) (DE) C7H 9/06 (2006.01) Correspondence Address: C7H 9/16 (2006.01) PHARMACA & UPJOHN C07H 19/052 (2006.01) 7000 Portage Road, KZO-300-104 C7H 9/056 (2006.01) KALAMAZOO, MI 49001 (US) A63L/702 (2006.01) A6IP3L/2 (2006.01) (73) Assignee: Pfizer Inc (52) U.S. Cl. .................. 424/184.1:536/28.4:536/27.21; (21) Appl. No.: 12/442,295 536/28.53: 536/28.8:536/28.7; 514/44 R (22) PCT Fled: Sep. 27, 2007 (57) ABSTRACT (86) PCT NO.: PCT/B2007/004389 The invention relates to oligonucleotides including at least one lipophilic Substituted nucleotide analog and a pyrimi S371 (c)(1), dine-purine dinucleotide. The invention also relates to phar (2), (4) Date: Dec. 7, 2009 maceutical compositions and methods of use thereof. A) Me NH Me 5'-O O n-so C,H-Edge ls -O F T '''2NH Q ? SN3 O O o2P-Q N2O Hoogsteen V V sy Sy 2'-Deoxyuridine (U) 2,4-Difluorotoluene (FF) C O \ 5-1,NH 8/ O O o-P-Q K N els1. d 3 O G \ O O N O M. T V V O 5-Bromo-2'-deoxyuridine (BU) 5-lodo-2'-deoxyuridine (JU) Patent Application Publication Jul. 1, 2010 Sheet 1 of 32 US 2010/0166780 A1 HN O ?ÌN O HNJE |?Inôl Patent Application Publication Jul. 1, 2010 Sheet 8 of 32 US 2010/0166780 A1 99:ONCIIDES-:- –e–000),L'ONCIIOES Zº:ONCIIOES?a, £?7:ONCIIOES-—?yº:ON CIIDES---- 99:ONCIIDES–E– O O O O O C OO CO V 00Z uffid eude-N | 09 09 xepuuopenus - Patent Application Publication Jul. 1, 2010 Sheet 9 of 32 US 2010/0166780 A1 fºtº:ONCIIDES-E- gz.ondibas–º– 9f9;'ONCIIDES•A gyºnCIIDES-º- C e v N CN Xepuuoenu)S 6?Infil Patent Application Publication Jul. 1, 2010 Sheet 15 of 32 US 2010/0166780 A1 O V cy) V c O v. S25 s O S Ods d O Z Z Z. a no Z e- 625 S.(; C.; C.; O V O C O c to C. L. C. O N D CN O V Xepuuoenu)S Patent Application Publication Jul. 1, 2010 Sheet 16 of 32 US 2010/0166780 A1 s d5 o 2 So C L c S St Y. O 9 O C U v- (). CD - O O) L t A. 3 s O o o o o O C N N V V (uffd) uoeueuoso Old O O (S O s L?) D v O) 9 D .9) S C V v (uffd) uoeueouo O-NL Patent Application Publication Jul. 1, 2010 Sheet 17 of 32 US 2010/0166780 A1 O N V SS Ot GD d Xepuuoenus Patent Application Publication Jul. 1, 2010 Sheet 18 of 32 US 2010/0166780 A1 V V SS O () CO XepuuoenuS Patent Application Publication Jul. 1, 2010 Sheet 19 of 32 US 2010/0166780 A1 i o C O O O O O V c N S2 XepuuoenuS Patent Application Publication Jul. 1, 2010 Sheet 20 of 32 US 2010/0166780 A1 [Wri]Ndo6o| • Xepuuoenus Patent Application Publication Jul. 1, 2010 Sheet 21 of 32 US 2010/0166780 A1 dwLOQ+89#beS dVLOCl+9ZI,#bºS 8£#bes 9ZI,#b?S l co O 99 N N w v Xepuuoenus 0 Z?un61– Patent Application Publication Jul. 1, 2010 Sheet 22 of 32 US 2010/0166780 A1 O N V. V. V. V. SS SS O. O. CD C) (V) () O O O O S. d cN w Xepuu OenuS Patent Application Publication Jul. 1, 2010 Sheet 23 of 32 US 2010/0166780 A1 €L#bes 8£I,#bøS 6€),#bøS Oyl,#bes ?,#bæS Xepuu Open uS ZZ?un61– Patent Application Publication Jul. 1, 2010 Sheet 24 of 32 US 2010/0166780 A1 C d d o O o O d d v cy N w L Xepuuoenus Patent Application Publication Jul. 1, 2010 Sheet 25 of 32 US 2010/0166780 A1 [wri401]NGO qyzeunfil Xepuuoenus 6 IWri„OLJNGO Xepu UO) en US 6 Patent Application Publication Jul. 1, 2010 Sheet 26 of 32 US 2010/0166780 A1 IWri„01]NGO Xepu-lo-era US-6Al GZ?un61– Patent Application Publication Jul. 1, 2010 Sheet 27 of 32 US 2010/0166780 A1 Uun!p3Ne GGbas---- 99bes–e– Z9bæS…A £9bøS----- u/fd) eude-N- 9Z?Inôl Patent Application Publication Jul. 1, 2010 Sheet 28 of 32 US 2010/0166780 A1 e P Z O O C) O O O O O O O O O O O O O O O o GN CO v N V y Patent Application Publication Jul. 1, 2010 Sheet 29 of 32 US 2010/0166780 A1 009 09:2 uffd) 9 egz.eun61 9Z?In6|- 009 Tuffd 9 Patent Application Publication Jul. 1, 2010 Sheet 30 of 32 US 2010/0166780 A1 uunIp3W 878-?) Sc|T EES [o]:[]A]od §§bæS ygbas £&bas 99bas #9bas 19bas OSIAlp Jege Sea) g 6Z?un61– uOSAIp lege Sile3 % Patent Application Publication Jul. 1, 2010 Sheet 31 of 32 US 2010/0166780 A1 2. ? O S 9. OO O. v. CN v N. L. O. O O CO CO CO CO LO CN O. O. O. O. O. O. O. O. CD CD CD () () CD (D CD CD CO CO of CO CO CAD CO 13 O O O O