Fusion proteins of ss2 microglobulin, HLA heavy chain polypeptides, and inhibitor of cd47-sirpa

Abstract

The invention relates to a fusion protein comprising a ß2m (beta 2 microglobulin) polypeptide connected by a ß2m linker peptide to an HLA heavy chain polypeptide comprising an HLA α3 domain; optionally, an Fc polypeptide connected to the HLA heavy chain polypeptide through a peptide linker, the optional Fc polypeptide being connected, optionally by a short peptide linker, to a polypeptide inhibitor of the interaction between cellular CD47 and cellular Signal-regulatory protein alpha (SIRPα). The fusion protein and dimers thereof are of particular use as a treatment for cancer.

Description

[0001]v -nrn r n, v n ,nn r urnnrnvnnn rrnunnvrnnnmnrr um,nun num wnunr. rnunrrv n nnn r nrnwn n n rur nn ,nm r. .rr uvrmrn,nnrrn rrn.rn. urmun n umr mr mrn.vmrvnnmn rnnnn r numr mr , w nrm ummunnumr- , m mrr rvrmmrmuunurvrn.nrr, nnnn mmun r.wvr,r mx r n r mr , w nu rmumrr n wnumrn u r mr w wnrnwrmr mr nm . r n r v r rn n . n nwr ru: r v , n rnrnv mrv .vn v,r w, rurnurmrrzur nr,-nmmr mr nrm u rr, mrx rmnn wrumrn. rn mr n v rn n n urn nx nr, mr u mmrn mun v.n nuumr ru , mu- urrumr nr rnn,urnumn,n m nvvnr wn r n .u nn, ru n r r-nnrn v nn, w nu n . u -r rnnrnr ru rnmmrn rn wxrur- mum nnnnnrur. n rrurn -, -n,n wnrmuxr n r r,n vn r r mn mrr nvnnumur mnrrn uvrnnmnn v.r m . nmmun rnn,nn mn vnn mr nn nn, .x.. : . rrrm n rnmmr.n. ur rur nrn,nrm mmun n , urrmr, n r r-m vn -n-rn. vnnvn rnmmr rn n-um . . ,. n.m. : . mmunu rnu v,vnumn ru rnnrxm,v n- . mnnn mv-mnnnn n-r, v rnnvnn rv mu. v n umr ru v n- n, wu u-mr nnnm rn xm,urnrnrrvnrunmmnn.r n nn m, numrmrnnnvnrn nn r nnr rn mr ,n m r vnnnunrrnrrnvu v mu nvvnrmmunnum. n. nmvmnun nxrmn w r mnn n w n r wn m munnn rnm nn n mr umur mr unrn rnn n .. ru mnr un n nunr v umnrmr mr nn r, mnr,nrurnmnn wn- r - nvnn . . m mn r unrnmrn: nr un mrn ,r un vn .nnn n,v m n nnr nm:rnn mn nr n v n ru n , n nnn , n r . r,: n r nrnwnur n urn- n mrr rnuvrrn un nv,nnn r. r mr rnvmrnmrnn,r mrm n r nrnwn n . nnr mr vnurrrurmmnnv,nunn rrn nurn nnvnnnmr mnvnn. n uv n nrxrur , ,r mnn v n,rr .nr mrrurmmn,mnn nmumunnrunnrrnz rnmvnnn, *,v-n rm-*, -*, -*, -*, - rn r*n, -*nv,nrn,-*.n r mrrurmmn un -*, v n rm -*, v -*, -, -*, -*n rrurmmn, nnv, w vmrrn ,mrnun n v n mr v. unrnmr -- ununrnm . nrnwrnn nnvnnmr r n,nn r nnr,rru rr umr umnnu. nnrn r.n nvnnnrmn rrmun nn rrr,rmn urrnnnur wn,nuwnurnnn v w vr.nn wvnnvr nnnnn r wn wn umnnrr rn rrn rmm mr uvrnn,”n , rm “ “r rv.n”, u “nnrnn”,,rnn “nnun”,nuvrnnm mrrm,n xnn n nmrm wnnn wr n mnnnnn xuv n u mrm,r mn m n mrm.r mmn,nn,r,n “m,rrnn”nmnn nnn,m,nnnn,n ..,nnn rmnn. u, nn n un ,n u nr mr r,nrmm uvn r r “mr”nmrrm n ”r “ ,nu ur mmn “nn r nn.” u rn vu rv, unr nrvnn vu, n mn rnwrnm,n unr nrxnrvrnn vunrw,w rnn, unrmnwr w rnnnu nur,u n xu mn rn. r nun r ur.m, rn xun rr nu mr v rrn “ vuu”r vrumrrrrm.rrxrmnn,urnn rrrrn v “rn r r u”nu ur un rrr “ nn,.” ununn n m, nurrm “,” “r,”n “”nu nmmnnn unrrw,nx nnr rnnr nn rrmw r u. ..,nrnuv m mnn nu mr,rznnun mr ur, murn, r mur,n n m m nr.,nmrr nu.r u nn: rrnu, . rnrr rrr,, rur rr,..nuu . n n,n ,rr n ur ,n rm.n mn mnx. r mr rn n r munn n. mmnn urnmnrn wr mn mn rnn w un rnrrmn r r.rnrm "mn un r u nrn rnnnurnnrmn "n "rn" rnmn ru u r. r mn ru un rvnn. un n rr-m rmmn rxrmnu.rdrr .wr rrmnn un n-r rr, mr, .. mn .un r wrn rn n rr rrnn-r - rmnu.n rn w nr n n rnrm mn rx nmn rr rrnmnrur,mnn ru un r rnnr,, rn n,, r ,, n w:nn ,, ,um u,, n ,, n ,, un ,,umnn, n ,, nn ,,nnn ,,rn ,,un u,, rnn r,,r nr,,rn r r,,rn r,, rmnxr nrxr n,rrn,v,n n ,. r,r , r -nru r - nrmnru, m rr nrn r , rrr rrnnr nunnrn nr r v,rn nrm r r ,nrmn ru. u r n nrnrnnr n n nrrum,nrxxr n m .. r m .nxr nu rmvr rur rruur mnu n m nur .xr n mmnm ,xrnn v rnrnnrn n,nr wr m nrrnru. vnrnnx rn n, rm un n,unmrn un mun n rr nunvrmr rrnn ru n. rrnnmrnmnunmrnw n un n un rmr rmrnr w-nwnn r.nmn rmn,v...n m: n,u nmm rm mn un,...: , rrmr mn rmrnmnn r....: r murzmmnn nrmmn,nun,u nm : , , rrrm , , , n .wr nn-nrmnn: u v ,..,ru n nrr nxm rmrnmn.n.nm.nu.nv. u n:x :rxn: ,rxnz:n xm m nurr rmn: urx: m n r m n umn:nn rv rn rrrxumn.n rw,un n vu ..:- vu unn uvnn u rrm u .,. rn n un wu nurrmnr vrurmn. n r un,run,n . r wrm.rmm nuun rmum. n rr nrrr.nurnrn r rmu m n rn nvnnrv nrmnmmn, rurn u rrnr, u rn, rmmnrn. m, n,urnrmu rrrnu nvn, rn nun n ,nxn,rrvv rxm,n r n, z , n n, rn n n, ,rrvv,ru,ru n,r,,nnr,xnn,mnnrnn,urn,wnn n,vrn , nr, wu nwn n r urxrmn,,mrmnn: nnr rm, . mmn rnrrmnn rrr..nr rrnn vm,mrn r rr..wnrrrnr run r runnu ,r n n mmr,rxm,wn, mrnmrrwn.nnrrmmn "rn"r "rmn" rr vnr n mrnun w m n rn r.r,nrnrm,.m.,n, "rznn"r "rmrnn" rrm mm,un ,..r, v znrnr nrwnmnr,rr,. r nrmnnrrvnn rnrmv “nnr”n “mnnn n un mmn”r ur rnnnrmrunwr.n.rur mnn nvnnnrmn um r u nmmn rn ur. rrnv nrmn u rr u mnn nvnnn m ,m n,rrmu mumnunrmrnum, um,rur ,n nx rn n, m vrrrm. vr n rm nr,rmn nr rr n .xmrm umnnnnrw uurrnnrrnvnnrn n mrnnrxm nmnnnnnr ,,,,,,,, rmn . nn- m wnnn v nnn w zn ,rxm,nnn - rmu unrn. r mnu nn v n, v nn nx n,nrurn r rnn n m nn mnmr,rrm r,mrruurvmn.numn,n v nn mn ,,n ,un nn-vn rnmv nn, wrrnxr,rur ruur wrnm -nn . mr n mrnxrurmnmr un v rnmmrnmn,nnnrurmn.nnn,n,nn mn, nnurm, rurrrn v nm wrn v rnrmn n mv n, rns o eav c nv n rm ae: nnr n . -an aees- - v unrm v wrnn nnxmnr rnu nr rr n v n un.rxm, vrn v n mn n wur-n,urrrn uunv nnru,u rrm rn, nurvrumrrn v n un rvrm. vrn n rrz unmr ,rur v n n nur urrnxrurmnn v nrm wmrrv.nnrn, w rn,mun v nrnm mr vvrn rnv nrm w r unnrrnnvv. n u vrnnrnvrnn nv mnn, n murnnx ,rrnn n .mr v vrn n unn uurnr,nrvnn ,mr vrnuvn nv n mur nnzm-nmmunrn m .n-v mrnun, rnu,nn ,,.. mxmnnrn unrn v -mxm r vrn - v n-nunnrnn n mxmu.r.xm,, urvxmn nn-v nrnn wnm -- ruur n nn xm w r . r r ru vrn mur r xm unn rr rxm n, rmn n,n rxm n. n nn rn nvnn,rvn xmn, nr wm rn w n-nrmnnrnnmn urr. v nnr mr, ur nvnr. r un unrn ., xm, nnrnn:,.,,.,.,.,un.rnmr,xrmr, unnuu . n n n-umn n nmmunrnrmr-n ,n nu m n un -,: unn nu rnnn.n, w, nmrn nmx nnmn mur rr wvn rxm mn rmn, r v. r-urnmrr n m nunrmxrurmn n nvnnnr vrn.n v n r vn nrx n, rr xrurrnn v nrn urrnrnn w mn uunv nnru n nur n nvvrmnrmnun. xrurrn n w n vrn r nrru mn,n mn,nn mn,mmunmur un rrnrnnnrrn w m rn nvnn. xrurmnxu mru m nr unr nmmrnmn,n rmuurnmrn. n n m rr unrn mnmrmrn n -mr unmmnun unn mn, w,r m nn n n znunrn m rr mrr rmnu,rnv, rm n nuunrn mm n ruunrn mnmr,n nx rn nmnr,,rurrn v zn mn. ,rm rr m-nm,rnuwnm,m, ,m mr unmrrmnr.rrrmn-m,rrxumn,nm n unrnrr-r ,nn, r- runrnrn,nrur -rnrm rn,n wn nx rnrnn,n rmv v urn rnr . n un rr n-rmn rrmurrn,rrn r , uu