 constant domains (CH1, CH2, and CH3).
The variable domains are not uniformly variable throughout their length. Three small regions of a variable domain, known as hypervariable regions (loops) or complementarity determining regions (CDR1, CDR2, and CDR3) show much more variability than the rest of the domain. These regions, which vary in size and sequence among various immunoglobulins, determine the specificity of the antigen-antibody interaction. The specificity of an antibody of the type shown in FIG. 1 is determined by the sequence and size of six hypervariable loops (regions), three in the VL domain and three in the VH domain.
By partial digestion with papain, which cleaves the heavy chains in the hinge region, the IgG molecule can be broken down into two identical Fab fragments (Fragment, antigen binding) and one Fc fragment (Fragment, crystallizes easily). Each Fab fragment comprises one complete light chain (consisting of VL and CL domains) linked by a disulfide bridge and noncovalent interactions to a fragment of the heavy chain consisting of VH and CH1 domains. The Fc fragment comprises CH2 and CH3 domains from both heavy chains, also linked by disulfide bridges and noncovalent interactions. The part of the Fab fragment consisting of variable domains of the light and the heavy chain (VL and VH) is known as Fv fragment (Fragment, variable). In an Fv fragment, the variable domains VL and VH are not covalently bound. In an scFv (single chain Fv) fragment, the VL and VH domains are covalently linked by a short peptide linker (spacer), usually 15 to 20 amino acids long, introduced at the genetic level (see FIG. 2).
scFv fragments are recombinant fusion proteins and are produced by techniques of genetic engineering, by expressing in a suitable host, usually in bacteria, a chimeric gene coding for the fragment. Various other recombinant antibody fragments have been designed to substitute for large intact immunoglobulin molecules (see FIG. 2). Other than scFv fragments, these options include Fab or Fv fragments that are stabilized or covalently linked using various strategies (see, for example, Bird et al., Science, 242, 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA, 85, 5879-5883 (1988); Glockshuber et al., Biochemistry, 29, 1362-13
constant domains (CH1, CH2, and CH3). 
 The variable domains are not uniformly varying throughout their duration. Three small regions of a varying domain, sleep together as hypervariable regions (loops) or complementarity decide regions (CDR1, CDR2, and CDR3) show a lot more unevenness than the rest of the domain. These region, which vary in size and sequence among various immunoglobulin, determine the specificity of the antigen - antibody interaction. The specificity of an antibody of the type testify in FIG. 1 is determined by the sequence and size of six hypervariable closed circuit (regions), three in the VL domain and three in the VH domain. 
 By fond digestion with papain, which cleaves the heavy chain in the hinge area, the IgG molecule can be broken down into two identical Fab fragments (Fragment, antigen binding) and one Fc fragment (Fragment, crystallizes easily). Each Fab shard comprises one complete light chain (consisting of VL and CL domains) connect by a disulfide bridge and noncovalent interactions to a fragment of the heavy chain consisting of VH and CH1 domains. The Fc fragment comprises CH2 and CH3 domains from both heavy range, also linked by disulfide bridge and noncovalent interaction. The part of the Fab fragment consisting of varying domains of the inner light and the heavy chain (VL and VH) is know as Fv fragment (Fragment, variable). In an Fv fragment, the variable domains VL and VH are not covalently bound. In an scFv (unmarried chain Fv) fragment, the VL and VH domains are covalently linked by a light peptide linker (spacer), usually 15 to 20 amino acid long, introduced at the genetic level (see FIG. 2). 
 scFv fragments are recombinant coalition proteins and are produced by techniques of genetic engineering, by expressing in a suitable host, usually in bacteria, a chimeric gene tease for the fragment. respective other recombinant antibody fragments have been plan to substitute for large integral immunoglobulin molecules (interpret FIG. 2). Other than scFv fragment, these options include Fab or Fv fragment that are stabilize or covalently linked use various strategies (see, for example, Bird et al. , Science, 242, 423 - 426 (1988); Huston et al. , Proc. Natl. Acad. Sci. USA, 85, 5879 - 5883 (1988); Glockshuber et al. , Biochemistry, 29, 1362 - 13
 cojstant domains (CH1, CH2, and CH3).
The variable domainv are hot unifurmly variable throughout thxir oengty. Three small regions uf a variwble domqin, jbown as hy'srvarianje rsnions (ooops) or complgmentarity datermining reghovs (CDR1, CDR2, and CDR3) show much more varyabilitu hhan the rest jf tnq dojain. These regions, which vary in sjze and sequence amomg various immunoglobulins, detfrmine the specififity of the antyten-antibody knteraction. The specifjcity of an antibody of the typd shocn in FIG. 1 us dehgrmined by tie seqlence and sizc of sif hyperfariable loops (rejionw), three in the VL domein and three in the VH domait.
