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Hitta Ko Na Ulit Ulit Aut Me a Tout HITTA KO NAULITUS 20180112180A1 ULIT AUTME A TOUT ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0112180 A1 Robbins et al. (43 ) Pub . Date : Apr. 26 , 2018 (54 ) CELLS WITH INCREASED Publication Classification IMMUNO -REGULATORY PROPERTIES AND METHODS FOR THEIR USE AND (51 ) Int. CI. MANUFACTURE C12N 5 / 0789 ( 2006 .01 ) CO7K 14 / 705 ( 2006 . 01) ( 71) Applicant: Fate Therapeutics, Inc ., San Diego , C12N 9 / 02 ( 2006 .01 ) CA (US ) A61K 35 / 28 ( 2006 .01 ) A61K 38 / 17 ( 2006 .01 ) ( 72 ) Inventors : David Robbins, San Diego, CA (US ) ; A61K 38 /44 ( 2006 .01 ) Betsy Rezner , San Diego , CA ( US ) ; A61P 37 /00 ( 2006 .01 ) Leah Mitchell , San Diego , CA (US ) ; A61P 29 /00 (2006 .01 ) Lisa Guerrettaz , San Diego , CA (US ) ; (52 ) U . S . Cl. Philippe Alessandro Parone, San CPC .. C12N 5 / 0647 ( 2013 .01 ) ; CO7K 14 / 70532 Diego , CA (US ) ; Robert Steven Tacke , (2013 .01 ) ; C12N 9 /0069 (2013 . 01 ) ; C12Y San Diego , CA (US ) ; Kevin Lai, San 113 / 11052 ( 2013 .01 ) ; A61K 35 /28 ( 2013 .01 ) ; Diego , CA (US ) ; Bahram Valamehr , A61K 2035 / 124 ( 2013 . 01 ) ; A61K 38 / 44 San Diego , CA (US ) (2013 .01 ) ; A61P 37/ 00 ( 2018 .01 ) ; A61P 29/ 00 ( 2018 . 01 ) ; C12N 2501 /02 ( 2013 .01 ) ; C12N (21 ) Appl . No. : 15 /546 , 255 2501/ 999 ( 2013. 01 ) ; A61K 38 / 1774 ( 2013 . 01 ) ( 22 ) PCT Filed : Jan . 26 , 2016 ( 86 ) PCT No. : PCT/ US2016 / 014942 (57 ) ABSTRACT $ 371 (c ) ( 1 ), ( 2 ) Date : Jul. 25 , 2017 The present invention is directed to compositions and meth ods to increase the expression of PD -L1 and / or IDO - 1 in a Related U . S . Application Data population of cells , the modulated cells expressing increased (60 ) Provisional application No . 62/ 107 ,517 , filed on Jan . PD - L1 and / or IDO - 1 , and methods related to the immuno 26 , 2015 , provisional application No. 62 / 112 ,653 , suppressive effects obtained by cells expressing increased filed on Feb . 6 , 2015 . PD -L1 and / or IDO - 1 . Patent Application Publication Apr . 26 , 2018 Sheet 1 of 15 US 2018 /0112180 A1 21 3 FoldChangePD-L1mRNA 4 5 .1i . 5 5 i L 5 . A o 21221 Untreated Dexamethasone FIG . 1A . G FoldChangePD-L1mRNA * * O glosen Untreated IFND FIG . 1B Patent Application Publication Apr . 26 , 2018 Sheet 2 of 15 US 2018 /0112180 A1 FoldChangePD-L1mRNA abesö ?????????????????????????? Untreated IFNy FIG . 1C FoldChangePD-L1mRNA is& ö Untreated Poly ( I : C ) FIG . 1D Patent Application Publication Apr . 26 , 2018 Sheet 3 of 15 US 2018 /0112180 A1 350 300 250 rrer FoldChangePD-L1mRNA 200 150 z100 je o rrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr Untreated INFL , INFy , & Poly ( I : C ) FIG . 1E1 cerrari a u ???????????? Fold-ChangePDL1MFI rrrrrrrrrrrr w N cucurrucucururi women o ???????????????????????????? Untreated IFNb FIG . 2A Patent Application Publication Apr . 26 , 2018 Sheet 4 of 15 US 2018 /0112180 A1 + ccccccc Fold-ChangePDL1MFI a ' N o Untreated IFNy FIG . 2B Fold-ChangePDL1MFI .Ö . - - - Untreated Poly ( I : C ) FIG . 2C Patent Application Publication Apr . 26 , 2018 Sheet 5 of 15 US 2018 /0112180 A1 a **-. Fold-ChangePDL1MFI si . - in Untreated IFND , IFNy, & Poly ( I : C ) FIG . 