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(12) Patent Application Publication (10) Pub. No.: US 2004/0043923 A1 Parma Et Al US 2004.0043923A1. (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0043923 A1 Parma et al. (43) Pub. Date: Mar. 4, 2004 (54) HIGHAFFINITY NUCLEIC ACID LIGANDS on Jun. 5, 1996, which is a continuation-in-part of TO LECTINS application No. 08/479,724, filed on Jun. 7, 1995, now Pat. No. 5,780.228, and which is a continuation (75) Inventors: David H. Parma, Boulder, CO (US); in-part of application No. 08/472,256, filed on Jun. 7, Brian Hicke, Boulder, CO (US); 1995, now Pat. No. 6,001,988, and which is a con Philippe Bridonneau, Boulder, CO tinuation-in-part of application No. 08/472,255, filed (US); Larry Gold, Boulder, CO (US) on Jun. 7, 1995, now Pat. No. 5,766,853, and which is a continuation-in-part of application No. 08/477, Correspondence Address: 829, filed on Jun. 7, 1995, now abandoned, which is SWANSON & BRATSCHUN L.L.C. a continuation-in-part of application No. 07/714, 131, 1745 S.HEA CENTER DRIVE filed on Jun. 10, 1991, now Pat. No. 5,475,096, which SUTE 330 is a continuation-in-part of application No. 07/536, HIGHLANDS RANCH, CO 80129 (US) 428, filed on Jun. 11, 1990, now abandoned. (73) Assignee: GILEAD SCIENCES, INC. Publication Classification (21) Appl. No.: 10/409,627 (51) Int. Cl." ......................... A61K 48/00; A61K 38/16; C12O 1/68 (22) Filed: Apr. 7, 2003 (52) U.S. Cl. ...................................... 514/8; 435/6; 514/44 Related U.S. Application Data (57) ABSTRACT (60) Continuation of application No. 09/849,928, filed on This invention discloses high-affinity oligonucleotide May 4, 2001, now Pat. No. 6,544.959, which is a ligands to lectins, Specifically nucleic acid ligands having division of application No. 08/952,793, filed on Nov. the ability to bind to the lectins, wheat germ agglutinin, 21, 1997, now Pat. No. 6,280,932, filed as 371 of L-Selectin, E-Selectin and P-Selectin. Also disclosed are the international application No. PCT/US96/09455, filed methods for obtaining Such ligands. Patent Application Publication Mar. 4, 2004 Sheet 1 of 19 US 2004/0043923 A1 C G U N G G G A G G C C C A. U G U A G A. A U c, d A. G-C A G G R0-4 R3-6 G-Cp G C N-N' N25 N G A. A 0-4 A. A. N-N: N-N: U C N-N: N-N: C-G N-N N-N' N-N' 1-5 1-5 5'- -3' 5- -3' 5'- -3' FIGURE 1A FIGURE 1B FIGURE 1C Patent Application Publication Mar. 4, 2004 Sheet 2 of 19 US 2004/0043923 A1 -o-Rnd 2 RNA -o- Rnd 9 RNA (PBMC) = 10"/ml 0. 1 O 2 O 3 0. 4 O 5 0 6 O RNA), nM FIGURE 2 Patent Application Publication Mar. 4, 2004 Sheet 3 of 19 US 2004/0043923 A1 35 40N7 3 O SEO D NO: 64 2 5 F14. 12 SECR O NO: 78 2 O 5 (PBMC) = 10"/ml 1 O O O 20 30 4 O 50 60 RNA), nM FIGURE 3 Patent Application Publication Mar. 4, 2004 Sheet 4 of 19 US 2004/0043923 A1 7 O 6 O F14.12) = 5 nM (SEQ IE) NO: 78) 5 O (PBMC) = 10"/m 1 4. O t 3 O 2 O 1 O 1 O O 10° 108 0 10 Competitor RNA FIGURE 4 Patent Application Publication Mar. 4, 2004 Sheet 5 of 19 US 2004/0043923 A1 -0- DREG-56 7- - Isotype Control F14.12) = 5 nM (PBMC) = 10'? m 1 10 Antibody), M FIGURE 5 Patent Application Publication Mar. 4, 2004 Sheet 6 of 19 US 2004/0043923 A1 8O OO 6 O 4 O 2 O 0 10 OO 1000 F14.12 (SEQ ID NO: 78) RNA), nM FIGURE 6 Patent Application Publication Mar. 4, 2004 Sheet 7 of 19 US 2004/0043923 A1 U G G U A G A G A G U A. U A : A. A A. C A A. A 5 k 3. FIGURE 7A FIGURE 7B 2- G 5'- CAAGGCGG - CCGCCACUU C UGAGUA-3' N-CAGUA’ FIGURE 7C Patent Application Publication Mar. 4, 2004 Sheet 8 of 19 US 2004/0043923 A1 Patent Application Publication Mar. 4, 2004 Sheet 9 of 19 US 2004/0043923 A1 Patent Application Publication Mar. 4, 2004 Sheet 10 of 19 US 2004/0043923 A1 HO^OH OO Patent Application Publication Mar. 4, 2004 Sheet 11 of 19 US 2004/0043923 A1 2 a. g 5 di O O O 2 o={ \ \ O C 2 2. O N1 C N c o1 o r Yo O O f O O iO Patent Application Publication Mar. 4, 2004 Sheet 12 of 19 US 2004/0043923 A1 40 35. 