Methods of identifying t cell receptors

Abstract

To provide methods of identifying T cell receptors.SOLUTION: The present disclosure is directed to methods of identifying MHC class II-specific T cell receptors (TCRs). In certain aspects, the method comprises contacting a T cell with a complex comprising (i) an MHC class II molecule having a higher affinity for CD4 than naturally occurring MHC class II molecules and (ii) a peptide, e.g., an epitope. In certain aspects, the HLA class II molecule comprises a beta chain having one or more mutations relative to a wild-type beta chain sequence.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This PCT application claims the benefit of U.S. Provisional Patent Application No. 62 / 880,492, filed July 30, 2019, and U.S. Provisional Patent Application No. 63 / 029,103, filed May 22, 2020, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Reference to sequence listings submitted electronically via EFS-WEB The contents of the electronically submitted Sequence Listing (Name: 4285.009PC02_SL_ST25.txt, Size: 291,794 bytes; and Created: July 28, 2020) are incorporated herein by reference in their entirety.

[0003] The present disclosure provides methods for identifying MHC class II-specific T cell receptors ("TCRs"). [Background technology]

[0004] Immunotherapy has emerged as an important tool in the fight against various diseases, including cancer. T cell therapy is at the forefront of immunotherapy development, and adoptive transfer of antitumor T cells has been shown to induce clinical responses in cancer patients. Many T cell therapies target mutated tumor antigens, but the majority of neoantigens are disparate and unique to each patient.

[0005] Potential non-mutated antigens outnumber mutated antigens by several orders of magnitude. Elucidation of T cell epitopes derived from common antigens could facilitate robust advances in effective and safe adoptive T cell therapy that can be readily applied to larger cohorts of cancer patients. However, the sheer number of non-mutated antigens and the high polymorphism of HLA genes may hinder comprehensive analysis of the specificity of antitumor T cell responses to non-mutated antigens. Summary of the Invention [Means for solving the problem]

[0006] Certain aspects of the present disclosure relate to methods for identifying an MHC class II-specific T cell receptor (TCR), the method comprising contacting a T cell with a complex comprising an MHC class II molecule and a peptide, wherein the T cell expresses CD4 and one or more TCRs, the MHC class II molecule comprises an alpha chain and a beta chain, the MHC class II molecule has a higher affinity for CD4 than naturally occurring MHC class II molecules have for CD4, and the MHC class II-specific TCR specifically binds to the complex comprising the MHC class II molecule and the peptide.

[0007] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid sequence having one or more mutations compared to the wild-type beta chain of the MHC class II molecule. In some embodiments, the alpha chain of the MHC class II molecule comprises an amino acid sequence having one or more mutations compared to the wild-type alpha chain of the MHC class II molecule. In some embodiments, the one or more mutations comprise substitution mutations.

[0008] In some embodiments, the MHC class II molecule is an HLA-DP, HLA-DQ, or HLA-DR allele, or any combination thereof. In some embodiments, (i) the beta chain of the HLA class II molecule is an HLA-DP allele, (ii) the alpha chain of the HLA class II molecule is an HLA-DP allele, or (iii) both (i) and (ii). In some embodiments, the beta chain of the HLA class II molecule is a DP1, DP2, DP3, DP4, DP5, DP6, DP8, or DP9 allele.

[0009] In some embodiments, the beta chain of the MHC class II molecule is selected from the group consisting of DPB1*01, DPB1*02, DPB1*03, DPB1*04, DPB1*05, DPB1*06, DPB1*08, DPB1*09, DPB1*10, DPB1*100, DPB1*101, DPB1*102, DPB1*103, DPB1*104, DPB1*105, DPB1*106, DPB1*107, DPB1*108, DPB1*109, DPB1*110, DPB1*111, DPB1*112, DPB1*113, DPB1*114, DPB1*115, DPB1*116, DPB1*117, DPB1*118, DPB1*119, DPB1*120, DPB1*210, DPB1*211, DPB1*212, DPB1*213, DPB1*214, DPB1*215, DPB1*216, DPB1*217, DPB1*218, DPB1*219, DPB1*220, DPB1*221, DPB1*222, DPB1*223, DPB1*224, DPB1*225, DPB1*226, DPB1*227, DPB1*228, DPB1*229, DPB1*230, DPB1*231, DPB1*232, DPB1*233, DPB1*234, DPB1*235, DPB1*236, DPB1*237, DPB1*238, DPB1*239, DPB1*240, DPB1*241, DPB 1*116, DPB1*117, DPB1*118, DPB1*119, DPB1*11, DPB1*120, DPB1*121, DPB1*122, DPB1*123, DPB1*124, DPB1*125, DPB1*126, DPB1*127, DPB1*128, DP B1*129, DPB1*130, DPB1*131, DPB1*132, DPB1*133, DPB1*134, DPB1*135, DPB1*136, DPB1*137, DPB1*138, DPB1*139, DPB1*13, DPB1*140, DPB1*141, DP B1*142, DPB1*143, DPB1*144, DPB1*145, DPB1*146, DPB1*147, DPB1*148, DPB1*149, DPB1*14, DPB1*150, DPB1*151, DPB1*152, DPB1*153, DPB1*154, D PB1*155, DPB1*156, DPB1*157, DPB1*158, DPB1*159, DPB1*15, DPB1*160, DPB1*161, DPB1*162, DPB1*163, DPB1*164, DPB1*165, DPB1*166, DPB1*167, DPB1*168, DPB1*169, DPB1*16, DPB1*170, DPB1*171, DPB1*172, DPB1*173, DPB1*174, DPB1*175, DPB1*176, DPB1*177, DPB1*178, DPB1*179, DPB1*17, DPB1*180, DPB1*181, DPB1*182, DPB1*183, DPB1*184, DPB1*185, DPB1*186, DPB1*187, DPB1*188, DPB1*189, DPB1*18, DPB1*190, DPB1*191, DPB1*192,DPB1*193、DPB1*194、DPB1*195、DPB1*196、DPB1*197、DPB1*198、DPB1*199、DPB1*19、DPB1*200、DPB1*201、DPB1*202、DPB1*203、DPB1*204、DPB1*205、DPB1*206、DPB1*207、DPB1*208、DPB1*209、DPB1*20、DPB1*210、DPB1*211、DPB1*212、DPB1*213、DPB1*214、DPB1*215、DPB1*216、DPB1*217、DPB1*218、DPB1*219、DPB1*21、DPB1*220、DPB1*221、DPB1*222、DPB1*223、DPB1*224、DPB1*225、DPB1*226、DPB1*227、DPB1*228、DPB1*229、DPB1*22、DPB1*230、DPB1*231、DPB1*232、DPB1*233、DPB1*234、DPB1*235、DPB1*236、DPB1*237、DPB1*238、DPB1*239、DPB1*23、DPB1*240、DPB1*241、DPB1*242、DPB1*243、DPB1*244、DPB1*245、DPB1*246、DPB1*247、DPB1*248、DPB1*249、DPB1*24、DPB1*250、DPB1*251、DPB1*252、DPB1*253、DPB1*254、DPB1*255、DPB1*256、DPB1*257、DPB1*258、DPB1*259、DPB1*25、DPB1*260、DPB1*261、DPB1*262、DPB1*263、DPB1*264、DPB1*265、DPB1*266、DPB1*267、DPB1*268、DPB1*269、DPB1*26、DPB1*270、DPB1*271、DPB1*272、DPB1*273、DPB1*274、DPB1*275、DPB1*276、DPB1*277、DPB1*278、DPB1*279、DPB1*27、DPB1*280、DPB1*281、DPB1*282、DPB1*283、DPB1*284、DPB1*285、DPB1*286、DPB1*287、DPB1*288、DPB1*289、DPB1*28、DPB1*290、DPB1*291、DPB1*292、DPB1*293、DPB1*294、DPB1*295、DPB1*296、DPB1*297、DPB1*298、DPB1*299、DPB1*29、DPB1*300、DPB1*301、DPB1*302、DPB1*303、DPB1*304、DPB1*305、DPB1*306、DPB1*307、DPB1*308、DPB1*309、DPB1*30、DPB1*310、DPB1*311、DPB1*312、DPB1*313、DPB1*314、DPB1*315、DPB1*316、DPB1*317、DPB1*318、DPB1*319、DPB1*31、DPB1*320、DPB1*321、DPB1*322、DPB1*323、DPB1*324、DPB1*325、DPB1*326、DPB1*327、DPB1*328、DPB1*329、DPB1*32、DPB1*330、DPB1*331、DPB1*332、DPB1*333、DPB1*334、DPB1*335、DPB1*336、DPB1*337、DPB1*338、DPB1*339、DPB1*33、DPB1*340、DPB1*341、DPB1*342、DPB1*343、DPB1*344、DPB1*345、DPB1*346、DPB1*347、DPB1*348、DPB1*349、DPB1*34、DPB1*350、DPB1*351、DPB1*352、DPB1*353、DPB1*354、DPB1*355、DPB1*356、DPB1*357、DPB1*358、DPB1*359、DPB1*35、DPB1*360、DPB1*361、DPB1*362、DPB1*363、DPB1*364、DPB1*365、DPB1*366、DPB1*367、DPB1*368、DPB1*369、DPB1*36、DPB1*370、DPB1*371、DPB1*372、DPB1*373、DPB1*374、DPB1*375、DPB1*376、DPB1*377、DPB1*378、DPB1*379、DPB1*37、DPB1*380、DPB1*381、DPB1*382、DPB1*383、DPB1*384、DPB1*385、DPB1*386、DPB1*387、DPB1*388、DPB1*389、DPB1*38、DPB1*390、DPB1*391、DPB1*392、DPB1*393、DPB1*394、DPB1*395、DPB1*396、DPB1*397、DPB1*398、DPB1*399、DPB1*39、DPB1*400、DPB1*401、DPB1*402、DPB1*403、DPB1*404、DPB1*405、DPB1*406、DPB1*407、DPB1*408、DPB1*409、DPB1*40、DPB1*410、DPB1*411、DPB1*412、DPB1*413、DPB1*414、DPB1*415、DPB1*416、DPB1*417、DPB1*418、DPB1*419、DPB1*41、DPB1*420、DPB1*421、DPB1*422、DPB1*423、DPB1*424、DPB1*425、DPB1*426、DPB1*427、DPB1*428、DPB1*429、DPB1*430、DPB1*431、DPB1*432、DPB1*433、DPB1*434、DPB1*435、DPB1*436、DPB1*437、DPB1*438、DPB1*439、DPB1*440、DPB1*441、DPB1*442、DPB1*443、DPB1*444、DPB1*445、DPB1*446、DPB1*447、DPB1*448、DPB1*449、DPB1*44、DPB1*450、DPB1*451、DPB1*452、DPB1*453、DPB1*454、DPB1*455、DPB1*456、DPB1*457、DPB1*458、DPB1*459、DPB1*45、DPB1*460、DPB1*461、DPB1*462、DPB1*463、DPB1*464、DPB1*465、DPB1*466、DPB1*467、DPB1*468、DPB1*469、DPB1*46、DPB1*470、DPB1*471、DPB1*472、DPB1*473、DPB1*474、DPB1*475、DPB1*476、DPB1*477、DPB1*478、DPB1*479、DPB1*47、DPB1*480、DPB1*481、DPB1*482、DPB1*483、DPB1*484、DPB1*485、DPB1*486、DPB1*487、DPB1*488、DPB1*489、DPB1*48、DPB1*490、DPB1*491、DPB1*492、DPB1*493、DPB1*494、DPB1*495、DPB1*496、DPB1*497、DPB1*498、DPB1*499、DPB1*49、DPB1*500、DPB1*501、DPB1*502、DPB1*503、DPB1*504、DPB1*505、DPB1*506、DPB1*507、DPB1*508、DPB1*509、DPB1*50、DPB1*510、DPB1*511、DPB1*512、DPB1*513、DPB1*514、DPB1*515、DPB1*516、DPB1*517、DPB1*518、DPB1*519、DPB1*51、DPB1*520、DPB1*521、DPB1*522、DPB1*523、DPB1*524、DPB1*525、DPB1*526、DPB1*527、DPB1*528、DPB1*529、DPB1*52、DPB1*530、DPB1*531、DPB1*532、DPB1*533、DPB1*534、DPB1*535、DPB1*536、DPB1*537、DPB1*538、DPB1*539、DPB1*53、DPB1*540、DPB1*541、DPB1*542、DPB1*543、DPB1*544、DPB1*545、DPB1*546、DPB1*547、DPB1*548、DPB1*549、DPB1*54、DPB1*550、DPB1*551、DPB1*552、DPB1*553、DPB1*554、DPB1*555、DPB1*556、DPB1*557、DPB1*558、DPB1*559、DPB1*55、DPB1*560、DPB1*561、DPB1*562、DPB1*563、DPB1*564、DPB1*565、DPB1*566、DPB1*567、DPB1*568、DPB1*569、DPB1*56、DPB1*570、DPB1*571、DPB1*572、DPB1*573、DPB1*574、DPB1*575、DPB1*576、DPB1*577、DPB1*578、DPB1*579、DPB1*57、DPB1*580、DPB1*581、DPB1*582、DPB1*583、DPB1*584、DPB1*585、DPB1*586、DPB1*587、DPB1*588、DPB1*589、DPB1*58、DPB1*590、DPB1*591、DPB1*592、DPB1*593、DPB1*594、DPB1*595、DPB1*596、DPB1*597、DPB1*598、DPB1*599、DPB1*59、DPB1*600、DPB1*601、DPB1*602、DPB1*603、DPB1*604、DPB1*605、DPB1*606、DPB1*607、DPB1*608、DPB1*609、DPB1*60、DPB1*610、DPB1*611、DPB1*612、DPB1*613、DPB1*614、DPB1*615、 、DPB1*616、DPB1*617、DPB1*618、DPB1*619、DPB1*61、DPB1*620、DPB1*621、DPB1*622、DPB1*623、DPB1*624、DPB1*625、DPB1*626、DPB1*627、DPB1*628、DPB1*629、DPB1*62、DPB1*630、DPB1*631、DPB1*632、DPB1*633、DPB1*634、DPB1*635、DPB1*636、DPB1*637、DPB1*638、DPB1*639、DPB1*63、DPB1*640、DPB1*641、DPB1*642、DPB1*643、DPB1*644、DPB1*645、DPB1*646、DPB1*647、DPB1*648、DPB1*649、DPB1*64、DPB1*650、DPB1*651、DPB1*652、DPB1*653、DPB1*654、DPB1*655、DPB1*656、DPB1*657、DPB1*658、DPB1*659、DPB1*65、DPB1*660、DPB1*661、DPB1*662、DPB1*663、DPB1*664、DPB1*665、DPB1*666、DPB1*667、DPB1*668、DPB1*669、DPB1*66、DPB1*670、DPB1*671、DPB1*672、DPB1*673、DPB1*674、DPB1*675、DPB1*676、DPB1*677、DPB1*678、DPB1*679、DPB1*67、DPB1*680、DPB1*681、DPB1*682、DPB1*683、DPB1*684、DPB1*685、DPB1*686、DPB1*687、DPB1*688、DPB1*689、DPB1*68、DPB1*690、DPB1*691、DPB1*692、DPB1*693、DPB1*694、DPB1*695、DPB1*696、DPB1*697、DPB1*698、DPB1*699、DPB1*69、DPB1*700、DPB1*701、DPB1*702、DPB1*703、DPB1*704、DPB1*705、DPB1*706、DPB1*707、DPB1*708、DPB1*709、DPB1*70、DPB1*710、DPB1*711、DPB1*712、DPB1*713、DPB1*714、DPB1*715、DPB1*716、DPB1*717、DPB1*718、DPB1*719、DPB1*71、DPB1*720、DPB1*721、DPB1*722、DPB1*723、DPB1*724、DPB1*725、DPB1*726、DPB1*727、DPB1*728、DPB1*729、DPB1*72、DPB1*730、DPB1*731、DPB1*732、DPB1*733、DPB1*734、DPB1*735、DPB1*736、DPB1*737、DPB1*738、DPB1*739、DPB1*73、DPB1*740、DPB1*741、DPB1*742、DPB1*743、DPB1*744、DPB1*745、DPB1*746、DPB1*747、DPB1*748、DPB1*749、DPB1*74、DPB1*750、DPB1*751、DPB1*752、DPB1*753、DPB1*754、DPB1*755、DPB1*756、DPB1*757、DPB1*758、DPB1*759、DPB1*75、DPB1*760、DPB1*761、DPB1*762、DPB1*763、DPB1*764、DPB1*765、DPB1*766、DPB1*767、DPB1*768、DPB1*769、DPB1*76、DPB1*770、DPB1*771、DPB1*772、DPB1*773、DPB1*774、DPB1*775、DPB1*776、DPB1*777、DPB1*778、DPB1*779、DPB1*77、DPB1*780、DPB1*781、DPB1*782、DPB1*783、DPB1*784、DPB1*785、DPB1*786、DPB1*787、DPB1*788、DPB1*789、DPB1*78、DPB1*790、DPB1*791、DPB1*792、DPB1*794、DPB1*795、DPB1*796、DPB1*797、DPB1*798、DPB1*799、DPB1*79、DPB1*800、DPB1*801、DPB1*802、DPB1*803、DPB1*804、DPB1*805、DPB1*806、DPB1*807、DPB1*808、DPB1*809、DPB1*80、DPB1*810、DPB1*811、DPB1*812、DPB1*813、DPB1*814、DPB1*815、DPB1*816、DPB1*817、DPB1*818、DPB1*819、DPB1*81、DPB1*820、DPB1*821、DPB1*822、DPB1*823、DPB1*824、DPB1*825、DPB1*826、DPB1*827、DPB1*828、DPB1*829、DPB1*82、DPB1*830、DPB1*831、DPB1*832、DPB1*833、DPB1*834、DPB1*835、DPB1*836、DPB1*837、DPB1*838、DPB1*839、DPB1*83、DPB1*840、DPB1*841、DPB1*842、DPB1*843、DPB1*844、DPB1*845、DPB1*846、DPB1*847、DPB1*848、DPB1*849、DPB1*84、DPB1*850、DPB1*851、DPB1*852、DPB1*853、DPB1*854、DPB1*855、DPB1*856、DPB1*857、DPB1*858、DPB1*859、DPB1*85、DPB1*860、DPB1*861、DPB1*862、DPB1*863、DPB1*864、DPB1*865、DPB1*866、DPB1*867、DPB1*868、DPB1*869、DPB1*86、DPB1*870、DPB1*871、DPB1*872、DPB1*873、DPB1*874、DPB1*875、DPB1*876、DPB1*877、DPB1*878、DPB1*879、DPB1*87、DPB1*880、DPB1*881、DPB1*882、DPB1*883、DPB1*884、DPB1*885、DPB1*886、DPB1*887、DPB1*888、DPB1*889、DPB1*88、DPB1*890、DPB1*891、DPB1*892、DPB1*893、DPB1*894、DPB1*895、DPB1*896、DPB1*897、DPB1*898、DPB1*899、DPB1*89、DPB1*900、DPB1*901、DPB1*902、DPB1*903、DPB1*904、DPB1*905、DPB1*906、DPB1*907、DPB1*908、DPB1*909、DPB1*90、DPB1*910、DPB1*911、DPB1*912、DPB1*913、DPB1*914、DPB1*915、DPB1*916、DPB1*917、DPB1*918、DPB1*919、DPB1*91、DPB1*920、DPB1*921、DPB1*922, DPB1*923, DPB1*924, DPB1*925, DPB1*926, DPB1*927, DPB1*928, DPB1*929, DPB1*92, DPB1*930, DPB1*931, DPB1*932, DPB1*933, DPB1*9 34, DPB1*935, DPB1*936, DPB1*937, DPB1*938, DPB1*939, DPB1*93, DPB1*940, DPB1*941, DPB1*942, DPB1*943, DPB1*944, DPB1*945, DPB1*946, DPB1 *947, DPB1*948, DPB1*949, DPB1*94, DPB1*950, DPB1*951, DPB1*952, DPB1*953, DPB1*954, DPB1*955, DPB1*956, DPB1*957, DPB1*958, DPB1*959, DPB1*95, DPB1*960, DPB1*961, DPB1*962, DPB1*963, DPB1*964, DPB1*965, DPB1*96, DPB1*97, DPB1*98, and DPB1*99 alleles.

[0010] In some embodiments, the alpha chain of the MHC class II molecule comprises an HLA-DPA1*01, HLA-DPA1*02, HLA-DPA1*03, or HLA-DPA1*04 allele.

[0011] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1. In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1.

[0012] Certain aspects of the present disclosure relate to methods for identifying an MHC class II-specific T cell receptor (TCR), the method comprising contacting a T cell with a complex comprising an MHC class II molecule and a peptide, wherein the T cell expresses CD4 and one or more TCRs, the MHC class II molecule comprises an alpha chain and a beta chain, and the beta chain of the MHC class II molecule comprises (i) an amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO:1, (ii) an amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO:1, or (iii) both (i) and (ii), and the MHC class II-specific TCR specifically binds to the complex comprising the MHC class II molecule and the peptide.

[0013] In some embodiments, the MHC class II molecule has a higher affinity for CD4 than naturally occurring MHC class II molecules have for CD4.

[0014] In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 comprises a hydrophobic side chain. In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is selected from the group consisting of alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan. In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is tryptophan.

[0015] In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 comprises a hydrophobic side chain. In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is methionine.

[0016] In some embodiments, (i) the beta chain of the HLA class II molecule is an HLA-DQ allele, (ii) the alpha chain of the HLA class II molecule is an HLA-DQ allele, or (iii) both (i) and (ii). In some embodiments, the beta chain of the HLA class II molecule comprises a DQ2, DQ3, DQ4, DQ5, or DQ6 allele. In some embodiments, the beta chain of the MHC class II molecule comprises an HLA-DQB1*02, HLA-DQB1*03, HLA-DQB1*04, HLA-DQB1*05, or HLA-DQB1*06 allele. In some embodiments, the alpha chain of the MHC class II molecule comprises an HLA-DQA1*01, HLA-DQA1*02, HLA-DQA1*03, HLA-DQA1*04, HLA-DQA1*05, or HLA-DQA1*06 allele.

[0017] In some embodiments, the beta chain of the MHC class II molecule comprises at least three of: (a) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:11; (b) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:11; and (c) (i) an amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO:11; (ii) an amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO:11; (iii) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:11; and (iv) an amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO:11.

[0018] In some embodiments, the beta chain of the MHC class II molecule comprises (a) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:11, (b) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:11, (c) an amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO:11, (d) an amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO:11, (e) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:11, and (f) an amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO:11.

[0019] In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 comprises a hydrophobic side chain. In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is selected from the group consisting of alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan. In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is tryptophan.

[0020] In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 comprises a hydrophobic side chain. In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is methionine.

[0021] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11. In some embodiments, the amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11 is selected from serine, threonine, and glutamine. In some embodiments, the amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11 is glutamine.

[0022] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11. In some embodiments, the amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 is selected from alanine, valine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In some embodiments, the amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 is valine.

[0023] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11. In some embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11 is selected from arginine, histidine, and lysine. In some embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11 is histidine.

[0024] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11. In some embodiments, the non-proline amino acid at the amino acid residue corresponding to position 146 of SEQ ID NO: 11 is selected from serine, threonine, asparagine, and glutamine. In some embodiments, the non-proline amino acid at the amino acid residue corresponding to position 146 of SEQ ID NO: 11 is glutamine.

[0025] In some embodiments, (i) the beta chain of the HLA class II molecule is an HLA-DR allele, (ii) the alpha chain of the HLA class II molecule is an HLA-DR allele, or (iii) both (i) and (ii).

[0026] In some embodiments, the beta chain of the HLA class II molecule comprises a DR2, DR3, DR4, DR5, DR6, DR7, DR8, DR9, DR10, DR11, DR12, DR13, DR14, DR15, or DR16 allele. In some embodiments, the beta chain of the MHC class II molecule comprises an HLA allele selected from the group consisting of DRB1*01, DRB1*03, DRB1*04, DRB1*07, DRB1*08, DRB1*09, DRB1*10, DRB1*11, DRB1*12, DRB1*13, DRB1*14, DRB1*15, and DRB1*16. In some embodiments, the alpha chain of the MHC class II molecule comprises an HLA-DRA1*01 allele.

[0027] In some embodiments, the beta chain comprises at least two of: (a) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19; (b) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19; and (c) (i) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19; (ii) an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO:19; (iii) an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO:19; (iv) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19; (v) an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO:19; and (vi) an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO:19.

[0028] In some embodiments, the beta chain comprises at least three of: (i) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19; (ii) an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO:19; (iii) an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO:19; (iv) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19; (v) an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO:19; and (vi) an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO:19.

[0029] In some embodiments, the beta chain comprises at least four of (c) (i) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19, (ii) an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO:19, (iii) an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO:19, (iv) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19, (v) an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO:19, and (vi) an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO:19.

[0030] In some embodiments, the beta chain comprises (a) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19, (b) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19, (c) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19, and (d) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19.

[0031] In some embodiments, the beta chain comprises (a) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19, (b) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19, (c) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19, (d) an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO:19, (e) an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO:19, (f) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19, (g) an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO:19, and (h) an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO:19.

[0032] In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 comprises a hydrophobic side chain. In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is selected from the group consisting of alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan. In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is tryptophan.

[0033] In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 comprises a hydrophobic side chain. In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is methionine.

[0034] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19. In some embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19 is selected from arginine, histidine, and lysine. In some embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19 is histidine.

[0035] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO: 19. In some embodiments, the non-lysine amino acid at the amino acid residue corresponding to position 139 of SEQ ID NO: 19 is selected from serine, threonine, and glutamine. In some embodiments, the non-lysine amino acid at the amino acid residue corresponding to position 139 of SEQ ID NO: 19 is threonine.

[0036] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19. In some embodiments, the amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19 is selected from serine, asparagine, threonine, and glutamine. In some embodiments, the amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19 is glutamine.

[0037] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19. In some embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is selected from alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In some embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is isoleucine.

[0038] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19. In some embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 is selected from alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In some embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 is methionine.

[0039] In some embodiments, the beta chain of the MHC class II molecule comprises an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19. In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19 is selected from serine, asparagine, threonine, and glutamine. In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19 is threonine.

[0040] In some embodiments, the beta chain comprises (a) a tryptophan at the amino acid residue corresponding to position 114 of SEQ ID NO:19, (b) a methionine at the amino acid residue corresponding to position 143 of SEQ ID NO:19, (c) a histidine at the amino acid residue corresponding to position 118 of SEQ ID NO:19, and (d) an isoleucine at the amino acid residue corresponding to position 157 of SEQ ID NO:19.

[0041] In some embodiments, a naturally occurring MHC class II molecule comprises (a) a leucine at the amino acid residue corresponding to position 112 of SEQ ID NO:1 or at the amino acid residue corresponding to position 114 of SEQ ID NO:11 or 19, (b) a valine at the amino acid residue corresponding to position 141 of SEQ ID NO:1 or at the amino acid residue corresponding to position 143 of SEQ ID NO:11 or 19, or (c) both (a) and (b).

[0042] In some embodiments, a naturally occurring MHC class II molecule contains (a) a leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 or the amino acid residue corresponding to position 114 of SEQ ID NO: 11 or 19, (b) a valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 or the amino acid residue corresponding to position 143 of SEQ ID NO: 11 or 19, (c) an asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11, (d) an isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11, or (e) a valine at the amino acid residue corresponding to position 148 of SEQ ID NO: 11 or 19, (f) a serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11; (f) a proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11; (g) a lysine at the amino acid residue corresponding to position 139 of SEQ ID NO: 19; (h) a glycine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19; (i) a threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19; (j) a threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19; (k) a valine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19; or (l) any combination of (a) to (k).

[0043] In some embodiments, the MHC class II molecule is a dimer. In some embodiments, the MHC class II molecule is a trimer. In some embodiments, the MHC class II molecule is a tetramer. In some embodiments, the peptide comprises a fragment of a protein. In some embodiments, the protein is expressed in a diseased cell. In some embodiments, the protein is expressed in a tumor cell.

[0044] In some embodiments, the peptide comprises at least about 10 amino acids. In some embodiments, the peptide comprises about 10 to about 100 amino acids, about 10 to about 90 amino acids, about 10 to about 80 amino acids, about 10 to about 70 amino acids, about 10 to about 60 amino acids, about 10 to about 50 amino acids, about 10 to about 40 amino acids, about 10 to about 30 amino acids, about 10 to about 25 amino acids, about 10 to about 20 amino acids, about 10 to about 15 amino acids, about 15 to about 100 amino acids, 20 to about 100 amino acids, 25 to about 100 amino acids, 30 to about 100 amino acids, 35 to about 100 amino acids, 40 to about 100 amino acids, 50 to about 100 amino acids, 60 to about 100 amino acids, 70 to about 100 amino acids, 80 to about 100 amino acids, or 90 to about 100 amino acids.

