ss
`I TER AT O A CO
`. 9
`9TH INTERNATIONAL CONGRESS
`OF M OLOG
`OF IMMUNOLOGY
`
`
`
`San Francisco, California .
`
`.
`
`.vl
`
`Apotex v. NOVartis
`IPR2017-00354
`
`NOVARTIS 2052
`
`
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2052
`
`1
`
`

`

`The 9th International Congress of Immunology gratefully acknowledges
`the educational grants provided by the following:
`
`Office of AIDS Research, NIH
`
`PharMingen
`Schering-Plough Research lnstititue
`Sandoz Pharma Ltd
`DNAX Research Institute of Molecular and Cellular Biology, Inc.
`Hoffmann-La Roche, Inc.
`Abbott Laboratories
`Genentech Inc.
`Glaxo Inc.
`lmmunex Research and Development Corporation
`
`Amgen Inc.
`Behringwerke AG
`Bristol-Myers Squibb Pharmaceutical Research Institute
`Glaxo Research Institute
`Merck Research Laboratories
`Syntex Discovery Research, Division of Syntex (USA) Inc.
`·
`Pfizer Inc.
`Zeneca Ph~rmaceuticals Group
`
`Calypte Biomedical Corporation
`Centocor Inc.
`BASF Bioresearch Corporation
`Wyeth-Ayerst Research
`Boehringer lngelhelm Pharmaceuticals, Inc.
`The DuPont Merck Pharmaceutical Company
`lmmunoblology Research Institute
`The R. W. Johnson Pharmaceutical Research Institute
`
`2
`
`

`

`864
`
`5124
`
`CYCLOSPOR JN A CSAHDIHMJN) 1REA1Hfl/T IN D£RKATO/P0lYHY0S I TI$, k 1 Qpnk6 Cy. St99edf.
`
`lrd Dept. of Htd. Univ. Htd. Schoel, Dcbrectn, Hungilry.
`
`A t reatnent with Cyclosporln A(S11ndimul) of 23 p.,tfm ts with
`
`derNto/·
`
`1
`
`pol)'ff:Ycslth (OIC/PH} Is descrl~. In 14 of the Zl pa tl,nt s Authloprlnc, In l o f
`
`tht111 Lyc.url:n, In 2 of th c,o Cycl opho,p/u,111 ld tre11t~ts had Men trlt'd c•rl ler b.Jt
`
`~re di &contlnucd bc:cau,e of sldo effects or leek of effic acy. At the ti~ of
`
`sta rting Cyclo1,porln A trutlfll:'flt(lnhial dose 5 :11S1/k9/doy}, all p.,tlents h&d
`
`scrfcu, fnvolvC!X'nt of the di sease. The duration of DH/PH rangt'd frcn 6 l:'IOnths t o
`
`16 yt:or• ot tho tll:'IC of lnltl11tlon of Cyclo1porln A trutll'ICnt . Tho response to
`
`Cyc.l osporln A lnclldt-d recovery of n n cle 1trM!3th end f\llCtlcn. It was possible t o
`
`stop or red.Jee tho steroid don, wf'llch hod previous ly been difficult In oil 2l
`
`potlcnu. In thue p,3tlent1 • 1:1i11 nttrunce d:,lly don wn batween Z.5·l 1111J/~g/doy .
`
`Leve l s of 0:: nnd LOH returned to noriN l after 2·3 ll'lOnths of trut·a,cJit . 2 p:atienu
`
`dh contlnucd Cyclos porln A because of hypertens ion. Hlnor ,ldo efft-cts occurred fn
`4 potltnts < hypertrfchosfa fn Z, nau,co In 1, 9lng lve hyperp l asia In 1). 8tCOl.l$t
`
`Cy(lnsporln A fs l!I f ast·octl ~ 11:D.MSI.Wt'Ul.,.e df"U9 , It app,e•r-$ to be • good
`
`c andldtte for the treatatnt o f refractory fcrm of DH/PH, with no increased rls\t
`
`of od'vene effects cocport"d with those usoc:tat cd Mith other drug, .
`
`fMMONOSOPPRBSSIVB AGENTS (5124- 5129)
`
`FRIDAY
`
`5125
`FTY720, A NOVEL IMMUNOSUPPRESSANT, POSSESSING UNIQUE MECHANISMS.