u-mn nnnn.nn rr n rnrm -rmnu .r , rrn n rnrmm rrr rn n, wznnnn,rn , run,r r .rr m nun rrmnnnr rm r wnwnn r,n urnnn- mnunnurrnr m,wxr rm urnn.nrn n m nnnurrrnn, v n rnrnznn n mr rnu mumn.rn nr m-r mmx rrn rn umwnrnz mrn rnw.n un u nnrn,nrn r vrm n ruruwrn urnrnn. nvnnr nnnr nn nrmrrn wnnrnn:xnnrrnnvnn r.rnrru nn nnn n. n nnn-7rv n n m m wnnn r,u nnn rrr ru,urnrnnrr-nm wn mnuruurvn mrm m nnnwnnnxr rmnrn n, rrm . r nnnnD un mnn rn mxm m urumnn murn nunmnn w rnmnn rvr mrr n n.nnm.xnxr..nn mnr-nnnrnnmmxn r wnr, nnnrnrnn unun wDu nnnnr r u,n nnnn u rn wnnrmu: mx. n:nnrnn : :nnrnn -nn *mnmxx r unrn n, rm-r off nn-r on r nn murr mnnnwnnnoffrr mnron nn r wr r nn. n n xrmn rmn unr. moffronrmn n m w n rn noffnonnn m ur mn mn. rn n nr mu rr rn rmu.: n u rmn nnnDun wn ^^nur urmr n-r vnu nnx rn n, rmn rr w n nun ,nmnnm-mnunnrumn , , , r w n rnnmrrn nr n r rrv nru.nr-nn u n. nv nwmvr nvnw n Hrnmnv,Hn,Hnnn r.nH. nvmnrnn rnn vr n vrm rn rrn mrv rnLnHnnn rnL. nnn rn mrn nmn,L. vr rn vn nnnnn nn nmrmun wnnn. nn rn n m m m.., un ur r,nun vru mmun rmnmr n- nrmnn mmn m.mr, nn n mnmr vn rn mnn ,nn rmn rmn -n mnunnr r mnn ux m r rn.n n rr-8mu n - mu r w n m.n n - munnm r rmrrn nn nn . rm urrnr,r,nnnr ,u nnrn r rn -n r n mm rnxn n m,r wnnn , , nurrn rnrr rn rrn. rmn - mu rv,rum nm , rvrmrm r rn, rr r run.n-r rrm rnn rvrm nn rvrmnrn-m mn,uurrnm nnurnnmn, n rr, m rnnmn , :-, rvrm nnrrn.wn..r, - :m--r,n,r uumn, m uur , m nnn rrmrnnm,nn,,,rmnx, r r nwn ,unzmnrunz- r n rn nrmrnnn mmnur-v. nn r rnrn mu r rvv rn rm nmmun un. wrnnrmr r rn rr mrn nrm r , rmummn r rrz r rm rnruur. n nnznm nv nnr vnx rn n rr n n w mn un n mr mnrn rvmrn nmn v numurnnr.unnumnn,u w rummunn wnmnr r umnzrmr nu-mmnznnm nnn wnnn unn . “nr nn ”, m. n :-, vrumnzn nx rn n, rm n rr nmm. r z rmn rn. rm rr un un ,nn n rnnn ,rmmun un mnmrmr wHnnHmun.nrn,rmnrmmrn wr rvn rn, mrnnmmun un w un u n.n n nnHnHmn,vnn nnwunrn mxu,mrmrrnn rnmn.nvnrn,nu nnnunrnn vw, -nrvruun,nur,vn,n m-,nrm rnr ur n.xm rurmmn mnvnnn u rnn nxu r ,n . nnn,m nn n, rmn r nrnwn nnv n , wnrmnr unrn rn u mrunnn rvnn.nnu wnurrn n m n rmnnn - rmn-rurrnnn r,r . ur r rr nr rr mmun un- run . nr . n n m nv r rn . nvnnnv rnn unrnmrn: umn mr un mrnrnn ,r mnrvn nn n w nn n m n v n .n v ru mnr n nn mrnn mn n,r,nrur nnn v n ru nnn , rrnvn nnr, , nn nrnwnur n urn rurrn r v m-nmrn wnr, -n n rm mn,rv r wn .n r n r nrnwnur n urn-ru mn rnrn mn,n.un nmun un.nrrunr wmnmnn r,vunnvurnn, rmn , w rrnn rrvn,..m,,,n r,rmn rmu nmrn,unrn. nn vunn,nun , w rw nnr n,, wwm-nnnnnnn,nnun-n n rmn mn rmnr z m w n run.rxmnmrm mnnm,mnm, m mr mrr rn .nrn .nrnmmn, mn mun n n .nrnmmn,r rn un rn un n .nmrnmmmr m mnrurnn n, unr m nunnx nvnnn w m.runrxnmn, nm un,x w rzn, nnnnur nn,n r wn r rn, r r w w nnnrrurmrmnn unn ,v. rmnu,nm n n mun n vn ,rur , , ,nrru . ,rmr mn, m n w mun n u,nwvn ,rur , , , m2nr. mun nnn nnrnnrmnnmrmnnn nm nr rrz nrnwnnrunn.nnmrnmrnm,n,m v rmunrr , wr nrzn,,unnn mnnnn n ru, mmn,nmmn wnn.nrnnrurmmn,rmn rrz . mn nn rm vn n -vmnn ,r.ur vrnunrv vnnmnr vrn v nxrurmn . nn-v rrz unmrn rnv v n unrnrxrrmumrrmnnv.vnrnu,n mr vrn v n mr nur rmmn, xrurmnrm w urrn v n v nxrurmn rv.nur vrrnrunrmmn,u vrn *,*,*,*,*,*,n rm -, n* n *. rn n m urxm unrn rn nnv rnrn . n nr nnmrr --mr unm nvnrvnzv n wunrn. urr n mnu vw rmrnun nr . wnurn, nn-vv rurrmnr,unrrvnnnunrnn nrru: urrmmmn, n-* .n mn, n-* .nrruurmmn, n-* .nrurrmmmmn, n-* .nrurmmnn,, nn-* .nnrurmmn, n--** ..nrruurmmn, n-* .nrurrmmmmn, n-* .nrurmmnn,, nn-* .nrurmmn, n--** .. vnrrnumrmnmn,v n-* . n r nrn n rurrn nnrn,r n mnurnn mumnn rn unrnmr nnr r u rn nvnn.nrurmmn, .mn,n rnmmrnmnr nrm v n ru rurrunu mvmunnnunr- w r nru vrmmun un- rnmmrn rn.mn mmr rn nrm r r.urrmr, nv n n nrnr w wn -rmnmnnrxurm nn r mn un, n rurmn nur urrn v n nnw ru unr rr n rmnnrn,u n rrnr n, w nn run,ur n,nrxurnmwnmrnm,runr . rnmr rruu v nxrurmn un un,mrn ,r xrurrnn v nrn w nr wu,n mn, rnnr unrnnrnmumnn, r m xruvu rmnnr . n nurrnurrnunrnn .nrurmmn, v nxrurmv n nur urrn v n wmmunmur n rur , n ur rnu w,urnn nnnmmun unn. vnxrrnurmmmnn,-.nv nrn unrn rvrm v n w rnurmmn,unrnmr u . - w un nnxrrnummn, v nrn unrn rvrmnrnrmn -*. n mmn, v nrn unrn rvrm,rnrnm,mxrn,urmnv -*. n , xrur nrn unrn rvrm,rnnrnm,mxrn, mn urmnv - -n*. *r.n unrn rvrm,r vnnrnm,mxnr,urmnv n-*r.nnruurnmrmn rvrm,r n mr un n n, vnurrmmn, v . n , xrurm nrn unrn rvrm,rnxrruurrmmnmnn, nv- un*. n,n w n v,rrn nur urrn v nrrmu rrz n nw,mnn uun numrn nrm ,, mn n r xrunr n xm rv .nr wr,nmn mn,rnr wnn r wn.n n,nrnmn rn, n r un nnn numrn mn rr nmnnr , n w ,r,n mn, wn n xrurmn r uunrr w r umr,,n. nvnrn w un, wvr u un vrn- unrnmrnrurmmn, . mr v n vrn -* , rnnn munr rxr nn ru,rrnn n nw .n mrru.rmmn, unrnmr,rnur mrnrrvurnmn vmn* n,n * . xm rv w* v n ,n munrunrmrmunr unnvnr’n. mr n unrunnrn rn nvnn, - * v nrn, rnu ,n mn nur urrn m mmunmu n w r n r r rnnrn wnrurmmnr n unrn rn nvnn. xrurmn , unrnmr vrn - v n uun w rrm, w runrz n,rwmn nxrurmn . - nurv-urrn v nm nwn vrn w unu n nnmurrn -*n:,n,n mnv u un, numrn -*: rnw rzn unurnun. rnunr w ur rrrmvr,vrxm,urnrnn nrmr rmn “*u”mnmun v m:wrwwm , nn. . u .: ,n mrr.u.r.ummmn, .m. urrnxrurm v n vrn nurwmn u nn- v-n un,n w n,r ,nn unnv nrrmu rrz n n xrur numrn nrm ,, mn n r n mn.n r wr,nmn rn n r wn numrn,nrnmmnn rrrn,nmnn rnr wunn nnnn. w r,n, mn, wn xrurmn r - rn, n run nu vmrnr-,,nu.nrnvnnmrnr uunrr wnrurmmn, m mr nu w un. n . nrn unnm mrrru vrrmnm-n,un vnn r.nn unrn mmn, mrrur . v n n n un nn mrrurrmnmn ,unnrmnnrn nurnvunrrn, vrn - rn,xn -rmn un-vn n v n rn ru xrurm ,r rnn-vn-rnmmrnmn n, wn - rnr nn m mmnn ,r rrr, “nnn ”. urnrurmmn, mr nr mr mun, rv -n,nv,n,r’,, urrn, r nwrmn nnr numrn nnn. nnrmr , nnnvrurmnvnr’nnn n n v u wu un, .nrruur w nrvn n -nn.rn nvnr v’rm mnnrn n rn n muunn,rvnn,n,v.n r mrr rr rr wmnm u n .nn mn -unr : wm: vr vr rn vrn. v THYRMERNYLFRYITAALMRYRYPNREEAPRFHIIAIVVYMVYDDTDVFVPRDFDRLDLARAHPDRMAAPYRDAPKWDIYEIAELNPEEDYLWDETRNMKAA IRKWEAARVAELRAYLELVEWLRRYLENKETLRADPPKTHVTH WTAADTAAI TLTWRDEDTDTELVETRPADRTFKWAAVVVPEE HPIDHEATLRWALFYPAEI VIVALAVLAVVVIAVVAAVMRRK K YAARDYTAHVDHELPKPLTLRWEP TVPI v un w ru mnnVLTA mr un : , , nvn w rn , , , , ,, , , , , , , , nenvenor , , , , . ,n vs’nmrmnnmmn, n,,,,,,,,,, n r rnn. nrrnnnrnruunr,nr ruurnvvn n r nrnrr nr m m nu n m nnnrv . n rvrr r r u ,u vr nr -rnn. mnm rnrrz .,numn r vn umn nx,* mr n -nunrn ,r nn wr,nrn nununnn w r r r.nrurmmvnn-- mnruur rn,unmvn n n mun n ,n v n,rurn , , , rmnu,u ,rmrmnu “mnr” nvn nmmr nnmn,nvmnnn mn.nrurmmn r, v n n . nn mn,n mn n-* v nn mrrurmm nn mn. rr rrzn ru, m n v n ,rur , , n ,r un vn unn ,r rmnnn unn “ v vrn v n ”v n,n n v mn nx rm- m r mnn am 2 2m+HLAseuence E IDN 17: n. IPTRETKPDKEIYAVYRHPAENKNFLNYVFHPDIEVDLLKNERIEKVEHDLFKDWFYLLYY TRFVVNRHFVDTLDAAPKPIRVMKEWPD TEFT AVYVDD RRADPMWIEEPEYWDETRNMKAATHYRMERNYLFRYITAALMRYRYPNREEAPRFHII v IEWRLMRYRYLDEVNPKDETRLLLRRADHPDPKTAHYVDTHKHDPYIIADLHNEEADTLLRWWTAALADFTYAPAAITRKWEAARVAELRAYLELV DRTFKWAAVVVPEERYTHVHELPKPLTLRWEP EITLTW.RDEDTDTELVETRPAnrurm,rmvnn,n unmmnruur vn n,rn mun n ,n v n urn ,,r, , rmnu,n,wrr mn. “mnr” nmrmnu n v n . n mnrurmnnmnnr, v n n-* v nnr-urmnrm.n,rw -,rrr nr mm-*nnmnn. mn nn n mn2 n r 2 n-rnnrm .nrurmmrnn n n-mr : wrn n,,,,n mrrurmmn,wr,mnmrn mnmr un. rr rrz un n,r v n ,rur , , , n un vn unn . n 2m-a-a am 42m+HLA seuence E IDN 1: IPTRETKPDKEIYAVYRVRNHHPVATELNKPKNIFVLKNWDYRVDMFHPDIEVDLLKNERIEKVDPEHPKDTLHVFTKDWFYLLYYTEFT LFYPAEITLTWRDEDTDTELVETRPADRTFKWAAVV HHPIDHEATLRWA DPPKTHVTHHPIDHEATLRWALFYPAE VPEERYTHVHELPKPLTLRWEP AAVVVPEERYTHVHELPKPLTLRWEP ITLTW.RDEDTDTELVETRPADRTFKWnnnrurmnnmvn rnn m,rn mmn m nr.nn w mun n n w2 rurmmn r, v m nn-mnrumrnxm.nrnm urrnn. mmm2nr n-rnnr rrn r n,nrn m2nrnrurmmmun rn, r :m wrn n,,,,. 2- nr.2- nr mnn n-nrnnmrnmrnn v ,,m.nnrunrm rrmn n n-mr : wrn n,,n mrrurmmnn,wr,mnrvnn mnmrn un. * w -n mrrrrmunr. rmrzmn ru,nm n v n ,rur , , , n ,r un vn -2m-uan n 2m -an am 2m+.HLAseuence E IDN 21: .. nn rr nnrrnwn n - - n rmn nm vr nwn n r nrn nnr n umn vnrunnnn. r.n,nrn.mmun.wn . mmu.. . nu n ,n r : mur nur n r r n mn,n -nrn w n,r rmnnrn wnnrrr xrrurrnn r mn r r .n mnrnnwnun m -nnn vr,u r nn r nunu u,rnrn. nr,-nrnwn n nwnn rnu r n ,r- urrumnru,,u-- nnrru,nvr ,- vmmun ru, nnv -,- r n ,mz n ,- nnrx,- u , x-rm - rm, un,- rmu , - rrxm, ru, nm mmunn rm,n - n , , ,nrurmm mmunn ru. xrurmnn,rn r w nrnnnwnn n-7rnwr vu v rvr-n9..nurrrurmmn, n nrn-8,nmmn r rrunrmnmnn,rnmn,rr nrnwn n mmn, n r nr nn - mu.n rrurrmn,rnn - mu.nwn n n ,nnnnrurrmmn, n r nrnwn n mr n m nmnn.nrrmunrmrmrnz, n rnnnrn.nw mnrrunr rmn,n r nrnwn n rmnnn nrz.nrnrnunrm n ,rur - nn rrz mn,nnnr .nrnwn n nn-nrnmn mrmn, wmnurn vrrnrnmnnv vmrn rnn ,r n v n nn nn n n mnn ,n r. n m n nn m nvn- vr mnrm vr n. n, unnm.nn - mnnu nn n v nu n r rn urrnr m r rn,u nnrn rrmn munu rnnnrnn,nnr. nvrnnn.nrrrzru nn r , n nn rmn,mrnnn rmmn, n r nn .n rrurmmnnnnrnrrz mrnnnnnnr , n r n nn rmn, mmn nvnnnrrz nn .nrrur mr,r n ,, nn-nnr nrn wn n vrn n-nnxru xrurmn r ,rn rr unr rmn r .nrurmmn, rurmmn,nnrn xrurmn.n nnrn ,-n,rr-n.wn nu rm mnnnvum n m . , n w n w - ur. umn un : .- n - r xrurnnmn n- n uu,r n r rvurrumru. ., ,r : - r,nu-,rxmn,, n v nwrnn- mm,unru.,unrrxm n.- n r run .,numm,unurr nm ,- ,rmr -,-,nrnmmn, nnr. :. .nrnmmr u ,.., r n xrurmn ,nu n, u mr u xrurrnn n mn n: , u n,n mn ur n n rnr -nnu, -x: ,r-u,rm-n vr.n umrnmn n numr w ,r - rnrnn wumu n , w vrn rn nnrurmmnn, unnn. ,n r,nnmrnr, m ,n n uu nnnrmn n-nr rm-. ,mnn, unr,nnmrnrn,nnmrm ,n n -. n n-nrurm,mnn, unrnmr r, m ,n n . ,n nnnnrmn n-nrurm,mnn, unr,nnmrnrn,nnmr ,n n -m n mn n-nrur rx. n ,mnn, unr,nnmrnrn,nnmrmn,nn rur- -n mrmnn, . ,n unr,nmr r, m ,n n mz n nnnnrmn n-nrurmrmmn,- rm. ,n unr,nmr r, m ,n n - u .n nnnnrmn n- vnrurm,mnn, unr,nnmrnrn, m ,n n - nnrmn n-nmmmnmm,unnnrrnur. nvnnr , wnun nwn n un rn rnr.nrmmn r , r nrn w nnnrnmmn , nrn nn-nnrn. ur ,xrurmn r nrnwnur nnurrurmmrn,rz nnr . .nnrnwnur nn r rurmmn, .nrnurrnwnur n ur rrz n ur mmnr,r n r nrnwnur n r nrnzwnu .nrurmmn, .nrurmmn, r nnurr rrz ur n ur rrz .nrnurrnwn n r nrn mmn, rr wnur n ur wnvnzrnm nn.wn vrn,nu rrunrmnmn munrnnnr,rmnnrur w- un rmn .n nr, v n ,n rmnru,z m rn,mmun unv nrmn , nx nr, n . rrnm n vrn mnn nvr nn nnrur,m w rvn r - mrmun. ,nmrnmnurnzrnn r,nrmnmmunrmnuu,nv nrv n ,n vrn , mn uunnnrrunnurnnn -nvnn-rnmmnr z xrurmnn rv n,mrr ,n v n - nrn.rrmu u, v n r,n n rnrrn rn m nrnn rm n rm zn ,nnn m -.nrur u mnuur n un nn v nn vn ummn,nvnr nr n.n rnmmun unr z rmn v urnrrvnurnxrrnnnurznn,rnn unrnnu r r nn mrzn unr rn nu runx n, w nrn vnrrnurunrn. .nmmn, zn unrn umn r rn m rn n vv - mun vv nn nvnn r rnn rurr. nzr r nr mrm uunzrnn w mn,u n. w v nrmrnrumrmnmvrn,n zvnn urn n .n znnn rn rn r urur n unrn, rnv mrv mrn .unvnrnr u vnrumumn.rvu nn nu umn mu,u vnr wr nvnr n nwn nn umumn, m rv zn . zn . nn - rnnrun,n nrnnrurm,mnn,rmunnrrznn, rrmnnmrmnu, vrmn ,n n r nrnmun unv n ur . wnur n rn, v,. n mmnmmmun unu , w rurvn n .nwn mun n wr n-,nu r m v,rnn n n ,u mrn mun nn nvnr n vr r muun,rnm . rmn nmrnwnn rur: r z . u wnn un r, nvnru n n r rn r n nrunwrun rm - mu .xr n n rn : . ,rvn n ,nr,r r n n wnumrnmmun .n -runnnnr-m unr v nnn nn r ,nn nxn. m nnnnr- xnn v n r n. nn r rnnr-- vnr mvrrmrurmrmn, nurnurunnmrrnu w x. mu w un . rrz munnrn . , wrrn n rn n uu rrn n rn un,.n nn v nr mn n n rn w n u mmnnvmr nn rn. n r rn mrnmnrr wrm vrru.nwn un nw u ru r - runn mr n -nn.-m x rn -nn - mmun. :– nu , vrnun ., vrn nn ., :.r. urn.n ur .,rnnnrn, nnn. n,nuum,u,, vrrn, –. r, vrnnm n r , vrn , , vrn vrn vrn , , , n vrn n , n r w rnrr rn rrnnrnr. nmmunuunnrr, mth.n rurn rv,nx,n, un. rn m nv n u -,rxm m nnn m- mnru um- n rmn mn nrr r n nn,nrnrumumn, w wu run m xr nnurr w nnn. unrrunrrmnmn, v n n wnn m nr.nrurmmn, nr un n n.n.n mrrurmmn nn nr unrrmnmmn,unn.nuunnrnr vn mr rrn xr n. r uu n r v urn rnr n n n mzurnr v nru. un rn mrrurm mnn mr nnrn. , rmnm,runnrn n n un n u n ,n . m , vrnxrurmn - vnrnmrmn,nunrnmnr n nr, n wn ,,,r run mnmmunn un r,uunnu.nn rrunrrmnnmn, nr nn- ,,,r n ruu n mrrurm. wn m wn,v nr u mn nn, w w mmn, n r mur n .n mr rurn mrrurmmnr,unrun . ,,,r mrnnmn n, v un n -*u n n vrn . rnxrurmn n n un n n rmmmrn, unrn vrnxrurmn -*u n , n m ,nrurmmn, unrn n vrn . r mnmrn n n rm mr. mrmr mr m m,nnmr,nv n mnmrnnn r mnmr r xrurmn u n rmn,n mrrm wm mmrru vrnurn,nn,rnurn m. nr nvnn r mrrnmr n rn.wunrn, r v mrnunrn,r n r .nrurmmn unrnmrn mrrnurumnmmun un . r un mmnnr, rnrrrz r, vnrnurn mnnwnnnn r uurnnrn, uz.n mv m , w rr un rn nrnrurmmn, . nr rrz mmnnu urnu.rmmn,wunrnnr rrz rnmnnnnr.urnmmrmnn,rnn mnvnnn,umnrrnmr wnnrurmmn nvnn, mrr . nmrn,rnn mn un nmr.w vnnrurnmmrmnn,rnn mnvnnn,umnrrnmr wnnrurmmn nvnn, mrr . nmrn,rnn mn un nmr.wnnrurnmmrmnn,rnn mnvnnn,umnrrnmr.w nur unnnn unrn rn nvnn rn vnvn r nu unnnunrn rv r r nvnn,nnmmnr. v mnu m nmrnunrn rn nn x mmn nvnn,n rmu uwn nr,. munrnrrvnn’n unnn mr.n nm nvnn,nrurr unnmnrn unrnrmu m nrrnrrm nnrvrn mn rnn n rmu, mmn,nrmurr un rn rn rnunnvnrmu m.n,rurr unrnnr, rn rn rmnmr unrn rn,n rmu n nnunnrmnrvn nr run v rmmu r ru. rmu m nurrnnw r rr.nurrmmn, m nmr nn u ru nmnnwnr r r,urrmr.u m n rnnvnn w vr nn m n ru m rm nm rr rur n w r n n nrn ,,x, , m nn, run rmn ruurnmxnnrn,m