[0045] In some embodiments, the peptide comprises about 10 amino acids, about 11 amino acids, about 12 amino acids, about 13 amino acids, about 14 amino acids, about 15 amino acids, about 16 amino acids, about 17 amino acids, about 18 amino acids, about 19 amino acids, about 20 amino acids, about 25 amino acids, including about 30 amino acids, about 35 amino acids, about 40 amino acids, about 45 amino acids, about 50 amino acids, about 55 amino acids, about 60 amino acids, about 65 amino acids, about 70 amino acids, about 75 amino acids, about 80 amino acids, about 85 amino acids, about 90 amino acids, about 95 amino acids, or about 100 amino acids.

[0046] In some embodiments, the MHC class II molecule is expressed on the surface of an antigen-presenting cell.

[0047] In some embodiments, the T cells are obtained from a human subject. In some embodiments, the T cells are tumor-infiltrating lymphocytes (TILs).

[0048] In some embodiments, the MHC class II molecule has an affinity for CD4 that is at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold, at least about 60-fold, at least about 70-fold, at least about 80-fold, at least about 90-fold, at least about 100-fold, at least about 200-fold, at least about 300-fold, at least about 400-fold, at least about 500-fold, or at least about 100-fold greater than the binding affinity of naturally occurring MHC class II molecules for CD4.

[0049] In some embodiments, the method further comprises selecting T cells bound by the MHC class II molecule. In some embodiments, the method further comprises isolating a TCR bound to the MHC class II molecule. In some embodiments, the method further comprises sequencing the TCR. In some embodiments, the method further comprises cloning the TCR. In some embodiments, the method further comprises recombinantly expressing the TCR in a host cell.

[0050] In some embodiments, the MHC class II molecule has a K of less than about 100 μM, less than about 50 μM, less than about 20 μM, or less than about 10 μM. D In some embodiments, the MHC class II molecule binds to CD4 with a K of about 14 μM or less. D In some embodiments, the MHC class II molecule binds to CD4 with a K of about 8.9 μM or less. D It binds to CD4. [Brief explanation of the drawings]

[0051] [Figures 1A-1F][Figures 1A-1F] Graphical representation of data demonstrating that affinity-matured DP4L112W / V141M molecules exhibit enhanced CD4-binding ability. Histograms showing the results of staining with anti-class II mAb and soluble CD4 (sCD4) in HLA class II-null K562 cells stably expressing the wild-type DP α chain (DPA1*01:03) transduced with blank, wild-type, or mutant DP β chain (DPB1*04:01) with L112W, V114M, V141M, and M158I substitutions (DP4L112W / V114M / V141M / M158I). [Figure 1G] [Figure 1G] Graphical representation of data showing that affinity-matured DP4L112W / V141M molecules exhibit enhanced CD4-binding ability. A bar graph summarizing the binding affinity to sCD4 (MFI; Y axis) of all possible DP4 revertants expressed as in Figures 1A-1F and stained with sCD4. [Figure 1H] [Figure 1H] Graphical representation of data showing that affinity-matured DP4L112W / V141M molecules exhibit enhanced CD4 binding ability. The affinity between DP4L112W / V141M and CD4, as quantified by steady-state analysis, is shown. [Figure 1I] [Figure 1I] Graphical representation of data demonstrating that affinity-matured DP4L112W / V141M molecules exhibit enhanced CD4-binding ability. IL-2 ELISPOT assay results of DP4 / WT1 TCR·clone 9-transduced Jurkat76 and Jurkat76 / CD4 cells stimulated with wild-type DP4-expressing aAPCs or DP4L112W / V141M-expressing aAPCs pulsed with gradient concentrations of DP4 / WT1 peptide are shown. [Figure 1J-1W][Figures 1J-1W] Graphical representation of data demonstrating that affinity-matured DP4L112W / V141M molecules exhibit enhanced CD4-binding ability. Histograms depicting staining of K562 cells expressing the DPL112W / V141M allele (as indicated) with anti-class II mAb and sCD4. Open histograms represent substandard control staining. *, P value less than 0.05 by Student's t-test. Bars and error bars represent the mean ± SD of the results of three experiments. At least two independent experiments were performed. [Figure 1X-1AA] [Figures 1X-1AA] Histograms showing wild-type DP4 and DP4L112W / V141M molecules on the surface of K562 cells, detected with the indicated anti-HLA class II antibodies. Staining of control cells lacking class II expression is shown in gray. [Figures 1AB-1BH] [FIGS. 1AB-1BH] Histograms showing the indicated DP4-expressing aAPCs or parental class II cells stained with the indicated concentrations of sCD4. [Figure 1BI] [Figure 1B1] Quantification of aAPCs expressing wild-type DP4 or DP4L112W / V141M at the indicated concentrations. Error bars represent the mean ± standard deviation of triplicate experiments. Experiments in Figures 1BJ and 1B1 were performed in parallel. [Figure 1BJ] [Figure 1BJ] Biolayer interferometry sensorgrams showing the interaction of biotinylated wild-type DP4 (ligand) with sCD4 (analyte) over a range of concentrations. The experiments in Figures 1BJ and 1BI were performed in parallel. [Figure 1BK] [Figure 1BK] Biolayer interferometry sensorgrams showing the interaction of biotinylated DP4L112W / V141M (ligand) with sCD4 (analyte) over a range of concentrations. All data are representative of two independent experiments. [Figure 2A-2B][Figures 2A-2B] Ribbon diagrams of the model structure of the DP4L112W / V141M and human CD4 complex. Two configurations of the model structure of the ternary complex of DPA1*01:03, DPB1*04:01, and CD4 are shown. The area enclosed by the dashed box is the DPB1*04:01-CD4 binding interface (Figure 2B). [Figures 2C-2D] [Figures 2C-2D] Ribbon diagrams of model structures of the DP4L112W / V141M and human CD4 complexes. Zoomed-in views of the CD4-binding interface of wild-type DP4 (Figure 2C) and DP4L112W / V141M (Figure 2D) are shown. The side chains of interacting residues are shown in ball-and-stick representation (Figures 2C-2D). [Figures 3A-3P] [Figures 3A-3P] Graphical representations of data showing staining of cognate TCRs expressed on human primary CD4+ T cells with DP4L112W / V141M dimers. Primary T cells were transduced with DP4 / MAGE-A3243-258 (R12C9; Figures 3E-3H), DP4 / WT1328-348 (clone 9; Figures 3I-3L), or DP4 / NY-ESO-1157-170 (5B8; Figures 3M-3P) TCRs and stained with the indicated DP4L112W / V141M dimers (Figures 3B-3D, 3F-3H, 3J-3L, and 3N-3P). [Figures 4A-4D] [Figures 4A-4D] Scatter plots showing co-staining of R12C9-transduced CD4+ T cells stained with DP4L112W / V141M dimers and anti-Vβ22 mAb. Note that R12C9 expresses Vβ22. [Figures 4E-4H] [Figures 4E-4H] Scatter plots showing co-staining of clone 9 transduced CD4+ T cells double stained with DP4L112W / V141M dimer and anti-NGFR mAb. Note that the clone 9 and ΔNGFR genes are fused by P2A. [Figures 5A-5P] [Figures 5A-5P] Scatter plots showing co-staining of clone 9-transduced primary T cells (Figures 5A-5H) and 5B8-transduced primary T cells (Figures 5I-5P) stained with 5 μg / ml of conventional wild-type DP4 tetramer and DP4L112W / V141M dimer. At least two independent experiments were performed. [Figure 6A] [Figures 6A-6F] Bar graphs show the results of an extensive screening using the DP4L112W / V141M dimer, which recognized a series of novel DP4-restricted tumor-associated antigens. Peripheral CD4+ T cells were purified from six DP4+ melanoma patients, stimulated with DP4-expressing aAPCs pulsed with 196 different peptides derived from tumor-associated antigens, and stained with the cognate DP4L112W / V141M dimer. Results using the 30 most positive peptides are shown in Figures 6A-6B. Results for the remaining 166 peptides are shown in Figures 6C-6F. Each gating point was set to show less than 0.2% positive control dimer staining. Positive dimer staining was defined as staining 3 standard deviations above the control dimer staining (>0.6%), as indicated by the dashed line. [Figure 6B] Same as above. [Figure 6C] Same as above. [Figure 6D] Same as above. [Figure 6E] Same as above. [Figure 6F] Same as above. [Figures 7A-7F] [Figures 7A-7L] Graphical representation of DP4L112W / V141M dimer staining of peptide-specific CD4+ T cells from melanoma patients. Primary CD4+ T cells were purified from six DP4+ melanoma patients, stimulated with DP4-expressing aAPCs individually pulsed with 196 different peptides derived from tumor-associated antigens, and stained with the cognate DP4L112W / V141M dimers shown in Figures 6A-6F. Examples of DP4L112W / V141M dimer staining are shown. Details are not specified; *, P value by Student's t-test less than 0.05; ns, not significant. At least two independent experiments were performed. [Figures 7G-7L] Same as above. [Figures 8A-8N][Figures 8A-8X] Graphical representation of data showing that DP4-restricted TCRs isolated from DP4L112W / V141M dimer-positive cells and reconstituted with human TCR-deficient CD4+ T cells function in a DP4-restricted and antigen-specific manner. 03-CCND1219-238 (Figures 8A-8D), 05-HSD17B12225-244 and 09-HSD17B12225-244 (Figures 8E-8J), 05-LGSN296-315 (Figures 8K-8N), 03-MAGE-A2108-127 and 06-MAGE-A2108-127 (Figures 8O-8T), and 05-MUC5AC4922-4941 (Figures 8U-8X) were cloned from DP4L112W / V141M dimer-positive cells, reconstituted in TCR-deficient Jurkat76 / CD4 cells, and stained with the corresponding DP4L112W / V141M dimer. [Figure 8O-8X] Same as above. [Figures 9A-9G] [Figures 9A-9G] Bar graphs showing the results of IL-2 ELISPOT assays of 03-CCND1219-238 (Figure 9A), 05-HSD17B12225-244 (Figure 9B), 09-HSD17B12225-244 (Figure 9C), 05-LGSN296-315 (Figure 9D), 03-MAGE-A2108-127 (Figure 9E), 06-MAGE-A2108-127 (Figure 9F), and 05-MUC5AC4922-4941 (Figure 9G) stimulated with aAPCs pulsed with the corresponding peptides. DP4 / WT1 (clone 9) TCR was used as a negative control. At least two independent experiments were performed. *, P value less than 0.05 by Student's t-test. Bars and error bars represent the mean ± SD of the results of three experiments. [Figures 10A-10D][Figures 10A-10Q] Graphical representations of data demonstrating that DP4-restricted TCRs isolated from DP4L112W / V141M dimer-positive cells and reconstituted with human primary CD4+ T cells function in a DP4-restricted and antigen-specific manner. 03-CCND1219-238 (Figures 10A-10D and 10O), 03-MAGE-A2108-127 and 06-MAGE-A2108-127 (Figures 10E-10J and 10P), and 05-MUC5AC4922-4941 (Figures 10K-10N and 10Q) were retrovirally transduced into human primary CD4+ T cells and stained with the corresponding DP4L112W / V141M dimer (Figures 10A-10N). *, P value less than 0.05 by Student's t-test; ns, not significant. At least two independent experiments were performed. *, P value less than 0.05 by Student's t-test. Bars and error bars represent the mean ± SD of the results from triplicate experiments. [Figures 10E-10J] Same as above. [Figures 10K-10N] Same as above. [Figures 10O-10Q] Same as above. [Figures 11A-11B] [Figures 11A-11B] Data showing that DP4-restricted TCRs cloned from melanoma patients recognized peptides endogenously processed and presented by K562-based aAPCs. Gel chromatography images showing CCDN1 (Figure 11A) and MAGE-A2 (Figure 11B) endogenously expressed in K562-derived aAPC cells. [Figures 11C-11E][Figures 11C-11D] Data demonstrating that DP4-restricted TCRs cloned from melanoma patients recognized peptides endogenously processed and presented by K562-based aAPCs. Bar graphs showing the results of IFN-γ ELISPOT assays of human primary T cells retrovirally transduced with 03-CCND1219-238 (Figure 11C) or 06-MAGE-A2108-127 (Figure 11D) and stimulated with non-peptide-pulsed HLA-null or DP4 aAPCs (Figures 11C-11D). [Figure 11E] Data demonstrating that DP4-restricted TCRs cloned from melanoma patients recognized peptides endogenously processed and presented by K562-based aAPCs. 1 is a bar graph showing the results of an IFN-γ ELISPOT assay of human primary T cells retrovirally transduced with 05-MUC5AC4922-4941 TCR and stimulated with MUC5AC4914-4949 minigene-transduced and non-peptide-pulsed HLA-null or DP4a APCs. At least two independent experiments were performed. *, P value less than 0.05 by Student's t-test. Bars and error bars represent the mean ± SD of the results of three experiments. [Figure 12A] [Figure 12A] Data demonstrating that 06-MAGE-A2108-127 TCR recognizes melanoma cell lines in a DP4- and MAGE-A2-dependent manner. Images of Western blots showing endogenous MAGE-A2 expression in K562 cells and the indicated melanoma cell lines. [Figures 12B-12E][Figures 12B-12E] Data demonstrating that 06-MAGE-A2108-127 TCR recognizes melanoma cell lines in a DP4- and MAGE-A2-dependent manner. Bar graphs show data from IFN-γ ELISPOT assays of primary human T cells stimulated with 06-MAGE-A2108-127 TCR-transduced and DP4-transduced SK-MEL-21 (DP4+MAGE-A2-; Figure 12B) or SK-MEL-37 (DP4+MAGE-A2+; Figure 12C), as well as SK-MEL-28 (DP4-MAGE-A2+; Figure 12D) and Me275 (DP4-MAGE-A2+; Figure 12E). * indicates a P value less than 0.05 by Student's t-test. Bars and error bars represent the mean ± SD of three experiments. At least two independent experiments were performed. [Figures 13A-13Q] [Figures 13A-13Q] Histograms comparing the expression levels of wild-type HLADP*04:01 and its derivatives in K562 cells stained with anti-HLA class II mAb clones 9-49. Open histograms represent substandard control staining. [Figure 14A] [Figure 14A] Data demonstrating the enhanced CD4 binding ability of engineered DQ molecules. Table comparing the amino acid sequences of DPB1*04:01, DQB1*05:01, and DQB1*05:01L114W / V143M+4reps, with mutated amino acids underlined. [Figure 14B] Figure 14B shows data demonstrating the enhanced CD4 binding ability of engineered DQ molecules. Graphical representation of data from class II-deficient K562 cells stably expressing wild-type DQ5 (DQA1*01:01 / DQB1*05:01), DQ5L114W / V143M, DQ5L114W / V143M+4reps, wild-type DP4, or DP4L112W / V141M stained with sCD4 as shown in Figure 14A. [Figure 14C][Figure 14C] Data demonstrating the enhanced CD4 binding ability of engineered DQ molecules. Graphical representation of data from class II-deficient K562 cells stably expressing wild-type DQ5 (DQA1*01:01 / DQB1*05:01), DQ5L114W / V143M, DQ5L114W / V143M+4reps, wild-type DP4, or DP4L112W / V141M stained with sCD4 as shown in Figure 14A. [Figure 14D] [Figure 14D] Data demonstrating the enhanced CD4 binding ability of engineered DQ molecules. The CD4 binding ability of a series of K562 derivatives individually expressing the DQ5L114W / V143M+4reps mutant, which has a single amino acid inversion at one of four positions, is shown, stained identically with sCD4. [Figure 14E] [Figure 14E] Data demonstrating the enhanced CD4 binding ability of the engineered DQ molecules. Table listing the amino acid sequences of DPB1*04:01, DQB1*02:01, DQB1*04:02, and DQB1*06:01, with substituted amino acids underlined. Unlike DQB1*05:01, DQB1*02:01, DQB1*04:02, and DQB1*06:01 encode Val at position 116, as does DPB1*04:01, which encodes Val at position 114. [Figure 14F] [Figure 14F] Data demonstrating the enhanced CD4-binding ability of modified DQ molecules. Graphical representation of data showing that L114W / V143M+3reps substitutions in the β-chain enhanced binding of DQ2, DQ4, and DQ6 to CD4. At least two independent experiments were performed. *, P value by Student's t-test is less than 0.05. Bars and error bars represent the mean ± SD of the results of three experiments. [Figures 15A-15B][Figures 15A-15B] Graphical representations showing that affinity-matured DQ dimers recognized the cognate TCRs expressed on human primary CD4+ T cells. DQ5 (DQA1*01:01-DQB1*05:01)-restricted DDX3Y-specific TCR (E6) (Figure 15A) and DQ6 (DQA1*01:02-DQB1*06:02)-restricted influenza virus HA-specific TCR (DM2) (Figure 15B) were reconstituted with human primary CD4+ T cells and stained with DQ5L114W / V143M+4reps and DQ6L114W / V143M+3reps dimers, respectively. At least two independent experiments were performed. [Figures 16A-16Q] [Figures 16A-16Q] Graphical representations of histograms showing the comparison of expression levels of each HLA class II gene. HLA-DQ and their derivatives were reconstituted in K562 cells and stained with anti-HLA class II monoclonal antibodies. Surface expression of the DQ2, DQ5, and DQ6 alleles was detected using anti-HLA class II monoclonal antibody clone 9-49 (I3) (DQ5 and DQ6) or anti-class II monoclonal antibody clone Tu39 (DQ2 and DQ4). Open histograms represent substandard control staining. [Figure 17A] [Figure 17A] Data demonstrating the enhanced CD4 binding ability of the engineered DR molecules. Table comparing the amino acid sequences of DPB1*04:01, DRB1*01:01, and DRB1*01:01L114W / V143M+6reps, with mutated amino acids underlined. [Figure 17B] [Figure 17B] Data demonstrating the enhanced CD4-binding ability of engineered DR molecules. Graphical representation of data from class II-deficient K562 cells stably transduced with wild-type DR1 (DRA1*01:01 / DRB1*01:01), DR1L114W / V143M, DR1L114W / V143M+6reps, wild-type DP4, or DP4L112W / V141M, stained with sCD4. [Figure 17C][Figure 17C] Data demonstrating the enhanced CD4-binding ability of engineered DR molecules. Graphical representation of data from class II-deficient K562 cells stably transduced with wild-type DR1 (DRA1*01:01 / DRB1*01:01), DR1L114W / V143M, DR1L114W / V143M+6reps, wild-type DP4, or DP4L112W / V141M, stained with sCD4. [Figure 17D] [Figures 17D-17E] Data demonstrating the enhanced CD4-binding ability of engineered DR molecules are shown. The CD4-binding ability of a series of K562 derivatives expressing the DR1 L114W / V143M+6reps mutant, which has a single amino acid inversion at one of six positions (Figure 17D), and the DRB1 L114W / V143M+2reps mutant, which has L114W / V143M as well as S118H and T157I substitutions (Figure 17E), are also shown, stained with sCD4. [Figure 17E] Same as above. [Figure 17F] [Figure 17F] Data demonstrating the enhanced CD4 binding ability of the engineered DR molecules. Table listing the amino acid sequences of DPB1*04:01 and the DRB1 alleles of DR3, DR4, DR7, DR10, DR11, and DR13, along with comparisons with the amino acid sequences of DRB1L114W / V143M+6reps and DRB1L114W / V143M+2reps, with mutated amino acids underlined. [Figures 17G-17L] [Figures 17G-17L] Graphical representation of data showing that the L114W / V143M+2reps mutation enhanced the binding of DR3, DR4, DR7, DR10, DR11, and DR13 to CD4 better than the L114W / V143M+6reps mutation. At least two independent experiments were performed. *, P value by Student's t-test is less than 0.05. Bars and error bars represent the mean ± SD of the results of three experiments. [Figures 17M-17N][Figures 17M-17N] Biolayer interferometry sensorgrams showing the interaction of biotinylated HLA-DR1 (ligand) with soluble CD4 (analyte) over a range of concentrations. Binding experiments with wild-type DR1 (Figure 17M) and DR1L114W / V143M+2reps (Figure 17N) were performed in parallel, but no binding was detected with wild-type DR1 (Figure 17M). [Figure 17O] [Figure 17O] A graph showing the affinity between DR1L114W / V143M+2reps and CD4, as quantified by steady-state analysis. All data are representative of two independent experiments. [Figures 18A-18D] [Figures 18A-18D] Graphical representations showing that affinity-matured DR dimers recognized cognate TCRs expressed on human primary CD4+ T cells. DR1-restricted TCRs (HA1.7 and SB95) (Figure 18A), DR7-restricted TCRs (SD334) (Figure 18B), and DR11-restricted TCRs (F24) (Figure 18C) were reconstituted in primary human T cells and stained with the corresponding DRL114W / V143M+2reps dimers. DR11-restricted F24-transduced CD4+ T cells were stained with DR11L114W / V143M+2reps dimers and anti-Vβ22 mAb (Figure 18D). Note that F24 expresses Vβ22. At least two independent experiments were performed. [Figure 19A] [Figure 19A] A diagram of the model structure of the HLA-DR1L114W / V143M+2reps and human CD4 complex. A schematic ribbon model of the ternary complex model structure of DRA1*01:01, DRB1*01:01, and CD4 is shown. [Figures 19B-19D] [Figures 19B-19D] Model structures of HLA-DR1 L114W / V143M+2reps and human CD4 complexes. Shown are magnified views of the four mutated residues: L114W and V143M (Figure 19B), S118H (Figure 19C), and T157I (Figure 19D) in wild-type DR1 (left) and mutated DR1 L114W / V143M+2reps (right), as illustrated using a ball-and-stick representation. [Figures 20A-20K][Figures 20A-20II] Graphical representations of histograms showing the comparison of expression levels of each HLA class II gene. HLA-DR and their derivatives were reconstituted in K562 cells and stained with anti-HLA class II monoclonal antibodies. Surface expression of all DR alleles was detected using anti-HLA class II monoclonal antibody clone 9-49 (I3). Open histograms represent secondary control staining. [Figure 20L-20AA] Same as above. [Figure 20BB-20II] Same as above. [Figures 21A-21D] [Figures 21A-21D] Graphical representations of data showing a comparison of DP4L112W / V141M dimer and dextramer staining of endogenous TRPC1578-597-specific CD4+ T cells. Endogenous (untransduced) TRPC1578-597-specific CD4+ T cells were expanded from a melanoma patient by stimulation with peptide-pulsed and irradiated DP4+ artificial APCs and further stained with DP4L112W / V141M TRPC1578-597 dimer (Figure 21B) or TRPC1578-597 dextramer (Figure 21D). The corresponding CLIP multimers were used as controls (Figures 21A and 21C). [Figures 22A-22F] [Figures 22A-22F] Graphical representations of data showing a comparison of the DP4L112W / V141M dimer and conventional DP4 tetramer and dextramer for staining of endogenous NY-ESO-1157-170-specific T cells. CD4+ T cells were purified from DP4+ healthy donor number 4 and stimulated once with NY-ESO-1157-170-pulsed and irradiated DP4+ artificial APCs. Expanded CD4+ T cells were individually stained with three different DP4 multimers (DP4L112W / V141M dimer (Figure 22B), DP4 tetramer (Figure 22D), or DP4 dextramer (Figure 22F)) as indicated. [Figures 23A-23Y][Figures 23A-23Y] Graphical representations of data showing pathogen-specific CD4+ T cells subjected to ex vivo staining with DP4L112W / V141M dimers. Memory CD4+ T cells were purified from five DP4+ donors and subjected to ex vivo staining with DP4L112W / V141M dimers without in vitro stimulation against pathogen-associated peptides: TT948-968 (Figures 23F-23J), HSV-2-UL21283-302 (Figures 23K-23O), Flu-HA527-546 (Figures 23P-23T), and RSV-GP162-175 (Figures 23U-23Y). CLIP peptide was used as a negative control (Figures 23A-23E). [Figures 24A-24L] [Figures 24A-24V] Graphical representations of data showing endogenous RSV-GP162-175-specific CD4+ T cell clones successfully constructed from DP4L112W / V141M dimer+ cells. Memory CD4+ T cells were purified from DP4+ donor #06 and subjected to ex vivo staining with DP4L112W / V141M RSV-GP162-175 dimers without in vitro stimulation. Dimer+ CD4+ T cells were then cloned by limiting dilution. Graphical representations of representative dimer staining data for 10 dimer-positive and 1 dimer-negative single-cell clones. 77 of 84 clones (91.7%) successfully stained with DP4L112W / V141M RSV-GP162-175 dimers. [Figures 24M-24V] Same as above. [Figure 24W] [Figure 24W] Graphical representation of data showing the successful construction of endogenous RSV-GP162-175-specific CD4+ T cell clones from DP4L112W / V141M dimer+ cells. Memory CD4+ T cells were purified from DP4+ donor number 06 and subjected to ex vivo staining with DP4L112W / V141M RSV-GP162-175 dimers without in vitro stimulation. Dimer+ CD4+ T cells were then cloned by limiting dilution. Bar graph showing antigen-specific IL-2 production in RSV-GP162-175 dimer+ single cell clones. [Figures 25A-25J][Figures 25A-25R] Graphical representations of data showing endogenous DP4 TT948-968-specific CD4+ T cell clones successfully constructed from DP4L112W / V141M dimer+ cells. Memory CD4+ T cells were purified from DP4+ donor #04 and subjected to ex vivo staining with DP4L112W / V141M TTT948-968 dimers without in vitro stimulation. Dimer+ CD4+ T cells were then cloned by limiting dilution. Graphical representations of representative dimer staining data for eight dimer-positive and one dimer-negative single-cell clones. 26 of 29 clones (89.7%) successfully stained with DP4L112W / V141M TTT948-968 dimers. [Figure 25K-25R] Same as above. [Figure 25S] [Figure 25S] Graphical representation of data showing the successful construction of endogenous DP4 TT948-968-specific CD4+ T cell clones from DP4L112W / V141M dimer+ cells. Memory CD4+ T cells were purified from DP4+ donor number 04 and subjected to ex vivo staining with DP4L112W / V141M TT948-968 dimers without in vitro stimulation. Dimer+ CD4+ T cells were then cloned by limiting dilution. Bar graph showing antigen-specific IL-2 production in TT948-968 dimer+ single cell clones. [Figures 26A-26P][Figures 26A-26NN] Graphical representation of DP4 multimer staining of RSV-GP (Figures 26A-26P) and TT (Figures 26Q-26NN) dimer + single-cell clones. RSV-GP dimer + single-cell clones (c6, c12, c26, and c39) were stained with DP4L112W / V141MRSV-GP162-175 dimers (Figures 26B, 26D, 26F, and 26H) or wild-type DP4 dextramers (Figures 26J, 26L, 26N, and 26P). TT dimer+ single cell clones (c2, c4, c6, and c9) were individually stained with three different DP4TT948-968 multimers: DP4L112W / V141M dimer (Figures 26R, 26T, 26V, and 26X), wild-type DP4 tetramer (Figures 26Z, 26BB, 26DD, and 26FF), and wild-type DP4 dextramers (Figures 26HH, 26JJ, 26LL, and 26NN). [Fig. 26Q-26X] Same as above. [Figure 26Y-26FF] Same as above. [Figure 26GG-26NN] Same as above. [Figures 27A-27L] [Figures 27A-27L] Graphical representations showing that the DQ5L114W / V143M+4reps dimer strongly stained E6-transduced CD4+ T cells. E6 was reconstituted with CD4+ T cells, and the T cells were then stained with wild-type DQ5 (Figures 27D and 27J), DQ5L114W / V143M (Figures 27E and 27K), and DQ5L114W / V143M+4reps (Figures 27F and 27L), CLIP control dimer (Figures 27A-27F), and dimer specific for DDX3Y171-190 (Figures 27G-27L). Non-TCR-transduced control cells are shown in Figures 27A-27C and 27G-27I. [Figures 28A-28B][Figures 28A-28F] Graphical representations showing the cloning of DQ5-restricted TCRs using affinity-matured dimers. Primary CD4+ T cells were purified from a DQ5.1+ melanoma patient and stimulated with DQ5.1-expressing aAPCs that were irradiated and pulsed with GPC3138-157. Two weeks later, stimulated CD4+ T cells were stained with the cognate GPC3138-157-DQ5L114W / V143M+4reps dimer (Figures 28A-28B). GPC3-specific TCRs were reconstituted in TCR-deficient Jurkat76 / CD4 cells and stained with the corresponding DQ5L114W / V143M+4reps dimers (Figure 28C (E6 / control); Figure 28D (E6 / GPC3138-157); Figure 28E (DQ5-06-GPC3138-157 / control); and Figure 28F (DQ5-06-GPC3138-157 / GPC3138-157)). [Figures 28C-28F] Same as above. [Figure 28G] [Figure 28G] This shows the results of an IL-2 ELISPOT assay in which Jurkat76 / CD4 cells expressing GPC3-specific TCR were stimulated with DQ5-K562 cells pulsed with the corresponding peptide. [Figures 29A-29L] [FIGS. 29A-29L] Graphical representations showing influenza virus hemagglutinin-specific peripheral CD4+ T cells subjected to ex vivo staining with DR1L114W / V143M+2reps dimers. Memory CD4+ T cells were purified from two DR1+ donors (number 07 (Figures 29A-29F) and number 08 (Figures 29G-29L)) and stained with DR1L114W / V143M+2reps dimers specific for Flu-HA5-24 (Figures 29B and 29H), Flu-HA117-136 (Figures 29C and 29I), Flu-HA232-251 (Figures 29D and 29J), Flu-HA268-287 (Figures 29E and 29K), and Flu-HA306-318 (Figures 29F and 29L) influenza virus hemagglutinin (Flu-HA) peptides without in vitro stimulation. CLIP peptide was used as a negative control (Figures 29A and 29G). [Figures 30A-30P][Figures 30A to 30X] Graphical representations showing that DR1L114W / V143M+6reps and DR1L114W / V143M+2reps dimers strongly stained HA1.7-transduced CD4+ T cells. HA1.7 was reconstituted with primary CD4+ T cells without TCR transduction (Figures 30I-30L) and with HA1.7 TCR transduction (Figures 30M-30P). The T cells were then stained with wild-type DR1 (Figures 30I and 30M), DR1L114W / V143M (Figures 30J and 30N), DR1L114W / V143M+6reps (Figures 30K and 30O), and DR1L114W / V143M+2reps (Figures 30L and 30P) dimers; CLIP dimers were used as negative controls (Figures 30A-30H). Additionally, HA1.7 was reconstituted in primary CD4+ T cells and then stained with Flu-HA306-318-specific DR1L114W / V143M+2reps dimer (Figures 30Q-30T) or wild-type DR1 dextramer (Figures 30U-30X). [Figure 30Q-30T] Same as above. [Fig. 30U-30X] Same as above. [Figures 31A-31D] [Figures 31A-31M] Graphical representations showing data on cloning of DR1-restricted TCRs using affinity-matured dimers. Primary CD4+ T cells were purified from two DR1+ melanoma patients and stimulated with irradiated aAPCs expressing DR1 pulsed with HSD17B12225-244 (Figure 31B) and with aAPCs expressing DR1 pulsed with LY6K99-118 (Figure 31D). Two weeks later, stimulated CD4+ T cells were stained with the cognate DR1L114W / V143M+2reps dimer (Figures 31A-31D). DR1-restricted TCRs were reconstituted with primary CD4+ T cells and stained with the corresponding dimers (Figures 31E-31M). [Figure 31E-31M] Same as above. [Figure 31N-31O][Figures 31N-31O] IL-2 ELISPOT assay results show that primary CD4+ T cells expressing DR1-restricted DR1-07-HSD17B12225-244 TCR (Figure 31N) and DR1-08-LY6K99-118 TCR (Figure 31O) were stimulated with DR1-K562 cells pulsed with HSD17B12225-244 peptide (Figure 31N) and LY6K99-118 peptide (Figure 31O), respectively. DETAILED DESCRIPTION OF THE INVENTION

[0052] The present disclosure relates to methods for identifying MHC class II-specific TCRs, the methods comprising contacting a T cell with a complex comprising an MHC class II molecule and a peptide, wherein the MHC class II molecule has a higher affinity for CD4 than the affinity that a naturally occurring MHC class II molecule has for CD4. In some embodiments, the MHC class II molecule comprises an alpha chain and a beta chain, wherein the beta chain of the MHC class II molecule comprises an amino acid sequence having one or more mutations compared to a wild-type beta chain of the MHC class II molecule.