2D 1 ?? p = 0 .000 foldchangefromcontrol 0 . 0 Vehicle9 . 8 . 320 , C xoood 13 IFNb + IFNg+ Poly ( 1: 0 ) FIG . 3 Patent Application Publication Apr . 26 , 2018 Sheet 6 of 15 US 2018 /0112180 A1 PowBoldChange(KT-ORCR) Sei .. .. .. .. w . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' . ' **W BetamethasoneClobetasol propionate Flumethasone Fluocinolone acetonide DMSO FIG . 4 Patent Application Publication Apr . 26 , 2018 Sheet 7 of 15 US 2018 /0112180 A1 222222222222222222222 - 222222222222222222222 7 rrrrrrrrrrrrrrrrrrr 6 FoldChangeID01mRNA 5 0 0 + s o Untreated IFND FIG . 5A < < rrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr! IDO1mRNAFoldChange < sporoooooo Ô rrrrrrr ? rrrrrrrr Š o Untreated IFNy FIG . 5B Patent Application Publication Apr . 26 , 2018 Sheet 8 of 15 US 2018 /0112180 A1 ?5 ,000 FoldChangeID01mRNA ?4 ,000 3 ,000 2 ,000 1 , 000 Untreated Poly ( I: C ) FIG . 5C 15 , 000 Surrrrrrrrrrrrrrrrrr FoldChangeIDO1mRNA 10, 000 5 ,000 errrrrrrrrrrrrrrrrrrrrr 0 errrrrrrrrrrrrrrrrrrrrrrrr Untreated IFNB , IFNy , & Poly ( I : C ) FIG . 5D Patent Application Publication Apr . 26 , 2018 Sheet 9 of 15 US 2018 /0112180 A1 . - : ? $ 24 . 97 ? ? ? ? s t r . , . , ; . , , . , . , . , . , . , . , . , . , . , ; . , ; . , ; , , ; . , ; . , ; . , ; . , , , , , , , , , , , , , ? ? ID01FoldChange(RT-PCR) ? ? ? .??????:- .. YYYY V . .????????? .? .? . ?. : :. DMSO Fluphenazine ProtriptylineTelenzepine Letrozole, GemcitabineIsomethepteneDihydrostreptomycin mucate sulfate Cyclobenzaprine Fludarabine4-aminosalicylic acid FIG . 6 Patent Application Publication Apr . 26 , 2018 Sheet 10 of 15 US 2018 /0112180 A1 Baselinew 6hr 24hr 148hr 20000 18000 WUUUUU LUXURY 16000 14000 12000 LLLLLLLLLLLLLLLLLLLLLLLLLL PD-L1MFI 100001000 8000 6000 % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % LLL * * * * * * * * * * * 4000 1 5 % * * * * * * * * * * WWWWWWWWWWWW 2000 O . V Vehicle FNB IFNA Polylc IFNg+Polyic ** * LilF FIG . 7 Patent Application Publication Apr . 26 , 2018 Sheet 11 of 15 US 2018 /0112180 A1 . S pewu de 26 do Sopy OOX .iiii 20000 : .iiiiiii www . 11.sini www . .iiii i www.ssn ? ??? ON Polyc ? ? ????? . FIG . 8 Patent Application Publication Apr 26, 2018 Sheet 12 of 15 US 2018 / 0112180 A1 T cell proliferation T cell proliferation unmatched HSC matched HSC : ' ?????? 8 . ?????????????? ???? foldchangefromvehiclecontrol * foldchange fromvehiclecontrol www t * ??????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????? ???????? vehicle betagamma+ trifecta vehicle betagamma+ trifecta vehicle gamma+beta trifecta vehicle betagamma+ trifecta FIG9A FIG . 9B Patent Application Publication Apr . 26 , 2018 Sheet 13 of 15 US 2018 /0112180 A1 T cell proliferation T cells cocultured1 VNT with HSC que ueu ngLILLLLLLLLLSccccccccccccc . PDL# to incuItured FIG . 10 Patent Application Publication Apr . 26 , 2018 Sheet 14 of 15 US 2018 /0112180 A1 04 AutoimmuneAuto HSC T cell suppression foldchangefrom controlcells 0 .0 Control HSC IDO FIG . 11 Patent Application Publication Apr . 26 , 2018 Sheet 15 of 15 US 2018 /0112180 A1 Autoimmune HSC T cell suppression ., . -. foldchangefrom .