rnmnnunnurrnrmn n r.nrnmmn, rmu m n n, m mnrnn ,r m mnnrnvnn w,r,rurm .nrurmm nv mnrvr,r w. n, mnn m mn v nrrxmur.n mmn.rrrnrnrmru nmurnrrmnwnn r, . , ,nrnrmn,nunrnnuur vrurm nr rn nvnnrv r unrn nn r v.rm-nn u n rrm mr -r n r -rnrn n rnnr,nvrnnr.rrn w rn - urrn unrnv nnn vrnnr, rnnrm m,r nvr nr, mr unnnrr,.vnm,rnr nr,rnr,nmnn w - : .r-n u w mr mnrrr nn n mnnmr mrnn-,r v n v n m,um, mm,unnr,nnr,nrunrn.m r n n m r w -nnnrunrmr.mn nn n vnruvn nnnr. rnrrnr nvnnrv r u r rmunn rnnr nvnn m,nn murnrnv-xnunun,n v.rnmu ummn, unrnrv r un n n wrur munm, m - n ..n rrurmm mnu, nrr.nrv r un n n w nr,r m n wnrmrrrurmnr.mnn m,rurunrrmnmrnv, rn urn n r r v.nrrurmmn, nrr r rn rrurmmn, nrumn r n r r v.nnrurmmn, unr mrw r r r v. w rmunnr.nu nrv r unrn n nnr rrrurmmn,unrnrv r u mrn, wnn n nn-mrnunnr .. mrnmnrn n nvnn m rn nr n,urrnm unrn rn nvnn. nvnnn v,r u,nn m n rnv , u unrn nr. mnuur m mnrrmnrrvnn vnr rmrn mrmuurrnrnnrrmm.nrnn,uruunu,nrvnu, nrxn m mu rrr nvnnurrrn. mmnnvur wnxm nur,rm w urr u n m n. nrwn. xm r mn ur nvnn n.rn ur wwurnrn n n mr n w r xrmnnnnumrn w, runnmmunurv n. wummr n r r n r n mr n nr x w wn ur nnurrnnnn m mn w n . wurr v n unrnnxurmrnrv. A46E / V97Runrn.unrnx r - .m -, r nAr46mE / V97Rnrn w -n -, v -nnxr-rn.rm. -, - unrrnnrnn mn rxr . um rmu vvnr wnr n.-Am46Er / Vz97R. wunA4v6E / mn nnn w nn-m- m--A4r6E / V97r R-V97Runrn,n - .-m .n n, -A46EA / 4V69E7 / RV97R.m m.ur n, -. n n,mnrn mn uun n ru .n w-nr v n . unr, unA46Em / V9u mmn,mnnn nr, un r nr un -7R.m uumrr w wn- rn- n .nr n rvrm n r u r-uur wumnrmr mr n w mur nnnu v-mn m.xrmn wr r un um, nunmm. um, um, um,n- n r w nn,nn- n um.rrrr, n =  w r mur ,nw r un. n w rrm unw- ***< n’ - n , *< ., **< ., r. . nnw, ****< nm .. m- nnunn,runrnmnnvnn: mr un m, , mr u,nr,nnxrnurm-mn v n,u wmrmunn,rn, xrurmn m, n nn wmun n ru nwr mn, , xrurmn rrnn m.rwrnr. r n-rmnnru. rmnnru wr n - . numr mn-rmnu umn wr. wn rmr rnmnnruunnrm.n -rmnunurmu . nr mu wr n mr un mn n r-r-r umn . w mnumn. wmr.nn vumnunrnurmnrmnurr u.nn wnz n r-rmr r n nnnr rr n . w nn m n nnn - vurrn. .nn wn un n r rxr nrnu r un z wmr. vunrnr rm n - vu nrnnrr rr nn r-rmr rn nn ..w n mnz. mr rm nn- .rm ru r nn munn m,m n n,mun wr r murnnnrn mr -u,nm -n.u,rr mrm-ru m.nr ,n -nnnrnnrnmmrv un. rwrr-n nm. rnxnnn un wnrm. un w mun rr nn r-rmr r un nnnr rn. n nn rn - vur ..wu mrmnr nrn mrmw n - un r rn. rnm n nrnn rn n n rrn n nrn . w m-r r . _ mm - nn un - _ - -,n n - - wnmr n - m--- m--. -- v xm nxrmvu. wrnrnn unrn nxrurmvnr,n unrn w n nn v .nr n -:u:n nn rm rn,mn ww m nn xr nn wrn n nur - xrurmn unmn ,unn vnnr uun nnn ru n A46E / V97R. n nrnn ,rvn vrn - , wu v nn urnvrn vrnn n-uru-nr-rnv.unnn rmnn - mu A46En / V9, 7 w Rrnnmmr xr rnnr,n w un-nn rnn. vn vrnrrurxrnnwnr-m- nu- mrn nu wr-rnnnn n mrvr n w m n r mrn mrrn unr n n n . - rr wr n wrrn r unrn mm:,:,:,:. vmnrw mnnnr-z- ur n w n nn mrx. wn u n mn mumnunurmnn rn . urmn v rnn wn ,nvu n wr - m,nrnu xun v m n wrrrm un rnmn unn mn.rrun n wr mur nr. , vn wrn n-.mn vxrnn - r vrnunrnmnA46Er / V97Rw n. rrnnwrn -A46E / V97R.m wrnurmmrn v nur - rr - rv m m n n n n,u n mn Ar46vnr xr n. n-umnuEr / V97R.n.murmxn wrnnn rmrvmrm un urnn rmrm, --w--ur wnrr u. rur,-rAn46E / V97Rrr nn w w wrmurnn.rnvrnnun r n rr m wr w n ,nuuA46E / V97R, rvr w wnm wr-u ununnrrn-,n w r™ unur, rm r . n unuzrxu.n nn,rv nn-m-m ru -A46E / V97Rv rmr- ur n w rr rmm unr r A46n E / V97Rumn,r-ur n um nrn.urx nn nr. mn urn.. m mnmrnn mr, . w u r rn. rn wmu ,n. m. r - xm .uunnrn nrn w nn-.m- r .m nvnr wnn n A46E / Vmmun rr m rvnumrmmun w w nrA46E / Vn97R-n-n u wrv97Rrm, n w - umnnn w rAn46E / Vu 9m7Rnrrnn. m,n- un m wn mrnmr nm,n - unrnmr mTMur un nzm-nmmunrn m . wr r-rmvnn n nnnn mu w, r wr nmmvznr.nnrnrunn m-n,ru-r.A46E / Vn97Rn nm wr u A46E / V97R.m nnrnn: ,n - nu .n n ,.,,.,.,.,.,. m w r -- w: uunn n-umn n nmmun n w w n urn n w wr urmr w n.xn, mn wvn nm nm, r v.r rm v. nn rmr n v. .n r-nrn rn m w u rmn n.-mrA46vE / V97Rnnn vrnn w-mu,nnrrunr wn w rv, r u n vrn mmunmur n .. w m, xxm n, nr n u umumr n vr mr um-nrmA46rE, Vm97Rr unrnrm mu mm, . w wr u . nr, n r u rnm, n . nmrn , n . n r nr n nmrn- n munnnunwnwunn .n n,xr w r .,munurmn m wu rnnvnnnn . -rnn- - n u n w . n nuru nunn v rmnr n rvrm n un umr wr-uur wumn mnur murr’rnru,nnr u umr w mnr rn r , - -.r unnrnu wnrunrn wv-mrn m rm r rn mnuurr’ ™ n-m nrunnuun w wr nn n wx rrrun.rv rm wn w-rrmrmr . v- n mrru. n un nunu w n- nm r w wrnz w w un r vnr.. wnr wnmn wnrnxn,nvr .nr w znrnn mnn r runA46E, V97Rr .nr ur m mnrr r- ur.rm-uurn.nnn r nm w rnrrn n, u rn n nr. mun w ur w n nn n- n , w rv r nu nmr n mm .n- n r nr,u n r n nr ,rn- n n n mm nv uwvr,mnn wn- n n n m.mr r n rr, wn w n,n-rv wnmnn- nu , v n.n- n nrn w r wnr nr, rwvr, n mnrrn mm mnnn.mnn xm: nru .. n-ru rm run m nmrnn ---- r - r -- :nru- m . v r:nwvnr rnru rn r rn un mn,rmn u vr w run n + ur n. unrm n unrnxru.n n m rnn runxr nnrun r- n - rvr rmw - xnr-nn wrr n ruun run. -,-,- r nruurur n.-nrvunn nnrrnrnrrznnmruz unnruwnn: n v n m -- mn.. r r w wnn w v wnnr vnrnrnr r - .. . rn n nnn nr nnv vrrn r .n.,ru ..,- n - , r mx u n -mn . n r rnrn r mn nurnnrnr vrn. vrnw r, nrmmnn, , nu unr, unn wnr.nnmmr xr n nru xrn rn n wrr n rnn. vr n w n n n n mrvr mr n n nrzr w w xr nn wrrrununrmnr nnnn mr.n.urrmnnn rmnnrn n wrrrm un - m,nrn vu nx v m .run n wr mur rnm n unn un mnrnur-,nv-n wwrn nr. rn nru, w vrwrn wr nurrr .rmrr urn r rr rurrr n, wrn xun- n n umnur nnurr un z- wmr.n mr ,rn rm r rrm v, um unr urrn nrurmurnn, rn w w w w w nu unnr -unur . rm™r-unuur, rm r . n zxun rnumn,rr n w rrm unurx v n -urn w rrmn runnnur n. r rnnnr rrnnr mwn-mr-urrnn w murr unn wrrnnnmn. v nwnr r munnnur:nmr.um- w,r mrm uumn r, m-rnn .r.unmr nn n, n w u rmrmrm. uwn n rvr rur n w n rmn un rnxr m rnn unrmnrnnnn u un . rrn znurr munn v nmn -n vrmnnn’ runnnr xr nr mnnn .rwrn mx xr unrnn- n w v rm rnurrvmr mrmxrn - munn mn mnn mn.nru - w rr n r mmunn urrvvrrnxr n wrr w.nnn ru xm:unnn mnuurnu unrnur n urrun,x nnnrr n,nur n mnuurnu n rrumnnn wnrrn rn wvrnru nv ,r ur rn. rmnnrunn,n mn, n .n . wrnru mr un rnr n n, umn . nr mu wr n m-rrmn mn mnumn r-r-rmnumn . urnrnnxr n r n n .rn wrurn wrr urnn unnur nw zxunrmr m urx umn.nur n w rrm rrv, rn . mrmr umn v. ur rn wr m nnr unmnr nnrr rn unuurn rn wr rmn un - n - . nmnrnnun n w nru - n w - w -rmn mn w nx u rnrrnnn v nrv vrn .n -rmn w ,unvnnr -rv, wr nrnrun nmn uun rrnnu nvrm . n nrnn unr - wvr n n r rnn. -,mnnr nr - w w wrxr nr, w mnuurnu n.rn- n wr w mrvr v rur mxruurummnn ,-,n wrnru ru n nxr rnnrmnn mu w v n wrurrur rr . xr , ur , n wrumurn n w . unr v. - n n n -rmnv urrmr rmn n umn r r mu w murmn.