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US 2017/0020926 A1 Mata-Fink Et Al US 20170020926A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0020926 A1 Mata-Fink et al. (43) Pub. Date: Jan. 26, 2017 (54) METHODS AND COMPOSITIONS FOR 62/006,825, filed on Jun. 2, 2014, provisional appli MMUNOMODULATION cation No. 62/006,829, filed on Jun. 2, 2014, provi sional application No. 62/006,832, filed on Jun. 2, (71) Applicant: RUBIUS THERAPEUTICS, INC., 2014, provisional application No. 61/991.319, filed Cambridge, MA (US) on May 9, 2014, provisional application No. 61/973, 764, filed on Apr. 1, 2014, provisional application No. (72) Inventors: Jordi Mata-Fink, Somerville, MA 61/973,763, filed on Apr. 1, 2014. (US); John Round, Cambridge, MA (US); Noubar B. Afeyan, Lexington, (30) Foreign Application Priority Data MA (US); Avak Kahvejian, Arlington, MA (US) Nov. 12, 2014 (US) ................. PCT/US2O14/0653O4 (21) Appl. No.: 15/301,046 Publication Classification (22) PCT Fed: Mar. 13, 2015 (51) Int. Cl. A6II 35/28 (2006.01) (86) PCT No.: PCT/US2O15/02O614 CI2N 5/078 (2006.01) (52) U.S. Cl. S 371 (c)(1), CPC ............. A61K 35/28 (2013.01); C12N5/0641 (2) Date: Sep. 30, 2016 (2013.01): CI2N 5/0644 (2013.01); A61 K Related U.S. Application Data 2035/122 (2013.01) (60) Provisional application No. 62/059,100, filed on Oct. (57) ABSTRACT 2, 2014, provisional application No. 62/025,367, filed on Jul. 16, 2014, provisional application No. 62/006, Provided are cells containing exogenous antigen and uses 828, filed on Jun. 2, 2014, provisional application No. thereof. Patent Application Publication Jan. 26, 2017. Sheet 1 of 27 US 2017/0020926 A1 ?---- 0!10 x-exexerxxxxxxxxx ? &~~~~~~~~);% |*g************ ?zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz) |61 seuuosod?TON unOO 961 unOO Patent Application Publication Jan. 26, 2017. Sheet 2 of 27 US 2017/0020926 A1 Expand Diff 1 Diff 2 Diff 3 Diff 3 Diff 3 Diff 3 D6 D5 D4 D2 D4 D6 D8 Fig 2 Patent Application Publication Jan. 26, 2017. Sheet 3 of 27 US 2017/0020926 A1 - Transgene + Transgene as R17 R18 s 1 O O vessexy syssessiyssessssssexesex Fig" 3A 100-corroriscorer100 to 1102103 104 105106 1OV0235 10 10%-10 1 0 1 0 10 - Transgene + Transgene Waasaasa-Ya- w88ws & woxx's systSSYYYYYYYYYYYYYYYYYYYYYYYYY. S R1 s R11 s s R1 SX S 8 3. s S. S 103 s S S 11 S s R17 Ss i O S 00.100101102103 Nasses &Ssssssss-xxx-xx-xx-104 105 106 100101102103*S-isssssss'. $xxxss- 104systesssss 10510Ks--sixx-xxs6 S3 + Transgene 1 O 57 O 2 Patent Application Publication Jan. 26, 2017. Sheet 4 of 27 US 2017/0020926 A1 s. Ya-Ya-YYYYYY---W. 2 y s Ww ---------- ''' ---. 2 -----...-- 2 % 2 . % 2 2 22 2 % W.% 22 2. 2. % --- % 2. * 2. 2 % 3 % 3 2. % - . - Patent Application Publication Jan. 26, 2017. Sheet 5 of 27 US 2017/0020926 A1 % % % ... ». 2. 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Fig 3T to 1OW 10 10 10 1 0 10 - Transgene + Transgene s 6 S. 1 s R 1 O 5 s& *s R17 -ressesssssss-exsessssss- assassessesssexes assissists&E 104 105 10 3 104 105 106 s Ss s 10.1 s 88.8 3xers"reyss-re-six;xxxix-sex-rvystroysey-s-s 102 10 106 Patent Application Publication Jan. 26, 2017. Sheet 9 of 27 US 2017/0020926 A1 - Transgene + Transgene systwyxypreservers104 106 105. 104. S. 103 'sS. 10983 0.0622 101 $ss-exissyrisonerswys76.9 & vessess 10 10 10 102 104 10 - Transgene + Transgene 1071.63 0.0497 1079.88xxxxxxxxxxxxx xxxxxxxxxxxxx 0.497 y 0.0622 101894 S.issisteresy:*siysk-sessrssegressessex: s&xxx xxxx ass sysexes: is-ories-s-s-s-s-s-s-s-ressex 102 10 10 6 102 10 10 6 Patent Application Publication Jan. 26, 2017. Sheet 10 of 27 US 2017/0020926 A1 c Transgene Transgene 0.45 1 04 105 o6 - Transgene Patent Application Publication Jan. 26, 2017. Sheet 11 of 27 US 2017/0020926 A1 v Transgene Transgene & a va 6 6 2 1 O R2 1 1 1 1 O 3. 