`I .Relationship belv.ecn immunosupjXCSSive effects and selective dcacase of peripheral
`mature T cells. K. Chiba K. Teshima A FujN Y. Masubt.lChi C Suwki K Adachi
`T. Mishina, S. Sasaki' and T. Fuirta t Yosllttomi Pharmaceutical lrdustries L m .. Saitama.
`Tatto Company•, Kobe, ard Kyoto Univ. t. Kyoto Japan.
`
`FTY720, a novel synthetic immunosuppressive agent. w·,s found through chemical
`modification of ISP·I. a natural product from /sa'ia sa,cian.
`In vivo administration of
`FTY720 resulted in a marked protongollon of rat s1<in allografl sul\'ival at a dose more than
`0.1~ p.o. and its effect was 10-fold more potent than lhat of FK506. Ho,iever.
`FTY720, at a cxiiicentration up to 100nM. had no offed on IL·2 and IL·3 productions, 1'.hich
`wcro inhibited b'{ both Cidosporin and Pr<506. from a!loantigeo-stimulaled T cells.
`'Mien
`0.1 rng,1<g of FTY720 was administrated orally to rat. the number of CD:l-positive T cells in
`peripheral blood markedly dcacased ,whin 3 h, vAlereas the number of peripheral B cees
`and P/v'.Ns ....re unaffected. Mer the adminislration f0< 5 days, CD3-pos.'!ive T cells in the
`spleen were seledlvely depleted, however bona marrow cells. thymocytes. and splenic B
`cells were not affected. Furthemiore. DNA of FTY720-administered rat spleen cells slla.ved
`ladder degradation t,/ agamse gel elcdroplloresis. These resul!s ind:cate that FTY720
`possesses powerful immunosuppressive adivity vhth unique mechnnisms distinct from
`those of FK503 and Cidosporin, and that the mechanisms of aaion of FTY720 is related to
`se!edlve decrease of mature T cells t,/ homirg and apoplosis.
`
`5126
`FiY720, A NOVEL IMMUNOSUPPRESSANT, POSSESSING UNIQUE MECHANISMS.
`n. S)'O(lflJistlc prolongation or ollograft sul\'ival In combination ~h Cidosporin In rat ard
`dog. Y Hos/lino K Chiba F Rahman. T. Kawag,Kl)i Y Amano H Higashi K Teshima
`T Knkefucta· nnd s. Suzui<J• Yoshi\omi Pharmaceutical lrdustries L m . Sailama, ard
`Natiorol Children Hospital', Tokyo, Japan.
`
`FTY720, a novel synthetic im~ c agent, posseses po.vedul lmmuno(cid:173)
`supprossivc adivity y,itJ1 unique mechanisms distinct rrom those of FK506 ard Cidosporin.
`Effects of FTY720 on rat skin, mt heart and dog kidney al!ogml\s v.ero examined. In ra1
`skin e'.lo[Jcneic trnnspnntotion with Wi<AH donor and F344 rocipienl, FTY720 prolonged
`the elloQan survival at a dose mom l!lan 0.1mgA(Q p.o. 111 a dose-Oependcnt manner, and
`soo,ycd sync,¢;tic e[ects In comllina!lon .,;tr, 5lJOO!Xlm:il daSo of Cidosponn.
`In rat
`hetorotropic heart
`logaft wtth WKAJ-1 end ACI s:rain combination. FTY720 was also
`effedlve at n dose of mom than 0.1~ p.o., and long:emi oran S<J1Vlvals (>IOOdays)
`v.ero obsetved in high dose (t0m9'l<o p.o.). F\Jrthesmoro, in dog lddney al!ogan v.ith
`~,OOJrel donor and Beagle recipiont, lor>Jlcnn SUIVivnls (>7Ddo1~) \'.1lnl also obtained t,/
`oral adminis:mtion of FTY720 5mg,1<g In oomtmation viilh Cidosporin 1 Dm9'l<o p.o ..
`These result., suggest that tho comlmalion of FTY720 and_ Cidos;X>rin sli<lY,-s synergistic
`effects in various animal
`neic 'lranspantations because of the unique mechanisms of
`FTY720 dislind from those of fl<5QS and Ciciosporin, lhus, FTY720 Is cxpeded to have
`d':nical po(ertial f0< organ transplantations.