3 O Kid = 1.6 - 0.2 nM 2 O (PBMC) = 10"/ml O 10 20 3 O 40 50 60 IssDNA), nM FIGURE 9 Patent Application Publication Mar. 4, 2004 Sheet 13 of 19 US 2004/0043923 A1 --DREG-56 - " - Isotype Control (ssDNA) = 2 nM PBMC) = 10"/ml 1 010 0° 108 1 O 10 (Antibody), M FIGURE 10 Patent Application Publication Mar. 4, 2004 Sheet 14 of 19 US 2004/0043923 A1 e 2. e O O y SunOO leo e 2. e SunOO leC) Patent Application Publication Mar. 4, 2004 Sheet 15 of 19 US 2004/0043923 A1 Base Pairs Y T5 G A. AT TA GC CG GT TG GA AG AA OTHER Y-R 2 13 3 6 - - - - - - - - - - - - G-A - - - - 3 - - - - - - 21 - - - - - - 10G-C - - - - 24 - - - - - - - - - - - - - - - A A. c-Go - - - - - - 24 - - - - - - - - - - - - A-T 18 4 1. 1 - - - - - - - - - - - Alk 5T-A 4 18 - - - - 1. -- 1 - - - - - - G A an as 8 - - - - - - - - 12 1, 2 1. N-N' 12 3 7 - - - - 1 - - - - - - 1. N-N35 2 8 11. 1 - - - - 2 -- -- N-N' 4 - - 1. 3 4 - - 2 - - 1. 9 5, N N-3, 1 - - 1. 3 1 - - 2 2 1. 13 FIGURE 12 Patent Application Publication Mar. 4, 2004 Sheet 16 of 19 US 2004/0043923 A1 Scrambled sequence NX 288 rt S2 5, 1.0 E d O ass O.5 r S O cells -- -- h - pmol DREG-56 na 13 - - nmol oligo O --- 4. 1. 0.4 FIGURE 13 Patent Application Publication Mar. 4, 2004 Sheet 17 of 19 US 2004/0043923 A1 scrambled sequence NX288 ret 92 (d 66 E O O c 33 S O cells -- -- -- -- a pmol DREG-56 -- 15 13 X nmol oligo O VDO 4. a- O 4 FIGURE 14 Patent Application Publication Mar. 4, 2004 Sheet 18 of 19 US 2004/0043923 A1 U U U U AU UA GC CG GU. UG AG GA OTHER G-C 21 Y-R 11 10 G-A 21 C-G 6 15 R-Y" 9 1 11 R Y R-Y' 13 1. 6 1. A YU C Y-R 13 5 3 N-N' 4 3 4. 6 2 1 1. R-Y' 7 3 7 3 1. G-C" 1. 2 13 3 2 N-N' 3 2 5 1. 2 8 N-N' 3 2 3 - 2 5 6 5 3 FIGURE 15 Patent Application Publication Mar. 4, 2004 Sheet 19 of 19 US 2004/0043923 A1 N2-16 N N N N AU UA GC CG SU OTHER R-Y 9 2 -- 1. 1. KM' wam as 4 8 war m amar 1 N3-5. A Y.R.' -- 2 -- 11 -- wer N-N' 4 - - - 6 3 - No-1 N C/A A A G-C 1. 11 1. up- or r C-G a 4m - 13 ams m A A C C-G -- - - - - - 13 -- e. U - A in 13 un- a- re C-G p.m. pm. -- . 11 2 FIGURE 16 US 2004/0043923 A1 Mar. 4, 2004 HIGHAFFINITY NUCLEIC ACID LIGANDS TO microbes but not mammalian glyco-conjugates. The binding LECTINS specificity of MBP constitutes a non-immune mechanism for distinguishing Self from non-Self and mediates host defense FIELD OF THE INVENTION through opSonization and complement fixation. Influenza 0001. Described herein are methods for identifying and Virus hemagglutinin mediates the initial Step of infection, preparing high-affinity nucleic acid ligands to lectins. Lec attachment to nasal epithelial cells, by binding Sialic acid tins are carbohydrate binding proteins. The method utilized residues of cell-Surface receptors. herein for identifying Such nucleic acid ligands is called 0005 The diversity of lectin mediated functions provides SELEX, an acronym for Systematic Evolution of Ligands by a vast array of potential therapeutic targets for lectin antago EXponential enrichment. Specifically disclosed herein are nists. Both lectins that bind endogenous carbohydrates and high-affinity nucleic acid ligands to wheat germ agglutinin those that bind exogenous carbohydrates are target candi (WGA), L-selectin, E-selectin, and P-selectin. dates. For example, antagonists to the mammalian Selecting, a family of endogenous carbohydrate binding lectins, may BACKGROUND OF THE INVENTION have therapeutic applications in a variety of leukocyte 0002 The biological role of lectins (non-enzymatic car mediated disease States Inhibition of Selectin binding to its bohydrate-binding proteins of non-immune origin; I J. Gold receptor blockS cellular adhesion and consequently may be stein et al., 1980, Nature 285:66) is inextricably linked to useful in treating inflammation, coagulation, transplant that of carbohydrates. One function of carbohydrates is the rejection, tumor metastasis, rheumatoid arthritis, reperfusion modification of physical characteristics of glyco-conjugates injury, Stroke, myocardial infarction, burns, psoriasis, mul (i.e., Solubility, Stability, activity, Susceptibility to enzyme or tiple Sclerosis, bacterial Sepsis, hypovolaemic and traumatic antibody recognition), however, a more interesting and Shock, acute lung injury, and ARDS.
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