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(12) Patent Application Publication (10) Pub. No.: US 2010/0306863 A1 Colonna Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0306863 A1 Colonna Et Al US 20100306863A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0306863 A1 Colonna et al. (43) Pub. Date: Dec. 2, 2010 (54) SCREENING, THERAPY AND DIAGNOSIS Related U.S. Application Data (60) Provisional application No. 60/961,615, filed on Jul. (75) Inventors: Marco Colonna, St. Louis, MO 23, 2007. (US); Julia Klesney-Tait, Iowa City, IA (US); Paola Panina, Milan Publication Classification (IT) (51) Int. Cl. CI2P 2L/00 (2006.01) Correspondence Address: AOIK 67/00 (2006.01) FOLEY AND LARDNER LLP C07K 6/8 (2006.01) SUTESOO A 6LX 39/395 (2006.01) CI2N 5/20 (2006.01) 3OOOK STREET NW A6IP37/00 (2006.01) WASHINGTON, DC 20007 (US) (52) U.S. Cl. ......... 800/6; 800/13: 530/389.2: 424/158.1; 435/326 (73) Assignee: Bioxell S.p.A. (57) ABSTRACT (21) Appl. No.: 12/452,813 A TREM-1 ligand is identified. This allows various deriva tives to be provided/identified that are capable of binding to the TREM-1 receptor. The TREM-1 ligand or the derivatives (22) PCT Filed: Jul. 23, 2008 can be used in screening for drugs/drug candidates. Sub stances that block or reduce binding of the TREM-1 ligand/ (86). PCT No.: PCT/EP2008/0596.68 derivative to a TREM-1 receptor may be useful for treating sepsis, particularly sepsis of bacterial or fungal origin. Anti S371 (c)(1), bodies to the ligand may be useful in diagnosing sepsis, (2), (4) Date: Aug. 5, 2010 particularly sepsis of bacterial or fungal origin. &x. - - - - - 8x. Š s & Š & S * S s s & SSS &gassis is. S& R&S &s &SS Patent Application Publication Dec. 2, 2010 Sheet 1 of 26 US 2010/0306863 A1 Ficure 1 mae 8xissis. ?:% |? ,•••• -aeuº- Fidure 2 Receptor LATANA C-Cl RaS/ERK Actin Patent Application Publication Dec. 2, 2010 Sheet 2 of 26 US 2010/0306863 A1 Figure 3 inhibitory signaling Activating signaling D-galactosamine-endotoxenia Authentic sepsis, endotoxenia Low LPS doses High PS doses Fict streptils fracophages.-- Microbia -------, c- sus- components *... High avidity - -Ligw avidity- : TREM2 igadi TREM- LRs AR h (talypas-independel r SHP- pathia's RAK P3 Gri Other inhibitory - RAFE to-ri rii irectarisis? KK Akt ERK N k - - Ca y * - - AP1 r - (Junp Fos) NEw Cytokine secretion Patent Application Publication Dec. 2, 2010 Sheet 3 of 26 US 2010/0306863 A1 Figure 4. Figure 4A 6.25 mg/kg 10D 100 g 80 g 80 60 60 E E 40 3 40 g L 20 20 O O d d 10 mg/kg 100 --- DAP12-1- 80 - WT 60 40 20 O O 1 2 3 4 5 6 7 d Figure 4B TNF-C. IL-10 3OOO 3COO 2000 Z DAP12-f 2000 E s 1COO OOO O - a O 2h 4 h 24h 2h 4h 24h IL-6 MCP-1 OOOOO 5OOO 75OOO 4OOOO E 30000 50000 R 2000 25OOO OOOO O 24h 4 24h Patent Application Publication Dec. 2, 2010 Sheet 4 of 26 US 2010/0306863 A1 Figure 5 Figure 5A 100 80 i- - -DAP12-- (n=19) S - WT (n=2O) - 60- - - - - - - , c 40 d 20 O