-rrm mn. urrrmmnr unrumnn wn un,z rnn n u -rmn n r rrn , wr u wrmmznrvn nr w , n -mn -mrn w r m u -m, nr rr rmmznn-u ur nr wrnuunnnrrnnrnn wnr r vn mu. r v rr. n ,u rrnurnnnunn nnnnnrmn wrmnmunn rmr wrrrm un n ... wr.nzm-n r wrrn w n w u ,r50un n.rvn w rn n n mn . . wnn-nr.nrnun rn-num wr wnrnur , w u nnrn n n nmmun rnn . n vu wr rr nm un – rn.nn unr w rrmrmwnr50 w u w nnnr .xr nn ur rr rm... nru: nn nr nr m mx. rr -- ---- .. -- m- -- -- - .. - m- - - - . v- m- - - - .- m- - - .- m- - - .-- -- .-- -.- - -_ -..- _ - .- --_ -- .- - - .--- -- v.-- .--- v.- .-- -.# .- - --.# .- - - --.# .- - - -- . .- --- -r_ - -.-_--_--r r-- .. v - _--- -r - - _--- -r - . - --_r- --.r.rnn rr nrunnnrru wnumnnr: n rrnn , , n . vu < n+++++ < n+++ r < n++ < n+. * vu, + < n+++ ame . = . n nn n nn n nn n nn - -αα- -- -cc++ - --mα-- c ++ -m-- --cα- -+ cα- -+++ -m--m-m- ---cαcα-- -++ +++ a -c- α-c++++++ +++++ +++- --c-a + --c- av.- +++++ -- +++++++++*+++*+++*+++**+++++++*++++++*+++++++ --cc-- av.--a+++++++++++++++++++++++++* v -- c---__-r---++++ ++++ ++- _- --c- -r-c-_-r- -c-- - ++ ++ + - nr ++ ++ -nnnnrn rrnv nnru . +umnurnru wrumnnu w w rn mmurun un rrn n rnn-nrnm. n nmmunnnnr w.rn,z wmr un un urnnn n r w wur wr w n r ur °. wr w nn rnu w mun r mnu °. vu wr nrn w nnu rn r rmr u nr rmr un n v. nnn n. wr nr nnvnr. umnvnn, - nn,nu ,nunrn mun rn -rumrnvrnm nn . rn n unrnn w run nrn r nn , nn wmrn-, nn -rmn nvr,mrn n nru nn rn.. rn m nnnmunnn nun r r w nru un rnmr nvr rn.. r n rnrnru wr rnnnrmrm. nnnn wnr wnun wr mun un nn- n nmmun r. z wmrrm , w n un urnnn r, wrr wrnu w mun r ur °. w n r w n w nnu r mnu °. r w nn nr r un n v. rn nnvr vu wrnr rm m nr vr wr nrr.mr un. rnu w nr nnnnnmunn nu rm r.nrrvu wn xn -r rnn r , wr mu -nrun nru w m n vv unn w n.rnrnnz v .mnun n,nmun u wnrnunr wn rmwnm°rn rnrm w nn rn - wwrn r.mnvnr r rnv n v n , r rn rnn .,. rnzm wunn munn w rrm rnrrn mumn rnru u w ur n un mnnu wrx, r,mmr wurr u mnun m.xr wrn urnn nwnr nnrun. w r r r n n u rmv.r rnrun, u runru runnn vum m n mrnn w r n u w °.mm rrrmun mn un, w - un w m un w .unr unn ,r nnrn rnrm. n w r nrun r run m-w , r nr rmn .r n nnu °n vrn.uur wr m vumn mnr ru2wr nrvrnnun. mr rm ,mmu.nn - nru wn ,n - w ru mnunn , -,-,- ,-,n r r v rm. nmr -,-,- r-rr nru wnr n r nrn n n vxxrn r r unrur nn urn mun. rnrn,rm-.rnn. nn °rrnuur. w n rnnn ,n mxurn mumnnn w mur wr ur rm m,n m wu . run vu w rn n n w u munrv mxmum. vu w:mxmum-mmxmum× . r-nrmrr rnrn nrnmrr.rn unv nnnr rurnrnn mznx-r nmrn n mn mnr nn n nnn n.,n . mn n v n rm . v - - nrz - nrz - nrz . - nrz . - nrz . - nrz . - nrz . - nrz . - nrz . - nrz . *uunnr wmr nrrum. nnru n-u,rrnn rnmrrnr mnn .-xrv4mwrr- wrnrw mn n wnu °.nrr nr - mr ,u-munnm- n w n wrnu °r m w -uur nr. nm w n mun wnnrnr.n xrmn, mr wrr w nr rrnvr wrn, w rrn w m rm r, n w w: r :.-uur w nuurr’nrunnu v mn m, nn- nx vr mnrr w w r urnr rn wrm vr v wnu wr v .un n . rnn wn nnmnn r nrvnrm rn r . nrn, rrun r n nrvnnr w u nrn n n zn rnrn . n rrmvnr wnxu rn rnr nn r w nrmzvr nun r w rrnn v xum² rrn nun. r n w rrmn nnv n vrrnn. n vr un,n..nrwn mnunrnunn w mwmn nn - r unnn r , rmnr nr rvnrnr - n -.r mm wnn uwn , -,n - wnmr ,r - n - uun,w mzn un vnnunr n nn x nunn.. ur vvu u rmr n.n mmrrm nmn-m unrnnur mxun wrrrrm , r . rnu mr ur,nn mnnrm r mr w nmr rumrrrurrwnmmun un w . mun,nr n n, un n ,n rrn wr uur r= r r .nurur - wr mnn r- .urnn wr nmmun unn uur .rurnvm n umr vum r, rwn n m w nnmn rrrumur znxn v,vum.rrmn unv nr w run w rnnr mnn ’ + nr , . nnuvumrnrzmrm wrmvumnrx nr. runumrum,z vvumr . mr rmn rmrumnm-n.n ’ + w mn mr z um nrm mm nr ---+ v --+ --+ -- urrn n: nnn.,..,r.x.. :: - , n. nurn.nrur ,n . vmr rr n numn n rn nrnrr B2MuSnE IDNO001: IDERYTAPCKRIVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNG iVnNkHeVrTLS ERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEK B2M-L SEPKIIVDKWNDORD0M02: GGGGSGGGGSGGGGSGGGGS LinkerMonomer;a3-linker,SE IDNO003: GGGGS Fc-linkerSE IDNO 004: GGGGSGGGGS SIRPα-linker SE IDNO005: GGGGS HLA-B57uniProt9MYI6:SE ID NO006: GESNHLSRMIRAYLFRYYTYANMSSREPAGGRSGHEIPIRFVIMAYVGGCYDVVDGDPTDGFRVLRLFRDGSHDDAASSAPYRDMGAKPDRYAIPAWLINEEDELGSPSEWYTWADAGDETTARANMIKIASRAKWTEYARA v ADVTVEALAVVEMTCRRPRAKGSDSRGTGFKGKGWSAYASVVAVAPCSSGDESERYTCHVHEGLPKPLTLRWEPSSSTVPIVGIVAGLAVLAVVVIG astAndGSDVSLTArdHLre row: row: row: , GSAH-SBM5R7YFAY4T6AEMSVR9P7GRRGE–PRaF1I-AaV2G-YaV3D:DTSFE IDNO007: ENLRIALRYYNSEAGSHIIRMYGCDV VRFDSDAASPRMEPRAPWIEEGPEYWDGETRNMKASATYR RVAELRAYLEGLCVEWLRRYL GPDGRLLRGHDSAYDGKDYIALNEDLSSWTAADTAAITRKWEAA DTELVETRPAGDRTFK ENGKETLRADPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWRDGEDT B57-A3:SE ID NOWA0AVVVPSGEERYTCHVHEGLPKPLTLRWEPSSS DPPKTHVTHHPISD 08: TCHVHEGLPKHEATLRCWALGFYPAEITLTWRDGEDTDTELVETRPAGDRTFKWAAVVVPSGEERY IG4S228PP-LFTcLRWESPESSISDNO009: EESKFYNGSPTPYCRPVPVCSPVALPTEVFLLHGGDPWSLVNFGLKFEPYPKKCPKDTLMISRTPEVTCVVVDVSEDPEVFNWYVDGVEVHNAKTKPRE VKGFYPSDIAVEWESNGPENNY KVSNKGLPSSIEKTISKAKGPREPVYTLPPSEEMTKNVSLTCL SLG KTTPPVLDSDGSFFLYSRLTVDKSRWEGNVFSCSVMHEALHNHYTKSLSL IDG1LALAPG_FcS YKNTSHTTYCRPVPVCSPVALPTEVALAHGGE DPWSLVI NFD GLKFN EPO YPKK0 CP1 KK0 VDST: NLKMAILSGRATPPIEEVKTTCIVSVKVADKVGSHPERDEPEVKFNWYVDGVEVHNAKTKPREE GFYPSDIAVEWESNGPENNYKTTPPVLDSDGSFFLYSKLTVDK PVYTLPPSRDELTKNVSLTCLVK GK SRWGNVFSCSVMHEALHNHYTKSLSLSP SIaRrPeα_wst rouwniprot:,P7832,4 m:areSEnI rDowNO011: EIESEIL RSPNV α-II ATLPP XADDKAS UGVSVAAGESAILHCTVTSLIPVGPIWFRGAGPARELIYNKEGHFPRVTTVSESTKRENMDFS SI ST2Y0Y1C9VK0F1R6K9G2S6P6DTAE1FKSGASGETELISDVRNAOKP0S13: EIEREILGAIIITPPADDKASGVTLYVYACAVGKEFTRAKTGLSRPCDTDIVTESLFPVGPIWFRGAGPGRELIYNREGPFPRVTTVSDTTKRNNMDFS SIRPα-K53RSIRPαK53RSEF IKDSGNAOGT0E1L4SV:RAKPS EIEREILGNVIITPPADDKASGVTLYVYAAGETATLRCTATSLIPVGPIWFRGAGPGRELIYNREGHFPRVTTVSDLTKRNNMDFS SIRPα-K53RTrilClViKuFmRKbGaScPkDbDoVnEeFKSGSAEGTEILDSVNROA015: EIESEILSNVIITPPADDKASGVTSYVYACAVGKEFSRAKIGLSHCTVTSLIPVGPIWFRGAGPARELIYNREGHFPRVTTVSESTKRENMDF TPrDiTlElFiKuSmG S SIRPα-K53R-100D-T102V AbGaTcEkLbSoVnReAKPSSE IDNO016: EIESEILSNVIITPPADDKASGVTSYVYACAVGKEFSRAKIGLSHPCDTDVVTESFLKISPGVAGGPIWFRGAGPARELIYNREGHFPRVTTVSESTKRENMDFS Claim23 ß2m+HLAsequenceSE IDTENLOSV0R1A7KP:S IDERYTAPCKRIVNVHYVSTRLHSPAPEKNIGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEK FVRFDSDA VKWDRDMGGGGSGGGGSGGGGSGGGGSGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDT GRLLRGHDASSAPYRDMGEKPDRYAIPAWLINEEDELGSPSEWYTWADAGDETTARANMIKTASRAKWTEYARAERNVLAREIALLRRAYYYLNEGSLECAVGESWHLIRIRYRLMEYNGGCKDEVTGLPDR v AYDTPCPHKVTHHVETGHLHPPKIPSLDTHLERAWTELPRSCWALGFYPAEITLTWRDGEDTDTELVETRPAGDRTFKWAAVVVPSGEER