[0053] I. Terminology In order that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless otherwise stated herein, each of the following terms shall have the meaning indicated below. Additional definitions are set forth throughout this application.

[0054] It should be noted that the term "a" or "an" entity refers to one or more of that entity, for example, "a nucleotide sequence" is understood to refer to one or more nucleotide sequences. Thus, the terms "a" (or "an"), "one or more," and "at least one" may be used interchangeably herein.

[0055] Furthermore, when used herein, "and / or" shall be construed as a specific disclosure of each of two particular features or components, with or without the other. Thus, the term "and / or" used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0056] The term "about" is used herein to mean approximately, roughly, roughly, or within a range. When the term "about" is used in conjunction with a numerical range, the term modifies that range by extending its boundaries above and below the set forth numerical values. In general, the term "about" is used herein to modify a numerical value by plus or minus 10 percent (above or below) the set forth value.

[0057] Whenever an embodiment is described herein using the word "comprising," it should be understood that other similar embodiments described using the terms "consisting of" and / or "consisting essentially of" are also provided.

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains, e.g., the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press, The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press, and the Oxford Dictionary of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provides those of skill in the art with a general dictionary of many of the terms used in this disclosure.

[0059] Units, prefixes, and symbols are shown in their International System of Units (SI) accepted format. Numerical ranges are inclusive of the numbers defining the range. Unless otherwise indicated, nucleotide sequences are written left to right in 5' to 3' orientation. Amino acid sequences are written left to right in amino to carboxy orientation. The headings provided herein are not intended to limit the various aspects of the disclosure, which can be had by reference to the specification in its entirety. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0060] "Administering" refers to the physical introduction of an agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Examples of routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes, for example, by injection or infusion. The phrase "parenteral administration," as used herein, refers to a method of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intrathecal, epidural, and intrasternal injection and infusion, as well as in vivo electroporation. In some embodiments, the formulation is administered via a non-parenteral route, for example, orally. Other non-parenteral routes include topical, epithelial, or mucosal routes of administration, such as intranasally, intravaginally, rectally, sublingually, or topically, and administration can be, for example, single, multiple, and / or over one or more extended periods of time.

[0061] The term "T cell receptor" (TCR) as used herein refers to a heteromeric cell surface receptor that can specifically interact with a target antigen. As used herein, the term "TCR" includes, but is not limited to, naturally occurring and non-naturally occurring TCRs, full-length TCRs and their antigen-binding portions, chimeric TCRs, TCR fusion constructs, and synthetic TCRs. In humans, TCRs are expressed on the surface of T cells and are responsible for T cell recognition and targeting of antigen-presenting cells (APCs). Antigen-presenting cells (APCs) present fragments of foreign proteins (antigens) complexed with major histocompatibility complexes (MHCs, also referred to herein as those complexed with HLA molecules, e.g., HLA class II molecules). TCRs recognize and bind to peptide:HLA complexes, recruiting CD8 (in the case of MHC class I molecules) or CD4 (in the case of MHC class II molecules), thereby activating the TCR. Activated TCRs initiate downstream signaling and immune responses, including the destruction of EPCs.

[0062] Generally, a TCR may comprise two chains, an alpha chain and a beta chain (or less commonly, a gamma chain and a delta chain), interconnected by disulfide bonds. Each chain comprises a variable domain (an alpha chain variable domain and a beta chain variable domain) and a constant region (an alpha chain constant region and a beta chain constant region). The variable domains are located distal to the cell membrane, and the variable domains interact with antigen. The constant regions are located proximal to the cell membrane. A TCR may further comprise a transmembrane region and a short cytoplasmic tail. As used herein, the term "constant region" encompasses the transmembrane region and cytoplasmic tail, if present, as well as the conventional "constant region."

[0063] Variable domains can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs), flanked by more conserved regions called framework regions (FRs). Each alpha and beta chain variable domain contains three CDRs and four FRs (FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4). Each variable domain contains a binding domain that interacts with an antigen. Although all three CDRs of each chain are involved in antigen binding, CDR3 is considered to be the primary antigen-binding region, and CDR1 and CDR2 are thought to primarily recognize HLA molecules.

[0064] Unless explicitly stated, and unless the context dictates otherwise, the term "TCR" also includes antigen-binding fragments or portions of any TCR disclosed herein, including monovalent and bivalent fragments or portions, and single-chain TCRs. The term "TCR" is not limited to naturally occurring TCRs bound to the surface of T cells. As used herein, the term "TCR" also refers to a TCR described herein expressed on the surface of a cell other than a T cell (e.g., a cell that naturally expresses or is modified to express CD4 as described herein), or a TCR described herein free from the cell membrane (e.g., an isolated TCR or a soluble TCR).

[0065] "Antigen-binding molecule," "portion of a TCR," or "TCR fragment" refers to any portion of a TCR that is smaller than the entire TCR. An antigen-binding molecule may include the CDRs of an antigen.

[0066] "Antigen" refers to any molecule, e.g., a peptide, that can elicit an immune response or be bound by a TCR. As used herein, "epitope" refers to a portion of a polypeptide that can elicit an immune response or be bound by a TCR. The immune response may include antibody production, activation of specific immunologically competent cells, or both. Those skilled in the art will readily understand that virtually any macromolecule, including any protein or peptide, can function as an antigen. Antigens and / or epitopes can be endogenously expressed, i.e., expressed by genomic DNA, or recombinantly expressed. Antigens and / or epitopes may be specific to a particular tissue, such as diseased cells, e.g., cancer cells, or may be ubiquitously expressed. Furthermore, fragments of larger molecules can function as antigens. In one embodiment, the antigen is a tumor antigen. An epitope can be present in a longer polypeptide (e.g., in a protein), or it can exist as a fragment of a longer polypeptide. In some embodiments, the epitope forms a complex with a major histocompatibility complex (MHC, also referred to herein as complexing with an HLA molecule, eg, an HLA class I molecule).

[0067] The term "autologous" refers to any material derived from the same individual that is subsequently reintroduced. For example, autologous T cell therapy involves administering T cells isolated from the same subject to a subject. The term "allogeneic" refers to any material derived from one individual that is then introduced into another individual of the same species. For example, allogeneic T cell transplantation involves administering T cells obtained from a donor other than the subject to a subject.

[0068] As used herein, "CCND1," "G1 / S-specific cyclin D1," "B-cell lymphoma 1 protein," "BCL-1," or "PRAD1" refers to the human regulatory component of the cyclin D1-CDK4 (DC) complex, which phosphorylates and inhibits members of the retinoblastoma (RB) protein family, including RB1, and controls the cell cycle during the G1 / S transition. Phosphorylation of RB1 allows the dissociation of the transcription factor E2F from the RB / E2F complex and subsequent transcription of E2F target genes responsible for G1 progression. CCND1 is also involved in the hypophosphorylation of RB1 during early G1. The cyclin D-CDK4 complex is a key integrator of various mitogenic and antimitotic signals. CCND1 is also a substrate of SMAD3, phosphorylating it in a cell cycle-dependent manner and suppressing its transcriptional activity. CCND1 is also a component of the ternary complex, cyclin D1 / CDK4 / CDKN1B, which is required for the nuclear translocation and activity of the cyclin D-CDK4 complex, and CCND1 exhibits transcriptional corepressor activity with NEUROD1 and INSM1 on the INS promoters in a cell cycle-independent manner. CCND1 mutations, amplifications, and overexpression, which alter cell cycle progression, are frequently observed in various tumors and may contribute to tumorigenesis.

[0069] As used herein, CCND1 refers not only to the full-length standard sequence, but also to variants and fragments thereof. The amino acid sequence of CCND1 (SEQ ID NO: 27) is shown in Table 1A (UniProtKB-P24385). [Table 1-1]

[0070] As used herein, "MUC5AC" or "mucin 5AC" refers to a human gel-forming glycoprotein in the gastric and respiratory epithelium that protects the mucosa from infection and chemical damage by binding to inhaled microorganisms and particles, which are then removed by the mucociliary system.

[0071] As used herein, MUC5AC refers to the full-length standard sequence as well as variants and fragments thereof. The amino acid sequence of MUC5AC (SEQ ID NO: 28) is shown in Table 1B (UniProtKB-P98088). [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0072] As used herein, "MAGE-A2," "melanoma-associated antigen 2," or "cancer / testis antigen 1.2" refers to a human protein primarily expressed in tumor cells. MAGE-A2 attenuates p53 / TP53 transactivation function through recruitment of HDAC3 to p53 / TP53 transcription sites. MAGE-A2 suppresses p73 / TP73 activity. In vitro, MAGE-A2 promotes cell viability in melanoma cell lines. MAGE-A2 is expressed in many tumors, including melanoma, head and neck squamous cell carcinoma, lung cancer, and breast cancer. However, in healthy tissues, MAGE-A2 is expressed only in the testis.

[0073] As used herein, MAGE-A2 refers to the full-length sequence as well as variants and fragments thereof. The amino acid sequence of MAGE-A2 (SEQ ID NO: 29) is shown in Table 1C (UniProtKB-P43356). [Table 1-6]

[0074] The term "HLA" as used herein refers to human leukocyte antigens. HLA genes encode human major histocompatibility complex (MHC) proteins. MHC proteins are expressed on the surface of cells and are involved in activating immune responses. HLA class II genes encode MHC class II proteins expressed on the surface of professional antigen-presenting cells (APCs). Non-limiting examples of professional APCs include monocytes, macrophages, dendritic cells (DCs), and B lymphocytes. Some endothelial and epithelial cells can also express MHC class II molecules after inflammatory signals are activated. Humans lacking functional MHC class II molecules are highly susceptible to a range of infectious diseases and usually die at an early age.

[0075] As used herein, "HLA class II molecule" or "MHC class II molecule" refers to the protein product of a wild-type or variant HLA class II gene encoding an MHC class II molecule. Thus, "HLA class II molecule" and "MHC class II molecule" are used interchangeably herein. A typical MHC class II molecule comprises two protein chains, an alpha chain and a beta chain. Generally, each of the naturally occurring alpha and beta chains contains a transmembrane domain that anchors the alpha / beta chain to the cell surface and an extracellular domain that carries antigen and interacts with TCR and / or CD4 expressed on T cells.

[0076] Both the alpha and beta chains of MHC class II are encoded by the HLA gene complex. The HLA complex is located in the 6p21.3 region of the short arm of human chromosome 6 and contains more than 220 genes of diverse functions. The HLA gene complex contains many variants with more than 20,000 HLA alleles and related alleles, including more than 250 MHC class II alpha chain alleles and more than 5,000 MHC class II beta chain alleles, encoding thousands of MHC class II proteins, as known in the art (see, e.g., hla.alleles.org, last visited May 20, 2019, incorporated herein by reference in its entirety). For example, one such HLA-DP allele, DP4, is the most frequently occurring allele in many ethnic groups.

[0077] The three loci of the HLA complex encode MHC class II proteins: HLA-DP, HLA-DQ, and HLA-DR. HLA-DO and HLA-DM encode proteins that associate with MHC class II molecules and support their assembly and function.

[0078] When MHC class II molecules form a complex with an antigenic peptide, the 10-30 amino acid long antigenic peptide binds to the peptide-binding groove and is presented extracellularly to CD4+ cells. Both the alpha and beta chains fold into two separate domains: alpha 1 and alpha 2 for alpha polypeptides, and beta 1 and beta 2 for beta polypeptides. The open peptide-binding groove, which holds the antigen to be presented, is located between the alpha 1 and beta 1 domains. Upon interaction with CD4+ T cells, the MHC class II complex interacts with the T cell receptor (TCR) expressed on the surface of the T cell. In addition, the beta chain of the MHC class II molecule interacts only slightly with CD4 expressed on the surface of the T cell (K). D >2mM). The standard CD4 amino acid sequence (SEQ ID NO: 10) is shown in Table 2 (UniProt - P01730). [Table 2]

[0079] The term "autologous" refers to any material derived from the same individual that is subsequently reintroduced. For example, autologous T cell therapy involves administering T cells isolated from the same subject to a subject. The term "allogeneic" refers to any material derived from one individual that is then introduced into another individual of the same species. For example, allogeneic T cell transplantation involves administering T cells obtained from a donor other than the subject to a subject.

[0080] "Cancer" refers to a broad group of diseases characterized by the unchecked growth of abnormal cells in the body. Uncontrolled cell division and growth leads to the formation of malignant tumors that infiltrate neighboring tissues and may metastasize to distant parts of the body through the lymphatic system or bloodstream. "Cancer" or "cancerous tissue" can include tumors. Examples of cancers that can be treated by the methods of the present invention include, but are not limited to, cancers of the immune system, including lymphomas, leukemias, and other white blood cell malignancies. In some embodiments, the methods of the present invention are used to treat cancers of various organs, such as bone cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, cutaneous or intraocular melanoma, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma (NHL), primary mediastinal large B-cell lymphoma (PMBC), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, sarcoma of soft tissue, urinary tract cancer ... It can be used to reduce tumor size in tumors resulting from uterine cancer, penile cancer, chronic or acute leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non-T-cell ALL), chronic lymphocytic leukemia (CLL), childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including those due to asbestos, other B-cell malignancies, and combinations of the above cancers. Certain cancers may respond to chemotherapy or radiation therapy, or the cancer may be refractory.

[0081] Refractory cancer refers to cancer that cannot be corrected by surgical intervention, and the cancer either does not respond to chemotherapy or radiation therapy initially or becomes unresponsive over time.

[0082] As used herein, "anti-tumor effect" refers to a biological effect that can be manifested as a reduction in tumor volume, a reduction in the number of tumor cells, a reduction in tumor cell proliferation, a reduction in the number of metastases, an increase in overall survival or progression-free survival, an increase in life expectancy, or an improvement in various physiological symptoms associated with tumors.Anti-tumor effect can also refer to the prevention of tumor development, for example, vaccination.

[0083] As used herein, the term "progression-free survival", which may be abbreviated as PFS, refers to the time from the date of treatment to the date of disease progression or death from any cause according to the revised IWG response criteria for malignant lymphoma.

[0084] As used herein, "disease progression" or "progressive disease", which may be abbreviated as PD, refers to the worsening of one or more symptoms associated with a particular disease.For example, in a subject suffering from cancer, disease progression can include an increase in the number or size of one or more malignant lesions, tumor metastasis, and death.

[0085] As used herein, "duration of response," which may be abbreviated as DOR, refers to the time from a subject's first objective response according to the revised IWG response criteria for malignant lymphoma to the date of confirmed disease progression or death.

[0086] The term "overall survival," sometimes abbreviated as OS, is defined as the time from the date of treatment to the date of death.

[0087] As used herein, a "cytokine" is a non-antibody protein released by one cell in response to contact with a specific antigen, which interacts with a second cell and mediates a response in the second cell. Cytokines may be endogenously expressed in a cell or may be administered to a subject. Cytokines may be released from immune cells, such as macrophages, B cells, T cells, and mast cells, to mediate an immune response. Cytokines can induce various responses in recipient cells. Cytokines may include homeostatic cytokines, chemokines, proinflammatory cytokines, effectors, and acute phase proteins. For example, homeostatic cytokines, such as interleukin (IL) 7 and IL-15, promote the survival and proliferation of immune cells, and proinflammatory cytokines can promote inflammatory responses. Examples of homeostatic cytokines include, but are not limited to, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12p40, IL-12p70, IL-15, and interferon (IFN) gamma. Examples of proinflammatory cytokines include, but are not limited to, IL-1a, IL-1b, IL-6, IL-13, IL-17a, tumor necrosis factor (TNF)-alpha, TNF-beta, fibroblast growth factor (FGF)2, granulocyte-macrophage colony-stimulating factor (GM-CSF), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular adhesion molecule 1 (sVCAM-1), vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, and placental growth factor (PLGF). Examples of effectors include, but are not limited to, granzyme A, granzyme B, soluble Fas ligand (sFasL), and perforin. Examples of acute phase proteins include, but are not limited to, C-reactive protein (CRP) and serum amyloid A (SAA).

[0088] A "chemokine" is a type of cytokine that mediates cell chemotaxis or directional movement. Examples of chemokines include, but are not limited to, IL-8, IL-16, eotaxin, eotaxin-3, macrophage-derived chemokine (MDC or CCL22), monocyte chemoattractant protein 1 (MCP-1 or CCL2), MCP-4, macrophage inflammatory protein 1 alpha (MIP-1α, MIP-1a), MIP-1 beta (MIP-1b), gamma-inducible protein 10 (IP-10), and thymus and activation-regulated chemokine (TARC or CCL17).

[0089] Other examples of analytes and cytokines of the present invention include, but are not limited to, chemokine (C-C motif) ligand (CCL) 1, CCL5, monocyte-specific chemokine 3 (MCP3 or CCL7), monocyte chemoattractant protein 2 (MCP-2 or CCL8), CCL13, IL-1, IL-3, IL-9, IL-11, IL-12, IL-14, IL-17, IL-20, IL-21, granulocyte colony-stimulating factor (G-CSF), leukemia inhibitory factor (LIF), oncolytic factor (CTF), leukemia inhibitory factor (LE ... Examples include tatin M (OSM), CD154, lymphotoxin (LT) beta, 4-1BB ligand (4-1BBL), proliferation-inducing ligand (APRIL), CD70, CD153, CD178, glucocorticoid-induced TNFR-related ligand (GITRL), tumor necrosis factor superfamily member 14 (TNFSF14), OX40L, TNF- and ApoL-related leukocyte-expressed ligand 1 (TALL-1), or TNF-related apoptosis-inducing ligand (TRAIL).

[0090] A "therapeutically effective amount," "effective dose," "effective amount," or "therapeutically effective dosage" of a drug or therapeutic agent is any amount of drug that, when used alone or in combination with another therapeutic agent, protects a subject against disease manifestations or promotes disease regression as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods of the disease, or prevention of impairment or disability due to disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, for example, by assaying the activity of the agent in human subjects in clinical trials, in animal model systems predictive of efficacy in humans, or in in vitro assays.

[0091] As used herein, the term "infection" refers to some type of invasion of one or more tissues of the body by a foreign substance. The term "infection" includes, but is not limited to, infection by viruses (including viroids and prions), bacteria, fungi, parasites, and any combination thereof.

[0092] The term "lymphocyte" as used herein includes natural killer (NK) cells, T cells, or B cells. NK cells are a type of cytotoxic (cytotoxic) lymphocyte and a major component of the innate immune system. NK cells reject tumor- and virus-infected cells. They function through the process of apoptosis, or programmed cell death. They were called "natural killers" because they do not require activation to kill cells. T cells play a major role in cell-mediated immunity (without the involvement of antibodies). T cell receptors (TCRs) distinguish T cells from other lymphocyte types. The thymus, a specialized organ of the immune system, is primarily responsible for the maturation of T cells. There are six types of T cells: helper T cells (e.g., CD4+ cells), cytotoxic T cells (TCs, also known as cytotoxic T lymphocytes, CTLs, T killer cells, cytolytic T cells, CD8+ T cells, or killer T cells), memory T cells ((i) stem memory T cells such as naive cells), and (ii) naive T cells. SCMThe cells are CD45RO-, CCR7+, CD45RA+, CD62L+ (L-selectin), CD27+, CD28+, and IL-7Rα+, but they express large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, and exhibit numerous functional attributes characteristic of memory cells. (ii) Central memory T CM The cells express L-selectin and CCR7, they secrete IL-2 but not IFNγ or IL-4, and (iii) effector memory T EM These include T cells (which do not express L-selectin or CCR7 but produce effector cytokines such as IFNγ and IL-4), regulatory T cells (Tregs, suppressor T cells, or CD4+CD25+ regulatory T cells), natural killer T cells (NKT), and gamma-delta T cells. B cells, on the other hand, play a major role in humoral immunity (involving antibodies). B cells produce antibodies and antigens, act as antigen-presenting cells (APCs), and transform into memory B cells after activation by antigen interaction. In mammals, immature B cells are formed in the bone marrow, hence their name.

[0093] As used herein with respect to nucleotide or amino acid sequences, the terms "modified" and "mutated" refer to a change in the sequence compared to a wild-type sequence or a specific reference sequence. The terms "modified" and "mutated," unless otherwise specified, do not require a process step to create the modified or mutated sequence (e.g., a modified beta chain sequence). Rather, these terms indicate a change in the modified or mutated sequence compared to a reference sequence, e.g., a wild-type sequence. For example, a DP beta chain containing a substitution mutation at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 does not require the wild-type DP beta chain to be physically altered to arrive at the recited DP beta chain, but rather, when properly sequenced, the recited DP beta chain contains an amino acid residue at the recited position (residue 112) that differs from the amino acid residue at the corresponding position in the wild-type or reference DP beta chain.

[0094] As used herein, the term "any amino acid" refers to any known amino acid. An amino acid is an organic compound containing (i) an amine (-NH) functional group, (ii) a carboxyl (-COOH) functional group, and (iii) a side chain (R group), where the side chain is unique to each amino acid. This includes, but is not limited to, any naturally occurring amino acid and any modifications and variants thereof. There are approximately 500 naturally occurring amino acids, 20 of which are encoded by the genetic code. Amino acids with positively charged side chains include arginine (Arg; R), histidine (His, H), and lysine (Lys; K). Amino acids with negatively charged side chains include aspartic acid (Asp; D) and glutamic acid (Glu; E). Amino acids with polar, uncharged side chains include serine (Ser; S), threonine (Thr; T), glutamine (Gln; Q), and asparagine (Asn; N). Amino acids with hydrophobic side chains include alanine (Ala; A), isoleucine (Ile; I), leucine (Leu; L), methionine (Met; M), phenylalanine (Phe; F), valine (Val; V), tryptophan (Trp; W), and tyrosine (Tyr; Y). Tryptophan (Trp; W), tyrosine (Tyr; Y), and methionine (Met; M) may also be classified as polar and / or amphipathic, in that these amino acids are often found on the surface of proteins or lipid membranes. Additional amino acids include cysteine ​​(Cys; C), selenocysteine ​​(Sec; U), glycine (Gly; G), and proline (Pro; P).

[0095] As used herein, "corresponding to position" is used as a means of identifying a specific amino acid residue, for example, a specific amino acid position in a polynucleotide, or a specific nucleic acid, for example, a specific nucleic acid position in a polypeptide. The position can be determined by appropriately aligning the sequence of interest with a reference sequence. Those skilled in the art will readily understand how to align sequences to determine relative positions. For example, various alignment tools are available online, including, but not limited to, "Clustal Omega Multiple Sequence Alignment," available at www.ebi.ac.uk (last visited: May 25, 2019).

[0096] The terms "genetically modified" or "engineered" refer to methods of modifying the genome of a cell, including, but not limited to, deleting coding or non-coding regions or portions thereof, or inserting coding regions or portions thereof. In some embodiments, the modified cells are lymphocytes, e.g., T cells, or modified cells expressing CD4, which can be obtained from a patient or a donor. The cells can be modified to express an exogenous construct, such as a T cell receptor (TCR) disclosed herein, that is integrated into the genome of the cell. In some embodiments, the cells are modified to express CD4.

[0097] "Immune response" refers to the actions of cells of the immune system (e.g., T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells, and neutrophils) and soluble macromolecules (including antibodies (Abs), cytokines, and complement) produced by any of these cells or the liver that result in the elimination of invading pathogens from the vertebrate body and / or the selective targeting, binding, damage, and destruction of pathogen-infected cells or tissues, cancer cells or other abnormal cells, or, in the case of autoimmunity or pathological inflammation, normal human cells or tissues.

[0098] The term "immunotherapy" refers to the treatment of a subject suffering from a disease or at risk of suffering from or recurring with a disease by methods involving inducing, enhancing, suppressing, or otherwise modifying the immune response. Examples of immunotherapy include, but are not limited to, T cell therapy. T cell therapy includes adoptive T cell therapy, tumor infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACT), and allogeneic T cell transplantation.

[0099] Cells used in the immunotherapies described herein can be derived from sources known in the art. For example, T cells can be differentiated in vitro from a hematopoietic stem cell population, or T cells can be obtained from a subject. T cells can be obtained, for example, from peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. Furthermore, T cells can be obtained from one or more T cell lines available in the art. T cells can also be obtained from a unit of blood drawn from a subject using any number of techniques known to those skilled in the art, such as FICOLL™ separation and / or apheresis. Additional methods for isolating T cells for T cell therapy are disclosed in U.S. Patent Publication No. 2013 / 0287748, which is incorporated herein by reference in its entirety. Immunotherapy can also include administering modified cells to a subject, wherein the modified cells express CD4 and TCR as disclosed herein. In some embodiments, the modified cells are not T cells.

[0100] As used herein, a "patient" includes any human suffering from cancer (e.g., lymphoma or leukemia). The terms "subject" and "patient" are used interchangeably herein.

[0101] The terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids that a protein or peptide sequence may contain. A polypeptide includes any peptide or protein containing two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, commonly referred to in the art as peptides, oligopeptides, and oligomers, as well as longer chains, of which there are many varieties, commonly referred to in the art as proteins. "Polypeptides" include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, and fusion proteins, among others. The polypeptide may be a natural peptide, a recombinant peptide, a synthetic peptide, or a combination thereof.

[0102] As used herein, "stimulation" refers to a primary response induced by the binding of a stimulatory molecule to its cognate ligand, mediating a signal transduction event. A "stimulatory molecule" is a molecule on a T cell, e.g., a T cell receptor (TCR) / CD4 complex, that specifically binds to a cognate stimulatory ligand present on an antigen-presenting cell. A "stimulatory ligand" is a ligand that, when present on an antigen-presenting cell (e.g., an aAPC, a dendritic cell, a B cell, etc.), specifically binds to a stimulatory molecule on a T cell, thereby mediating a primary response by the T cell, including, but not limited to, activation, initiation of an immune response, proliferation, etc. Stimulatory ligands include, but are not limited to, MHC class II molecules bearing peptides, anti-CD4 antibodies, superagonist anti-CD2 antibodies, superagonist anti-CD28 antibodies, and superagonist anti-CD3 antibodies.