- HSCtransducednon- -. - DO+HSC 100+HSC #1LmTryp FIG . 12 US 2018 /0112180 A1 Apr. 26 , 2018 CELLS WITH INCREASED [ 0006 ] Thus, what is needed in the art is a method for IMMUNO - REGULATORY PROPERTIES AND producing HSPCs having increased PD -L1 and / or IDO - 1 METHODS FOR THEIR USE AND expression without exposing the cells to the stress of in vitro MANUFACTURE processes and prolonged cell culture . [ 0007 ] The invention addresses these limitations through CROSS -REFERENCE TO RELATED the identification of a number of molecules or compounds APPLICATIONS which , in a short - term incubation , independently or in combination , pharmacologically up - regulate PD -L1 and / or [0001 ] This application claims the benefit under 35 U . S . C . IDO - 1 expression on cells , including HSPCs. $ 119 ( e ) of U . S . Provisional Application No . 62 / 107 ,517 filed Jan . 26 , 2015 and U . S . Provisional Application No. BRIEF SUMMARY OF THE INVENTION 62 / 112 ,653 filed on Feb . 6 , 2015 which are each herein [0008 ] The present disclosure provides compositions and incorporated by reference in their entireties . methods to modulate the immune system through the immuno - regulatory properties of cells expressing increased BACKGROUND levels of programmed death ligand 1 ( PD -L1 ) and indoleam ine 2 , 3 - dioxygenase 1 ( IDO - 1 ) . The present disclosure is [ 0002 ] Uncontrolled immune activation can be lethal, and directed to compositions and methods to increase the expres so the immune system is tightly regulated , in part by sion of PD -L1 and / or IDO - 1 in a population of cells , the pathways responsive to inflammation that modify immune modulated cells expressing increased PD -L1 and /or IDO - 1 , cell functions. and methods related to the immunosuppressive effects 10003 ] PD -L1 , also known as B7 -H1 , is a transmembrane obtained by cells expressing increased PD - L1 and / or IDO - 1 . protein that belongs to the B7 family of T cell co - inhibitory [0009 ] A first object of the invention includes methods for molecules . The binding of PD -L1 to its receptor PD - 1 modulating a population of cells comprising : incubating the dampens T cell activation , decreases proliferation and cyto population of cells in the presence of one or more exogenous toxicity , and induces apoptosis . The immuno - regulatory agents capable of increasing PD -L1 and / or IDO - 1 expres property ofhematopoietic stem and progenitor cells (HSPC ) sion to obtain a population of cells having increased expres is enhanced upon increased expression of PD -L1 . PD -L1 has sion of PD -L1 and / or IDO - 1 . been described in cancer immunotherapy for its role in [0010 ] In one aspect , the incubation is in vitro or ex vivo . blocking T cell activation and proliferation . More specifi [0011 ] In one aspect, the incubation is between about 5 cally , PD -L1 is capable of preventing T cell activation minutes to about 72 hours. In a further aspect, the incubation through competition for costimulatory molecules on the T is between about 4 hours to about 48 hours . cell ( e . g . B7 - 1 and / or B7 - 2 ) and through direct engagement [ 0012 ] In one aspect
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