aI1-RaT2P-KaI3VYCSlRaHiPmA2ENGcKoSnS NsFtS LrNuCcYtVSfGuFlHlPSlDeInEVtDhLLsKeNquenceSE IDNO018: DEYACRVNHVTLSPKIVKWDRDMGGGGS GERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEK FVRFDSDAASPRMEP GGGGSGGGGSGGGGSGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDT GRLLRG RAPWIEEGPEYWDGETRNMKASATYRENLRIALRYYNSEAGSHIIRMYGCDVGPD ADPPKTHHDVTSHAHYPDIGSKDDHYEIAATLLNRECDWLASLSGWFTYAPAADETIATALTIWTRRDKGWEEDAATRVDATEELLVREATYRLPEAGGLDCRVTEFWLKRWRYLENGKETLR YTCHVHEGLPKPLTLRWEPSSSGGGGSGGGGSESKYGPPCPPCPAPEFLGGPSVFLFPPKPAKADVTVLVMPISSGRETEPERV IDERYTAPCKRIVNVHYVSTRLHSPAPEKNIGVKKSWNDFRLDNMCGYGVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEK NGERIEKVEHSDLS GGSGGGGSIRTPKIVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLK GGSDPPKTHVTHHPFISSKDDHWESAFTYLLRLCYWYATLEGFFTYPPTAEEKIDTELYTAWCRRVDNGHEVDTLTSDPTKEILVVKEWTDRRPDAMGGDGRGTGFSGKGWGAGSGGGGSGG RYTCHVHEGLPKPLTLRWEPSSSGGGGSGGGGSDPPKTHVTHHPISDHEATL AVVVPSGEE EDTDTELVETRPAGDRTFKWAAVVVPSGEERYTCHVHEGLPKP RCWALGFYPAEITLTWRDG ß2m-ß2m DEYACRI-a VNV3 HY- VSa TR3 LHSPAC PEl KNa IGi VKm KSWN6 DFRLDNMCGYf LTLRWEPSSS IRTPK GVu GSl GGl SFGHl GPe GSn GDSIt IEhVRDs TLe PLq KKu INeGn VEc YRe SIREHKS PVE AEEHNSI GDD KLSSN NFO FSLK0D2W2SF:YLLYYTEFTPTEK NGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNH NCYVSGFHPSDIEVDLLK GGSDPPKTHVTHHPISDHEATLRCWALGFY VTLSPKIVKWDRDMGGGGSGGGGSGGGGSGG RYTCHVHEGLPKPLTLRWEP PAEITLTWRDGEDTDTELVETRPAGDRTFKWAAVVVPSGEE EDTDTELVET SSSGGGGSGGGGSDPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWRDG PCP RPAGDRTFKWAAVVVPSGEERYTCHVHEGLPKPLTLRWEPSSSGGGGSGGGGSESKYGP YRVPVCSPVALPTEVFLLHGGDPWSLVNFGLKFEPYPKKCPKKVDSTNLKMGILSPRSTSPIEEVKTTCIVSVKVADKVGSPERDEPPEVVYFTNLWPYPVSDGEVEVHNAKTKPREEFNST SDIAVEWESNGPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWEG EMTKNVSLTCLVKGFYP GSEEELVIPDKSVLVAAGETATLRCTATSLIPV NVFSCSVMHEALHNHYTKSLSLSLGGGG FSIRIGNITPADAGTYYCVKFRK GPIWFRGAGPGRELIYNREGHFPRVTTVSDLTKRNNMD HLA-CW08a1 GSPDDVEFKSGAGTELSVRA CSHSMRYFYTA-VaS2R-PaG3SE IDNO023 VSLRNLRGYYNSEAGRSGHETPLRFRIMAYVGGCYDVLDGDPTDGFRVLLFRDGSYDNAAFSAPYRDGGEKPDRYAIPAWLVNEEDELGRPSEWYTWADARDEKTAAKYIKTRRAKWTEDARA v REDATEELRVREATYRLPEAGGTDCGVTEFWLKRWRAYALVEVNVGPKSKGTELERRAYETHPKTHVTHHPVSDHEATLRCWALGFYPAEITLTWRDGEDT SE IDN CHVHEGLPEPLTLRWGPSSP GESNHLSRMIRAYLFO RYYT0 YA2 NM4SSREPAGGRSGH HEL IPA IR-FB RI5 MA8 YVGGa CY1 DV- LDa GD2 PT-a DGF3 RVLRLFRDGSHDDAASPRTEPRAPWIEEGPEYWDGETRNMKASATYR RVAELRAYLEGLCVEWLR SAYDGKDYIALNEDLSSWTAADTAAITRKWEAA DTELVETRPAGDRTFKWRAYALVEVNVGPKSEGTELERRAYDTPCPHKVTHHVETGHLHPPKVPSLDTHLERAWTELPRSCSWASLGFYPAEITLTWRDGEDT SGESHSIMDRYNFOST0S2V5SRPGSGHELPAR-FAI3A0:01a1-a2-a3 VDLGTL VGYVDDTFVRFDSDAASRMEPRAPWIEERPEYWDETRNVKASTDR RWAELRRGAYYYLNEGSTECAVGESWHLTRIRYILMEYNGGCKDEVTGLSDRGTRDFPLPRKGTYHEMTHHAYDGKDYIALNEDLRSWTAADMAAITRKWEAA DTELVETRPAGDGTFKWAA HPISDHEATLRCWALGFYPAEITLTWRDGEDT SE IDNO0 VVVPSGEERYTCHVHEGLPKPLTLRWELSSP IRT 26 IOS-2024 DEYAPCKRIVNVHYVSTRLHSPAPEKNIGVKKSWNDFRLDNMCGYGVGSGGSFGHGPGSGDSIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEK FVRFDSDAASPRMEPRAPWIEEGPEYWDGETRGNGMGKGASSGAGGTGYSRGESNHLSRMIRAYLFRYYTYANMSSREPAGGRSGHEIPIRFRIAVGYVDDT GRLLRGHDSAYDGKDYIALNEDLSSWTAADTAAITRKWEAAR MYGCDVGPD ADPPKTHVTHHPISDHEATLRCWA VAELRAYLEGLCVEWLRRYLENGKETLR YTCHVHEGLPKPLTLRWEPSSSLGGGFGYGPSAGEGIGTGLSTEWSKRYDGGPEPDCPTPCDPTAEPLEVFELTGRGPPASGVDFRLTFKWAAVVVPSGEER TCVVVDVSEDPEVFNWYVDGVEVHNAKTKPREEF FPPKPKDTLMISRTPEV TISKAKGPREPVYTL NSTYRVVSVLTVLHDWLNGKEYKCKVSNKGLPSSIEK LTVDKSRWEGNVFSCSPVPMSHEEAELMHTNKHNYTVSKLSTLCSLLVSKLGGFGYGPGSGDSIEAEVEELWEVSINGPPENNYKTTPPVLDSDGSFFLYSR GPIWFRAGKAPGSPARELIYNKEGHFPRVTT DKSVSVAAGESAILHCTVTSLIPV TELSVR VSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAG SE IDNO027 IOS-2025 IPTRETKPDKEIYAVCYRSVRNHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFT AVGYVDDTFVRHFVDTSLDSAAPSKPIRVMKEWPDRRADPMWGIGEGGESGGPGEGYGWSDGGGEGTGRSNGMGKGAGSSGSHSMRYFYTAMSRPGRGEPRFI IRMYGCDVGPDGRLLRGHDSAYDGKDYIA ATYRENLRIALRYYNSEAGSHI EWLRRYLENGKETL LNEDLSSWTAADTAAITRKWEAARVAELRAYLEGLCV GDRTFKWAAVVVPSRGAEDEPPRKYTTHCVHTVHHHPEIGSLDPHKEPALTTLLRRCWWEAPLSGSFYSPGAGEGIGTSLGTGWGGRSDGEDTDTELVETRPA GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSED ESKYGPPCPPCPAPEFL TVLHDWLNGKEYKCKVS PEVFNWYVDGVEVHNAKTKPREEFNSTYRVVSVL AVEWESNGPENNYKTTPNPKVGLLDPSSDSGISEFKFTLIYSSKRALKTGVDPKRSERPWVEYGTNLVPFPSSCSEVEMMHTEKANLHVSLTCLVKGFYPSDI GGSEEELVIPDKSVSVAAGESAILHCTVTSLIPVGPI NHYTKSLSLSLGGG RENMDFSISISNITPADAGTY WFRGAGPARELIYNREGHFPRVTTVSESTK SE IDNO028 IOS-Y2C0V2K6FRKGSPDTEFKSGAGTELSVRAKPS IPTRETKPDKEIYAVCYRSVRNHHPVATELNSGKPSKNIFVLKNWCDYRVDSMGGFGHGPGSSDGIGEGVGDSLGLGKNGERIEKVEHSDLSFSKDWSFYLLYYTEFT AVGYVDDTFVRFDSDAASPR GGSGGGGSGSHSMRYFYTAMSRPGRGEPRFI IRMYGCDVGPDGRLLRGHDMSEAPYRDAGPKWDIYEIAELGNPEEDYLWSDSGWETTARANDMTKAAASAITTYRRKEWNELARAIRAVLAREYYNSEAGSHI EWLRRYLENGKETLRADPPKTHVTHHPISDHEATLRCWALG LRAYLEGLCV GDRTFKWAAVVVPSGEERYTCHVHE FYPAEITLTWRDGEDTDTELVETRPA GGPSVFLFPPKPKDTLMISRTPEVTCVVGVLDPVKSPLETDLPREWVEPFSNSWYSVGDGGGVGESVGHGNGAGKSTEKSPKRYEGEPPFCNPSPTCPAPEFL TVLHDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPVYTLPP YRVVSVL AVEWESNGPENNYKTTPPVLDSDGSFFLY SEEMTKNVSLTCLVKGFYPSDI GGSEEELVIPDKSVSVAAGESAILHCTVSTRSLLTIVPDVKGSPRIWWEFGRNGVAFGSPCASRVEMLHIEYANLHRNEHGYHTFPKRSVLTSTLVSSLEGGG RENMDFSISISNITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRA STK SE ID PTEKDEINO YAVCY0 RS2 VR9 KPS IRTPK NHHPVATELNSGIKO PSS KN- IF2 VL0 KN2 WC7 DYRVDSMGGFGHGPGSSDGIGEGVGDSLGLGKGNGGSEGRGIGEGKSVGESHHSSDMLRSRFFSYKTDAWMSSFRYPLGLRYGYTEFT AVGYVDDTFVRFDSDAASPRMEPRAPWIEEGPEYWDGETRNMKASA EPRFI IRMYGCDVGPDGRLLRGHDSAYDGKDYIAL TYRENLRIALRYYNSEAGSHI EWLRRYLENGKETLRADPPKTHVTHHPISDHNEEADTLLSRSCWWTAALAGDFTYAPAAEIITTLRTKWWERADAGREVDAETLDRTAEYLLVEEGTLRCPVA v GGDGRPTSFVFKLWFAPAPVKVPVKPDSTGLEMEISRRYTTPCEHVVTCHVEVGVLDPVKSPLETDLPRWEPSSSGGGGSGGGGSESKYGPPCPPCPAPEFL TVLHDWLNGKEYKCKVSNK EVFNWYVDGVEVHNAKTKPREEFNSTYRVVSVL AVEWE GLPSSIEKTISKAKGPREPVYTLPPSEEMTKNVSLTCLVKGFYPSDI GGSEESENLGVPIENPNDYKKSTVTLPVPAVALGDESTDAGTSLFRFCLTYASTRSLLTIVPDVKGSPRIWWEFGRNGVFSCSVMHEALHNHYTKSLSLSLGGG RNNMDFSIRIGNITPADAGTYYCVKF AGPGRELIYNREGHFPRVTTVSDLTK SE IDNO035 IOS-1213RKGHSLPADBD5V7EFαK3SG-AGGT4ESLS-VIRgAG4S228PFc DTPCPHKVTHHVETGHLHPPKIPSLDTHLERAWTELPRSCSWASLGGGFYPAEITLTWRDGEDTDTELVETRPAGDRTFKWAAVVVPSGEERY VSEDPEVFNWYVDGVEVHNAKTKGPGRSEEESKFYNGSPTPYCRPVPVCSPVALPTEVFLLHGGDPWSLVNFGLKFEPYPKKCPKKVDTLMISRTPEVTCVVVD GPREPVYTLPPSEEMTKNVSLTCLVKGFYPSDIAV SNKGLPSSIEKTISKAK RWEGNVFSCSVMHEALH EWESNGPENNYKTTPPVLDSDGSFFLYSRLTVDKS SE IDNO036 INOHSY-T12K1S4LSLSHLLGAB57α32-G4S-IgG4S228PFc DTPCPHKVTHHVETGHLHPPKIPSLDTHLERAWTELPRSCSWASLGGGFGYGPSADEPIPTKLTTHWRDGEDTDTELVETRPAGDRTFKWAAVVVPSGEERY