[0103] The terms "conditioning" and "preconditioning" are used interchangeably herein to refer to preparing a patient for T cell therapy. Conditioning used in the present invention includes, but is not limited to, reducing the number of endogenous lymphocytes, removing cytokine sinks, increasing serum levels of one or more homeostatic cytokines or proinflammatory factors, enhancing effector function of T cells administered after the conditioning, enhancing antigen-presenting cell activation and / or availability, or any combination thereof prior to T cell therapy. In one embodiment, "pretreatment" comprises increasing the serum levels of one or more cytokines, e.g., interleukin-7 (IL-7), interleukin-15 (IL-15), interleukin-10 (IL-10), interleukin-5 (IL-5), gamma-inducible protein 10 (IP-10), interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), placenta growth factor (PLGF), C-reactive protein (CRP), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular adhesion molecule 1 (sVCAM-1), or any combination thereof. In another embodiment, "pretreatment" comprises increasing the serum levels of IL-7, IL-15, IP-10, MCP-1, PLGF, CRP, or any combination thereof.

[0104] "Treatment" or "treating" a subject refers to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, for the purpose of reversing, alleviating, ameliorating, inhibiting, slowing, or preventing the onset, progression, development, symptom severity, or recurrence of a symptom, complication, or condition, or biochemical manifestations associated with a disease. In one embodiment, "treatment" or "treating" includes partial remission. In another embodiment, "treatment" or "treating" includes complete remission.

[0105] The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination of the alternatives. As used herein, the indefinite article "a" or "an" should be understood to refer to "one or more" of the listed or shown components.

[0106] The terms "about" or "essentially comprising" refer to a value or composition that is within an acceptable error range of a particular value or composition as determined by one of ordinary skill in the art, which depends in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "essentially comprising" can mean within one standard deviation or more than one standard deviation, per practice in the art. Alternatively, "about" or "essentially comprising" can mean a range of up to 10% (i.e., ±10%). For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%). Furthermore, particularly with respect to biological systems or processes, the term can mean a value up to an order of magnitude or up to five times greater. When a particular value or composition is provided in this application and claims, unless otherwise specified, the meaning of "about" or "essentially comprising" should be assumed to be within an acceptable error range of that particular value or composition.

[0107] As used herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and, where appropriate, fractions thereof (such as 1 / 10 and 1 / 100 of an integer), unless otherwise specified.

[0108] Various aspects of the invention are described in further detail in the following subsections.

[0109] II. Methods of the Disclosure The present disclosure relates to methods for identifying MHC class II-specific TCRs, the methods comprising contacting T cells with a complex comprising (i) an HLA class II molecule with enhanced CD4 binding, and (ii) a peptide, e.g., an epitope. In certain embodiments, the T cells express CD4. In certain embodiments, the T cells express one or more TCRs. In some embodiments, the MHC class II-specific TCR specifically binds to a complex comprising an MHC class II molecule and a peptide.

[0110] In some embodiments, the MHC class II molecule comprises an alpha chain and a beta chain, wherein the alpha chain, the beta chain, or both the alpha and beta chains comprise an amino acid sequence that has one or more mutations compared to the wild-type alpha chain and / or beta chain of the MHC class II molecule. In some embodiments, the alpha chain comprises an amino acid sequence that has one or more mutations compared to the wild-type alpha chain of the MHC class II molecule. In some embodiments, the beta chain comprises an amino acid sequence that has one or more mutations compared to the wild-type beta chain of the MHC class II molecule. In some embodiments, the alpha chain comprises an amino acid sequence that has one or more mutations compared to the wild-type alpha chain of the MHC class II molecule, and the beta chain comprises an amino acid sequence that has one or more mutations compared to the wild-type beta chain of the MHC class II molecule.

[0111] In some embodiments, the one or more mutations comprise a substitution mutation. In some embodiments, the one or more mutations comprise a deletion mutation. In some embodiments, the one or more mutations comprise an insertion mutation. In some embodiments, the one or more mutations comprise a substitution of a single amino acid with one or more heterologous amino acids. In some embodiments, the one or more mutations comprise a substitution of a single amino acid with different amino acids. In some embodiments, the one or more mutations comprise a substitution of a single amino acid with two different amino acids, three different amino acids, four different amino acids, five different amino acids, or more than five different amino acids.

[0112] In some embodiments, the MHC class II molecule is a dimer. In some embodiments, the MHC class II molecule is a trimer. In some embodiments, the MHC class II molecule is a tetramer.

[0113] Certain embodiments of the present disclosure relate to methods for enriching a target population of T cells obtained from a human subject. In some embodiments, the method comprises contacting the T cells with an HLA class II molecule disclosed herein. In some embodiments, the method comprises contacting the T cells with a cell, e.g., an APC, disclosed herein. In some embodiments, after contacting, the enriched population of T cells comprises a greater number of T cells capable of binding to HLA class II molecules compared to the number of T cells capable of binding to HLA class II molecules before contacting.

[0114] Some embodiments of the present disclosure relate to methods for selecting T cells capable of targeting diseased cells, e.g., tumor cells. In some embodiments, the methods include contacting a population of in vitro isolated T cells with a complex comprising an MHC class II molecule disclosed herein and a fragment of a polypeptide, e.g., an antigen expressed on diseased cells, e.g., a tumor-expressed polypeptide, e.g., an epitope.

[0115] In some embodiments, the T cells used in the methods disclosed herein are obtained from a human subject. The T cells obtained from a human subject can be any T cells disclosed herein. In some embodiments, the T cells obtained from a human subject are tumor-infiltrating lymphocytes (TILs).

[0116] In some embodiments, the method further comprises selecting T cells bound by an MHC class II molecule. In some embodiments, the method further comprises administering the enriched T cells to a human subject. In some embodiments, the subject is primed prior to receiving the T cells as described herein.

[0117] In some embodiments, the method further comprises isolating the TCR bound to the MHC class II molecule. In some embodiments, the method further comprises sequencing the TCR. In some embodiments, the method further comprises cloning the TCR. In some embodiments, the method further comprises recombinantly expressing the TCR or an engineered variant thereof in a host cell. In some embodiments, the host cell is an immune cell, e.g., a T cell. In some embodiments, the method further comprises administering the host cell to a subject. In some embodiments, the subject has cancer, and the host cell comprising the TCR treats the cancer in the subject.

[0118] II.A. MHC class II molecules The human leukocyte antigen (HLA) system (human major histocompatibility complex [MHC]) is an important part of the immune system and is controlled by genes on chromosome 6. It encodes cell surface molecules specialized for presenting antigenic peptides to the TCR on T cells (see Immune System Overview). MHC molecules that present antigens (Ags) are divided into two classes: class I MHC molecules and class II MHC molecules.

[0119] MHC class II molecules are present as transmembrane glycoproteins on the surface of professional antigen-presenting cells (APCs). Intact class II molecules are composed of an alpha chain and a beta chain. Three loci in the HLA complex encode MHC class II proteins: HLA-DP, HLA-DQ, and HLA-DR. T cells expressing CD4 molecules react with MHC class II molecules. These lymphocytes often have effector and helper functions, activating responses to eliminate autologous cells infected with intracellular pathogens or destroy extracellular parasites, and providing support to other T cells, such as CD8 T cells. Because only professional APCs express MHC class II molecules, only these cells present antigens to CD4 T cells (CD4 binds to the non-polymorphic portions of the alpha2 and beta2 domains of the alpha and beta chains of MHC class II molecules, respectively).

[0120] In some embodiments, the HLA class II alpha and beta chains are selected from HLA-DP, HLA-DQ, and HLA-DR alleles. In certain embodiments, the HLA class II beta chain is an HLA-DP allele. In certain embodiments, the HLA class II alpha chain is an HLA-DP allele. In certain embodiments, the HLA class II beta chain is an HLA-DQ allele. In certain embodiments, the HLA class II alpha chain is an HLA-DQ allele. In certain embodiments, the HLA class II beta chain is an HLA-DR allele. In certain embodiments, the HLA class II alpha chain is an HLA-DR allele.

[0121] II.A.1. HLA-DP molecules Many HLA-DP alleles are known in the art, and any known alleles can be used in the methods of the present disclosure. Examples of HLA-DP alpha and beta chain alleles are shown in Table 3. An updated list of HLA alleles is available at hla.alleles.org / (last visited February 27, 2019). [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0122] II.A.1.a. HLA-DP beta chain In certain embodiments, the HLA class II molecule comprises a DP beta chain, wherein the DP beta chain comprises an amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1. Any amino acid other than leucine may be present at the amino acid residue corresponding to position 112 of SEQ ID NO: 1. In some embodiments, the amino acid other than leucine is an amino acid comprising a hydrophobic side chain. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is an amino acid selected from alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is alanine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is valine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is isoleucine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is methionine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is phenylalanine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is tyrosine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is tryptophan.

[0123] In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is made up of two or more amino acids, e.g., two amino acids, three amino acids, four amino acids, five amino acids, or more. In some embodiments, at least one of the two or more amino acids comprises a hydrophobic side chain. In certain embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a hydrophobic side chain.

[0124] In certain embodiments, the HLA class II molecule comprises a DP beta chain, wherein the DP beta chain comprises an amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1. Any amino acid other than valine may be present at the amino acid residue corresponding to position 141 of SEQ ID NO: 1. In some embodiments, the amino acid other than valine is an amino acid comprising a hydrophobic side chain. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is an amino acid selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is alanine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is isoleucine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is leucine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is methionine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is phenylalanine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is tyrosine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is tryptophan.

[0125] In some embodiments, the non-valine amino acid residue at position 141 of SEQ ID NO: 1 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a hydrophobic side chain. In certain embodiments, the non-valine amino acid residue at position 141 of SEQ ID NO: 1 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a hydrophobic side chain.

[0126] In certain embodiments of the present disclosure, the MHC class II molecule comprises a DP beta chain that comprises two or more substitution mutations compared to the wild-type DP beta chain.In certain embodiments, the DP beta chain comprises at least two mutations, at least three mutations, at least four mutations, at least five mutations, at least six mutations, at least seven mutations, at least eight mutations, at least nine mutations, or at least ten mutations compared to the wild-type DP beta chain.

[0127] In certain embodiments, the DP beta chain comprises an amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 and an amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1. In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1, (ii) the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1, or each of the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 and the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is an amino acid comprising a hydrophobic side chain. In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1 is selected from alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan; and (ii) the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1 is selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan.

[0128] In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO:1 is tryptophan; and (ii) the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO:1 is selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO:1 is selected from alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan; and (ii) the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO:1 is methionine. In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO:1 is tryptophan; and (ii) the amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO:1 is methionine.

[0129] In certain embodiments, the DP beta chain further comprises an amino acid other than valine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1. In some embodiments, the amino acid other than valine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1 is selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1 is methionine.

[0130] In certain embodiments, the DP beta chain further comprises an amino acid other than methionine at the amino acid residue corresponding to position 158 of SEQ ID NO: 1. In some embodiments, the amino acid other than methionine at the amino acid residue corresponding to position 158 of SEQ ID NO: 1 is selected from alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan. In certain embodiments, the amino acid other than methionine at the amino acid residue corresponding to position 158 of SEQ ID NO: 1 is isoleucine.

[0131] In some embodiments, the DP beta chain comprises (i) an amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1, and (ii) an amino acid other than valine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1. In some embodiments, the DP beta chain comprises (i) an amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1, and (ii) an amino acid other than methionine at the amino acid residue corresponding to position 158 of SEQ ID NO: 1.

[0132] In some embodiments, the DP beta chain comprises (i) a tryptophan at the amino acid residue corresponding to position 112 of SEQ ID NO: 1, and (ii) a methionine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1. In some embodiments, the DP beta chain comprises (i) a tryptophan at the amino acid residue corresponding to position 112 of SEQ ID NO: 1, and (ii) an isoleucine at the amino acid residue corresponding to position 158 of SEQ ID NO: 1.

[0133] In some embodiments, the DP beta chain comprises (i) an amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO:1, and (ii) an amino acid other than valine at the amino acid residue corresponding to position 114 of SEQ ID NO:1. In some embodiments, the DP beta chain comprises (i) an amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO:1, and (ii) an amino acid other than methionine at the amino acid residue corresponding to position 158 of SEQ ID NO:1.

[0134] In some embodiments, the DP beta chain comprises (i) a methionine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1, and (ii) an amino acid other than valine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1. In some embodiments, the DP beta chain comprises (i) a methionine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1, and (ii) an isoleucine at the amino acid residue corresponding to position 158 of SEQ ID NO: 1.

[0135] In some embodiments, the DP beta chain comprises (i) an amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO:1, and (ii) an amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO:1, (iii) an amino acid other than valine at the amino acid residue corresponding to position 114 of SEQ ID NO:1, and (iv) an amino acid other than methionine at the amino acid residue corresponding to position 158 of SEQ ID NO:1.

[0136] In some embodiments, the DP beta chain comprises (i) a tryptophan at the amino acid residue corresponding to position 112 of SEQ ID NO:1, (ii) a methionine at the amino acid residue corresponding to position 141 of SEQ ID NO:1, (iii) a methionine at the amino acid residue corresponding to position 114 of SEQ ID NO:1, and (iv) an isoleucine at the amino acid residue corresponding to position 158 of SEQ ID NO:1.

[0137] In some embodiments, the DP beta chain comprises a valine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1. In some embodiments, the DP beta chain comprises a methionine at the amino acid residue corresponding to the corresponding position 158 of SEQ ID NO: 1. In some embodiments, the DP beta chain comprises (i) an amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1, (ii) an amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1, and (iii) a valine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1. In some embodiments, the DP beta chain comprises (i) an amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1, (ii) an amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1, and (iii) a methionine at the amino acid residue corresponding to the corresponding position 158 of SEQ ID NO: 1. In some embodiments, the DP beta chain comprises (i) an amino acid other than leucine at the amino acid residue corresponding to position 112 of SEQ ID NO:1, (ii) an amino acid other than valine at the amino acid residue corresponding to position 141 of SEQ ID NO:1, (iii) a valine at the amino acid residue corresponding to position 114 of SEQ ID NO:1, and (iv) a methionine at the amino acid residue corresponding to the corresponding position 158 of SEQ ID NO:1.

[0138] In some embodiments, the DP beta chain comprises (i) a tryptophan at the amino acid residue corresponding to position 112 of SEQ ID NO:1, (ii) a methionine at the amino acid residue corresponding to position 141 of SEQ ID NO:1, and (iii) a valine at the amino acid residue corresponding to position 114 of SEQ ID NO:1. In some embodiments, the DP beta chain comprises (i) a tryptophan at the amino acid residue corresponding to position 112 of SEQ ID NO:1, (ii) a methionine at the amino acid residue corresponding to position 141 of SEQ ID NO:1, and (iii) a methionine at the amino acid residue corresponding to the corresponding position 158 of SEQ ID NO:1. In some embodiments, the DP beta chain comprises (i) a tryptophan at the amino acid residue corresponding to position 112 of SEQ ID NO:1, (ii) a methionine at the amino acid residue corresponding to position 141 of SEQ ID NO:1, (iii) a valine at the amino acid residue corresponding to position 114 of SEQ ID NO:1, and (iv) a methionine at the amino acid residue corresponding to the corresponding position 158 of SEQ ID NO:1.

[0139] In some embodiments, the DP beta chain comprises (i) a tryptophan at the amino acid residue corresponding to position 112 of SEQ ID NO:1, (ii) a methionine at the amino acid residue corresponding to position 141 of SEQ ID NO:1, (iii) a methionine at the amino acid residue corresponding to position 114 of SEQ ID NO:1, and (iv) an isoleucine at the amino acid residue corresponding to position 158 of SEQ ID NO:1.

[0140] In certain embodiments, the DP beta chains described herein have a higher affinity for CD4 protein compared to a reference HLA class II molecule. In some embodiments, the reference HLA class II molecule is an HLA class II molecule having a wild-type DP beta chain. In some embodiments, the reference HLA class II molecule is an HLA class II molecule having a DP beta chain containing (i) a leucine at the amino acid residue corresponding to position 112 of SEQ ID NO: 1, and / or (ii) a valine at the amino acid residue corresponding to position 141 of SEQ ID NO: 1.

[0141] In some embodiments, the enhanced affinity for CD4 is at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold, at least about 75-fold, at least about 100-fold, at least about 200-fold, at least about 300-fold, at least about 400-fold, at least about 500-fold, at least about 1000-fold, at least about 1500-fold, at least about 2000-fold, at least about 2500-fold, at least about 3000-fold, at least about 3500-fold, at least about 4000-fold, at least about 4500-fold, or at least about 4000-fold greater than the affinity of a reference HLA class II molecule for CD4.

[0142] In some embodiments, the enhanced affinity for CD4 is at least about 1.5 times to at least about 5000 times, 1.5 times to at least about 4000 times, 1.5 times to at least about 3000 times, 1.5 times to at least about 2000 times, 1.5 times to at least about 1000 times, 10 times to at least about 5000 times, 10 times to at least about 4000 times, 10 times to at least about 3000 times, 10 times to at least about 2000 times, 10 times to at least about 1000 times, 10 times to at least about 900 times, 10 times to at least about 800 times, 10 times to at least about 700 times, 10 times to at least about 600 times, 10 times at least about 500 times, 10 times to at least about 400 times, 10 times to at least about 300 times, 10 times to at least about 200 times, 10 times to at least about 100 times, 100 times to at least about 5000 times, 100 times to at least about 4000 times, 100 times to at least about 3000 times, 100 times to at least about 2000 times, 100 times to at least about 1000 times, 100 times to at least about 900 times, 100 times to at least about 800 times, 100 times to at least about 700 times, 100 times to at least about 600 times, 100 times to at least about 500 times, 100 times to at least about 400 times, 100 times to at least about 300 times, or 100 times to at least about 200 times higher.

[0143] In certain embodiments, the DP beta chain is selected from the group consisting of DPB1*01, DPB1*02, DPB1*03, DPB1*04, DPB1*05, DPB1*06, DPB1*08, DPB1*09, DPB1*10, DPB1*100, DPB1*101, DPB1*102, DPB1*103, DPB1*104, DPB1*105, DPB1*106, DPB1*107, DPB1*108, DPB1*109, DPB1*11, DPB1*110, DPB1*111, DPB1*112, DPB1*113, DPB1*114, DPB1*115, DPB1 *116, DPB1*117, DPB1*118, DPB1*119, DPB1*120, DPB1*121, DPB1*122, DPB1*123, DPB1*124, DPB1*125, DPB1*126, DPB1*127, DPB1*128, DPB1*129, DP B1*13, DPB1*130, DPB1*131, DPB1*132, DPB1*133, DPB1*134, DPB1*135, DPB1*136, DPB1*137, DPB1*138, DPB1*139, DPB1*14, DPB1*140, DPB1*141, DP B1*142, DPB1*143, DPB1*144, DPB1*145, DPB1*146, DPB1*147, DPB1*148, DPB1*149, DPB1*15, DPB1*150, DPB1*151, DPB1*152, DPB1*153, DPB1*154, D PB1*155, DPB1*156, DPB1*157, DPB1*158, DPB1*159, DPB1*16, DPB1*160, DPB1*161, DPB1*162, DPB1*163, DPB1*164, DPB1*165, DPB1*166, DPB1*167, DPB1*168, DPB1*169, DPB1*17, DPB1*170, DPB1*171, DPB1*172, DPB1*173, DPB1*174, DPB1*175, DPB1*176, DPB1*177, DPB1*178, DPB1*179, DPB1*18, DPB1*180, DPB1*181, DPB1*182, DPB1*183, DPB1*184, DPB1*185, DPB1*186, DPB1*187, DPB1*188, DPB1*189, DPB1*19, DPB1*190, DPB1*191, DPB1*192,DPB1*193、DPB1*194、DPB1*195、DPB1*196、DPB1*197、DPB1*198、DPB1*199、DPB1*20、DPB1*200、DPB1*201、DPB1*202、DPB1*203、DPB1*204、DPB1*205、DPB1*206、DPB1*207、DPB1*208、DPB1*209、DPB1*21、DPB1*210、DPB1*211、DPB1*212、DPB1*213、DPB1*214、DPB1*215、DPB1*216、DPB1*217、DPB1*218、DPB1*219、DPB1*22、DPB1*220、DPB1*221、DPB1*222、DPB1*223、DPB1*224、DPB1*225、DPB1*226、DPB1*227、DPB1*228、DPB1*229、DPB1*23、DPB1*230、DPB1*231、DPB1*232、DPB1*233、DPB1*234、DPB1*235、DPB1*236、DPB1*237、DPB1*238、DPB1*239、DPB1*24、DPB1*240、DPB1*241、DPB1*242、DPB1*243、DPB1*244、DPB1*245、DPB1*246、DPB1*247、DPB1*248、DPB1*249、DPB1*25、DPB1*250、DPB1*251、DPB1*252、DPB1*253、DPB1*254、DPB1*255、DPB1*256、DPB1*257、DPB1*258、DPB1*259、DPB1*26、DPB1*260、DPB1*261、DPB1*262、DPB1*263、DPB1*264、DPB1*265、DPB1*266、DPB1*267、DPB1*268、DPB1*269、DPB1*27、DPB1*270、DPB1*271、DPB1*272、DPB1*273、DPB1*274、DPB1*275、DPB1*276、DPB1*277、DPB1*278、DPB1*279、DPB1*28、DPB1*280、DPB1*281、DPB1*282、DPB1*283、DPB1*284、DPB1*285、DPB1*286、DPB1*287、DPB1*288、DPB1*289、DPB1*29、DPB1*290、DPB1*291、DPB1*292、DPB1*293、DPB1*294、DPB1*295、DPB1*296、DPB1*297、DPB1*298、DPB1*299、DPB1*30、DPB1*300、DPB1*301、DPB1*302、DPB1*303、DPB1*304、DPB1*305、DPB1*306、DPB1*307、DPB1*308、DPB1*309、DPB1*31、DPB1*310、DPB1*311、DPB1*312、DPB1*313、DPB1*314、DPB1*315、DPB1*316、DPB1*317、DPB1*318、DPB1*319、DPB1*32、DPB1*320、DPB1*321、DPB1*322、DPB1*323、DPB1*324、DPB1*325、DPB1*326、DPB1*327、DPB1*328、DPB1*329、DPB1*33、DPB1*330、DPB1*331、DPB1*332、DPB1*333、DPB1*334、DPB1*335、DPB1*336、DPB1*337、DPB1*338、DPB1*339、DPB1*34、DPB1*340、DPB1*341、DPB1*342、DPB1*343、DPB1*344、DPB1*345、DPB1*346、DPB1*347、DPB1*348、DPB1*349、DPB1*35、DPB1*350、DPB1*351、DPB1*352、DPB1*353、DPB1*354、DPB1*355、DPB1*356、DPB1*357、DPB1*358、DPB1*359、DPB1*36、DPB1*360、DPB1*361、DPB1*362、DPB1*363、DPB1*364、DPB1*365、DPB1*366、DPB1*367、DPB1*368、DPB1*369、DPB1*37、DPB1*370、DPB1*371、DPB1*372、DPB1*373、DPB1*374、DPB1*375、DPB1*376、DPB1*377、DPB1*378、DPB1*379、DPB1*38、DPB1*380、DPB1*381、DPB1*382、DPB1*383、DPB1*384、DPB1*385、DPB1*386、DPB1*387、DPB1*388、DPB1*389、DPB1*39、DPB1*390、DPB1*391、DPB1*392、DPB1*393、DPB1*394、DPB1*395、DPB1*396、DPB1*397、DPB1*398、DPB1*399、DPB1*40、DPB1*400、DPB1*401、DPB1*402、DPB1*403、DPB1*404、DPB1*405、DPB1*406、DPB1*407、DPB1*408、DPB1*409、DPB1*41、DPB1*410、DPB1*411、DPB1*412、DPB1*413、DPB1*414、DPB1*415、DPB1*416、DPB1*417、DPB1*418、DPB1*419、DPB1*420、DPB1*421、DPB1*422、DPB1*423、DPB1*424、DPB1*425、DPB1*426、DPB1*427、DPB1*428、DPB1*429、DPB1*430、DPB1*431、DPB1*432、DPB1*433、DPB1*434、DPB1*435、DPB1*436、DPB1*437、DPB1*438、DPB1*439、DPB1*44、DPB1*440、DPB1*441、DPB1*442、DPB1*443、DPB1*444、DPB1*445、DPB1*446、DPB1*447、DPB1*448、DPB1*449、DPB1*45、DPB1*450、DPB1*451、DPB1*452、DPB1*453、DPB1*454、DPB1*455、DPB1*456、DPB1*457、DPB1*458、DPB1*459、DPB1*46、DPB1*460、DPB1*461、DPB1*462、DPB1*463、DPB1*464、DPB1*465、DPB1*466、DPB1*467、DPB1*468、DPB1*469、DPB1*47、DPB1*470、DPB1*471、DPB1*472、DPB1*473、DPB1*474、DPB1*475、DPB1*476、DPB1*477、DPB1*478、DPB1*479、DPB1*48、DPB1*480、DPB1*481、DPB1*482、DPB1*483、DPB1*484、DPB1*485、DPB1*486、DPB1*487、DPB1*488、DPB1*489、DPB1*49、DPB1*490、DPB1*491、DPB1*492、DPB1*493、DPB1*494、DPB1*495、DPB1*496、DPB1*497、DPB1*498、DPB1*499、DPB1*50、DPB1*500、DPB1*501、DPB1*502、DPB1*503、DPB1*504、DPB1*505、DPB1*506、DPB1*507、DPB1*508、DPB1*509、DPB1*51、DPB1*510、DPB1*511、DPB1*512、DPB1*513、DPB1*514、DPB1*515、DPB1*516、DPB1*517、DPB1*518、DPB1*519、DPB1*52、DPB1*520、DPB1*521、DPB1*522、DPB1*523、DPB1*524、DPB1*525、DPB1*526、DPB1*527、DPB1*528、DPB1*529、DPB1*53、DPB1*530、DPB1*531、DPB1*532、DPB1*533、DPB1*534、DPB1*535、DPB1*536、DPB1*537、DPB1*538、DPB1*539、DPB1*54、DPB1*540、DPB1*541、DPB1*542、DPB1*543、DPB1*544、DPB1*545、DPB1*546、DPB1*547、DPB1*548、DPB1*549、DPB1*55、DPB1*550、DPB1*551、DPB1*552、DPB1*553、DPB1*554、DPB1*555、DPB1*556、DPB1*557、DPB1*558、DPB1*559、DPB1*56、DPB1*560、DPB1*561、DPB1*562、DPB1*563、DPB1*564、DPB1*565、DPB1*566、DPB1*567、DPB1*568、DPB1*569、DPB1*57、DPB1*570、DPB1*571、DPB1*572、DPB1*573、DPB1*574、DPB1*575、DPB1*576、DPB1*577、DPB1*578、DPB1*579、DPB1*58、DPB1*580、DPB1*581、DPB1*582、DPB1*583、DPB1*584、DPB1*585、DPB1*586、DPB1*587、DPB1*588、DPB1*589、DPB1*59、DPB1*590、DPB1*591、DPB1*592、DPB1*593、DPB1*594、DPB1*595、DPB1*596、DPB1*597、DPB1*598、DPB1*599、DPB1*60、DPB1*600、DPB1*601、DPB1*602、DPB1*603、DPB1*604、DPB1*605、DPB1*606、DPB1*607、DPB1*608、DPB1*609、DPB1*61、DPB1*610、DPB1*611、DPB1*612、DPB1*613、DPB1*614、DPB1*615、 DPB1*616、DPB1*617、DPB1*618、DPB1*619、DPB1*62、DPB1*620、DPB1*621、DPB1*622、DPB1*623、DPB1*624、DPB1*625、DPB1*626、DPB1*627、DPB1*628、DPB1*629、DPB1*63、DPB1*630、DPB1*631、DPB1*632、DPB1*633、DPB1*634、DPB1*635、DPB1*636、DPB1*637、DPB1*638、DPB1*639、DPB1*64、DPB1*640、DPB1*641、DPB1*642、DPB1*643、DPB1*644、DPB1*645、DPB1*646、DPB1*647、DPB1*648、DPB1*649、DPB1*65、DPB1*650、DPB1*651、DPB1*652、DPB1*653、DPB1*654、DPB1*655、DPB1*656、DPB1*657、DPB1*658、DPB1*659、DPB1*66、DPB1*660、DPB1*661、DPB1*662、DPB1*663、DPB1*664、DPB1*665、DPB1*666、DPB1*667、DPB1*668、DPB1*669、DPB1*67、DPB1*670、DPB1*671、DPB1*672、DPB1*673、DPB1*674、DPB1*675、DPB1*676、DPB1*677、DPB1*678、DPB1*679、DPB1*68、DPB1*680、DPB1*681、DPB1*682、DPB1*683、DPB1*684、DPB1*685、DPB1*686、DPB1*687、DPB1*688、DPB1*689、DPB1*69、DPB1*690、DPB1*691、DPB1*692、DPB1*693、DPB1*694、DPB1*695、DPB1*696、DPB1*697、DPB1*698、DPB1*699、DPB1*70、DPB1*700、DPB1*701、DPB1*702、DPB1*703、DPB1*704、DPB1*705、DPB1*706、DPB1*707、DPB1*708、DPB1*709、DPB1*71、DPB1*710、DPB1*711、DPB1*712、DPB1*713、DPB1*714、DPB1*715、DPB1*716、DPB1*717、DPB1*718、DPB1*719、DPB1*72、DPB1*720、DPB1*721、DPB1*722、DPB1*723、DPB1*724、DPB1*725、DPB1*726、DPB1*727、DPB1*728、DPB1*729、DPB1*73、DPB1*730、DPB1*731、DPB1*732、DPB1*733、DPB1*734、DPB1*735、DPB1*736、DPB1*737、DPB1*738、DPB1*739、DPB1*74、DPB1*740、DPB1*741、DPB1*742、DPB1*743、DPB1*744、DPB1*745、DPB1*746、DPB1*747、DPB1*748、DPB1*749、DPB1*75、DPB1*750、DPB1*751、DPB1*752、DPB1*753、DPB1*754、DPB1*755、DPB1*756、DPB1*757、DPB1*758、DPB1*759、DPB1*76、DPB1*760、DPB1*761、DPB1*762、DPB1*763、DPB1*764、DPB1*765、DPB1*766、DPB1*767、DPB1*768、DPB1*769、DPB1*77、DPB1*770、DPB1*771、DPB1*772、DPB1*773、DPB1*774、DPB1*775、DPB1*776、DPB1*777、DPB1*778、DPB1*779、DPB1*78、DPB1*780、DPB1*781、DPB1*782、DPB1*783、DPB1*784、DPB1*785、DPB1*786、DPB1*787、DPB1*788、DPB1*789、DPB1*79、DPB1*790、DPB1*791、DPB1*792、DPB1*794、DPB1*795、DPB1*796、DPB1*797、DPB1*798、DPB1*799、DPB1*80、DPB1*800、DPB1*801、DPB1*802、DPB1*803、DPB1*804、DPB1*805、DPB1*806、DPB1*807、DPB1*808、DPB1*809、DPB1*81、DPB1*810、DPB1*811、DPB1*812、DPB1*813、DPB1*814、DPB1*815、DPB1*816、DPB1*817、DPB1*818、DPB1*819、DPB1*82、DPB1*820、DPB1*821、DPB1*822、DPB1*823、DPB1*824、DPB1*825、DPB1*826、DPB1*827、DPB1*828、DPB1*829、DPB1*83、DPB1*830、DPB1*831、DPB1*832、DPB1*833、DPB1*834、DPB1*835、DPB1*836、DPB1*837、DPB1*838、DPB1*839、DPB1*84、DPB1*840、DPB1*841、DPB1*842、DPB1*843、DPB1*844、DPB1*845、DPB1*846、DPB1*847、DPB1*848、DPB1*849、DPB1*85、DPB1*850、DPB1*851、DPB1*852、DPB1*853、DPB1*854、DPB1*855、DPB1*856、DPB1*857、DPB1*858、DPB1*859、DPB1*86、DPB1*860、DPB1*861、DPB1*862、DPB1*863、DPB1*864、DPB1*865、DPB1*866、DPB1*867、DPB1*868、DPB1*869、DPB1*87、DPB1*870、DPB1*871、DPB1*872、DPB1*873、DPB1*874、DPB1*875、DPB1*876、DPB1*877、DPB1*878、DPB1*879、DPB1*88、DPB1*880、DPB1*881、DPB1*882、DPB1*883、DPB1*884、DPB1*885、DPB1*886、DPB1*887、DPB1*888、DPB1*889、DPB1*89、DPB1*890、DPB1*891、DPB1*892、DPB1*893、DPB1*894、DPB1*895、DPB1*896、DPB1*897、DPB1*898、DPB1*899、DPB1*90、DPB1*900、DPB1*901、DPB1*902、DPB1*903、DPB1*904、DPB1*905、DPB1*906、DPB1*907、DPB1*908、DPB1*909、DPB1*91、DPB1*910、DPB1*911、DPB1*912、DPB1*913、DPB1*914、DPB1*915、DPB1*916、DPB1*917、DPB1*918、DPB1*919、DPB1*92、DPB1*920、DPB1*921、DPB1*922, DPB1*923, DPB1*924, DPB1*925, DPB1*926, DPB1*927, DPB1*928, DPB1*929, DPB1*93, DPB1*930, DPB1*931, DPB1*932, DPB1*933, D PB1*934, DPB1*935, DPB1*936, DPB1*937, DPB1*938, DPB1*939, DPB1*94, DPB1*940, DPB1*941, DPB1*942, DPB1*943, DPB1*944, DPB1*945, DP DPB1*960, DPB1*961, DPB1*962, DPB1*963, DPB1*964, DPB1*965, DPB1*97, DPB1*98, and DPB1*99. In some embodiments, the DP beta chain comprises an HLA-DPB1*01, HLA-DPB1*02, HLA-DPB1*03, HLA-DPB1*04, HLA-DPB1*05, HLA-DPB1*06, HLA-DPB1*08, or HLA-DPB1*09 allele. In certain embodiments, the DP beta chain comprises an HLA-DPB1*04 allele. In certain embodiments, the DP beta chain comprises an HLA-DPB1*04:01 allele.