O 2 4 6 8 10 12 14 d Figure 5B TNF-0 IL-10 3OO 15COO - WT DAP12-i- - 200 10000 E Sh S. O o OO 5000 O O h h IL-6 6OOOO 3OOOO 400CC 20000 S E S. O O 2OOOO 1OOOO Patent Application Publication Dec. 2, 2010 Sheet 5 of 26 US 2010/0306863 A1 Figure 6 A 7.5 O k Y 5.0 ke e al k es e C 2.5 Sk kk ke C k WT DAP12-/- B 9 75 Macrophages k E 50 k k Granulocytes 2 * * * * * * k 25 k kk O SS WT DAP12-/- WT DAP12-/- C 10 15 1010 105 100 WT DAP12-/- Patent Application Publication Dec. 2, 2010 Sheet 6 of 26 US 2010/0306863 A1 Figure 7 Figure 7A TNF- IL-10 7000 800 - 600 5OO 5000 His 400 - Se 4000 S 30 3000 o k 200 200 m 1OOO 1OO % % %M O Z 2. LPS -- -- LPS -- (1 giml) (1 lug/ml) IL-6 MCP-1 1000 1000 k k as 50 750 E E 500 2 500 d X 250 22 250 ill O a 3 O % LPS - LPS - (1 g/ml) (1 g/ml) Figure 7B TNF-ct, IL-10 3OOO 1500 WT 2000 DAP12-f- 1000 2. E S % 2 V 2 3. 1OOO %%M. % 3. 500 %- O % 2 % O 3 & 3 PS PS (ngin) O 10 100 1000 (ngi ml) O 10 100 1000 IL-6 MCP-1 7500 3OOOO 5OOO 2OOOO Y -- I s s 3 % s ed % 3. 2500 1OOOO %% -&% O O- % 2 LPS PS (ngi ml) O 10 100 1OOO (ngi ml) O 10 100 1000 Patent Application Publication Dec. 2, 2010 Sheet 7 of 26 US 2010/0306863 A1 Figure 8 WT DAP12-1- 1 Ug/ml LPS (min) O 10 30 60 90 120 O 10 30 6O 90 120 Figure 9 Endogenous TREM-1 b- TREM-3 1 K 2 3 4 K 1 2 3 K 5' probe 3' probe Targeting construct Long arm MC1 neopA Short arm kb loxP OxP Final deletion Patent Application Publication Dec. 2, 2010 Sheet 8 of 26 US 2010/0306863 A1 Figure 10 HEK293-TREM-3 HEK293 Patent Application Publication Dec. 2, 2010 Sheet 9 of 26 US 2010/0306863 A1 Figure 11 g m s re 3. d d - ogwa-lue 3.a. -o-N-lue ssa : | 8: . is gif 8: - 3. Patent Application Publication Dec. 2, 2010 Sheet 10 of 26 US 2010/0306863 A1 Figure 12 O a REM 1/3 -f- (n-30) is 75 ---. TREM1.f3-ft (n=20) s it 50 e 25 4 8. 8 O 4 lays Figure 13 100---------------------- 1O. - - - - Sham, n=9 - - - - Sham, n=10 8) - Septic, n=24 8. - Septic, n=25 S 60 2 2 40 SS SS 2 O O 24 48 72 96 120 144 168 192 24 4.8. 2 95 120 144 68 Hors Hours Patent Application Publication Dec. 2, 2010 Sheet 11 of 26 US 2010/0306863 A1 Figure 14 hTREM1 ectodomain B Septic patient Septic patient an c ra s 3. 5 i CD16i. s: 8 Yosefs C PWA treated RMA s healthy donor fo Af - ctr, tetramer REM- rise tetrainers: PMA - S3 RE- tetaster s - RE.8. Earners m) Patent Application Publication Dec. 2, 2010 Sheet 12 of 26 US 2010/0306863 A1 Fi ure 15 quæqedo?des Patent Application Publication Dec. 2, 2010 Sheet 13 of 26 US 2010/0306863 A1 Figure 16 s & ife s . fixis,838 s s E. & & i rw s i Sy * & S & S 3 a s R. s S: & S. t; ra s . - xxx 3.8 ck-X wS: xa& ; & & s & E v ; s:4:: * s R8 at 88 888 A. FS: 333 is transfeied with sas?ids 283 (esitansfected with sistidis 2S3&sistansfected withiasinids isolated for the first FACS enrichmeist. isolate for Fiate 48 caising: States for ice. At eities: Patent Application Publication Dec. 2, 2010 Sheet 14 of 26 US 2010/0306863 A1 Figure 