O N. N V (uyf5d) uope Jueauoo e-N Patent Application Publication Jul. 1, 2010 Sheet 32 of 32 US 2010/0166780 A1 S an R h L L e * s ILL ELOW. O. O . Sun ver o uu eunior Jour Crd D 9 o CS O) O) O) i US 2010/01 66780 A1 Jul. 1, 2010 CPG OLGONUCLEOTIDE ANALOGS induces IFN-O.; this class has been termed the C-class. The CONTAINING HYDROPHOBC TANALOGS C-class CpG nucleic acids, as first characterized, typically are WITHENHANCED IMMUNOSTIMULATORY fully stabilized, include a B class-type sequence and a GC ACTIVITY rich palindrome or near-palindrome. This class has been described in co-pending U.S. provisional patent application FIELD OF THE INVENTION 60/313,273, filed Aug. 17, 2001 and U.S. Ser. No. 10/224,523 filed on Aug. 19, 2002 and related PCT Patent Application 0001. The present invention relates generally to the field of PCT/US02/26468 published under International Publication immunology. More specifically the invention relates to thera Number WO O3/O15711. peutic oligonucleotides with enhanced immunostimulatory capacity. SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION 0005. The invention relates to an oligonucleotide which comprises one or more modifications that elicits enhanced 0002 Bacterial DNA has immune stimulatory effects to immunostimulatory capacity. In particular, the invention is activate B cells and natural killer cells, but vertebrate DNA based on the finding that specific Sub-classes of oligonucle does not (Tokunaga, T., et al., 1988. Jpn. J. Cancer Res. otides having at least one lipophilic Substituted nucleotide 79:682-686: Tokunaga, T., et al., 1984, JNCI 72:955-962: analog are highly effective in mediating immune response. Messina, J. P., et al., 1991, J. Immunol. 147: 1759-1764; and These oligonucleotides are useful therapeutically and pro reviewed in Krieg, 1998. In: Applied Oligonucleotide Tech phylactically for inducing an immune response and for treat nology, C. A. Stein and A. M. Krieg, (Eds.), John Wiley and ing diseases and disorders such as cancer and viral infections. Sons, Inc., New York, N.Y., pp. 431-448). It is now under 0006. In one aspect, the invention is a composition com stood that these immune stimulatory effects of bacterial DNA prising the sequence: RYZR, wherein RandR representa are a result of the presence of unmethylated CpG dinucle lipophilic Substituted nucleotide analog (L), a nucleotide, and otides in particular base contexts (CpG motifs), which are a linkage, wherein at least one of R and R is a lipophilic common in bacterial DNA, but methylated and underrepre Substituted nucleotide analog (L), wherein Y is a pyrimidine sented in vertebrate DNA (Kriegetal, 1995 Nature 374:546 nucleotide and wherein Z is a purine, a pyrimidine, or an 549; Krieg, 1999 Biochim. Biophys. Acta 93321:1-10). The abasic residue. immune stimulatory effects of bacterial DNA can be mim icked with synthetic oligodeoxynucleotides (ODN) contain 0007. In some embodiments, L comprises a 5- or 6-mem ing these CpG motifs. Such CpG ODN have highly stimula bered ring nucleobase analog. tory effects on human and murine leukocytes, inducing B cell 0008. In other embodiments of the aspect of the invention, proliferation; cytokine and immunoglobulin secretion; natu L is a group of formula I. ral killer (NK) cell lytic activity and IFN-y secretion; and activation of dendritic cells (DCs) and other antigen present ing cells to express costimulatory molecules and secrete Formula I cytokines, especially the Th1-like cytokines that are impor tant in promoting the development of Th1-like T cell airls1. responses. These immune stimulatory effects of native phos BSSn1 - -D phodiester backbone CpG ODN are highly CpG specific in that the effects are dramatically reduced if the CpG motif is methylated, changed to a GpC, or otherwise eliminated or altered (Krieg et al., 1995 Nature 374:546-549; Hartmann et having the following elements: A, B, X, D, E, and F are C al, 1999 Proc.
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