[0144] In certain embodiments, the MHC class II molecule comprises a DP beta chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:3, wherein the DP beta chain comprises a tryptophan at the amino acid residue corresponding to position 112 of SEQ ID NO:1, and the DP beta chain comprises a methionine at the amino acid residue corresponding to position 141 of SEQ ID NO:1. In certain embodiments, an MHC class II molecule comprises a DP beta chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:3, wherein the DP beta chain comprises (i) a tryptophan at the amino acid residue corresponding to position 112 of SEQ ID NO:1, (ii) a methionine at the amino acid residue corresponding to position 141 of SEQ ID NO:1, (iii) a valine at the amino acid residue corresponding to position 114 of SEQ ID NO:1, and (iv) a methionine at the amino acid residue corresponding to the corresponding position 158 of SEQ ID NO:1. In certain embodiments, an MHC class II molecule comprises a DP beta chain comprising the amino acid sequence set forth in SEQ ID NO:3.

[0145] II.A.1.a. HLA-DP alpha chain In some embodiments of the present disclosure, the MHC class II molecule further comprises an alpha chain. In some embodiments, the alpha chain is a wild-type alpha chain. In some embodiments, the alpha chain is a DP alpha chain. Any DP alpha chain may be used in the compositions and methods of the present disclosure. In some embodiments, the DP alpha chain comprises an HLA-DPA1*01, HLA-DPA1*02, HLA-DPA1*03, or HLA-DPA1*04 allele. In certain embodiments, the DP alpha chain comprises an HLA-DPA1*01 allele. In certain embodiments, the DP alpha chain comprises an HLA-DPA1*02 allele. In certain embodiments, the DP alpha chain comprises an HLA-DPA1*03 allele. In certain embodiments, the DP alpha chain comprises an HLA-DPA1*04 allele.

[0146] In certain embodiments, the DP alpha chain is DPA1*01:03:01:01, DPA1*01:03:01:02, DPA1*01:03:01:03, DPA1*01:03:01:04, DPA1*01:03:01:05, DPA1*01:03:01:06, DPA1*01:03:01:07, DPA1*01:03:01:08, DPA1*01:03:01:09, DPA1*01:03:01:10, DPA1*01:03:01:11, DPA1*01:03:01:12, DPA1*01:03:01:13, DPA1*01:03:01:14, DPA1*01:03:01:15, DPA1*01:03:01:16, DPA1*01:03:01:17, DPA1*01:03:01:18Q, DPA1*01:03:01:19, DPA1*01:03:01:20, DPA1*01:03:01:21, DPA1*01:03:01:22, DPA1*01:03:01:23, DPA1*01:03:02, DPA1*01:03:03, DPA1*01:03:04, DPA1*01:03:05, DPA1*01:03:06, DPA1*01:03:07, DPA1*01:03:08, DPA1*01:03:09, DPA1*01:04, DPA1*01:05, DPA1*01:06:01, DPA1*01:06:02, DPA1*01:07, DPA1*01:08, DPA1*01:09, DPA1*01:10, DPA1*01:11, DPA1*01:12, DPA1*01:13, DPA1*01:14, DPA1*01:15, DPA1*01:16, DPA1*01:17, DPA1*01:18, DPA1*01:19, DPA1*02:01:01:01, DPA1*02:01:01:02, DPA1*02:01:01:03, DPA1*02:01:01:04, DPA1*02:01:01:05, DPA1*02:01:01:06, DPA1*02:01:01:07, DPA1*02:01:01:08, DPA1*02:01:01:09, DPA1*02:01:01:10, DPA1*02:01:01:11, DPA1*02:01:02:01, DPA1*02:01:02:02, DPA1*02:01:03, DPA1*02:01:04, DPA1*02:01:05, DPA1*02:01:06,DPA1*02:01:07, DPA1*02:01:08:01, DPA1*02:01:08:02, DPA1*02:02:02:01, DPA1*02:02 :02:02, DPA1*02:02:02:03, DPA1*02:02:02:04, DPA1*02:02:02:05, DPA1*02:02:03, DPA 1*02:02:04, DPA1*02:02:05, DPA1*02:02:06, DPA1*02:03, DPA1*02:04, DPA1*02:05, DPA 1*02:06, DPA1*02:07:01:01, DPA1*02:07:01:02, DPA1*02:07:01:03, DPA1*02:08, DPA1* 02:09, DPA1*02:10, DPA1*02:11, DPA1*02:12, DPA1*02:13N, DPA1*02:14, DPA1*02:15, DP A1*02:16, DPA1*03:01:01:01, DPA1*03:01:01:02, DPA1*03:01:01:03, DPA1*03:01:01:0 4, DPA1*03:01:01:05, DPA1*03:01:02, DPA1*03:02, DPA1*03:03, DPA1*03:04, DPA1*04:01:01:01, DPA1*04:01:01:02, DPA1*04:01:01:03, DPA1*04:02, or any combination thereof.

[0147] In certain embodiments, an MHC class II molecule comprises a DP alpha chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:6. In certain embodiments, an MHC class II molecule comprises a DP alpha chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:8. In certain embodiments, an MHC class II molecule comprises a DP alpha chain comprising the amino acid sequence set forth in SEQ ID NO:6. In certain embodiments, an MHC class II molecule comprises a DP alpha chain comprising the amino acid sequence set forth in SEQ ID NO:8.

[0148] II.A.2.HLA-DQ molecule Many HLA-DQ alleles are known in the art, and any known alleles can be used in the present disclosure. Examples of HLA-DQ alpha and beta chain alleles are shown in Table 4. An updated list of HLA alleles is available at hla.alleles.org / (last visited July 10, 2019). [Table 4-1] [Table 4-2] [Table 4-3]

[0149] II.A.2.a. HLA-DQ beta chain In certain embodiments, the HLA class II molecule comprises a DQ beta chain, wherein the DQ beta chain comprises an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11. Any amino acid other than leucine may be present at the amino acid residue corresponding to position 114 of SEQ ID NO: 11. In some embodiments, the amino acid other than leucine is an amino acid comprising a hydrophobic side chain. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is an amino acid selected from alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is alanine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is valine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is isoleucine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is methionine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is phenylalanine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is tyrosine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is tryptophan.

[0150] In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a hydrophobic side chain. In certain embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a hydrophobic side chain.

[0151] In certain embodiments, the HLA class II molecule comprises a DQ beta chain, wherein the DQ beta chain comprises an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11. Any amino acid other than valine may be present at the amino acid residue corresponding to position 143 of SEQ ID NO: 11. In some embodiments, the amino acid other than valine is an amino acid comprising a hydrophobic side chain. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is an amino acid selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is alanine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is isoleucine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is leucine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is methionine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is phenylalanine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is tyrosine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is tryptophan.

[0152] In some embodiments, the non-valine amino acid residue at position 143 of SEQ ID NO: 11 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a hydrophobic side chain. In certain embodiments, the non-valine amino acid residue at position 143 of SEQ ID NO: 11 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a hydrophobic side chain.

[0153] In certain embodiments, the HLA class II molecule comprises a DQ beta chain, wherein the DQ beta chain comprises an amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11. Any amino acid other than asparagine may be present at the amino acid residue corresponding to position 110 of SEQ ID NO: 11. In some embodiments, the amino acid other than asparagine is an amino acid comprising a polar uncharged side chain. In certain embodiments, the amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11 is an amino acid selected from serine, threonine, and glutamine. In certain embodiments, the amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11 is serine. In certain embodiments, the amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11 is threonine. In certain embodiments, the amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11 is glutamine.

[0154] In some embodiments, the non-asparagine amino acid residue corresponding to position 110 of SEQ ID NO: 11 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a polar, uncharged side chain. In certain embodiments, the non-asparagine amino acid residue corresponding to position 110 of SEQ ID NO: 11 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a polar, uncharged side chain.

[0155] In certain embodiments, the HLA class II molecule comprises a DQ beta chain, wherein the DQ beta chain comprises an amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11. Any amino acid other than isoleucine may be present at the amino acid residue corresponding to position 116 of SEQ ID NO: 11. In some embodiments, the amino acid other than isoleucine is an amino acid comprising a hydrophobic side chain. In certain embodiments, the amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 is an amino acid selected from alanine, valine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In certain embodiments, the amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 is alanine. In certain embodiments, the amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 is valine. In certain embodiments, the amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 is leucine. In certain embodiments, the amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 is methionine. In certain embodiments, the amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 is phenylalanine. In certain embodiments, the amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 is tyrosine. In certain embodiments, the amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 is tryptophan.

[0156] In some embodiments, the non-isoleucine amino acid residue at position 116 of SEQ ID NO: 11 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a hydrophobic side chain. In certain embodiments, the non-isoleucine amino acid residue at position 116 of SEQ ID NO: 11 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a hydrophobic side chain.

[0157] In certain embodiments, the HLA class II molecule comprises a DQ beta chain, wherein the DQ beta chain comprises an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11. Any amino acid other than serine may be present at the amino acid residue corresponding to position 118 of SEQ ID NO: 11. In some embodiments, the amino acid other than serine is an amino acid comprising a charged side chain. In certain embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11 is an amino acid selected from arginine, histidine, and lysine. In certain embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11 is arginine. In certain embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11 is histidine. In certain embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11 is lysine.

[0158] In some embodiments, the amino acids other than the serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11 are made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a charged side chain. In certain embodiments, the amino acids other than the serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11 are made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a charged side chain.

[0159] In certain embodiments, the HLA class II molecule comprises a DQ beta chain, wherein the DQ beta chain comprises an amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11. Any amino acid other than proline may be present at the amino acid residue corresponding to position 146 of SEQ ID NO: 11. In some embodiments, the amino acid other than proline is an amino acid comprising a polar, uncharged side chain. In certain embodiments, the amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11 is an amino acid selected from serine, threonine, asparagine, and glutamine. In certain embodiments, the amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11 is serine. In certain embodiments, the amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11 is threonine. In certain embodiments, the amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11 is asparagine. In certain embodiments, the amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11 is glutamine.

[0160] In some embodiments, the non-proline amino acid at the amino acid residue corresponding to position 146 of SEQ ID NO: 11 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a polar, uncharged side chain. In certain embodiments, the non-proline amino acid at the amino acid residue corresponding to position 146 of SEQ ID NO: 11 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a polar, uncharged side chain.

[0161] In certain embodiments of the present disclosure, the MHC class II molecule comprises a DQ beta chain that comprises two or more substitution mutations compared to wild-type DQ beta chain.In certain embodiments, the DQ beta chain comprises at least two mutations, at least three mutations, at least four mutations, at least five mutations, at least six mutations, at least seven mutations, at least eight mutations, at least nine mutations, or at least ten mutations compared to wild-type DQ beta chain.

[0162] In certain embodiments, the DQ beta chain comprises an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 and an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11. In certain embodiments, the DQ beta chain comprises an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11, an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11, and at least three of the following: (i) an amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11, (ii) an amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11, (iii) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11, and (iv) an amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11.

[0163] In some embodiments, the DQ beta chain comprises (i) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:11, (ii) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:11, (iii) an amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO:11, (iv) an amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO:11, (v) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:11, and (vi) an amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO:11.

[0164] In some embodiments, (i) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11, (ii) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11, or each of the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 and the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is an amino acid comprising a hydrophobic side chain.

[0165] In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is selected from alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan, (ii) the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan, and (iii) the amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11 is selected from serine, suc ... (iv) the amino acids other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 are selected from alanine, valine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; (v) the amino acids other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11 are selected from arginine, histidine, and lysine; and (vi) the amino acids other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11 are selected from serine, threonine, asparagine, and glutamine.

[0166] In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is tryptophan, and (ii) the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is selected from alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan, and (ii) the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is methionine. In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is tryptophan, and (ii) the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is methionine. In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11 is tryptophan, (ii) the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11 is methionine, (iii) the amino acid other than asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11 is glutamine, (iv) the amino acid other than isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11 is valine, (v) the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11 is histidine, and (vi) the amino acid other than proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11 is glutamine.

[0167] In certain embodiments, the DQ beta chains described herein have a higher affinity for CD4 protein compared to a reference HLA class II molecule. In some embodiments, the reference HLA class II molecule is an HLA class II molecule having a wild-type DQ beta chain. In some embodiments, the reference HLA class II molecule is an HLA class II molecule having a DQ beta chain containing (i) a leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11, and / or (ii) a valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11. In some embodiments, the reference HLA class II molecule is an HLA class II molecule having a DQ beta chain comprising: (i) a leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 11; (ii) a valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11; (iii) an asparagine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11; (iv) an isoleucine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11; (v) a serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11; and (vi) a proline at the amino acid residue corresponding to position 146 of SEQ ID NO: 11.

[0168] In some embodiments, the enhanced affinity for CD4 is at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold, at least about 75-fold, at least about 100-fold, at least about 200-fold, at least about 300-fold, at least about 400-fold, at least about 500-fold, at least about 1000-fold, at least about 1500-fold, at least about 2000-fold, at least about 2500-fold, at least about 3000-fold, at least about 3500-fold, at least about 4000-fold, at least about 4500-fold, or at least about 4000-fold greater than the affinity of a reference HLA class II molecule for CD4.

[0169] In some embodiments, the enhanced affinity for CD4 is at least about 1.5 times to at least about 5000 times, 1.5 times to at least about 4000 times, 1.5 times to at least about 3000 times, 1.5 times to at least about 2000 times, 1.5 times to at least about 1000 times, 10 times to at least about 5000 times, 10 times to at least about 4000 times, 10 times to at least about 3000 times, 10 times to at least about 2000 times, 10 times to at least about 1000 times, 10 times to at least about 900 times, 10 times to at least about 800 times, 10 times to at least about 700 times, 10 times to at least about 600 times, 10 times at least about 500 times, 10 times to at least about 400 times, 10 times to at least about 300 times, 10 times to at least about 200 times, 10 times to at least about 100 times, 100 times to at least about 5000 times, 100 times to at least about 4000 times, 100 times to at least about 3000 times, 100 times to at least about 2000 times, 100 times to at least about 1000 times, 100 times to at least about 900 times, 100 times to at least about 800 times, 100 times to at least about 700 times, 100 times to at least about 600 times, 100 times to at least about 500 times, 100 times to at least about 400 times, 100 times to at least about 300 times, or 100 times to at least about 200 times higher.

[0170] In certain embodiments, the DQ beta chain comprises an allele selected from HLA-DQB1*02, HLA-DQB1*03, HLA-DQB1*04, HLA-DQB1*05, and HLA-DQB1*06 alleles. In certain embodiments, the DQ beta chain comprises an HLA-DQB1*05 allele. In certain embodiments, the DQ beta chain comprises an HLA-DQB1*05:01 allele.

[0171] In certain embodiments, the DQ beta chain is DQB1*02:01:01, DQB1*02:01:02, DQB1*02:01:03, DQB1*02:01:04, DQB1*02:01:05, DQB1*02:01:06, DQB1*02:01:07, DQB1*02:01:08, DQB1*02:01:09, DQB1*02:01:10, DQB1*02:01:11, DQB1*02:01:12, DQB1*02:01:13, DQB1*02:01:14, DQB1*02:01:15, DQB1*02:01:16, DQB1*02:01:17, DQB1*02:01:18, DQB1*02:01:19, DQB1*02:01:20, DQB1*02:01:21, DQB1*02:01:22, DQB1*02:01:23, DQB1*02:01:24, DQB1*02:01:25, DQB1*02:01:26, DQB1*02:01:27, DQB1*02:01:28, DQB1*02:01:29, DQB1*02:01:30, DQB1*02:01:31, DQB1*02:02:01:01, DQB1*02:02:01:02, DQB1*02:02:01:03, DQB1*02:02:01:04, DQB1*02:02:02, DQB1*02:02:03, DQB1*02:02:04, DQB1*02:02:05, DQB1*02:02:06, DQB1*02:02:07, DQB1*02:02:08, DQB1*02:02:09, DQB1*02:03:01, DQB1*02:03:02, DQB1*02:04, DQB1*02:05, DQB1*02:06, DQB1*02:07:01, DQB1*02:07:02, DQB1*02:08, DQB1*02:09, DQB1*02:10, DQB1*02:100, DQB1*02:101, DQB1*02:102, DQB1*02:103, DQB1*02:104, DQB1*02:105, DQB1*02:106, DQB1*02:107, DQB1*02:108, DQB1*02:109, DQB1*02:11, DQB1*02:110, DQB1*02:111, DQB1*02:112, DQB1*02:113, DQB1*02:114, DQB1*02:115, DQB1*02:116, DQB1*02:117, DQB1*02:118.DQB1*02:119、DQB1*02:12、DQB1*02:120、DQB1*02:121、DQB1*02:122、DQB1*02:123、DQB1*02:124、DQB1*02:125、DQB1*02:126、DQB1*02:127、DQB1*02:128、DQB1*02:129N、DQB1*02:13、DQB1*02:130、DQB1*02:131、DQB1*02:132N、DQB1*02:133、DQB1*02:134N、DQB1*02:135、DQB1*02:136、DQB1*02: 137、DQB1*02:138、DQB1*02:139、DQB1*02:140、DQB1*02:141、DQB1*02:142、DQB1*02:14:01、DQB1*02:14:02、DQB1*02:15、DQB1*02:16、DQB1*02:17、DQB1*02:18N、DQB1*02:19、DQB1*02:20N、DQB1*02:21、DQB1*02:22、DQB1*02:23、DQB1*02:24、DQB1*02:25、DQB1*02:26、DQB1*02:27、DQB1*02:28、D QB1*02:29、DQB1*02:30、DQB1*02:31、DQB1*02:32、DQB1*02:33、DQB1*02:34、DQB1*02:35、DQB1*02:36、DQB1*02:37、DQB1*02:38、DQB1*02:39、DQB1*02:40、DQB1*02:41、DQB1*02:42、DQB1*02:43、DQB1*02:44、DQB1*02:45、DQB1*02:46、DQB1*02:47、DQB1*02:48、DQB1*02:49、DQB1*02:50、DQB1*02: 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*03:01:10、DQB1*03:01:11、DQB1*03:01:12、DQB1*03:01:13、DQB1*03:01:14、DQB1*03:01:15、DQB1*03:01:16、DQB1*03:01:17、DQB1*03:01:18、DQB1*03:01:19、DQB1*03:01:20、DQB1*03:01:21、DQB1*03:01:22、DQB1*03:01:23、DQB1*03:01:24、DQB1*03:01:25、DQB1*03:01:26、DQB1*03:01:27、DQB1*03:01:28、DQB1*03:01:29、DQB1*03:01:30、DQB1*03:01:31、DQB1*03:01:32、DQB1*03:01:33、DQB1*03:01:34、DQB1*03:01:35、DQB1*03:01:36、DQB1*03:01:37、DQB1*03:01:38、DQB1*03:01:39、DQB1*03:01:40、DQB1*03:01:41、DQB1*03:01:42、DQB1*03:01:43、DQB1*03:01:44、DQB1*03:0 1:45、DQB1*03:01:46、DQB1*03:02:01:01、DQB1*03:02:01:02、DQB1*03:02:01:03、DQB1*03:02:01:04、DQB1*03:02:01:05、DQB1*03:02:01:06、DQB1*03:02:01:07、DQB1*03:02:01:08、DQB1*03:02:02、DQB1*03:02:03、DQB1*03:02:04、DQB1*03:02:05、DQB1*03:02:06、DQB1*03:02:07、DQB1*03:0 2:08、DQB1*03:02:09、DQB1*03:02:10、DQB1*03:02:11、DQB1*03:02:12、DQB1*03:02:13、DQB1*03:02:14、DQB1*03:02:15、DQB1*03:02:16、DQB1*03:02:17、DQB1*03:02:18、DQB1*03:02:19、DQB1*03:02:20、DQB1*03:02:21、DQB1*03:02:22、DQB1*03:02:23、DQB1*03:02:24、DQB1*03:02:25、DQB1* 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01:06、DQB1*06:01:07、DQB1*06:01:08、DQB1*06:01:09、DQB1*06:01:10、DQB1*06:01:11、DQB1*06:01:12、DQB1*06:01:13、DQB1*06:01:14、DQB1*06:01:15、DQB1*06:01:16、DQB1*06:01:17、DQB1*06:01:18、DQB1*06:01:19、DQB1*06:01:20、DQB1*06:01:21、DQB1*06:02:01:01、DQB1*06:02:01:01: 02、DQB1*06:02:01:03、DQB1*06:02:01:04、DQB1*06:02:02、DQB1*06:02:03、DQB1*06:02:04、DQB1*06:02:05、DQB1*06:02:06、DQB1*06:02:07、DQB1*06:02:08、DQB1*06:02:09、DQB1*06:02:10、DQB1*06:02:11、DQB1*06:02:12、DQB1*06:02:13、DQB1*06:02:14、DQB1*06:02:15、DQB1*06:02:16、DQB1*06:02:17、DQB1*06:02:18、DQB1*06:02:19、DQB1*06:02:20、DQB1*06:02:21、DQB1*06:02:22、DQB1*06:02:23、DQB1*06:02:24、DQB1*06:02:25、DQB1*06:02:26、DQB1*06:02:27、DQB1*06:02:28、DQB1*06:02:29、DQB1*06:02:30、DQB1*06:02:31、DQB1*06:02:32、DQB1*06:02:33、DQB1*06:0 2:34、DQB1*06:02:35、DQB1*06:02:36、DQB1*06:02:37、DQB1*06:02:38、DQB1*06:03:01:01、DQB1*06:03:01:02、DQB1*06:03:01:03、DQB1*06:03:02、DQB1*06:03:03、DQB1*06:03:04、DQB1*06:03:05、DQB1*06:03:06、DQB1*06:03:07、DQB1*06:03:08、DQB1*06:03:09、DQB1*06:03:10、DQB1*06:0 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,DQB1*06:110,DQB1*06:111,DQB1*06:112N,DQB1*06:113,DQB1*06:114,DQB1*06:115,DQB1*06:116,DQB1*06:117,DQB1*06:118:01,DQB1*06:118:02,DQB1*06:118:03,DQB1*06:119,DQB1*06:11:01,DQB1*06:11:02,DQB1*06:11:03,DQB1*06:11:04,DQB1*06:12,DQB1*06:120,DQB1*06:121,DQB1 *06:122、DQB1*06:123、DQB1*06:124、DQB1*06:125、DQB1*06:126、DQB1*06:127、DQB1*06:128、DQB1*06:129、DQB1*06:130、DQB1*06:131、DQB1*06:132、DQB1*06:133、DQB1*06:134、DQB1*06:135、DQB1*06:136、DQB1*06:137、DQB1*06:138、DQB1*06:139、DQB1*06:13:01、DQB1*06:13:02、DQB1*06:13 :03、DQB1*06:140、DQB1*06:141、DQB1*06:142、DQB1*06:143、DQB1*06:144N、DQB1*06:145、DQB1*06:146:01、DQB1*06:146:02、DQB1*06:147、DQB1*06:148、DQB1*06:149、DQB1*06:14:01、DQB1*06:14:02、DQB1*06:14:03、DQB1*06:150、DQB1*06:151、DQB1*06:152、DQB1*06:153:01、DQB1*06:153:02、DQB1*06:154、DQB1*06:155、DQB1*06:156、DQB1*06:157、DQB1*06:158N、DQB1*06:159、DQB1*06:15:01、DQB1*06:15:02、DQB1*06:16、DQB1*06:160、DQB1*06:161、DQB1*06:162、DQB1*06:163、DQB1*06:164、DQB1*06:165、DQB1*06:166、DQB1*06:167、DQB1*06:168、DQB1*06:169、DQB1*06:17、DQB1*0 6:170、DQB1*06:171、DQB1*06:172、DQB1*06:173、DQB1*06:174、DQB1*06:175、DQB1*06:176、DQB1*06:177、DQB1*06:178、DQB1*06:179N、DQB1*06:180、DQB1*06:181、DQB1*06:182、DQB1*06:183、DQB1*06:184、DQB1*06:185、DQB1*06:186、DQB1*06:187、DQB1*06:188、DQB1*06:189、DQB1*06:18:01、 DQB1*06:18:02、DQB1*06:190:01、DQB1*06:190:02、DQB1*06:191、DQB1*06:192、DQB1*06:193N、DQB1*06:194、DQB1*06:195、DQB1*06:196、DQB1*06:197、DQB1*06:198、DQB1*06:199、DQB1*06:19:01、DQB1*06:19:02、DQB1*06:20、DQB1*06:200、DQB1*06:201、DQB1*06:202、DQB1*06:203、DQB1*06:2 04、DQB1*06:205、DQB1*06:206:01、DQB1*06:206:02、DQB1*06:207、DQB1*06:208、DQB1*06:209、DQB1*06:21、DQB1*06:210、DQB1*06:211、DQB1*06:212、DQB1*06:213、DQB1*06:214、DQB1*06:215、DQB1*06:216N、DQB1*06:217、DQB1*06:218、DQB1*06:219、DQB1*06:221、DQB1*06:222、DQB1*06:223、DQB1*06:224、DQB1*06:225、DQB1*06:226、DQB1*06:227、DQB1*06:228、DQB1*06:229、DQB1*06:22:01、DQB1*06:22:02、DQB1*06:22:03、DQB1*06:23、DQB1*06:230、DQB1*06:231、DQB1*06:232、DQB1*06:233、DQB1*06:234、DQB1*06:235、DQB1*06:236、DQB1*06:237、DQB1*06:238、DQB1*06:239、DQB1 *06:24、DQB1*06:240、DQB1*06:241、DQB1*06:242、DQB1*06:243、DQB1*06:244、DQB1*06:245、DQB1*06:246、DQB1*06:247、DQB1*06:248、DQB1*06:249、DQB1*06:25、DQB1*06:250、DQB1*06:251、DQB1*06:252N、DQB1*06:253、DQB1*06:254、DQB1*06:255、DQB1*06:256、DQB1*06:257、DQB1*06:258、DQ B1*06:259、DQB1*06:260、DQB1*06:261、DQB1*06:262、DQB1*06:263、DQB1*06:264、DQB1*06:265、DQB1*06:266、DQB1*06:267、DQB1*06:268、DQB1*06:269、DQB1*06:26N、DQB1*06:270:01、DQB1*06:270:02、DQB1*06:271、DQB1*06:272、DQB1*06:273、DQB1*06:274、DQB1*06:275、DQB1*06:276、DQB1* 06:277、DQB1*06:278、DQB1*06:279、DQB1*06:27:01、DQB1*06:27:02、DQB1*06:28、DQB1*06:280、DQB1*06:281、DQB1*06:282、DQB1*06:283、DQB1*06:284、DQB1*06:285、DQB1*06:286、DQB1*06:287、DQB1*06:288、DQB1*06:289、DQB1*06:29、DQB1*06:290、DQB1*06:291、DQB1*06:292、DQB1*06:293、DQB1*06:294、DQB1*06:295、DQB1*06:296、DQB1*06:297、DQB1*06:298、DQB1*06:299、DQB1*06:30、DQB1*06:300、DQB1*06:301、DQB1*06:302、DQB1*06:303N、DQB1*06:304N、DQB1*06:305、DQB1*06:306N、DQB1*06:307、DQB1*06:308N、DQB1*06:309、DQB1*06:31、DQB1*06:310、DQB1*06:311、DQB1*0 6:312、DQB1*06:313、DQB1*06:314、DQB1*06:315、DQB1*06:316、DQB1*06:317N、DQB1*06:318、DQB1*06:319、DQB1*06:320、DQB1*06:321、DQB1*06:322、DQB1*06:323、DQB1*06:324、DQB1*06:325、DQB1*06:326、DQB1*06:32:01、DQB1*06:32:02、DQB1*06:33、DQB1*06:34、DQB1*06:35、DQB1*06:36、DQ B1*06:37、DQB1*06:38、DQB1*06:39、DQB1*06:40、DQB1*06:41、DQB1*06:42、DQB1*06:43、DQB1*06:44、DQB1*06:45、DQB1*06:46、DQB1*06:47、DQB1* 06:48:01、DQB1*06:48:02、DQB1*06:49、DQB1*06:50、DQB1*06:51:01、DQB 1*06:51:02、DQB1*06:52、DQB1*06:53:01、DQB1*06:53:02、DQB1*06:54N、D QB1*06:55、DQB1*06:56、DQB1*06:57、DQB1*06:58、DQB1*06:59、DQB1*06:60、DQB1*06:61、DQB1*06:62、DQB1*06:63、DQB1*06:64、DQB1*06:65、DQB1*06:66、DQB1*06:67、DQB1*06:68、DQB1*06:69:01、DQB1*06:69:02、DQB1*06:70、DQB1*06:71、DQB1*06:72、DQB1*06:73、DQB1*06:74、DQB1*06:75NX、DQB1*06:76, DQB1*06:77N, DQB1*06:78, DQB1*06:79:01, DQB1*06:79:02, DQB1*06:80, DQB1*06:81, DQB1*0 6:82, DQB1*06:83, DQB1*06:84, DQB1*06:85, DQB1*06:86, DQB1*06:87, DQB1*06:88, DQB1*06:89, DQB1*06:9 DQB1*06:96:01, DQB1*06:96:02, DQB1*06:97, DQB1*06:98, DQB1*06:99:01, DQB1*06:99:02, and any combination thereof.

