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( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2020/0246398 A1 US 20200246398A1 IN (19 ) United States ( 12) Patent Application Publication (10 ) Pub . No.: US 2020/0246398 A1 Chatila et al. (43 ) Pub . Date : Aug. 6 , 2020 (54 ) THERAPEUTIC MICROBIOTA FOR THE (60 ) Provisional application No.62 /250,277 , filed on Nov. TREATMENT AND /OR PREVENTION OF 3 , 2015 . FOOD ALLERGY Publication Classification ( 71) Applicants : THE BRIGHAM AND WOMEN'S (51 ) Int. Ci. HOSPITAL , INC . , Boston , MA (US ) ; A61K 35/742 ( 2006.01) CHILDREN'S MEDICAL CENTER A61K 9/00 ( 2006.01 ) CORPORATION , Boston , MA (US ) A61P 37/08 (2006.01 ) A61P 37/00 (2006.01 ) ( 72 ) Inventors : Talal A. Chatila , Belmont, MA (US ) ; A61K 35/745 (2006.01 ) Lynn Bry , Jamaica Plain , MA (US ) ; A61K 35/744 (2006.01 ) Georg Gerber , Boston , MA (US ) ; Azza A61K 35/741 (2006.01 ) Abdel -Gadir , Boston , MA (US ) ; Rima A61K 35/74 ( 2006.01) Rachid , Belmont , MA ( US ) A61K 45/06 (2006.01 ) ( 73 ) Assignees : THE BRIGHAM AND WOMEN'S (52 ) U.S. CI. HOSPITAL , INC . , Boston , MA ( US ) ; CPC A61K 35/742 (2013.01 ) ; A61K 9/0053 CHILDREN'S MEDICAL CENTER (2013.01 ) ; A61P 37/08 ( 2018.01 ) ; A61P 37/00 CORPORATION , Boston , MA (US ) (2018.01 ) ; A61K 35/745 ( 2013.01) ; A61K 9/19 ( 2013.01 ) ; A61K 35/741 ( 2013.01 ) ; A61K 35/74 ( 2013.01 ) ; A61K 45/06 (2013.01 ) ; YO2A ( 21) Appl. No .: 16 /568,711 50/473 ( 2018.01 ) ; A61K 35/744 (2013.01 ) ( 22 ) Filed : Sep. 12 , 2019 ( 57 ) ABSTRACT Disclosed are methods and compositions for the prevention Related U.S. Application Data and treatment of food allergy . In particular, described herein (63 ) Continuation of application No. 15 /801,830 , filed on are microbial consortia , including minimal microbial con Nov. 2 , 2017 , now abandoned , which is a continu sortia , that can prevent and/ or cure food allergy . In certain ation of application No. PCT/ US2016 / 060353 , filed embodiments , the consortia comprise certain members of on Nov. 3 , 2016 . the taxa Clostridiales and /or Bacteroidetes. Patent Application Publication Aug 6 , 2020_Sheet 1 of 52 US 2020/024398 A1 ??? ??? ?? ?? ??non DC Mast Cell? ILC2 ILC2 R ? Th2 C FIG . 1 Patent Application Publication Aug. 6 , 2020 Sheet 2 of 52 US 2020/0246398 A1 IL-4raF709mice:MutationITIM(Y-> GainoffunctiontheIL-4R IL-4Ra. FIG.2 Lako L-4 IL-4and13Geneexpression STAT6 SHP Proliferation Differentiation YC 8 STATO :4RIL-IType 8 STATO dimer Nucleus Patent Application Publication Aug. 6 , 2020 Sheet 3 of 52 US 2020/0246398 A1 -MastcellscountsSI -TemperaturedropTotal IgEserum-OVAspecific- IgEserum Challenge)OVA5mg( -MCP-1 678 Ess OVA-SEB (250ug/10ug) Weeks FIG.3 1234 IL4raF709mutantmice Patent Application Publication Aug. 6 , 2020 Sheet 4 of 52 US 2020/0246398 A1 OVA PBS LPF/ cells Mast Nbr 20 15 114raF709 )ml / ug( 1 - MMCP OVA SEB PBS PBS 30 20 4 )ml / ng( IgE Total )ml / ug( IgE - OVA FIG.4 ww MW 14raf709HOVA-SEB *** Time(min) OVA-SEBWT WV orogoro WW 6040501020300 WTPBS 1/4raf709+PBS 000mW 2 ) C °( Temperature A Patent Application Publication Aug. 6 , 2020 Sheet 5 of 52 US 2020/0246398 A1 OVA 0 2 0 2.57 2.01 ) x104( 114raf709 * IFN- *CD4 % * IFN- * CD4 Nbr SEB U PBS 2 0 2 ) x108( FIG.4(cont) ** L * CD4 % 45 - IL * CD4 Nbr %10+91 1.5.0.4% OVA-SEB lubenimsLaissbritansninmiscudindol IL4raF709 OVA-SEB IFN-Y 0.2%0.9 com %2.9+0.2 ??????????????????????????? 