LVETRPAGDRTFKW VTHHPISDHEATLRCWALGFYPAEITLTWRDGEDTDTE PSVFLFPPKPKDTLMAIASVRVTVPPESVGTECEVVRVYDTVCSHVEDHPEEGVLPFKNPWLYTVLDRGWVEEPVSHSNSGGGGSESKYGPPCPPCPAPEFLGG WLNGKEYKCKVSNKGLPSSIEKTISKAK AKTKPREEFNSTYRVVSVLTVLHD ENNYKTTPPV GPREPVYTLPPSEEMTKNVSLTCLVKGFYPSDIAVEWESNGP SE IDNOL0D3S7DGSFFILOYSS-R1L2T1V5DKSRHWLAEBG5N7VFαS3CS3V-MHGE4ASLH-NIHgYGT4KSS2L2S8LPSLFGc DTPCPHKVTHHVETGHLHPPKIPSLDTHLERAWTELPRSCSWASLGGGFGYGPSADEPIPTKLTTHWVTRHDHGPEIDSDTHEDATTELLRVCEWTARPAGDRTFKWAAVVVPSGEERY LVETRPAGDRTFKWAAVVVPSGEERYTCHVH LGFYPAEITLTWRDGEDTDTE RCWALGFYPAEI EGLPKPLTLRWEPSSSGGGGSDPPKTHVTHHPISDHEATL SSSGGGGSESKTYLGTPWPCRPDPGCEPDAPTEFDLTGEGLPVSEVTFRLPFAPGPDKRPTKFDTKLWMAIASVRVTVPPSGEERYTCHVHEGLPKPLTLRWEP HNAKTKPREEFNSTYRVVSVLTVLHDW EVTCVVVDVSEDPEVFNWYVDGVEV KNVSLTCLV LNGKEYKCKVSNKGLPSSIEKTISKAKGPREPVYTLPPSEEMT H KGFYPSDIAVEWESNGPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWEGNVFSCSVMHEALHN SYETKISDLSNLOSL0G38 IOS-1216 B2m-G4S3-HLAB57α3-G4S-IgG4S228PFc IPTRETKPDKEIYAVCYRSVRNHHPVAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFT LTWRDGEDTDTTELLSVEPTKRIPVAKGWDDRRTDFMGKGWGAGASVGVGVGPGSSGGEGEGGRSYDTPCPHKVTHHVETHHPISDHEATLRCWALGFYPAEIT GPPCPPCPAPEFLGGPSVFLFPPKPKDT GLPKPLTLRWEPSSSGGGGSESKY STYRVVSV LMISRTPEVTCVVVDVSEDPEVFNWYVDGVEVHNAKTKPREEFN YPSDIAVELWTEVSLNHGDPWELNNNGYKKETYTKPCPKVVLSDNSKDGGLSPFSFSLIYESKRTLITSVKDAKKSGPREPVYTLPPSEEMTKNVSLTCLVKGF SE IDNO039 IOS-1217 B2m-G4S3-HLABR5W7EαG3NV2F-SCGS4VSMH-EIAgLGH4NHSY2T28KPSLFScLSLG IPTRETKPDKEIYAVCYRSVRNHHPVATELNSGKPSKNIFVLKNWCDYRVDSMGGFGHGPGSSDGIGEGVGDSLGLGKGNGGSEDRPIPEKKTVHEVHTSHDHLPSIFSSDKHDEWASFYLLYYTEFT LTWRDGEDTDTELVETRPAGDRTFKWAAVVVPSGEER TLRCWALGFYPAEIT THVTHHPISDHEATLRCWALG YTCHVHEGLPKPLTLRWEPSSSGGGGSDPPK HEGLPKPLTLRWEPSSSGGFGYGPSAEESIKTYLGTPWPCRPDPGCEPDAPTEFDLTGEGLPVSEVTFRLPFAPGPDKRPTKFDTKLWAAVVVPSGEERYTCHV DPEVFNWYVDGVEVHNAKTKPREEFNSTYRVVSVL MISRTPEVTCVVVDVSE EPVYTLPPSEEMTKNV TVLHDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPR GNVFSCSVMHEALHNHYTSKLSTLCSLLVSKGFYPSDIAVEWESNGPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWE SE IDNO040 IOS-1218LGB2m-G4S3-HLAB57α33-G4S-IgG4S228PFc IPTRETKPDKEIYAVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFT LTWRDGECDRVTNHDVTTELLSVEPTKRIPVAKGWDDRRTDFMGKGWGAGASVGVGVGPGSSGGEGEGGRSYDPPKTHVTHHPISDHEATLRCWALGFYPAEIT THVTHHPISDHEATLRCWALGF TCHVHEGLPKPLTLRWEPSSSGGGGSDPPK HEGL YPAEITLTWRDGEDTDTELVETRPAGDRTFKWAAVVVPSGEERYTCHV RPAGDPRKTPFLTKLWRAWAEVPVSVSPSSGGEGEGGRSYDTPCPHKVTHHVETGHLHPPKIPSLDTHLERAWTLRCWALGFYPAEITLTWRDGEDTDTELVET LFPPKPKDTLMISRTPEVTCVVVDVSEDPEVFNWYVDGVEEPVSHSNASKGTGKGPGRSEEESKFYNGSPTPYCRPVPVCSPVALPTEVFLLHGGDPWSLVNFG v IDERYTAPCKRIVNVHYVSTRLHSPAPEKNIGVKKSWNDFRLDNMCGYGVGSGGSFGHGPGSGDSIGEGVGDGLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEK FVRFDSDAASPRMEPRAPW SGGGGSGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDT GRLLR IEEGPEYWDGETRNMKASATYRENLRIALRYYNSEAGSHIIRMYGCDVGPD ADPPKGTHHDVTSHAHYPDIGSKDDHYEIAATLLNRECDWLASLSGWFTYAPAADETIATALTIWTRRDKGWEEDAATRVDATEELLVREATYRLPEAGGLDCRVTEFWLKRWRAYALVEVNVGPKSEGTELERR IDERYTAPCKRIVNVHYVSTRLHSPAPEKNIGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEK FVRFDSDAASPRMEPRVAKPWWDIREDMEGGGPGEGYSWGDGGGEGTSRGNGMGKGASSGAGGTGYSRGESNHLSRMIRAYLFRYYTYANMSSREPGRGEPRFIAVGYVDDT GRLLRGHDSAYDGKDYIALNEDLSSWTAADTAAITRKWEA AGSHIIRMYGCDVGPD ADPPKTHVTHHPTSDHEATLRCWALG ARVAELRAYLEGLCVEWLRRYLENGKETLR YTCHVHEGLPKPLTLRWEPSSSGGFGYGPSAGEGIGTGLSTEWSKRYDGGPEPDCPTPCDPTAEPLEVFELTGRGPPASGVDFRLTFFPPKKWPAKADVTVLVMPISSGEER TCVVVDVSEDPEVFNWYVDGVEVHNAKTKPREEFNSTYRDVIVASVVELWTEVSLNHGDPWEL RTPEV TISKAKGPREPVYTLPPSEEMTKNVSLTCLVKGFYPS NNNGYKKETYTKPCPKVVLSDNSKDGGLSPFSFSLIYESKR - Ir DERYTPKIVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEK FVARCFRDVSNDHAVATSLPSRMPEKPIRVAKPWWDIREDMEGGGPGEGYSWGDGGGEGTSRGNGMGKGASSGAGGTGYSRGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDT GRLLRGHDSAYDGSKDDFYEIAATLLNRECDWLASLSGWFT ENLRIALRYYNSEAGSHIIRMYGCDVGPD ADPPKTHVTHHPI YAPAADETIATALTIWTRRDKGWEEDAATRVDATEELLVREATYRLPEAGGLDCRVTEFWLKRWRAYALVEVNVGPKSEGTELERR - Ir DERYTAPCKRIVNVHYVSTRLHSPAPEKNIGVKKSWNDFRLDNMCGYGVGSGGSFGHGPGSGDSIGEGVGDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEK FVRFDSDAASPRMEPRAP GSGGGGSGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDT GRLLRGHDSAYDGKDYIAWLINEEDELGSPSEWYTWADAGDETTARANMIKTASRAKWTEYARAERNVLAREIALLRRAYYYLNEGSLECAVGESWHLIRIRRMYGCDVGPD ADPPKTHVTHHPTSDFEATLRCWALGFYPAEITLTWRDGEDTDTEL YLENGKETLR YTCHVHEGLPKPLTLRWEPSSSGGGGSGGGGS VETRPAGDRTFKWAAVVVPSGEER TCVVVDVSEDPEVFNWYVDGVEVHNAKTKPREEESKFYNGSPTPYCRPVPVCSPVALPTEVFLLHGGDPWSLVNFGLKFEPYPKKCPKKVDSTNLKMGILSPRSTSPIEEVK v IDERYTAPCKRIVNVHYVSTRLHSPAPEKNIGVKKSWNDFRLDNMCGYGVGSGGSFGHGPGSGDSIGEGVGDGLSLGKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEK FVRFDSDAASAYRDMGEKPDRYAIPAWLIKEEDE GGGSGSHSMRYFSTSVSRPGRGEPRFIAVGYVDDT GRFLRGYHY LGRPSEWYTWADAEDEMTAGAKVIKTAKHRSKWTEDARAEHNVLAREIALRRAYYYLNEGSTECAVGESWHLTRLRYRLMEFNGGCKDEVTGLSDR linker GSGEGGSIGDGGNGOS059SIRPα-linker GSGEGGSIGDGGNGOSG0G6G0GSSIRPα-linker GSG GEGGS ESNHLSIG RMDGG IRAYNG LFOSG RSYT0G YS6G NV1GS SSRHG EPLG AGAG GR_G SGAS HE2 TP4 LRFM RI9 MA7 FVR GGCYDVVDGDSTDGFRVFRLFRDGSYDHAASRMEPRAPWIEEGPEYWDEETGKVKAHSTDR HVAERAYLEGTCVEWLRRYLENG YAYDGKDYIALKEDLRSWTAADMAAITKRKWEAA DTELVETRP KETLRTDPPKTHMTHHPISDHEATLRCWALGFYPAEITLTWRDGEDT SE IDNOA0G6D2GTFKWAAVVVPSGEERYTCHVHEGLPKPLTLRWEPSSP GSHSMR _ ENLRIAYLFRYYTYANMSSREPAGGRSGHEIPIRFRIMAYVGGCYDVVDGDPTDGFRVLRLFRDGSHDDAASSAPYRDMGEKPDRYAIPAWIEEGPEYWDGETRNMKASATYR RVAELRAYLEGLCVEWLRRYLEVNVGPKSEGTELERRAYDTPCPHK LNEDLSSWTAADTAAITRKWEAA DTELVETRPAGDRTFKWAAV VTHHVETGHLHPPKTPSLDTHLERAWTELPRSCSWASLGFYPAEITLTWRDGEDT SE IDNO063 GSHSMRYFYTAMSRPG _ E RGEPRFIAVGYVDDTFVRFDSDAASPRMEPRAPWIEEGPEYWDGETRNMKASATYR RNVLAREIALLRRAYYYLNEGSLECAVGESWHLIRIRYRLMEYNGGCKDEVTGLPDRGARDLPLPRKGTHHDVTSHAHYPDIGSKDDYIALNEDLSSWTAADTAAITRKWEAA DTELVETRPAGDRTFKWAAVVVPSGEERY FEATLRCWALGFYPAEITLTWRDGEDT SE IDNO064 TCHVHEGLPKPLTLRWEPSSS GESNHLSRMIRAYLFRYYTYANMSSREPAGGRSGHEIPIRF_ RIMAYVGGCYDVVDGDPTDGFRVLRLFRDGSHDDAASSAPYRDMGEKPDRYAIPAWLINEEDELGSPSEWYTWADAGDETTARANMIKTASRAKWTEYR RVAELRAYLEGLCVEWLRRYLENGKETLRADPPKTHVTHHPISDFEATLRCWAL AA DTELVETRPAGDRTFKWAAVVVPSGEERYTCHVHEGLPKP GFYPAEITLTWRDGEDT SE IDNO065 LTLRWEPSSS GESNHLSRMIRAYLFRYYTYANMSSREPAGGRSGHEIPIRF- RIAVG_YVDDTFVRFDSDAASPRMEPRAPWIEEGPEYWDGETRNMKASATYR RVAELRAYLEGLCVEWLRRYLMEYNGGCKDEVTGLPDRGARDLPLPRKGTHHDVTSHAHYPDTGSKDDFYEIAATLLNRECDWLASLSGWFTYAPAADETIATALITRKWEAA DTELVETRPAGDRTFKWAAVVVPSGEERYTCHVHEGLPKPLTLRWEPSS TWRDGEDT Leend: S IBtoalldic––LBnektea-2-microlubulin Underlined–rHLA v RUenduelralrin–edIdGo-tFtced-Sirp-alpha