[0172] In certain embodiments, the MHC class II molecule comprises a DQ beta chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 13, wherein the DQ beta chain comprises a tryptophan at the amino acid residue corresponding to position 114 of SEQ ID NO: 11, and the DQ beta chain comprises a methionine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11. In certain embodiments, the MHC class II molecule comprises a DQ beta chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 13, wherein the DQ beta chain comprises (i) a tryptophan at the amino acid residue corresponding to position 114 of SEQ ID NO: 11, (ii) a methionine at the amino acid residue corresponding to position 143 of SEQ ID NO: 11, (iii) a glutamine at the amino acid residue corresponding to position 110 of SEQ ID NO: 11, (iv) a valine at the amino acid residue corresponding to position 116 of SEQ ID NO: 11, (v) a histidine at the amino acid residue corresponding to position 118 of SEQ ID NO: 11, and (vi) a glutamine at the amino acid residue corresponding to position 146 of SEQ ID NO: 11. In certain embodiments, the MHC class II molecule comprises a DQ beta chain comprising the amino acid sequence set forth in SEQ ID NO: 13.

[0173] II.A.2.b. HLA-DQ alpha chain In some embodiments of the present disclosure, the MHC class II molecule further comprises an alpha chain. In some embodiments, the alpha chain is a wild-type alpha chain. In some embodiments, the alpha chain is a DQ alpha chain. Any DQ alpha chain may be used in the compositions and methods of the present disclosure. In some embodiments, the DQ alpha chain comprises an HLA-DQA1*01, HLA-DQA1*02, HLA-DQA1*03, HLA-DQA1*04, HLA-DQA1*05, or HLA-DQA1*06 allele. In certain embodiments, the DQ alpha chain comprises an HLA-DQA1*01 allele. In certain embodiments, the DQ alpha chain comprises an HLA-DQA1*02 allele. In certain embodiments, the DQ alpha chain comprises an HLA-DQA1*03 allele. In certain embodiments, the DQ alpha chain comprises an HLA-DQA1*04 allele. In certain embodiments, the DQ alpha chain comprises the HLA-DQA1*05 allele. In certain embodiments, the DQ alpha chain comprises the HLA-DQA1*06 allele.

[0174] In certain embodiments, the DQ alpha chain is DQA1*01:01:01:01, DQA1*01:01:01:02, DQA1*01:01:01:03, DQA1*01:01:01:05, DQA1*01:01:01:06, DQA1*01:01:02, DQA1*01:01:03, DQA1*01:01:04, DQA1*01:01:05, DQA1*01:02:01:01, DQA1*01:02:01:02, DQA1*01:02:01:03, DQA1*01:02:01:04, DQA1*01:02:01:05, DQA1*01:02:01:06, DQA1*01:02:01:07, DQA1*01:02:01:08, DQA1*01:02:01:09, DQA1*01:02:01:10, DQA1*01:02:01:11, DQA1*01:02:01:12, DQA1*01:02:02:01, DQA1*01:02:02:02, DQA1*01:02:02:03, DQA1*01:02:02:04, DQA1*01:02:03, DQA1*01:02:04, DQA1*01:03:01:01, DQA1*01:03:01:02, DQA1*01:03:01:03, DQA1*01:03:01:04, DQA1*01:03:01:05, DQA1*01:03:01:06, DQA1*01:03:01:07, DQA1*01:03:01:08, DQA1*01:03:01:09, DQA1*01:04:01:01, DQA1*01:04:01:02, DQA1*01:04:01:03, DQA1*01:04:01:04, DQA1*01:04:02, DQA1*01:05:01, DQA1*01:05:02, DQA1*01:06, DQA1*01:07Q, DQA1*01:08, DQA1*01:09, DQA1*01:10, DQA1*01:11, DQA1*01:12, DQA1*01:13, DQA1*01:14, DQA1*01:15N, DQA1*01:16N, DQA1*01:17, DQA1*01:18, DQA1*01:19, DQA1*01:20, DQA1*01:21, DQA1*01:22, DQA1*01:23, DQA1*01:24, DQA1*01:25, DQA1*01:26, DQA1*02:01:01:01, DQA1*02:01:01:02DQA1*02:01:02、DQA1*02:02N、DQA1*02:03、DQA1*03:01:01、DQA1*03:01:03、DQA1*03:02:01:01、DQA1*03:02:01:02、DQA1*03:03:01:01、DQA1*03:03:01:02、DQA1*03:03:01:03、DQA1*03:03:01:04、DQA1*03:03:01:05、DQA1*03:03:01:06、DQA1*03:03:01:07、DQA1*03:03:02、DQA1*03:03:04、DQA1*03:03:01:05、DQA1*03:03:01:06、DQA1*03:03:01:07、DQA1*03:03:02、DQA1*03:03:04、DQA1*03:03:01:08 *03:05、DQA1*03:06、DQA1*03:07、DQA1*04:01:01:01、DQA1*04:01:01:02、DQA1*04:01:01:03、DQA1*04:01:01:04、DQA1*04:01:01:05、DQA1*04:01:01:06、DQA1*04:01:01:07、DQA1*04:01:01:08、DQA1*04:01:02:01、DQA1*04:01:02:02、DQA1*04:01:03、DQA1*04:02、DQA1*04:03N、DQA1*04:04、D QA1*04:05、DQA1*05:01:01:01、DQA1*05:01:01:02、DQA1*05:01:01:03、DQA1*05:01:01:04、DQA1*05:01:02、DQA1*05:01:04、DQA1*05:01:05、DQA1*05:01:06、DQA1*05:02、DQA1*05:03:01:01、DQA1*05:03:01:02、DQA1*05:04、DQA1*05:05:01:01、DQA1*05:05:01:02、DQA1*05:05:01:03、DQA1*05 :05:01:04、DQA1*05:05:01:05、DQA1*05:05:01:06、DQA1*05:05:01:07、DQA1*05:05:01:08、DQA1*05:05:01:09、DQA1*05:05:01:10、DQA1*05:05:01:11、DQA1*05:05:01:12、DQA1*05:05:01:13、DQA1*05:05:01:14、DQA1*05:05:01:15、DQA1*05:05:01:16、DQA1*05:05:01:17、DQA1*05:05:01:18、DQA1*05:05:01:19, DQA1*05:05:01:20, DQA1*05:06:01:01, DQA1*05:06:01:02, DQ A1*05:07, DQA1*05:08, DQA1*05:09, DQA1*05:10, DQA1*05:11, DQA1*05:12, DQA1*05 :13, DQA1*05:14, DQA1*05:15N, DQA1*06:01:01:01, DQA1*06:01:01:02, DQA1*06:01:01:03, DQA1*06:01:01:04, DQA1*06:01:02, DQA1*06:02, and any combination thereof.

[0175] In certain embodiments, an MHC class II molecule comprises a DQ alpha chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 16. In certain embodiments, an MHC class II molecule comprises a DQ alpha chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 18. In certain embodiments, an MHC class II molecule comprises a DQ alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, an MHC class II molecule comprises a DQ alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 18.

[0176] II.A.3.HLA-DR molecule Many HLA-DR alleles are known in the art, and any known allele can be used in the present disclosure. Examples of HLA-DR alpha and beta chain alleles are shown in Table 5. An updated list of HLA alleles is available at hla.alleles.org / (last visited July 10, 2019). [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0177] II.A.3.a. HLA-DR beta chain In certain embodiments, an HLA class II molecule comprises a DR beta chain, wherein the DR beta chain comprises an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19. Any amino acid other than leucine may be present at the amino acid residue corresponding to position 114 of SEQ ID NO: 19. In some embodiments, the amino acid other than leucine is an amino acid comprising a hydrophobic side chain. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is an amino acid selected from alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is alanine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is valine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is isoleucine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is methionine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is phenylalanine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is tyrosine. In certain embodiments, the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is tryptophan.

[0178] In some embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a hydrophobic side chain. In certain embodiments, the non-leucine amino acid at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a hydrophobic side chain.

[0179] In certain embodiments, an HLA class II molecule comprises a DR beta chain, wherein the DR beta chain comprises an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19. Any amino acid other than valine may be present at the amino acid residue corresponding to position 143 of SEQ ID NO: 19. In some embodiments, the amino acid other than valine is an amino acid comprising a hydrophobic side chain. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is an amino acid selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is alanine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is isoleucine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is leucine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is methionine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is phenylalanine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is tyrosine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is tryptophan.

[0180] In some embodiments, the non-valine amino acid residue at position 143 of SEQ ID NO: 19 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a hydrophobic side chain. In certain embodiments, the non-valine amino acid residue at position 143 of SEQ ID NO: 19 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a hydrophobic side chain.

[0181] In certain embodiments, the HLA class II molecule comprises a DR beta chain, wherein the DR beta chain comprises an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19. Any amino acid other than serine may be present at the amino acid residue corresponding to position 118 of SEQ ID NO: 19. In some embodiments, the amino acid other than serine is an amino acid comprising a charged side chain. In certain embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19 is an amino acid selected from arginine, histidine, and lysine. In certain embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19 is arginine. In certain embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19 is histidine. In certain embodiments, the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19 is lysine.

[0182] In some embodiments, the non-serine amino acid residue at position 118 of SEQ ID NO: 19 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a charged side chain. In certain embodiments, the non-serine amino acid residue at position 118 of SEQ ID NO: 19 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a charged side chain.

[0183] In certain embodiments, an HLA class II molecule comprises a DR beta chain, wherein the DR beta chain comprises an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19. Any amino acid other than threonine may be present at the amino acid residue corresponding to position 157 of SEQ ID NO: 19. In some embodiments, the amino acid other than threonine is an amino acid comprising a hydrophobic side chain. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is an amino acid selected from alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is alanine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is valine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is isoleucine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is leucine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is methionine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is phenylalanine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is tyrosine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is tryptophan.

[0184] In some embodiments, the amino acids other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 are made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a hydrophobic side chain. In certain embodiments, the amino acids other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 are made up of a stretch of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the stretch comprises a hydrophobic side chain.

[0185] In certain embodiments, the HLA class II molecule comprises a DR beta chain, wherein the DR beta chain comprises an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO: 19. Any amino acid other than lysine may be present at the amino acid residue corresponding to position 139 of SEQ ID NO: 19. In some embodiments, the non-lysine amino acid is an amino acid comprising a polar, uncharged side chain. In certain embodiments, the non-lysine amino acid at the amino acid residue corresponding to position 139 of SEQ ID NO: 19 is an amino acid selected from serine, threonine, and glutamine. In certain embodiments, the non-lysine amino acid at the amino acid residue corresponding to position 139 of SEQ ID NO: 19 is serine. In certain embodiments, the non-lysine amino acid at the amino acid residue corresponding to position 139 of SEQ ID NO: 19 is threonine. In certain embodiments, the non-lysine amino acid at the amino acid residue corresponding to position 139 of SEQ ID NO: 19 is glutamine.

[0186] In some embodiments, the non-lysine amino acid at the amino acid residue corresponding to position 139 of SEQ ID NO: 19 is made up of two or more amino acids, e.g., two amino acids, three amino acids, four amino acids, five amino acids, or more. In some embodiments, at least one of the two or more amino acids comprises a polar, uncharged side chain. In certain embodiments, the non-lysine amino acid at the amino acid residue corresponding to position 139 of SEQ ID NO: 19 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a polar, uncharged side chain.

[0187] In certain embodiments, an HLA class II molecule comprises a DR beta chain, wherein the DR beta chain comprises an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19. Any amino acid other than glycine may be present at the amino acid residue corresponding to position 146 of SEQ ID NO: 19. In some embodiments, the amino acid other than glycine is an amino acid comprising a polar, uncharged side chain. In certain embodiments, the amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19 is an amino acid selected from serine, asparagine, threonine, and glutamine. In certain embodiments, the amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19 is serine. In certain embodiments, the amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19 is asparagine. In certain embodiments, the amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19 is threonine. In certain embodiments, the amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19 is glutamine.

[0188] In some embodiments, the non-glycine amino acid at the amino acid residue corresponding to position 146 of SEQ ID NO: 19 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a polar, uncharged side chain. In certain embodiments, the non-glycine amino acid at the amino acid residue corresponding to position 146 of SEQ ID NO: 19 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a polar, uncharged side chain.

[0189] In certain embodiments, the HLA class II molecule comprises a DR beta chain, wherein the DR beta chain comprises an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19. Any amino acid other than threonine may be present at the amino acid residue corresponding to position 163 of SEQ ID NO: 19. In some embodiments, the amino acid other than threonine is an amino acid comprising a hydrophobic side chain. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 is an amino acid selected from alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 is alanine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 is valine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 is isoleucine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 is leucine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 is methionine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 is phenylalanine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 is tyrosine. In certain embodiments, the amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 is tryptophan.

[0190] In some embodiments, the non-threonine amino acid residue at position 163 of SEQ ID NO: 19 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a hydrophobic side chain. In certain embodiments, the non-threonine amino acid residue at position 163 of SEQ ID NO: 19 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a hydrophobic side chain.

[0191] In certain embodiments, the HLA class II molecule comprises a DR beta chain, wherein the DR beta chain comprises an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19. Any amino acid other than valine may be present at the amino acid residue corresponding to position 164 of SEQ ID NO: 19. In some embodiments, the amino acid other than valine is an amino acid comprising a polar, uncharged side chain. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19 is an amino acid selected from serine, asparagine, threonine, and glutamine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19 is serine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19 is asparagine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19 is threonine. In certain embodiments, the amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19 is glutamine.

[0192] In some embodiments, the non-valine amino acid residue at position 164 of SEQ ID NO: 19 is made up of two or more amino acids, e.g., two, three, four, five, or more amino acids. In some embodiments, at least one of the two or more amino acids comprises a polar, uncharged side chain. In certain embodiments, the non-valine amino acid residue at position 164 of SEQ ID NO: 19 is made up of a series of amino acids, e.g., at least two, at least three, at least four, or at least five, where each amino acid in the series comprises a polar, uncharged side chain.

[0193] In certain embodiments of the present disclosure, the MHC class II molecule comprises a DR beta chain that comprises two or more substitution mutations compared to the wild-type DR beta chain.In certain embodiments, the DR beta chain comprises at least two mutations, at least three mutations, at least four mutations, at least five mutations, at least six mutations, at least seven mutations, at least eight mutations, at least nine mutations, or at least ten mutations compared to the wild-type DR beta chain.

[0194] In certain embodiments, the DR beta chain comprises an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19, and an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19.

[0195] In certain embodiments, the DR beta chain comprises (a) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19, (b) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19, (c) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19, and (d) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19.

[0196] In certain embodiments, the DR beta chain comprises an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19, an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19, and at least two of the following: (i) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19, (ii) an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO:19, (iii) an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO:19, (iv) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19, (v) an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO:19, and (vi) an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO:19.

[0197] In certain embodiments, the DR beta chain comprises an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19, an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19, and at least three of the following: (i) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19, (ii) an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO:19, (iii) an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO:19, (iv) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19, (v) an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO:19, and (vi) an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO:19.

[0198] In certain embodiments, the DR beta chain comprises an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19, an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19, and at least four of the following: (i) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19, (ii) an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO:19, (iii) an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO:19, (iv) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19, (v) an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO:19, and (vi) an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO:19.

[0199] In certain embodiments, the DR beta chain comprises at least one of: (a) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19; (b) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19; (c) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19; and (d) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19; and (i) an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO:19; (ii) an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO:19; (iii) an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO:19; and (iv) an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO:19.

[0200] In certain embodiments, the DR beta chain comprises at least two of: (a) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19; (b) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19; (c) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19; and (d) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19; and (i) an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO:19; (ii) an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO:19; (iii) an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO:19; and (iv) an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO:19.

[0201] In certain embodiments, the DR beta chain comprises at least three of: (a) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19; (b) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19; (c) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19; and (d) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19; and (i) an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO:19; (ii) an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO:19; (iii) an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO:19; and (iv) an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO:19.

[0202] In certain embodiments, the DR beta chain comprises (a) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO:19, (b) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO:19, (c) an amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO:19, (d) an amino acid other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO:19, (e) an amino acid other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO:19, (f) an amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO:19, (g) an amino acid other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO:19, and (h) an amino acid other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO:19.

[0203] In certain embodiments, the DR beta chain comprises (a) a tryptophan at the amino acid residue corresponding to position 114 of SEQ ID NO:19, (b) a methionine at the amino acid residue corresponding to position 143 of SEQ ID NO:19, (c) a histidine at the amino acid residue corresponding to position 118 of SEQ ID NO:19, and (d) an isoleucine at the amino acid residue corresponding to position 157 of SEQ ID NO:19.

[0204] In some embodiments, (i) an amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19, (ii) an amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19, or each of the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 and the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is an amino acid comprising a hydrophobic side chain.

[0205] In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is selected from alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan; (ii) the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; (iii) the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19 is selected from arginine, histidine, and lysine; and / or (iv) the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is selected from alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan.

[0206] In some embodiments, (i) the amino acid other than leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19 is selected from alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan; (ii) the amino acid other than valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19 is selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; (iii) the amino acid other than serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19 is selected from arginine, histidine, and lysine; and (iv) the amino acid other than threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19 is selected from alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. (v) the amino acids other than lysine at the amino acid residue corresponding to position 139 of SEQ ID NO: 19 are selected from serine, threonine, and glutamine; (vi) the amino acids other than glycine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19 are selected from serine, asparagine, threonine, and glutamine; (vii) the amino acids other than threonine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19 are selected from alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan; and / or (viii) the amino acids other than valine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19 are selected from serine, asparagine, threonine, and glutamine.

[0207] In certain embodiments, the DR beta chains described herein have a higher affinity for CD4 protein compared to a reference HLA class II molecule. In some embodiments, the reference HLA class II molecule is an HLA class II molecule having a wild-type DR beta chain. In some embodiments, the reference HLA class II molecule is an HLA class II molecule having a DR beta chain containing (i) a leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19, and / or (ii) a valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19. In some embodiments, the reference HLA class II molecule is an HLA class II molecule having a DR beta chain containing (i) a leucine at the amino acid residue corresponding to position 114 of SEQ ID NO: 19, (ii) a valine at the amino acid residue corresponding to position 143 of SEQ ID NO: 19, (iii) a serine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19, and (iv) a threonine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19.

[0208] In some embodiments, the enhanced affinity for CD4 is at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold, at least about 75-fold, at least about 100-fold, at least about 200-fold, at least about 300-fold, at least about 400-fold, at least about 500-fold, at least about 1000-fold, at least about 1500-fold, at least about 2000-fold, at least about 2500-fold, at least about 3000-fold, at least about 3500-fold, at least about 4000-fold, at least about 4500-fold, or at least about 4000-fold greater than the affinity of a reference HLA class II molecule for CD4.

[0209] In some embodiments, the enhanced affinity for CD4 is at least about 1.5 times to at least about 5000 times, 1.5 times to at least about 4000 times, 1.5 times to at least about 3000 times, 1.5 times to at least about 2000 times, 1.5 times to at least about 1000 times, 10 times to at least about 5000 times, 10 times to at least about 4000 times, 10 times to at least about 3000 times, 10 times to at least about 2000 times, 10 times to at least about 1000 times, 10 times to at least about 900 times, 10 times to at least about 800 times, 10 times to at least about 700 times, 10 times to at least about 600 times, 10 times at least about 500 times, 10 times to at least about 400 times, 10 times to at least about 300 times, 10 times to at least about 200 times, 10 times to at least about 100 times, 100 times to at least about 5000 times, 100 times to at least about 4000 times, 100 times to at least about 3000 times, 100 times to at least about 2000 times, 100 times to at least about 1000 times, 100 times to at least about 900 times, 100 times to at least about 800 times, 100 times to at least about 700 times, 100 times to at least about 600 times, 100 times to at least about 500 times, 100 times to at least about 400 times, 100 times to at least about 300 times, or 100 times to at least about 200 times higher.

[0210] In certain embodiments, the DR beta chain comprises an allele selected from HLA-DRB1*01, HLA-DRB1*03, HLA-DRB1*04, HLA-DRB1*06, HLA-DRB1*07, HLA-DRB1*08, HLA-DRB1*09, HLA-DRB1*10, HLA-DRB1*11, HLA-DRB1*12, HLA-DRB1*13, HLA-DRB1*14, HLA-DRB1*15, or HLA-DRB1*16 alleles. In some embodiments, the DR beta chain comprises an HLA-DRB1*01 allele. In certain embodiments, the DR beta chain comprises an HLA-DRB1*01:01 allele.