0 Lunistuu whicken wwws 106 Patent Application Publication Aug. 6 , 2020 Sheet 6 of 52 US 2020/0246398 A1 -SEBOVA IL4raF709 OVA-SEB 901 15.1+0.4% 8.7+0.1% wehandmadwandenendenkenndimmmmmhisnabelului Spleen 102 ????????????????????????????????FOL ww 105w 10 GOLO 15,711.4% 11.8+0.2% FIG.5 matinadamualaridadesdelseumembinadakamandesde801 olulintasmakanannawalannintendentiellementationdan103 May 0 re! Ol 104 103 105 1 105 met 11.5.0.7% } IS disebabadanabawalcrendimienionellendeleidmatandanda Lucidumadamimdinlandimtmw.emilialleihinOLOOL 104 w Patent Application Publication Aug. 6 , 2020 Sheet 7 of 52 US 2020/0246398 A1 Spleen SEB 2 SEB 1/4raf709 MLN QVAPBS FIG.5(cont) 2.5, 2 mi 5.1 IMO SI PBSOVA 0.5 ) x106 ( *Foxp3 *CD4 Nbr Patent Application Publication Aug. 6 , 2020 Sheet 8 of 52 US 2020/0246398 A1 114raF709 105 4.2 + 0.3 % 104 104Ikind www 102 102 Žodoo ????? 102 W 104 105 CD4 PBS 200 50 Counts Ota to 10 BT1102 // 4raF709 105 0 102 103 104 105POOS FIG . 5 ( cont. ) Patent Application Publication Aug. 6 , 2020 Sheet 9 of 52 US 2020/0246398 A1 W %CD4+Foxp3 PBS SEB 80 ** 60 %Prolif.CD4*Foxp3 PBS OVA SEB O WT 1/ 4raf709 FIG . 5 (cont . ) Patent Application Publication Aug. 6 , 2020 Sheet 10 of 52 US 2020/0246398 A1 Bacteroidetes PorphyromonadaceaeA051CL(48371)C4 PorphyromonadaceaeCL(48689)M12113 Vnclassified(35554)Ruminococcaceae LachnospiraceaeRuminococcus(4721) 2727)adhufec250CL(Lachnospiraceae RikenellaceaelUnclassified(45986) Rikenellaceaellrc215CL(45444) Rikenellaceaelirc547CL(46111) RikenellaceaelC20a11(46187) Rikenellaceaellc9E14CL(46257) RikenellaceaelC40241(46591) RikenellaceaellUnclassified(46312) RikenellaceaelM35082(48287) CatabacteriaceaeC10102(38750) 1003C18a09()LachnospiraceaeCL LachnospiraceaeEubacterium(3887) ClostrodialesUnclassified(1727) FIG.6 sosLactobacillaceae(9680) Faecalibacterium(36920) Catabacteriaceae(38832) Clostridium(2199) Clostridiaceae(39465) abundantLessO 0.251 . www 20 39 Phylum*Bacteroidetes Elusimicrobia Proteobacteria Rikenellaceae(46917) 12142)Saprospiraceae( Bacteroidaceae(44071) UnclassifiedNB1CL(55101) UnclassifiedB38(18934) UnclassifiedRSM47(13243) 7405)LachnospiraceaeC22006( 42301)LachnospiraceaeRF6( ClostrodialesUnclassified(3739) 1920)CL(LachnospiraceatM10122 6153)F27CL(LachnospiraceaeRs 1806CL(5963)LachnospiraceaeM2 5512)LachnospiraceaeF24FIOCL( 41031)Peptostreptococcaceae( Johnsonella(3508)Lachnospiraceae 6052)Clostridium(Lachnospiraceae 3204()LachnospiraceaeC23c19CL Coprococcus(2933)Lachnospiraceae 2293P19)C13CL(Lachnospiraceae 114raF709PBS 6808)Eubacterium(Lachnospiraceae 1/4raF709OVA+SEB Bacteroidetes Proteobacteria $ CA Patent Application Publication Aug. 6 , 2020 Sheet 11 of 52 US 2020/0246398 A1 ChallengeOVA)150mg ( (100ug) 12345678 Weeks Microbiota WTGF mice FIG.7 HHH //4raF709 Patent Application Publication Aug. 6 , 2020 Sheet 12 of 52 US 2020/0246398 A1 Week8 WTGF4raF709Flora OWTGFFlora )ml / ng( 1 - mMCP FIG.8 ***)spooooo Timemin() OVAChallenge:150mg 0102030405060 WTGFnifer||4raf709Flora OWTGF+WTFlora -400goon ) C ° ( Temperature A Patent Application Publication Aug. 6 , 2020 Sheet 13 of 52 US 2020/0246398 A1 Gated on proliferating CD3 + CD4 + T cells: WT GF meter 1/ 4raf709 Flora 104 173 109????? 