Claims

1. A fusion protein comprising:a. a B2m (beta 2 microglobulin) polypeptide;a B2m linker peptide;b. an HLA heavy chain polypeptide comprising an HLA oc3 domain;optionally, an Fc polypeptide connected to the HLA heavy chain polypeptide through a peptide linker, particularly a peptide linker having a length of 5 to 25 aa, the optional Fc polypeptide being connected, optionally by a short peptide linker, toc. a polypeptide inhibitor of the interaction between CD47 and Signal-regulatory protein alpha (SIRPa).

2. The fusion protein according to claim 1, wherein the B2m polypeptide consists of a single copy of the B2m sequence and the HLA heavy chain polypeptide consists of an HLA heavy chain comprised of an a1 domain, an a2 domain and an a3 domain,particularly wherein the HLA heavy chain polypeptide consists of an HLA-B*57 heavy chain comprised of an oc1 domain, an oc2 domain and an oc3 domain.

3. The fusion protein according to claim 2, wherein the B2m polypeptide and the HLA heavy chain polypeptide together are characterized by the sequence of SEQ ID NO 017, or a sequence having at least (>)85% identity to SEQ ID NO 017 and at least 75% of the biological function of SEQ ID NO 017.

4. The fusion protein according to claim 1, wherein the B2m polypeptide consists of a single copy of the B2m sequence and the HLA heavy chain polypeptide consists of one, two or three HLA a3 domains,particularly wherein the HLA heavy chain polypeptide consists of one, two or three HLA-B*57 oc3 domains.

5. The fusion protein according to claim 4, wherein the B2m polypeptide and the HLA heavy chain polypeptide together are characterized by the sequence of SEQ ID NO 019, or a sequence having at least (>)85%, particularly >90%, >93%, >96%, >98% identity to SEQ ID NO 019 and at least 75% of the biological function of SEQ ID NO 019.

6. The fusion protein according to claim 1, wherein the B2m polypeptide consists of two copies of the B2m sequence connected by an internal (B2m)2 peptide linker and the HLA heavy chain polypeptide consists of two HLA a3 domains,particularly wherein the HLA heavy chain polypeptide consists of two HLA-B*57 oc3 domains.

7. The fusion protein according to claim 6, wherein said internal (U2m)2 peptide linker is a glycine-serine linker composed of 1 to 30 amino acids,particularly wherein the internal (U2m)2 peptide linker is represented by formula (GGGGS)n (SEQ ID No: 003) wherein n is 1,2, 3, 4, 5.

8. The fusion protein according to claim 6 or 7, wherein the U2m polypeptide and the HLA heavy chain polypeptide together are characterized by the sequence of SEQ ID NO 021, or a sequence having at least (>)85%, particularly >90%, >93%, >96%, >98% identity to SEQ ID NO 021 and at least 75% of the biological function of SEQ ID NO 021.

9. The fusion protein according to the preceding claims 4 to 8, wherein the first oc3 domain and the second oc3 domain are connected by a (oc3)2-peptide linker, wherein said («.3)2-peptide linker is a glycine-serine linker composed of 1 to 30 amino acids and is represented by an n-mer of (GGGGS) (SEQ ID No: 005) wherein n is 1,2, 3, 4, 5.

10. The fusion protein according to any one of the preceding claims, wherein a U2m linker peptide having a length of 1-30 amino acids, particularly of 10 to 20 amino acids, connects the U2m polypeptide to the HLA heavy chain polypeptide.

11. The fusion protein according to any one of the preceding claims 2 to 11, wherein the HLA heavy chain polypeptide is selected from the group consisting of a B*57 polypeptide, a B*58 polypeptide, a B*27 polypeptide, a B*44 polypeptide, a B*81 polypeptide, a C*08 polypeptide, and a C*12 polypeptide.

12. The fusion protein according to any one of the preceding claims 1 , 2, 4, 6, 7, 9 or 10, wherein the HLA heavy chain polypeptide is selected from the group consisting of an HLA-A*11 polypeptide, an A*24 polypeptide, an A*25 polypeptide, an A*45 polypeptide, a B*78 polypeptide, a B*81 polypeptide, a C*06 polypeptide, and a C*12 polypeptide.

13. The fusion protein according to any one of the preceding claims 1 to 11, wherein the HLA heavy chain polypeptide is a B*57 polypeptide.

14. The fusion protein according to anyone of the claims 8 to 12, wherein the HLA heavy chain polypeptide comprises one or more mutations, relative to the B*57 sequence of SEQ ID NO 006, selected from positions- 7,46,97,143,194,197.

15. The fusion protein according to any one of the claims 8 to 12, wherein the HLA heavy chain polypeptide comprises the mutations, relative to the B*57 sequence of SEQ ID NO 006, of A46E and V97R.

16. The fusion protein according to any one of the claims 8 to 12, wherein the HLA heavy chain polypeptide comprises the mutations, relative to the B*57 sequence of SEQ ID NO 006, of A46E, V97R and I194T.

17. The fusion protein according to any one of the claims 8 to 12, wherein the HLA heavy chain polypeptide comprises the mutations, relative to the B*57 sequence of SEQ ID NO 006, of A46E, V97R, and H197F.

18. The fusion protein according to any one of the claims 8 to 12, wherein the HLA heavy chain polypeptide comprises the mutations, relative to the B*57 sequence of SEQ ID NO 006, of A46E, V97R, I194T, and H197F.

19. The fusion protein according to any one of the claims 1-4, 7, or 10-18, wherein the HLA heavy chain polypeptide comprises, or consists of a polypeptide selected from SEQ ID NO 007, 061, 62, 63, and 64.

20. The fusion protein according to any one of the preceding claims, wherein the polypeptide inhibitor of the interaction between CD47 and SIRPoc is a SIRP a extracellular domain polypeptide.

21. The fusion protein according to any one of the preceding claims, wherein the polypeptide inhibitor of the interaction between CD47 and SIRPoc is characterized by a sequence selected from the group of: SEQ ID NO 011, 012, 013, 014, 015, 016, particularly SEQ ID NO 014.

22. The fusion protein according to claim 15 or 16, wherein the fusion protein comprises an Fc polypeptide, and a SIRPoc linker peptide having a length of 10 to 20 amino acids, particularly 10 to 15 amino acids connecting the Fc polypeptide to the polypeptide inhibitor of the interaction between CD47 and SIRPoc.

23. The fusion protein according to any one of the preceding claims, wherein the fusion protein comprises, or consists of, from N to C terminus, of the U2m polypeptide, the U2m linker peptide, the HLA heavy chain polypeptide, an IgG fragment crystallizable (Fc) region of an immunoglobulin heavy chain fragment polypeptide, SIRPoc linker peptide, and the polypeptide inhibitor of the interaction between CD47 and SIRPoc.

24. The fusion protein according to any one of the preceding claims, wherein the fusion protein consists, from N to C terminus, of U2m polypeptide, the HLA heavy chain polypeptide, an IgG fragment crystallizable (Fc) region of an immunoglobulin heavy chain fragment polypeptide, and the polypeptide inhibitor of the interaction between CD47 and SIRPoc.

25. A dimeric protein comprising a fusion protein specified in any one of the proceeding claims, wherein the fusion protein comprises an Fc region of human immunoglobulin G (IgG).

26. The dimeric protein according to claim 25, wherein the Fc region is characterized by SEQ ID NO 009 or 010, or a sequence at least 95% identical to SEQ ID NO 009 or 010.

27. The dimeric protein according to any one of the preceding claims 25 or 26, wherein both polypeptide chains are characterized by the same amino acid sequence.

28. The dimeric protein according to the preceding claims 25 or 26, wherein the two polypeptide chains are characterized by a different amino acid sequence.

29. A nucleic acid encoding a fusion protein or dimeric protein as specified in any one of claims 1 to 28.

30. A pharmaceutical composition comprising a fusion protein according to any one of claims 1 to 24, or a dimeric protein according to any one of claims 25 to 28, and a pharmaceutically acceptable excipient.

31. A fusion protein according to any one of claims 1 to 24, or a dimeric protein according to any one of claims 25 to 28, for use in in medicine.

32. A pharmaceutical composition according to claim 30, a fusion protein according to any one of claims 1 to 24, or a dimeric protein according to any one of claims 25 to 28, for use in treatment or prevention of cancer.

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