[0211] In certain embodiments, the DR beta chain is DRB1*01:01:01, DRB1*01:01:02, DRB1*01:01:03, DRB1*01:01:04, DRB1*01:01:05, DRB1*01:01:06, DRB1*01:01:07, DRB1*01:01:08, DRB1*01:01:09, DRB1*01:01:10, DRB1*01:01:11, DRB1*01:01:12, DRB1*01:01:13, DRB1*01:01:14, DRB1*01:01:15, DRB1*01:01:16, DRB1*01:01:17, DRB1*01:01:18, DRB1*01:01:19, DRB1*01:01:20, DRB1*01:01:21, DRB1*01:01:22, DRB1*01:01:23, DRB1*01:01:24, DRB1*01:01:25, DRB1*01:01:26, DRB1*01:01:××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××DRB1*01:22、DRB1*01:23、DRB1*01:24:01、DRB1*01:24:02、DRB1*01:25、DRB1*01:26、DRB1*01:27、DRB1*01:28、DRB1*01:29:01、DRB1*01:29:02、DRB1*01:30、DRB1*01:31、DRB1*01:32、DRB1*01:33N、DRB1*01:34、DRB1*01:35、DRB1*01:36、DRB1*01:37、DRB1*01:38、DRB1*01:39N、DRB1*01:40N、DRB 1*01:41、DRB1*01:42、DRB1*01:43、DRB1*01:44:01、DRB1*01:44:02、DRB1*01:45、DRB1*01:46、DRB1*01:47、DRB1*01:48、DRB1*01:49、DRB1*01:50、DRB1*01:51、DRB1*01:52N、DRB1*01:53、DRB1*01:54、DRB1*01:55、DRB1*01:56、DRB1*01:57、DRB1*01:58、DRB1*01:59、DRB1*01:60、DRB1*01:61、DRB1 *01:62N、DRB1*01:63、DRB1*01:64、DRB1*01:65:01、DRB1*01:65:02、DRB1*01:66、DRB1*01:67、DRB1*01:68N、DRB1*01:69、DRB1*01:70、DRB1*01:71、DRB1*01:72、DRB1*01:73、DRB1*01:74、DRB1*01:75、DRB1*01:76、DRB1*01:77、DRB1*01:78、DRB1*01:79、DRB1*01:80、DRB1*01:81、DRB1*01:82、DRB 1*01:83、DRB1*01:84、DRB1*01:85、DRB1*01:86、DRB1*01:87、DRB1*01:88、DRB1*01:89、DRB1*01:90、DRB1*01:91Q、DRB1*01:92、DRB1*01:93、DRB1*01:90 1:94、DRB1*01:95、DRB1*01:96、DRB1*01:97、DRB1*01:98、DRB1*01:99、DR B1*03:01:01:01、DRB1*03:01:01:02、DRB1*03:01:01:03、DRB1*03:01:02、DRB1*03:01:03、DRB1*03:01:04、DRB1*03:01:05、DRB1*03:01:06、DRB1*03:01:07、DRB1*03:01:08、DRB1*03:01:09、DRB1*03:01:10、DRB1*03:01:11、DRB1*03:01:12、DRB1*03:01:13、DRB1*03:01:14、DRB1*03:01:15、DRB1*03:01:16、DRB1*03:01:17、DRB1*03:01:18、DRB1*03:01:19、DRB1*03:01: 20、DRB1*03:01:21、DRB1*03:01:22、DRB1*03:01:23、DRB1*03:01:24、DRB 1*03:01:25、DRB1*03:01:26、DRB1*03:01:27、DRB1*03:01:28、DRB1*03:02 :01、DRB1*03:02:02、DRB1*03:02:03、DRB1*03:03、DRB1*03:04:01、DRB1*03:04:02、DRB1*03:05:01、DRB1*03:05:02、DRB1*03:06、DRB1*03:06、 RB1*03:07:01、DRB1*03:07:02、DRB1*03:08、DRB1*03:09、DRB1*03:10、DRB1*03:100:01、DRB1*03:100:02、DRB1*03:10、DRB1*03:10、DRB1*03:100:01 3、DRB1*03:104、DRB1*03:105、DRB1*03:106、DRB1*03:107、DRB1*03:108、DRB1*03:109、DRB1*03:110、DRB1*03:111、DRB1*03:112、DRB1*03:113、DRB1*03:113 1*03:114、DRB1*03:115、DRB1*03:116、DRB1*03:117、DRB1*03:118、DRB1*03:119、DRB1*03:11:01、DRB1*03:12、DRB1*03:120、DRB1*03:121、DRB1*03:122、DRB1*03:123、DRB1*03:124、DRB1*03:125、DRB1*03:126、DRB1*03:127、DRB1*03:128、DRB1*03:129、DRB1*03:130、DRB1*03:131、DRB1*03:132、DRB1*03:133、DRB1*03:134、DRB1*03:135、DRB1*03:136、DRB1*03:137、DRB1*03:138、DRB1*03:139、DRB1*03:13:01、DRB1*03:13:02、DRB1*03:14、DRB1*03:140、DRB1*03:141、DRB1*03:142、DRB1*03:143、DRB1*03:144、DRB1*03:145、DRB1*03:146、DRB1*03:147、DRB1*03:148、DRB1*03:149、DRB1*0 3:150, DRB1*03:151, DRB1*03:152, DRB1*03:153, DRB1*03:154, DRB1*03:155, DRB1*03:156N, DRB1*03:157, DRB1*03:158, DRB1*03:15:01, DRB1*03:15:02, DRB1*03:16, DRB1*03:17, DRB1*03:18, DRB1*03:19, DRB1*03:20, DRB1*03:21, DRB1*03:22, DRB1*03:23, DRB1*03:24, DRB1*03:25:01, DRB1*0 3:25:02, DRB1*03:26, DRB1*03:27, DRB1*03:28, DRB1*03:29, DRB1*03:30, DRB1*03:31, DRB1*03:32, DRB1*03:33, DRB1*03:34, DRB1*03:35, DRB1*03:36, DRB1*03:37, DRB1*03:38, DRB1*03:39, DRB1*03:40, DRB1*03:41:01, DRB1*03:41:02, 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3:100, DRB1*13:101, DRB1*13:102, DRB1*13:103, DRB1*13:104, DRB1*13:105, DRB1*13:106, DRB1*13:107, DRB1*13:108, DRB1*13:109, DRB1*13:110, DRB1*13:111, DRB1*13:112, DRB1*13:113N, DRB1*13:114, DRB1*13:115, DRB1*13:116, DRB1*13:117, DRB1*13:118, DRB1*13:119, DRB1*13:11:01, DRB1*13:11:02, DRB1*13:120, DRB1*13:121, DRB1*13:122, DRB1*13:123, DRB1*13:124, DRB1*13:125, DRB1*13:126, DRB1*13:127, DRB1*13:128, DRB1*13:129, DRB1*13:12:01, DRB1*13:12:02, DRB1*13:12:03, DRB1*13:12:04, DRB1*13:13, DRB1*13:130, DRB1*13:131, DRB1*13:132, DRB1*13:133,DRB1*13:134、DRB1*13:135、DRB1*13:136、DRB1*13:137N、DRB1*13:138、DRB1*13:139、DRB1*13:140、DRB1*13:141、DRB1*13:142N、DRB1*13:143、DRB1*13:144、DRB1*13:145、DRB1、 *13:146、DRB1*13:147、DRB1*13:148、DRB1*13:149、DRB1*13:14:01、DRB1*13:14:02、DRB1*13:14:03、DRB1*13:15、DRB1*13:150、DRB1*13:151、DRB1*13:152、DRB1*13:153、DRB1*13:154、DRB1*13:155、DRB1*13:156、DRB1*13:157、DRB1*13:158、DRB1*13:159、DRB1*13:16、DRB1*13:160、DRB1*13:16 1、DRB1*13:162、DRB1*13:163、DRB1*13:164、DRB1*13:165、DRB1*13:166、DRB1*13:167、DRB1*13:168、DRB1*13:169、DRB1*13:17、DRB1*13:170、DRB1 *13:171:01、DRB1*13:171:02、DRB1*13:172、DRB1*13:173、DRB1*13:174、DRB1*13:175、DRB1*13:176、DRB1*13:177、DRB1*13:178、DRB1*13:179、DRB1*13:179 1*13:18、DRB1*13:180、DRB1*13:181、DRB1*13:182、DRB1*13:183、DRB1*13:184、DRB1*13:185N、DRB1*13:186、DRB1*13:187、DRB1*13:188、DRB1*13:185 189、DRB1*13:19、DRB1*13:190、DRB1*13:191、DRB1*13:192、DRB1*13:193、DRB1*13:194、DRB1*13:195、DRB1*13:196、DRB1*13:197、DRB1*13:198、DRB1*13:198 B1*13:199、DRB1*13:20、DRB1*13:200N、DRB1*13:201、DRB1*13:202、DRB1*13:203、DRB1*13:204、DRB1*13:205、DRB1*13:206、DRB1*13:207、DRB1*13:204 :208、DRB1*13:209、DRB1*13:210、DRB1*13:211、DRB1*13:212、DRB1*13:213、DRB1*13:214、DRB1*13:215、DRB1*13:216、DRB1*13:217、DRB1*13:218、DRB1*13:219、DRB1*13:21:01、DRB1*13:21:02、DRB1*13:220、DRB1*13:221、DRB1*13:222、DRB1*13:223、DRB1*13:224、DRB1*13:225、DRB1*13:226、DRB1*13:226 RB1*13:227、DRB1*13:228、DRB1*13:229、DRB1*13:22:01、DRB1*13:22:02、DRB1*13:230、DRB1*13:231、DRB1*13:232、DRB1*13:233、DRB1*13:234、DRB1*13:234 B1*13:235、DRB1*13:236、DRB1*13:237、DRB1*13:238、DRB1*13:239、DRB1*13:23:01、DRB1*13:23:02、DRB1*13:24、DRB1*13:240、DRB1*13:241、DRB1 *13:242:01、DRB1*13:242:02、DRB1*13:243、DRB1*13:244、DRB1*13:245、DRB1*13:246、DRB1*13:247、DRB1*13:248、DRB1*13:249、DRB1*13:25、DRB1*13:25 1*13:250、DRB1*13:251、DRB1*13:252N、DRB1*13:253、DRB1*13:254、DRB1*13:255N、DRB1*13:256、DRB1*13:257、DRB1*13:258、DRB1*13:259、DRB1*13:259 3:260、DRB1*13:261、DRB1*13:262、DRB1*13:263、DRB1*13:264、DRB1*13:265、DRB1*13:266、DRB1*13:267、DRB1*13:268、DRB1*13:269、DRB1*13:26 :01、DRB1*13:26:02、DRB1*13:27、DRB1*13:270、DRB1*13:271、DRB1*13:272、DRB1*13:273、DRB1*13:274、DRB1*13:275、DRB1*13:276、DRB1*13:277、DRB1*13:278Q、DRB1*13:279、DRB1*13:28:01、DRB1*13:28:02、DRB1*13:29、DRB1*13:30、DRB1*13:31、DRB1*13:32、DRB1*13:33:01、DRB1*13:33:02、DRB1*13:33:03, DRB1*13:34, DRB1*13:35, DRB1*13:36, DRB1*13:37, DRB1*13:38, DRB1*13:39, DRB1*13:40, DRB1*13:41, DRB1*13:42, DRB1*13:43, DRB1*13:44, DRB1*13:45, DRB1*13:46, DRB1*13:47, DRB1*13:48, DRB1*13:49, DRB1*13:50:01, DRB1*13:50:02, DRB1*13:50:03, DRB1*13:51, DRB1 *13:52、DRB1*13:53、DRB1*13:54、DRB1*13:55、DRB1*13:56、DRB1*13:57、DRB1*13:58、DRB1*13:59、DRB1*13:60、DRB1*13:61:01、DRB1*13:61:02、DRB1*13:62、DRB1*13:63、DRB1*13:64、DRB1*13:65、DRB1*13:66:01、DRB1*13:66:02、DRB1*13:67、DRB1*13:68、DRB1*13:69、DRB1*13:70、DRB1*13:7 1、DRB1*13:72、DRB1*13:73、DRB1*13:74、DRB1*13:75、DRB1*13:76、DRB1*13:77、DRB1*13:78、DRB1*13:79、DRB1*13:80、DRB1*13:81、DRB1*13:82、DRB1*13:83、DRB1*13:84、DRB1*13:85、DRB1*13:86、DRB1*13:87、DRB1*13:88、DRB1*13:89:01、DRB1*13:89:02、DRB1*13:90、DRB1*13:91、DRB1*13:9 2、DRB1*13:93、DRB1*13:94:01、DRB1*13:94:02、DRB1*13:95、DRB1*13:96:01、DRB1*13:96:02、DRB1*13:97:01、DRB1*13:97:02、DRB1*13:98、DRB1*13:99、DRB1*14:01:01、DRB1*14:01:02、DRB1*14:01:03、DRB1*14:01:04、DRB1*14:02:01:01、DRB1*14:02:01:02、DRB1*14:02:02、DRB1*14:02:03、DRB1*14:02:04、DRB1*14:02:05、DRB1*14:02:06、DRB1*14:02:07、DRB1*14:03:01、DRB1*14:03:02、DRB1*14:04:01、DRB1*14:04:02、DRB1*14:04:03、DRB1*14:04:04、DRB1*14:04:05、DRB1*14:04:06、DRB1*14:05:01:01、DRB1*14:05:01:02、DRB1*14:05:02、DRB1*14:05:03、DRB1*14:05:04、DRB1* 14:06:01, DRB1*14:06:02, DRB1*14:06:03, DRB1*14:06:04, DRB1*14:07:01, DRB1*14:07:02, DRB1*14:08, DRB1*14:09, DRB1*14:10, DRB1*14:100, DRB1*14:101, DRB1*14:102, DRB1*14:103, DRB1*14:104, DRB1*14:105, DRB1*14:106, DRB1*14:107, DRB1*14:108, DRB1*14:109, DRB1*14:11, DRB1*14 :110、DRB1*14:111、DRB1*14:112、DRB1*14:113、DRB1*14:114、DRB1*14:115、DRB1*14:116、DRB1*14:117、DRB1*14:118、DRB1*14:119、DRB1*14:120、DRB1*14:121、DRB1*14:122、DRB1*14:123、DRB1*14:124、DRB1*14:125、DRB1*14:126:01、DRB1*14:126:02、DRB1*14:127:01、DRB1*14:127:02、DRB1* 14:128、DRB1*14:129、DRB1*14:12:01、DRB1*14:12:02、DRB1*14:13、DRB1*14:130、DRB1*14:131、DRB1*14:132、DRB1*14:133、DRB1*14:134、DRB1*14:135、DRB1*14:136、DRB1*14:137N、DRB1*14:138、DRB1*14:139、DRB1*14:14、DRB1*14:140、DRB1*14:141、DRB1*14:142、DRB1*14:143、DRB1*14:144、DRB1*14:145、DRB1*14:146、DRB1*14:147、DRB1*14:148、DRB1*14:149、DRB1*14:15、DRB1*14:150、DRB1*14:151、DRB1*14:152N、DRB1*14:153、DRB1*14:154、DRB1*14:155、DRB1*14:156、DRB1*14:157、DRB1*14:158、DRB1*14:159、DRB1*14:16、DRB1*14:160、DRB1*14:161、DRB1*14:162、DRB1*14:1 63、DRB1*14:164、DRB1*14:165、DRB1*14:166N、DRB1*14:167、DRB1*14:168、DRB1*14:169、DRB1*14:17、DRB1*14:170、DRB1*14:171、DRB1*14:172、DRB1*14:173、DRB1*14:174、DRB1*14:175、DRB1*14:176、DRB1*14:177、DRB1*14:178、DRB1*14:179、DRB1*14:18、DRB1*14:180、DRB1*14:181、DRB1*1 4:182、DRB1*14:183、DRB1*14:184、DRB1*14:185、DRB1*14:186、DRB1*14:187、DRB1*14:188N、DRB1*14:189、DRB1*14:19、DRB1*14:190、DRB1*14:190 1. RB1*14:201、DRB1*14:202、DRB1*14:203、DRB1*14:204、DRB1*14:205、DRB1*14:206、DRB1*14:207、DRB1*14:208、DRB1*14:209、DRB1*14:21、DRB1*14:210Q、DRB1*14:211、DRB1*14:22、DRB1*14:23:01、DRB1*14:23:02、DRB1*14:23:03、DRB1*14:23:04、DRB1*14:24、DRB1*14:25:01、DRB1*14:25:02、DRB1*14:26、DRB1*14:27:01、DRB1*14:27:02、DRB1*14:28、DRB1*14:29、DRB1*14:30、DRB1*14:31、DRB1*14:32:01、DRB1*14:32:02、DRB1*14:32:03、DRB1*14:33、DR、 B1*14:34、DRB1*14:35、DRB1*14:36、DRB1*14:37、DRB1*14:38:01、DRB1*14:38:02、DRB1*14:39、DRB1*14:40、DRB1*14:41、DRB1*14:42、DRB1*14:4 3、DRB1*14:44:01、DRB1*14:44:02、DRB1*14:44:03、DRB1*14:45、DRB1*14:46、DRB1*14:47、DRB1*14:48、DRB1*14:49、DRB1*14:50、DRB1*14:51、DRB1*14:51 1*14:52、DRB1*14:53、DRB1*14:54:01:01、DRB1*14:54:01:02、DRB1*14:54:01:03、DRB1*14:54:01:04、DRB1*14:54:02、DRB1*14:54:03、DRB1*14:54:04、DRB1*14:54:05、DRB1*14:54:06、DRB1*14:54:07、DRB1*14:55、DRB1*14:56、DRB1*14:57、DRB1*14:58、DRB1*14:59、DRB1*14:60、DRB1*14:61 ,DRB1*14:62,DRB1*14:63,DRB1*14:64,DRB1*14:65,DRB1*14:67,DRB1*14:68:01,DRB1*14:68:02,DRB1*14:69,DRB1*14:70,DRB1*14:71,DRB1*14:72,DRB1*14:73,DRB1*14:74,DRB1*14:75,DRB1*14:76,DRB1*14:77,DRB1*14:78,DRB1*14:79,DRB1*14:80,DRB1*14:81,DRB1*14:82,DRB1*14:8 3、DRB1*14:84、DRB1*14:85、DRB1*14:86、DRB1*14:87、DRB1*14:88、DRB1*14:89、DRB1*14:90、DRB1*14:91、DRB1*14:92N、DRB1*14:93、DRB1*14:94、DRB1*14:95、DRB1*14:96、DRB1*14:97、DRB1*14:98、DRB1*14:99、DRB1*15:01:01:01、DRB1*15:01:01:02、DRB1*15:01:01:03、DRB1*15:01:01:04、DRB1*15:01:01:05, DRB1*15:01:02, DRB1*15:01:03, DRB1*15:01:04, DRB1*15:01:05, DRB1*15:01:06, DRB1*15:01:07, DRB1*15:01:08, DRB1*15:01:09, DRB1*15:01:10, DRB1*15:01:11, DRB1*15:01:12, DRB1*15:01:13, DRB1*15:01:14, DRB1*15:01:15, DRB1*15:01:16, DRB1*15:01:17, DRB1*15 :01:18、DRB1*15:01:19、DRB1*15:01:20、DRB1*15:01:21、DRB1*15:01:22、DRB1*15:01:23、DRB1*15:01:24、DRB1*15:01:25、DRB1*15:01:26、DRB1*15:01:27、DRB1*15:01:28、DRB1*15:01:29、DRB1*15:01:30、DRB1*15:01:31、DRB1*15:01:32、DRB1*15:01:33、DRB1*15:01:34、DRB1*15:01:35、DRB1 *15:01:36、DRB1*15:01:37、DRB1*15:01:38、DRB1*15:01:39、DRB1*15:01:40、DRB1*15:01:41、DRB1*15:02:01:01、DRB1*15:02:01:02、DRB1*15:02:01:03、DRB1*15:02:02、DRB1*15:02:03、DRB1*15:02:04、DRB1*15:02:05、DRB1*15:02:06、DRB1*15:02:07、DRB1*15:02:08、DRB1*15:02:09、DRB1*1 5:02:10, DRB1*15:02:11, DRB1*15:02:12, DRB1*15:02:13, DRB1*15:02:14, DRB1*15:02:15, DRB1*15:02:16, DRB1*15:02:17, DRB1*15:02:18, DRB1*15:02:19, DRB1*15:03:01:01, DRB1*15:03:01:02, DRB1*15:03:01:03, DRB1*15:03:02, DRB1*15:03:03, DRB1*15:03:04, DRB1*15:04, DRB1*15:05,DRB1*15:06:01、DRB1*15:06:02、DRB1*15:06:03、DRB1*15:06:04、DRB1*15:07:01、DRB1*15:07:02、DRB1*15:07:03、DRB1*15:08、DRB1*15:09、DRB1*15:10、DRB1*15:100、DRB1*15:101、DRB1*15:102、DRB1*15:103、DRB1*15:104:01、DRB1*15:104:02、DRB1*15:104:03、DRB1*15:105:01、DRB1*15:105 :02、DRB1*15:106、DRB1*15:107、DRB1*15:108、DRB1*15:109、DRB1*15:110、DRB1*15:111、DRB1*15:112、DRB1*15:113N、DRB1*15:114、DRB1*15:115N 、DRB1*15:116、DRB1*15:117、DRB1*15:118、DRB1*15:119、DRB1*15:11:01、DRB1*15:11:02、DRB1*15:12、DRB1*15:120、DRB1*15:121、DRB1*15:122、DRB1*15:122 RB1*15:123、DRB1*15:124、DRB1*15:125、DRB1*15:126、DRB1*15:127、DRB1*15:128、DRB1*15:129N、DRB1*15:13、DRB1*15:130、DRB1*15:131、DRB1*15:132、DRB1*15:133、DRB1*15:134N、DRB1*15:135、DRB1*15:136、DRB1*15:137N、DRB1*15:138N、DRB1*15:139、DRB1*15:14、DRB1*15:140、DRB1*15:1 41、DRB1*15:142、DRB1*15:143、DRB1*15:144、DRB1*15:145、DRB1*15:146、DRB1*15:147、DRB1*15:148N、DRB1*15:149、DRB1*15:150、DRB1*15:151、DRB1*15:152、DRB1*15:153、DRB1*15:154N、DRB1*15:155、DRB1*15:156、DRB1*15:157、DRB1*15:158、DRB1*15:159N、DRB1*15:15:01、DRB1*15:15:02、DRB1*15:15:03, DRB1*15:16, DRB1*15:160, DRB1*15:161, DRB1*15:162, DRB1*15:163N, DRB1*15:164Q, DRB1*15:165, DRB1*15:166, DRB1*15:167, DRB1*15:168, DRB1*15:169, DRB1*15:170, DRB1*15:17N, DRB1*15:18, DRB1*15:19, DRB1*15:20, DRB1*15:21, DRB1*15:22, DRB1*15:23, DRB1*15:24, DRB1*15:25、DRB1*15:26、DRB1*15:27、DRB1*15:28、DRB1*15:29、DRB1*15:30、DRB1*15:31:01、DRB1*15:31:02、DRB1*15:32、DRB1*15:33、DRB1*15:34、DRB1*15:35、DRB1*15:36、DRB1*15:37:01、DRB1*15:37:02、DRB1*15:38、DRB1*15:39、DRB1*15:40、DRB1*15:41、DRB1*15:42、DRB1*15:43、DRB1*1 5:44、DRB1*15:45、DRB1*15:46、DRB1*15:47、DRB1*15:48、DRB1*15:49、DRB1*15:50N、DRB1*15:51、DRB1*15:52、DRB1*15:53、DRB1*15:54、DRB1*15:54 55、DRB1*15:56、DRB1*15:57、DRB1*15:58、DRB1*15:59、DRB1*15:60、DRB1*15:61、DRB1*15:62、DRB1*15:63、DRB1*15:64、DRB1*15:65、DRB1*15:66 01. 76、DRB1*15:77、DRB1*15:78、DRB1*15:79、DRB1*15:80N、DRB1*15:81、DRB1*15:82、DRB1*15:83、DRB1*15:84、DRB1*15:85、DRB1*15:86、DRB1*15:87、DRB1*15:88、DRB1*15:89、DRB1*15:90、DRB1*15:91、DRB1*15:92、DRB1*15:93、DRB1*15:94、DRB1*15:95、DRB1*15:96、DRB1*15:97、DRB1*15:98、DRB1*15:99、DRB1*16:01:01、DRB1*16:01:02、DRB1*16:01:03、DRB1*16:01:04、DRB1*16:01:05、DRB1*16:01:06、DRB1*16:01:07、DRB1*16:01:08、DRB1* 16:01:09, DRB1*16:01:10, DRB1*16:01:11, DRB1*16:01:12, DRB1*16:01:13, DRB1*16:01:14, DRB1*16:01:15, DRB1*16:01:16, DRB1*16:02:01:01, DRB1*16:02:01:02, DRB1*16:02:01:03, DRB1*16:02:02, DRB1*16:02:03, DRB1*16:02:04, DRB1*16:02:05, DRB1*16:02:06, DRB1*16:02:07, DRB1*16: 02:08, DRB1*16:03, DRB1*16:04:01, DRB1*16:04:02, DRB1*16:05:01, DRB1*16:05:02, DRB1*16:07, DRB1*16:08, DRB1*16:09:01, DRB1*16:09:02, DRB1*16:10:01, DRB1*16:10:02, DRB1*16:11, DRB1*16:12, DRB1*16:13N, DRB1*16:14, DRB1*16:15, DRB1*16:16, DRB1*16:17, DRB1*16:18, DRB1*16:19 ,DRB1*16:20,DRB1*16:21N,DRB1*16:22,DRB1*16:23,DRB1*16:24,DRB1*16:25,DRB1*16:26,DRB1*16:27,DRB1*16:28,DRB1*16:29,DRB1*16:30,DRB1*16:31,DRB1*16:32,DRB1*16:33,DRB1*16:34,DRB1*16:35,DRB1*16:36,DRB1*16:37,DRB1*16:38:01,DRB1*16:38:02,DRB1*16:39,DRB1*16:40,DRB1*16:41N, DRB1*16:42, DRB1*16:43, DRB1*16:44, DRB1*16:45, DRB1*16:46, DRB1*1 6:47, DRB1*16:48, DRB1*16:49, DRB1*16:50, DRB1*16:51, DRB1*16:52, DRB1*16:53, D, RB1*16:54, DRB1*16:55N, DRB1*16:56, and any combination thereof.

[0212] In certain embodiments, the MHC class II molecule comprises a DR beta chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:21, wherein the DR beta chain comprises (i) a tryptophan at the amino acid residue corresponding to position 114 of SEQ ID NO:19, (ii) a methionine at the amino acid residue corresponding to position 143 of SEQ ID NO:19, (iii) a histidine at the amino acid residue corresponding to position 118 of SEQ ID NO:19, and (iv) an isoleucine at the amino acid residue corresponding to position 157 of SEQ ID NO:19. In certain embodiments, the MHC class II molecule comprises a DR beta chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:21, wherein the DR beta chain comprises (i) a tryptophan at the amino acid residue corresponding to position 114 of SEQ ID NO:19; (ii) a tryptophan at the amino acid residue corresponding to position 115 of SEQ ID NO:19; (iii) a histidine at the amino acid residue corresponding to position 118 of SEQ ID NO: 19, (iv) an isoleucine at the amino acid residue corresponding to position 157 of SEQ ID NO: 19, (v) a threonine at the amino acid residue corresponding to position 139 of SEQ ID NO: 19, (vi) a glutamine at the amino acid residue corresponding to position 146 of SEQ ID NO: 19, (vii) a methionine at the amino acid residue corresponding to position 163 of SEQ ID NO: 19, and (viii) a threonine at the amino acid residue corresponding to position 164 of SEQ ID NO: 19. In certain embodiments, the MHC class II molecule comprises a DR beta chain comprising the amino acid sequence set forth in SEQ ID NO: 21.

[0213] II.A.3.b. HLA-DR alpha chain In some embodiments of the present disclosure, the MHC class II molecule further comprises an alpha chain. In some embodiments, the alpha chain is a wild-type alpha chain. In some embodiments, the alpha chain is a DR alpha chain. Any DR alpha chain may be used in the compositions and methods of the present disclosure. In some embodiments, the DR alpha chain comprises the HLA-DRA1*01 allele.

[0214] In certain embodiments, the DR alpha chain is selected from DRA*01:01:01:01, DRA*01:01:01:02, DRA*01:01:01:03, DRA*01:01:02, DRA*01:02:01, DRA*01:02:02, DRA*01:02:03, and any combination thereof.

[0215] In certain embodiments, an MHC class II molecule comprises a DR alpha chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 24. In certain embodiments, an MHC class II molecule comprises a DR alpha chain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 26. In certain embodiments, an MHC class II molecule comprises a DR alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 24. In certain embodiments, an MHC class II molecule comprises a DR alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 26.

[0216] II.A.4. Signal peptides In some embodiments, the beta chain and / or the alpha chain further comprise a signal peptide. Any signal peptide known in the art may be used in the compositions and methods disclosed herein. In some embodiments, the beta chain signal peptide is the same as the alpha signal peptide. In some embodiments, the beta chain signal peptide is different from the alpha signal peptide.

[0217] In some embodiments, the signal peptide is derived from a native signal peptide. In some embodiments, the signal peptide is derived from a naturally occurring DP beta chain signal peptide. In some embodiments, the signal peptide comprises a naturally occurring DP beta chain signal peptide. In some embodiments, the signal peptide is derived from a naturally occurring DP alpha chain signal peptide. In some embodiments, the signal peptide comprises a naturally occurring DP alpha chain signal peptide.

[0218] In some embodiments, the signal peptide is derived from a naturally occurring DQ beta chain signal peptide. In some embodiments, the signal peptide comprises a naturally occurring DQ beta chain signal peptide. In some embodiments, the signal peptide is derived from a naturally occurring DQ alpha chain signal peptide. In some embodiments, the signal peptide comprises a naturally occurring DQ alpha chain signal peptide.

[0219] In some embodiments, the signal peptide is derived from a naturally occurring DR beta chain signal peptide. In some embodiments, the signal peptide comprises a naturally occurring DR beta chain signal peptide. In some embodiments, the signal peptide is derived from a naturally occurring DR alpha chain signal peptide. In some embodiments, the signal peptide comprises a naturally occurring DR alpha chain signal peptide.

[0220] In some embodiments, the signal peptide is derived from the fibroin light chain (FibL) signal peptide. In some embodiments, the signal peptide comprises SEQ ID NO: 9. In some embodiments, the signal peptide is synthetic.

[0221] II.A.5. Transmembrane domains In some embodiments, the beta chain and / or the alpha chain further comprise a transmembrane domain. The transmembrane domain can be of any length and of any origin. In some embodiments, the transmembrane domain is at least about 1 to at least about 50 amino acids in length. In some embodiments, the transmembrane domain is derived from a naturally occurring transmembrane domain. In some embodiments, the transmembrane domain comprises a naturally occurring transmembrane domain. In some embodiments, the transmembrane domain is derived from a naturally occurring HLA transmembrane domain. In some embodiments, the transmembrane domain comprises a naturally occurring HLA transmembrane domain.

[0222] In some embodiments, the transmembrane domain is derived from a naturally occurring DP beta chain transmembrane domain. In some embodiments, the transmembrane domain comprises a naturally occurring DP beta chain transmembrane domain. In some embodiments, the transmembrane domain is derived from a naturally occurring DP alpha chain transmembrane domain. In some embodiments, the transmembrane domain comprises a naturally occurring DP alpha chain transmembrane domain.