`
`5127
`FTY720, A NOVEL IMMUNOSUPPRESSAf/T, POSSESSING UNIQUE Mc:Cl-'.ANISMS.
`lll. Pharmacological activities in several autdmmune end lnflammaloty models.
`K. Teshirna T. lmnyoshi• M. Matsuura• S. Yamagudli• K Chbtl And M. Teras.:rHn•
`Yosl'oitoml Phannaceutlcal Industries. LlU. Saitama and Fulwol<a", Japan.
`
`FTY720, a potent rnrnutlOSIJ!ll>e agent that prevents o,gan graft rejedioo on animal
`models of transplantation, possesses mechanisms of actions distinct rrnm those of
`Cidosporin and FK506. In this study, phanna<olog:cal activities of FTY720 in several
`autoimmune and lnOammatory models v.ere assessed in oroer to make dear its potential
`util~ as a drug for autoimmune diseases. FTY720 signif,canUy inllilited methytaled human
`scrum albumin--tnduced delayed-type hypersensitivity in a dOS&<fependent manner at a
`dose of rrore than 0.03 rngAqj p.o. da,ly in mice. In rat adjuvan!anduced artlvi'.is, FTY720
`lnhilli!ed joint deslrudion completely as wen as paw edema at a dose of more than 0.1
`mg,1qJ p.o. on a da:Jy dosirg sdledule. FTY720 was also effective In collages>induced
`arthritis at a dose of more than 0.3 mg/,qi p.o. dO:ly in rats. Fl.flhennoro. in another T cell·
`med'iated model, experimental al..'llJIC encepll3lomyellli, FiY720 inh:t;ted the paralysis
`oompletely at a dose of more than 0.1 mg,!;g p.o. da3y in ra!s. These resul!s indicate that
`FTY720 may be effective in the treatment of meumatoid arthritis, multiple sderosis and
`other autoimmune d~.
`
`5128
`RAPAMYCIN INHIBITS SYNTHESIS OF [L.2 DY T CTLLS.
`J Zh,ng O Xiang and N K Dnmle Wyeth·Aycrst Research. Princeton.
`NJ 08543, USA.
`
`Upon activation via the CD3/TCR complex. T cells synthesize both IL-2
`and functional receptors for IL-2 to bring •bout T·cell clon•I expnnsion.
`Rapamycin (RAPA) mediates its inununosuppressive effects by interfering in
`the cell cycle progression from GI to S phase. and thereby inhibiting cellular
`proliferation. It is commonly believed that RAPA inhibits growth factor·
`induced intracellular responses ra1her th•n the synthesis of the growth
`factor(s). 11,e present study examines the effect of RAPA on the production
`of IL-2 as well as IL-2 responsiveness of murine T cells. Pl,stic(cid:173)
`immobilized anti·CD3 mAb induced a strong prolifcrntive response by CD4+
`T cells. This response was largely dependent on the IL-2: IL-2R interaction
`as evidenced by the inhibitory effect of anti·IL-2R inAb. Stimulation ofT
`cells with n nti·CD3 in the presence but not absence of anti·IL-2R mAb
`allowed significruit accumulation of soluble IL-2 in the culture supcmatants
`reflective of the inhibition of consumption of endogenous n..2. Under these
`conditions. a combinotion of anti·IL-2R mAb and RAPA, but not its
`nonimmunosuppressivc analog, caused a profound reduction in the
`accumulntion of IL-2. While Cyclosporin A almost completely blocked the
`expression of both IL-2 and IL-2R. RAPA had no effect on the exl'rcssion
`of IL-2R. These results suggest thnt-RAPA can inhibit T-cell proliferation
`not only by interfering with JL.2.induccd cell-cycle progression but also by
`inhibiting the production of IL·2 without affecting the expression of
`functionnl IL-2R. lt remains to be determined whether this inhibitory effect
`is at the level of transcription of the IL-2 gene or posHmnscriptional events
`during IL-2 expression.
`
`5129
`CYI'DKINE SEOUmDN IN SMAU. CEll. UJNG CANCER MAY DE MODULATED
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