18 IO 20 30 4 O 50 60 msa villall gifilplpgvg aLLCOFGTVO HVWKVSDLPROWTPKNTSCD SGLGCODTLM 7 O 8O 9 O 100. ll O 12 O LIESGPOVSL VLSKGCTEAK DOEPRVTEHR MGPGLSLISY TFVCROEDFC NNLVNSLPLW 130 140 150 160 170 180 APOPPADPGS LRCPVCLSME GCLEGTTEEI CPKGTTHCYD GLLRLRGGGI FSNLRVOGCM 190 200 210 220 230 240 POPGCNLLNG TOEIGPVGMT ENCNRKDFLT CHRGTTIMTH GNLAOEPTDW TTSNTEMCEV 250 260 270 280 290 300 GOVCOETLLL LDVGLTSTLV GTKGCSTVGA ONSOKTTIHS APPGVLVASY THFCSSDLCN 310 320 330 340 350 360 SASSSSVLL.N SLPPQAAPWP GDROCPTCWO PLGTCSSGSP RMTCPRGATH CYDGYIHLSG 370 380 390 400 410 420 GGLSTKMSIO GCVAOPSSFL LNHTROIGIF SAREKRDVCP PASQHEGGGA EGLESITWGV 430 GLALAPALWTN GVVCPSC Patent Application Publication Dec. 2, 2010 Sheet 15 of 26 US 2010/0306863 A1 Figure 19 10. 20 30 40 50 60 mnsip vitli gvitall pc Vp al. TCOKSSAO AVRNVAELPL RWWGAGEKTC EVSEGCODLI 70 80 90 100 110 120 LYNGPKVN LVIIKGCTEV EDOEPKVIWL RTGPGLSVVS YTRVCRHGDL CNDVNSTKIL 130 140 150 160 170 180 EELPTPTVPG SLRCPLCLSN DSCENAPEOV CPVGSTHCYD GVLRLRGDGI RTNLKVOGCM 190 200 210 220 230 240 AOPDCNLLNG TOAIGTLYMS ENCDLIGPOA LDCNSGSLET VRNVSDL HLS WTTGWOTCEA 250 260 270 280 290 300 GEGCYETVML IONGHEFHMV LTKGCTRDMN KKARLTRHRT GPGISIVSYV HVCRDRDFCN 310 320 330 340. 350 360 DLSTTDPLWT PPPDTELGTL RCRHCLSTGS CVSASELVCP AGSTHCYSGV LSLRGGGVIS 370 380 390 400 410 420. DLKVOGCISO SQPGCNLLNG TOTIGPWDVR EDCGLOLDAL KCOHGTLKTI ODISKLPLOW 430 440 450 460 470 480 TAGOKICNVG EGCODTLMLI ENGEOVNLVL TKGCTTAKDO EAKVTEHRTG PGLSVTSYTR 490. 500 510 520 530 540. VCRKKDFCND LSTTAPLWAP PPVTAPGTTR CPLCFSEOAC ENAPEOVCPA GSTHCYSGVL 550 560. 570 580. 590 600 SLRGGGIISD LKVOGCMSOP GCNLLNGTOT IGPVDVSERC SPPSETTELS CYRGVMFELG 610 620 630 640 650 660 NGFAEEPVKW TAPGSOVCAP DEICOETLLL IDVGOKSAFL GSKGCSSPGA ODNIGVSIFS 670 680 690 700 710 720 RLPGMLVASY TKFCSSHLCN GADSSSVILLS. IILPRPDVPPP GDVOCPMCVE LFGSCKSTDS 730. 740 750 760. 770 780. VTCPRGATHC YKGDIALOGG GLTTRVSIOG CMAPPIKPLL GDSKTIGIFS AEESSNYRHE 790. 800 810 DDVTSAPSLA WTLRISAWMIL, GLSALLSSLY AGICPLC Patent Application Publication Dec. 2, 2010 Sheet 17 of 26 US 2010/0306863 A1 Figure 21A(i) 10 20 30 40 50 60 ATGAGCGCGG TATTACTGCT GGCCCTCCTG GGGTTCATCC TCCCACTGCC AGGAGTGCAG 70 80. 90 100 110 120 GCGCTGCTCT, GCCAGTTTGG GACAGTTCAG CATGTGTGGA AGGTGTCCGA, CCTGCCCCGG 130 140 150 160 170 180 CAATGGACCC (CTAAGAACAC CAGCTGCGAC AGCGGCTTGG GGTGCCAGGA CACGTTGATG 190 200 210 220 230 240 CTCATTGAGA GCGGACCCCA, AGTGAGCCTG GTGCTCTCCA AGGGCTGCAC GGAGGCCAAG 250 260 270 280 290 300 GACCAGGAGC CCCGCGTCAC TGAGCACCGG ATGGGCCCCG GCCTCTCCCT GATCTCCTAC 310 320 330 340 350 360 ACCTTCGTGT, GCCGCCAGGA. GGACTTCTGC AACAACCTCG TTAACTCCCT CCCGCTTTGG 370 380 390 400 410 420 GCCCCACAGC CCCCAGCAGA CCCAGGATCC TTGAGGTGCC CAGTCTGCTT GTCTATGGAA 430 440 450 460 470 480 GGCTGTCTGG AGGGGACAAC AGA AGAGATC TGCCCCA AGG GGACCACACA CTGTTATGAT 490 500 51O. 520 530 540 GGCCTCCTCA. GGCTCAGGGG AGGAGGCATC TTCTCCAATC TGAGAGTCCA.
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