1 O 2 1 O 1 s 1 O i R4 R5 O " ... R5 100s100101102103 10'105106 1O 1001011021030405106* Yixery series SS - Transgene + Transgene - opo S R2 S R3 S S s s s as s x 100 ---- anol R -- 100101102 2103 104 105 106 R3 s 100 acrosses area Fig 3AE 0 1 2 3 4 5 oô Patent Application Publication Jan. 26, 2017. Sheet 12 of 27 US 2017/0020926 A1 - Transgene + Transgene 1 O O Neyeseiosyo-eR4 NeR5 1 O0 iyessR4 - - - - exemyeR5 Fig 3AF 10010110210° 10'105106 100101102103 104 105106 - Transgene +-Transgene 89systery's Nysseyreysseysis 102 104 106 - Transgene 0.0256 s v. .. 3.8 *res-s-s-s-six-x-xx-s-s-s-s-s-sers:-102 104 106 Patent Application Publication Jan. 26, 2017. Sheet 13 of 27 US 2017/0020926 A1 - Transgene +Transgene s 1 O 6 4 1 4 1 O 2 O S. 14.9 0 irregri.104 10510 - s & OO 46 &s s s. & O 2 s O s Fig 3AJ -s-s-s-s-s-rrrrrrrrrrrrrrr-e-r-sers0 10 10° 10 & Patent Application Publication Jan. 26, 2017. Sheet 14 of 27 US 2017/0020926 A1 - Transgene + Transgene 7 R G F P s 243 1 $$$$...isS3. Fig 3AM 10010110210°s 10'10° 106 +Transgene 69. 8 1 O 6 1 O 4 r S 0.0703 8 s | s swiss-sixstows-sex102 104 106 years-w sewers10 x: s rare Patent Application Publication Jan. 26, 2017. Sheet 15 of 27 US 2017/0020926 A1 Transgene * Transgene 1070.361 106. 105. Ep 104 103. 102. 101 99.1 resswynwyswyswyswyx Sis sessessessexei Fig 3AQ 102 104 106 102 104 106 - Transgene Transgene XX 0.246 107,0.0318 1 O 6.: s ' 0.318 : s 75.7 series-crossero4" "6 Šs s^ess s&sseswaxswaisy's104 106 - Transgene +Transgene 0.246 1070.0471 18.1 O 2. 10199.1 0.318101.i issessive8 systerseesi3. s 2.28 Fig 3AS 102 04 106 Patent Application Publication Jan. 26, 2017. Sheet 16 of 27 US 2017/0020926 A1 % 2 2. % 3 W. Patent Application Publication Jan. 26, 2017. Sheet 17 of 27 US 2017/0020926 A1 &&******** Oy61 d=15) unoC) Patent Application Publication Jan. 26, 2017. Sheet 18 of 27 US 2017/0020926 A1 gC Transduced D to N CNS sS OOS 53 . S - I - E E E 52 E E SE SE SE SE 51 ... D C C C C ?h - 50 -------------. d 3 49 or 48 a v- a v. W. W. v- a v- a - a - m a a V a m - m - a v- a v- a O 47 ... 46 - 45 . d-tubulin 44 ................ B-actin - Transgene N+ Transgene FiOI9 5A Fig 5B Transduced O-tubulin - Transgene 3-ac-actin R+ Transgene Fig 5C Fig 5D Patent Application Publication Jan. 26, 2017. Sheet 19 of 27 US 2017/0020926 A1 IC SBSA + IgG s s s IC binding Fig 6A 25000 Ceis only i20000 OBSA-IgG e siC 15000 10000 5000 Patent Application Publication Jan. 26, 2017. Sheet 20 of 27 US 2017/0020926 A1 g/61 CI/61 8 Patent Application Publication Jan. 26, 2017. Sheet 21 of 27 US 2017/0020926 A1 NoHA tag Yes HA tag O.O11% 0.017% 0.006% 0.0176 roll ses-Kirir-es-s-s & 6.4(e.3 10 1O 10 10 10 106 BL1-H: BL 1-H BL1-H: BL 1-H CFSE Fig 8A 28 8. 8. s si SCO ityye mir -- No Ceis - - No Surface Capture vases. With Surface Capture Fig 8B Patent Application Publication Jan. 26, 2017. Sheet 22 of 27 US 2017/0020926 A1 No Biotinylation Yes Biotinylation 5 E 10 wO 4.$3 iE 10°."19. C 2 10 S 10' 0.877 99.1 *xross-ressessers-s-typer-r102 10 x-rrysgress-s-s106 s: 102so: as x t 10s? 9 : 3 xSix:106 BL 1-H: BL 1-H BL 1-H: BL1-H CFSE Fig 8C si {{ s 8: Time mir -0- No Cells No Surface Capture ver, with Surface Capture Fig 8D Patent Application Publication Jan. 26, 2017. Sheet 23 of 27 US 2017/0020926 A1 rever-ressessesserteger-ses cOshu RBC 1 O O y 10 Cultured 80 V w W Cultured + intraCell. Prot mam Cultured + Surf Prot hours post-injection Fig 9B Jan. 26, 2017. Sheet 24 of 27 US 2017/0020926 A1 (u/au) Suoleuueouoo Patent Application Publication Jan. 26, 2017. Sheet 25 of 27 US 2017/0020926 A1 Time (hours) Fig 11A Time post-injection Cells + Intracell. Prot. Recombinant Protein Anti-HAWestern Blot Fig 11B Patent Application Publication Jan. 26, 2017. Sheet 26 of 27 US 2017/0020926 A1 **** Fig 12A - Transgene +Transgene 1724 8.21 88.1 29 2.34 1.
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