6.89 3 boood! 103 103 102 102 0- 83.3 103 104 105 103 104 105 IFN -Y 107 30 . ole %IFN-** 20 *IL% O 2 Quo DWT GF WT Flora WT GR + ]4raf709 Flora FIG . 9 Patent Application Publication Aug. 6 , 2020 Sheet 14 of 52 US 2020/0246398 A1 ChallengeOVA150mg)( önoon)( Weeks 81654321GF114raF709 Microbiota mice FIG.10 th WTOR //4raF709 Patent Application Publication Aug. 6 , 2020 Sheet 15 of 52 US 2020/0246398 A1 0.5 ATemperature(°C) -0.5 0000000000 * -1.04 -2.04 11 -2.0 0 10 20 30 40 50 60 Time (min ) 0 1 4raf709 GF WT Flora 1 /4raf709 GF + ] [4raf709 Flora FIG . 11A 20 wwy TotalIgE(ug/ml) Home OVA-IgE(ug/ml) 0.44 0.2 ??? wwwwww 114raf 709 GF WT Flora 1/ 4raF709 GF ll4raf709 Flora FIG . 11B Patent Application Publication Aug. 6 , 2020 Sheet 16 of 52 US 2020/0246398 A1 1/ 4raf709 GF //4raF709 GF + WT Flora + 1 /4raF709 Flora 105 ) 1.1 % 105 16.1 % 200up 103 103 -103 13.5 % -103 0 103 0 FIG . 11C 15 20 wind CD4+IFN-** CD4*L** %OVA-specific 10 %OVA-specific 5 1 / 4raf 709 GA * WT Flora 114raf709 GF 114raf709 Flora FIG . 11D Patent Application Publication Aug. 6 , 2020 Sheet 17 of 52 US 2020/0246398 A1 1 /4raF709 GF 1 /4raF709 GF + WT Flora + 114raF709 Flora 105 105 ................ .... Foxp3 103 103 as( we er FIG . 12A 12 pood Oooo %CD4*Foxp3* NbrCD4*Foxp3 (x105) 2 0 1/ 4raf709 GALWT Flora 114ram 709 GA i ll4ra - 709 Flora FIG . 12B Patent Application Publication Aug. 6 , 2020 Sheet 18 of 52 US 2020/0246398 A1 Live CD4 + Foxp3 1/ 4raF709 GF 114raF709 GF other WT Flora ohn 114raF709 Flora mvh hanaburiniranh. Foxp3 103 103 w 1 -1030 0 103 104 105 -103 0 103 104 105 Violet Proliferative Dye FIG . 12C 807 CD4+Foxp3* 60 %Proliferating 20 0 114raf709 GF o WT Flora 1/ 4raf709 GF 114ra 709 Flora FIG . 12D Patent Application Publication Aug. 6 , 2020 Sheet 19 of 52 US 2020/0246398 A1 Cecum Jejunum FIG.13 Deinococcus0%-ThermusBacteria; Actinobacteria0%Bacteria: Deferribacteres20%Bacteria; Bacteria;Fusobacteria0% Bacteria;Proteobacteria13% Spirochaetes0%Bacteria, Tenericutes0%;Bacteria BacteriaVerrucomicrobia0%; unclassified0%Bacteria; Aquificae0%Bacteria;Bacteroidetes39% Bacteria;O 26%OBacteria;Firmicutes TM72%Bacteria; Patent Application Publication Aug. 6 , 2020 Sheet 20 of 52 US 2020/0246398 A1 FIG.14 TaxaLineage Otu000420.06020.0095971.80E-05Bacteria.Bacteroidetes.BacteroidiaBacteroidalesPorphyromonadaceae.unclassified Otu000570.06020.015150.000218Bacteria.BacteroidetesBacteroidiaBacteroidalesPorphyromonadaceae.unclassified OVAJejunumOtu000850.00380.0028011.60E-05Bacteria.BacteroidetesBacteroidia.BacteroidalesPorphyromonadaceae.unclassified Lachnospiraceae.unclassifiedFirmicutes.Clostridia.ClostridialesBacteria.Otu004590.09192.80E-055.00E06OVA,Jejunum 0.000545Bacteria.Firmicutes.Clostridia.ClostridialesRuminococcaceaeOscillibacterOVA,JejunumOtu000410.09190.004207 OtuO01070.06020.0049060.000155Bacteria.Bacteroidetes.Bacteroidia.Bacteroidales.Porphyromonadaceae.unclassified unclassified.unclassified.unclassifiedBacteria.Bacteroidetes.unclassified0.0190590.000216Otu000630.0602 Bacteroidetes.Bacteroidia.Bacteroidales.Porphyromonadaceae.unclassifiedOVA,DuodenumOtu000850.01610.0040711.00E-04Bacteria.
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