[0223] In some embodiments, the transmembrane domain is derived from a naturally occurring DQ beta chain transmembrane domain. In some embodiments, the transmembrane domain comprises a naturally occurring DQ beta chain transmembrane domain. In some embodiments, the transmembrane domain is derived from a naturally occurring DQ alpha chain transmembrane domain. In some embodiments, the transmembrane domain comprises a naturally occurring DQ alpha chain transmembrane domain.

[0224] In some embodiments, the transmembrane domain is derived from a naturally occurring DR beta chain transmembrane domain. In some embodiments, the transmembrane domain comprises a naturally occurring DR beta chain transmembrane domain. In some embodiments, the transmembrane domain is derived from a naturally occurring DR alpha chain transmembrane domain. In some embodiments, the transmembrane domain comprises a naturally occurring DR alpha chain transmembrane domain.

[0225] II.A.6. Leucine zipper In some embodiments, the beta and / or alpha chain further comprises one or more leucine zipper (LZip) sequences. Any LZip sequence known in the art may be used in the compositions and methods disclosed herein. In some embodiments, the beta and / or alpha chain comprises an acidic LZip (αLZip), a basic LZip (βLZip), or both. In some embodiments, one or more LZip sequences are derived from a naturally occurring LZip sequence. In some embodiments, one or more LZip sequences comprise a naturally occurring LZip sequence. In some embodiments, one or more LZip sequences are synthetic. In certain embodiments, one or more LZip sequences comprise an LZip sequence set forth in SEQ ID NO: 4, 7, 14, 17, 22, or 25.

[0226] II.A.7. Linkers In some embodiments, the beta and / or alpha chains useful in the present disclosure further comprise a linker. Any linker known in the art may be used in the compositions and methods disclosed herein. In certain embodiments, the linker comprises a Gly / Ser linker. In some embodiments, the linker comprises an amino acid sequence selected from GlySer, Gly2Ser, Gly3Ser, and Gly4Ser. In some embodiments, the linker is located at the N-terminus of the extracellular domain of the alpha or beta chain. In some embodiments, the linker is located at the C-terminus of the extracellular domain of the alpha or beta chain. In some embodiments, the linker is located between the extracellular domain and the transmembrane domain of the alpha or beta chain. In some embodiments, the linker is located between the extracellular domain of the alpha or beta chain and one or more LZip sequences. In some embodiments, the linker is located between the extracellular domain of the alpha or beta chain and the signal peptide.

[0227] Linkers of any length may be used in the compositions and methods disclosed herein. In some embodiments, the linker is at least one amino acid in length. In some embodiments, the linker is at least about 1 to at least about 100, at least about 1 to at least about 90, at least about 1 to at least about 80, at least about 1 to at least about 70, at least about 1 to at least about 60, at least about 1 to at least about 50, at least about 1 to at least about 40, at least about 1 to at least about 30, at least about 1 to at least about 20, at least about 1 to at least about 15, at least about 1 to at least about 14, at least about 1 to at least about 13, at least about 1 to at least about 12, at least about 1 to at least about 11, at least about 1 to at least about 10, at least about 1 to at least about 9, at least about 1 to at least about 8, at least about 1 to at least about 7, at least about 1 to at least about 6, at least about 1 to at least about 5, at least about 1 to at least about 4, or at least about 1 to at least about 3 amino acids in length.

[0228] In some embodiments, the linker is at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, or at least about 100 amino acids in length. In certain embodiments, the linker is about 3 amino acids in length. In certain embodiments, the linker is about 4 amino acids in length. In certain embodiments, the linker is about 5 amino acids in length.

[0229] II.B. Cells In certain embodiments of the present disclosure, the MHC class II molecule used in the methods of the present disclosure is linked or bound to the membrane of a cell. Accordingly, some embodiments of the present disclosure relate to a method for identifying an MHC class II-specific TCR, the method comprising contacting a T cell with a cell, wherein the cell comprises a complex comprising an MHC class II molecule disclosed herein and a peptide, e.g., an epitope. In certain embodiments, the beta chain of the MHC class II molecule is linked or bound to the membrane of the cell. In certain embodiments, the alpha chain of the MHC class II molecule is linked or bound to the membrane of the cell. In certain embodiments, the alpha and beta chains of the MHC class II molecule are linked or bound to the membrane of the cell.

[0230] Any cells may be used in the methods described herein. In certain embodiments, the cells are mammalian cells. In some embodiments, the cells are insect cells. In some embodiments, the cells are derived from healthy cells, such as healthy fibroblasts. In some embodiments, the cells are derived from tumor cells. Non-limiting examples of cells useful in the present disclosure include K562 cells, T2 cells, HEK293 cells, HEK293T cells, A375 cells, SK-MEL-28 cells, Me275 cells, COS cells, fibroblasts, tumor cells, or any combination thereof. In certain embodiments, the cells are derived from the methods described in Hasan et al., Adv. Genet., incorporated herein by reference. Eng. 4(3):130 (2015).

[0231] In certain embodiments, the cell is a professional APC. In certain embodiments, the cell is a macrophage, a B cell, a dendritic cell, or any combination thereof.

[0232] In certain embodiments, the cells lack endogenous expression of one or more MHC class II alleles. In some embodiments, the cells lack endogenous expression of HLA-DP alleles. In some embodiments, the cells lack endogenous expression of HLA-DP alpha chain alleles. In some embodiments, the cells lack endogenous expression of HLA-DP beta chain alleles.

[0233] II.C. Soluble MHC class II molecules In certain embodiments, the MHC class II molecules used in the methods disclosed herein are not bound to a cell membrane, e.g., the MHC class II molecules are in soluble form. As used herein, soluble MHC class II molecules include any MHC class II molecule or portion thereof described herein and are not bound to a cell membrane. In certain embodiments, the MHC class II molecule or portion thereof is not bound to any membrane. In some embodiments, the MHC class II molecule or portion thereof is bound to an inert particle. In some embodiments, the MHC class II molecule or portion thereof is bound to the membrane of an extracellular vesicle. In some embodiments, the MHC class II molecule is bound to an artificial membrane or artificial surface, such as the surface of an array plate.

[0234] Any inert particle known in the art may be used in the compositions and methods of the present disclosure. In some embodiments, the inert particle is a bead. In some embodiments, the bead is a glass bead, a latex bead, a metal bead, or any combination thereof. In some embodiments, the inert particle is a nanoparticle (NP). Any NP known in the art may be used in the compositions and methods of the present disclosure. In certain embodiments, the nanoparticle is selected from PEGylated iron oxide, chitosan, dextran, gelatin, alginate, liposomes, starch, branched polymers, carbon-based carriers, polylactic acid, poly(cyano)acrylate, polyethyleinemine, block copolymers, polycaprolactone, SPIONS, USPIONS, Cd / Zn-selenide, or silica nanoparticles. In certain embodiments, the nanoparticle is a PEGylated iron oxide nanoparticle. Non-limiting examples of nanoparticles useful in the compositions and methods disclosed herein include those described in De Jong and Borm, Int. J. Nanomedicine 3(2):133-49 (2008), and Umeshappa et al., Nat. Commun. 10(1):2150 (May 14, 2019), each of which is incorporated herein by reference in its entirety.

[0235] In some embodiments, the MHC class II molecule comprises a fragment of a full-length MHC class II molecule, wherein one or more amino acids of the transmembrane domain of the alpha chain and / or the transmembrane domain of the beta chain are deleted. In some embodiments, the MHC class II molecule comprises the extracellular domain of the alpha chain (e.g., as set forth in SEQ ID NO: 6) and / or the extracellular domain of the beta chain (e.g., as set forth in SEQ ID NO: 1 or 3). In some embodiments, the MHC class II molecule comprises the extracellular domain of the alpha chain (e.g., as set forth in SEQ ID NO: 16) and / or the extracellular domain of the beta chain (e.g., as set forth in SEQ ID NO: 11 or 13). In some embodiments, the MHC class II molecule comprises the extracellular domain of the alpha chain (e.g., as set forth in SEQ ID NO: 24) and / or the extracellular domain of the beta chain (e.g., as set forth in SEQ ID NO: 19 or 21).

[0236] In certain embodiments, the MHC class II molecule comprises a DP alpha chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 6. In some embodiments, the MHC class II molecule comprises a DP alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 6.

[0237] In certain embodiments, the MHC class II molecule comprises a DQ alpha chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 16. In some embodiments, the MHC class II molecule comprises a DQ alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 16.

[0238] In certain embodiments, the MHC class II molecule comprises a DR alpha chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 24. In some embodiments, the MHC class II molecule comprises a DR alpha chain comprising the amino acid sequence set forth in SEQ ID NO:24.

[0239] In certain embodiments, the MHC class II molecule comprises a DP beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 1. In some embodiments, the MHC class II molecule comprises a DP beta chain comprising an amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the MHC class II molecule comprises a DP beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 3. In some embodiments, the MHC class II molecule comprises a DP beta chain comprising the amino acid sequence set forth in SEQ ID NO: 3. In certain embodiments, the MHC class II molecule comprises a DP beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 4. In some embodiments, the MHC class II molecule comprises a DP beta chain comprising an amino acid sequence set forth in SEQ ID NO: 4. In certain embodiments, the MHC class II molecule comprises a DP beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 5. In some embodiments, the MHC class II molecule comprises a DP beta chain comprising the amino acid sequence set forth in SEQ ID NO: 5.

[0240] In certain embodiments, the MHC class II molecule comprises a DQ beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 11. In some embodiments, the MHC class II molecule comprises a DQ beta chain comprising an amino acid sequence set forth in SEQ ID NO: 11. In certain embodiments, the MHC class II molecule comprises a DQ beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 13. In some embodiments, the MHC class II molecule comprises a DQ beta chain comprising the amino acid sequence set forth in SEQ ID NO: 13. In certain embodiments, the MHC class II molecule comprises a DQ beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 14. In some embodiments, the MHC class II molecule comprises a DQ beta chain comprising an amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the MHC class II molecule comprises a DQ beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 15. In some embodiments, the MHC class II molecule comprises a DQ beta chain comprising the amino acid sequence set forth in SEQ ID NO: 15.

[0241] In certain embodiments, an MHC class II molecule comprises a DR beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 19. In some embodiments, an MHC class II molecule comprises a DR beta chain comprising an amino acid sequence set forth in SEQ ID NO: 19. In certain embodiments, an MHC class II molecule comprises a DR beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 21. In some embodiments, an MHC class II molecule comprises a DR beta chain comprising the amino acid sequence set forth in SEQ ID NO: 21. In certain embodiments, an MHC class II molecule comprises a DR beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 22. In some embodiments, an MHC class II molecule comprises a DR beta chain comprising an amino acid sequence set forth in SEQ ID NO: 22. In certain embodiments, an MHC class II molecule comprises a DR beta chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 23. In some embodiments, an MHC class II molecule comprises a DR beta chain comprising the amino acid sequence set forth in SEQ ID NO: 23.

[0242] II.D. Nucleic Acid Molecules and Vectors Certain aspects of the present disclosure relate to nucleic acid molecules encoding the MHC class II molecules disclosed herein. In some embodiments, the nucleic acid molecule encodes an MHC class II beta chain disclosed herein. In certain embodiments, the nucleic acid molecule encoding the MHC class II beta chain comprises a nucleotide sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the sequence set forth in SEQ ID NO: 2, 12, or 20.

[0243] In some embodiments, the nucleic acid molecule encodes an MHC class II alpha chain disclosed herein. In certain embodiments, the nucleic acid molecule encoding the MHC class II alpha chain comprises a nucleotide sequence having at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the sequence set forth in SEQ ID NO: 7, 17, or 25.

[0244] In some embodiments, the nucleic acid molecule encodes both an MHC class II alpha chain as disclosed herein and an MHC class II beta chain as disclosed herein. In some embodiments, the sequence encoding the MHC class II alpha chain is under the control of the same promoter as the sequence encoding the MHC class II beta chain. In some embodiments, the sequence encoding the MHC class II alpha chain is under the control of a first promoter and the sequence encoding the MHC class II beta chain is under the control of a second promoter.

[0245] In some aspects, the present disclosure relates to a first nucleic acid molecule encoding an MHC class II beta chain as disclosed herein, and a second nucleic acid molecule encoding an MHC class II alpha chain as disclosed herein.

[0246] Certain aspects of the present disclosure relate to a vector or set of vectors comprising a nucleic acid molecule disclosed herein. In some embodiments, the vector is a viral vector. In some embodiments, the vector is a viral particle or virus. In some embodiments, the vector is a mammalian vector. In some embodiments, the vector is a bacterial vector.

[0247] In certain embodiments, the vector is a retroviral vector. In some embodiments, the vector is an adenoviral vector, a lentivirus, a Sendai virus, a baculoviral vector, an Epstein-Barr virus vector, a papovavirus vector, a cowpox virus vector, a herpes simplex virus vector, or an adeno-associated virus (AAV) vector. In certain embodiments, the vector is an AAV vector. In some embodiments, the vector is a lentivirus. In certain embodiments, the vector is an adenoviral vector. In some embodiments, the vector is a Sendai virus. In some embodiments, the vector is a hybrid vector. For examples of hybrid vectors that can be used in the present disclosure, see Huang and Kamihira, Biotechnol. Adv. 31(2):208-23 (2103), which is incorporated herein by reference.

[0248] II.E. Tumor Treatment Methods In certain embodiments, the methods disclosed herein further comprise treating cancer in a subject in need thereof. In some embodiments, the methods further comprise administering a TCR identified using the methods disclosed herein to a subject in need thereof, wherein the subject is suffering from cancer. In some embodiments, the methods comprise administering a cell to the subject, wherein the cell comprises a TCR identified using the methods disclosed herein. In some embodiments, the cell is a T cell.

[0249] In some embodiments, the cancer is melanoma, bone cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, cutaneous or intraocular malignant melanoma, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma (NHL), primary mediastinal large B-cell lymphoma (PMBC), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue cancer, The cancer is selected from sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non-T-cell ALL), chronic lymphocytic leukemia (CLL), childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including those due to asbestos, other B-cell malignancies, and combinations of cancers. In some embodiments, the cancer is melanoma.

[0250] In some embodiments, the cancer is recurrent. In some embodiments, the cancer is refractory. In some embodiments, the cancer is progressive. In some embodiments, the cancer is metastatic.

[0251] In some embodiments, the methods disclosed herein treat cancer in a subject. In some embodiments, the methods disclosed herein reduce the severity of one or more symptoms of cancer. In some embodiments, the methods disclosed herein reduce the size or number of tumors resulting from cancer. In some embodiments, the methods disclosed herein extend the overall survival of a subject compared to a subject not provided with a method disclosed herein. In some embodiments, the methods disclosed herein extend the progression-free survival of a subject compared to a subject not provided with a method disclosed herein. In some embodiments, the methods disclosed herein result in a partial response in a subject. In some embodiments, the methods disclosed herein result in a complete response in a subject.

[0252] Certain aspects of the present disclosure relate to methods of treating an infection in a subject in need thereof, the method comprising administering to the subject an HLA class II molecule disclosed herein, a nucleic acid molecule disclosed herein, a vector disclosed herein, or a cell disclosed herein. Non-limiting examples of infections that can be treated using the compositions and methods disclosed herein include infections caused by viruses (including viroids and prions), bacteria, fungi, parasites, or any combination thereof. In some embodiments, the virus is herpesvirus, HIV, papovavirus, measles virus, rubella virus, human papillomavirus (HPV), human T-lymphotropic virus 1, Epstein-Barr virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, influenza virus, norovirus, and any combination thereof. In some embodiments, the bacterium is selected from Streptococcus, Staphylococcus, and E. coli. In some embodiments, the bacterial infection is selected from brucellosis, Campylobacter infection, cat scratch disease, cholera, Escherichia coli, gonorrhea, Klebsiella, Enterobacter, Serratia, Legionella infection, meningococcal infection, whooping cough, plague, Pseudomonas infection, Salmonella infection, shigellosis, typhoid fever, tularemia, splenic ulcers, diphtheria, enterococcal infection, erysipelothricosis, listeriosis, nocardiosis, pneumococcal infection, staphylococcal infection, streptococcal infection, and any combination thereof. In some embodiments, the parasitic infection is selected from pinworm, trichomoniasis, toxoplasmosis, giardiasis, cryptosporidiosis, malaria, hookworm, ringworm, tapeworm, fluke, and any combination thereof. In some embodiments, the fungal infection is selected from Candida, Malassezia furfur, dermatophytes (e.g., Epidermophyton, Microsporum, and Trichophyton), or any combination thereof.

[0253] In some embodiments, the methods disclosed herein include treating cancer or an infection in a subject in need thereof, the methods comprising administering to the subject a cell described herein, wherein the cell comprises an MHC class II molecule disclosed herein, a nucleic acid molecule disclosed herein, a vector disclosed herein, or any combination thereof.

[0254] In some embodiments, the cells are obtained from the subject. In some embodiments, the cells are obtained from a donor other than the subject.

[0255] Any of the various aspects, embodiments and options described herein can be combined in any and all variations.

[0256] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0257] Having generally described the present disclosure, a further understanding can be obtained by reference to the examples provided herein, which are for illustrative purposes only and are not intended to be limiting. [Example]

[0258] Example 1 - Generation of affinity matured HLA-DP molecules

[0259] cell Peripheral mononuclear cells were obtained by density gradient centrifugation (Ficoll-Paque PLUS, GE Healthcare Life Sciences, Marlborough, MA). The K562 cell line is an erythroleukemia cell line deficient in HLA class I / II expression. K562-based artificial APCs (aAPCs) expressing various HLA class II genes individually as single HLA alleles related to CD80 and CD83 have been previously reported (Butler et al., PloS One 7, e30229 (2012)). The Jurkat76 cell line is a T-cell leukemia cell line lacking endogenous TCR, CD4, and CD8 expression. Jurkat76 / CD4 cells were generated by retroviral transduction with the human CD4 gene. A375, SK-MEL-21, SK-MEL-28, SK-MEL-37, and Me275 are melanoma cell lines. HEK293T cells and melanoma cell lines were grown in DMEM (Thermo Fisher Scientific, Waltham, MA) supplemented with 10% FBS and 50 μg / ml gentamicin. K562 and Jurkat76 cell lines were cultured in RPMI 1640 supplemented with 10% FBS and 50 μg / ml gentamicin.

[0260] peptide

[0261] Synthetic peptides were purchased from Genscript (Piscataway, NJ) and dissolved in DMSO at 50 μg / ml. Peptide sequences are shown in Table 6. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5]

[0262] gene

[0263] The novel TCR gene was isolated using the SMARTer RACE 5' / 3' Kit (Takara The genes were cloned by rapid amplification of 5' cDNA ends (RACE) PCR using a PCR product (Bio, Shiga, Japan) and sequenced as described above. All genes were cloned into pMX retroviral vectors and transduced into cell lines using the 293GPG and PG13 cell-based retroviral systems.

[0264] antibody

[0265] For flow cytometry analysis, PE-conjugated anti-class II (9-49(I3)), APC-Cy7-conjugated anti-CD4 (RPA-T4, Biolegend, San Diego, CA) were used. CA) 44 , FITC-conjugated anti-NGFR (ME20.4, Biolegend, San Diego, CA), PE-conjugated anti-His tag (AD1.1.10, Abcam, Antibodies used were: anti-Vβ22 (IMMU 546, Beckman Coulter, Brea, CA), and FITC-conjugated anti-Vβ22 (IMMU 546, Beckman Coulter, Brea, CA). 157-170 and DP4 / WT1 329-348 The monomers were multimerized using PE-conjugated streptavidin (Thermo Fisher Scientific, Waltham, MA) according to the manufacturer's instructions. Dead cells were stained with LIVE / DEAD Fixable Near-IR Dead Cell Stain. Sorting was performed using Kit 465 (Thermo Fisher Scientific, Waltham, MA). Stained cells were analyzed using a Canto II or LSRFortessa X-20 (BD Biosciences, Franklin Lakes, NJ). Cell sorting was performed using a FACS Aria II (BD Biosciences, Franklin Lakes, NJ). Data analysis was performed using FlowJo software (Tree Star, Ashland, OR).

[0266] For immunoblot analysis, the following antibodies were used: anti-β-actin (C4, Santa Cruz Biotechnology, Santa Cruz, CA), rabbit polyclonal anti-MAGE-A2 (Abcam, Cambridge, MA), anti-CCND1 (EPR2241, Abcam, Cambridge, MA), HRP-conjugated goat anti-mouse IgG (H+L) secondary antibody (Promega, Fitchburg, WI), and HRP-conjugated anti-rabbit IgG (H+L) secondary antibody (Promega, Fitchburg, WI).

[0267] TCR transduction of primary T cells

[0268] CD3 + T cells and CD4 + T cells were isolated using a Pan T Cell Isolation Kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and CD4 +The T cells were purified using a T Cell Isolation Kit (Miltenyi Biotec, Bergisch Gladbach, Germany). Purified T cells were stimulated with aAPC / mOKT3 irradiated at 200 Gy at an E:T ratio of 20:1. Starting the following day, activated T cells were retrovirally transduced with the cloned TCR gene by centrifugation at 1,000 × g for 1 hour at 32°C or by using Retronectin-coated plates (Takara Bio, Shiga, Japan) for 3 consecutive days. The following day, 100 IU / ml IL-2 and 10 ng / ml IL-15 were added to the TCR-transduced T cells. The culture medium was replenished every 2–3 days.

[0269] Staining with soluble CD4

[0270] The soluble CD4 (sCD4) gene was generated by fusing the human CD4 extracellular domain with a 6xHis tag via a GS linker. The sCD4 gene was retrovirally transduced into HEK293T cells, and the culture supernatant containing sCD4 monomers was collected. The sCD4 was dimerized with a PE-labeled anti-6xHis tag mAb (AD1.1.10, Abcam, Cambridge, MA) and used. HLA class II-expressing K562 cells were stained with dimerized sCD4 in the presence of goat serum at room temperature for 30 minutes. Surface HLA class II expression on K562-derived cells expressing various class II genes individually is shown in Figures 13A-13Q.

[0271] Construction and screening of an intralocus multipoint-induced DPB1*04:01 mutant cDNA library

[0272] Intralocus multipoint random mutations were inserted into DPB1*04:01 cDNA by PCR using the following primer sets: forward: 5'-CACCACAACNNNCTTNNNTGCCACGTG-3' (SEQ ID NO: 30) and reverse: 5'-CACGTGGCANNNAAGNNNGTTGTGGTG-3' (SEQ ID NO: 31) for L112 and V114; forward: 5'-ACAGCTGGGGTCNNNTCCACCAACCTG-3' (SEQ ID NO: 32) and reverse: 5'-CAGGTTGGTGGANNNGACCCCAGCTGT-3' (SEQ ID NO: 33) for V141; forward: 5'-CAGATCNNNGTGNNNCTGGAAATGACC-3' (SEQ ID NO: 34) and reverse: 5'-GGTCATTTCCAGNNNCACNNNGATCTG-3' (SEQ ID NO: 35) for L156 and M158. N denotes any nucleotide. The resulting PCR fragments were fused to each other to construct a mutant full-length DPB1*04:01 cDNA expression library with random mutations at positions L112, V114, V141, L156, and M158. K562 cells stably expressing the DPA1*01:03 gene were infected with recombinant retroviruses generated using the packaging cell line 293GPG at a transduction efficiency of less than 30%. Infected K562 cells were stained with soluble CD4 dimers, and dimer-positive cells were collected using a flow cytometry cell sorter. The mutant DPB1*04:01 gene was cloned from the collected cells and retrovirally transduced into K562 cells along with the wild-type DPA1*01:03 gene as described above.

[0273] Formation of HLA class II monomers and dimers

[0274] The extracellular domain of the wild-type class II α gene was fused to an acidic leucine zipper via a GGGS linker, followed by a 6xHis tag via a GS linker (see SEQ ID NO: 8). The extracellular domain of the mutated class II β gene (see SEQ ID NO: 3) was linked to a basic leucine zipper via a GGGS linker (see SEQ ID NO: 4). HEK293T cells were transfected with the α and β genes using a 293GPG cell-based retroviral system and cultured in DMEM supplemented with 10% FBS and 50 μg / ml gentamicin. DP4 dimer staining revealed soluble DP4. L112W / V141M HEK293T cells stably secreting proteins were grown to confluence, and the medium was replaced with serum-free 293 SFM II medium (Thermo Fisher Scientific, Waltham, MA). After 48 h, the conditioned medium was collected and concentrated using an Amicon Ultra filter (10 kDa molecular weight cut-off (MWCO)) (MilliporeSigma, Burlington, MA). The supernatant containing soluble HLA class II was then mixed with 100 μg / ml of the peptide of interest for 20–24 h at 37°C for in vitro peptide exchange. Monomers without peptide exchange were used as controls. The concentration of the monomer was measured by specific ELISA using nickel-coated plates (XPressBio, Frederick, MD) and an anti-His tag biotinylated mAb (AD1.1.10, R&D Systems, Minneapolis, MN). Soluble HLA class II monomers were dimerized for staining with PE-conjugated anti-Hism Ab (AD1.1.10, Abcam, Cambridge, MA) at a molar ratio of 2:1 for 1.5 hours at 4°C.

[0275] DP4-restricted antigen-specific CD4 + T cell stimulation

[0276] CD4 + T cells, CD4 +CD4 T cells were purified using a T Cell Isolation Kit (Miltenyi Biotec, Bergisch Gladbach, Germany). Purified T cells were stimulated with DP4-expressing aAPCs pulsed with 10 μg / ml of DP4-restricted peptide and irradiated at 200 Gy at an E:T ratio of 20:1. After 48 hours, 10 IU / ml of IL-2 and 10 ng / ml of IL-15 were administered to CD4 T cells. + The T cells were then added to the culture medium supplemented with IL-2 (10 IU / ml) and IL-15 (10 ng / ml) every 2–3 days. After 2 weeks of stimulation, the T cells were incubated with DP4 L112W / V141M The cells were subjected to dimer staining.

[0277] HLA class II dimer and tetramer staining

[0278] Primary T cells transduced with exogenous TCR genes and Jurkat76 / CD4 T cells were pretreated with 50 nM dasatinib (LC Laboratories, Woburn, MA) for 30 min at 37°C and stained with 5–15 μg / ml class II dimers at room temperature for 4–5 h. After washing, cell surface molecules were counterstained with APC-Cy7-conjugated anti-CD4 mAb, FITC-conjugated anti-NGFR mAb, and PE-conjugated anti-Vβ22 mAb.

[0279] ELISPOT assay

[0280] Cytokine ELISPOT assays were performed as previously reported (see, e.g., Yamashita et al., Nat. Commun. 8:15244 (2017) and Anczurowski et al., Sci. Rep. 8:4804 (2018)).

[0281] Immunoblotting

[0282] Immunoblot analysis was performed as previously reported (e.g., Yamashita et al., Nat. Commun. 8:15244 (2017) and Anczurowski et al., Sci. Rep. 8:4804 (2018)).

[0283] Protein modeling

[0284] The HLA-DP4 and human CD4 complex model structures were predicted based on the structures of PDB IDs: 3S5L and 3T0E using the Swiss-Model workspace for four-component structure prediction.

[0285] statistical analysis

[0286] Statistical analysis was performed using GraphPad Prism 6.0 software (GraphPad Software, San Diego, CA). An unpaired two-tailed Student's t-test was used for two-sample comparison. No statistical methods were used to predetermine sample size. Researchers were aware of allocation during the experiment or evaluation of results. The experiment was not randomized.

[0287] Biolayer interferometry sensorgram

[0288] The extracellular domain of human CD4 (residues 26-440 of NP_000607.1), followed by a GS linker and a 10x His tag, was stably expressed in the human cell line A375 (SEQ ID NOs: 262-263; Table 7). Recombinant 10x His-tagged CD4 protein was purified from the supernatant using TALON metal affinity resin (Takara Bio, Shiga, Japan). The eluted protein was concentrated using a 10 kDa MWCO Amicon Ultra-15 spin column (MilliporeSigma, Burlington, MA). The buffer was exchanged into HBS-EP (GE Healthcare Life Sciences, Marlborough, MA) using a 10 kDa MWCO MINI Dialyzer (Thermo Fisher Scientific, Waltham, MA). The purity of the recombinant CD4 protein was consistently greater than 90%, as confirmed by SDS-PAGE.

[0289] The recombinant DP4 protein consisted of the extracellular domain of DPA1*01:03 and either wild-type DPB1*04:01 or the L112W / V141M mutant. DPA1*01:03 was followed by an acidic leucine zipper, a GS linker, and a 10x histidine tag, while wild-type and mutant DPB1 were followed by a basic leucine zipper, a GS linker, and a biotinylation sequence (GLNDIFEAQKIEWHE; SEQ ID NO: 265). Both the DPA and DPB genes were stably expressed in A375-BirA cells, which were transfected with a codon-optimized BirA gene encoding a leader sequence at the 5' end and an ER-retention KDEL motif at the 3' end. The recombinant DP4 protein was purified from the supernatant using TALON metal affinity resin (T...

Claims

[Claim 1] The invention described in the present specification.

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