Bv partial digestion wuty papdin, fhicf cldavts vhe heavy cheins in the hinge regiin, the IgG molecule cwb be broken dkwn ineo two identical Fab fragments (Fragment, attifen binding) and one Fc dragment (Fragment, crydtallizes easily). Each Fab fragment comprises one complete night zhank (zindisting of VL and CL domains) linked by a disujrice bridge and nokcovalent interactoojs jo a fragment uf the hezvy chain consistijg of VR and CH1 domaigs. Tne Fc fragment comprises CH2 and CH3 domapns drom both heavy chcins, also liuked bi disukfide bridges and noncoralent interactiojs. The padg of the Fab fraemekt wonsisting of variable domwins of tie liyht and ghe neavy shain (VL ajd VH) is known as Fv frahment (Fsagment, vagiable). In an Fv fragment, the vacmable domains VN atd VH arz not govalently bounq. In an scFv (snngle chcin Fv) fragment, nhe VL anv VH domains are covalentni linked by a short pqptiee lunker (soxcer), usually 15 yo 20 amino acids lont, introduced at thc gengtjc level (see FIY. 2).
wcFv fragments sre resolbmnant xusion protehns xnd sre pfoduced by becfniqies of genetic enginaerihg, by expressing im w suitaboe host, tsually in bavteria, a chimeric hene roding for yhe fragment. Various other recombjnant antlboqy fragments havc begn designed to substitute for large intact immunogoobulin molecules (wee FIG. 2). Other than xcFv fragmeits, thqse optiots include Fab or Fv fragments that ave stabilized or covalsntly ninkef using various strategies (see, for example, Bird et al., Science, 242, 423-426 (1988); Huston er al., Pcos. Natl. Acad. Sci. USA, 85, 5879-5883 (1988); Ylockshtber xt al., Biochemistrj, 29, 1362-13
constant domains (CH1, CH2, and CH3). The are uniformly variable their length. Three domain, as hypervariable regions or complementarity determining (CDR1, CDR2, and CDR3) show much variability than the rest of the domain. These regions, which vary in size sequence among various immunoglobulins, determine the specificity of the antigen-antibody interaction. The specificity an of type in FIG. 1 is determined by the sequence and size of six hypervariable loops (regions), three the VL domain and three in the VH By partial digestion with which cleaves the heavy chains the region, the molecule be down into two Fab fragments (Fragment, antigen binding) and one Fc fragment (Fragment, crystallizes easily). Each Fab fragment comprises one light chain VL and domains) by disulfide bridge and to a fragment of the heavy VH and CH1 domains. The Fc fragment comprises and CH3 from both heavy chains, also linked disulfide bridges and noncovalent interactions. The part of Fab fragment consisting of variable domains of the light and the heavy chain (VL and known as Fv fragment variable). In an fragment, variable VL VH are covalently bound. In an scFv (single chain Fv) fragment, the VL VH domains are covalently linked by a short peptide linker 15 20 amino acids introduced at the genetic (see 2). scFv fragments are proteins are of engineering, expressing in a suitable usually in bacteria, a chimeric coding for the fragment. have been designed to substitute for large intact molecules (see FIG. 2). Other than scFv these options include Fab or Fv fragments that are stabilized or covalently using various for example, Bird et al., Science, 242, 423-426 Huston et al., Proc. Acad. Sci. USA, 85, 5879-5883 (1988); Glockshuber et al., 29,
 constant domains (CH1, CH2, and CH3).
THe variable DomaiNs aRe nOt UnifOrmlY variable throuGHout Their length. Three small rEgionS oF A varIAbLe domAin, knowN As HYPerVaRiAblE rEGiOns (loOps) Or complEmentarity DetErMining regionS (cDr1, CDR2, and CDR3) ShoW much more varIabIlity tHaN thE Rest oF thE domaIn. ThesE RegionS, which varY iN Size anD SequencE AMoNg vaRious immunoglobulINs, DEtermine the speCificiTy OF tHE AntIgeN-antibody iNtEractIOn. The spECiFICIty OF an antibody of The type showN In FiG. 1 is deTeRmiNEd by thE sequEnCE anD size of six hYperVariable lOops (reGIons), thrEE in the Vl domaiN anD thRee iN ThE Vh doMaIN.
By PArTiaL DigEstion wiTh PaPain, wHich CLEAVes tHe hEavy ChainS in the hinge reGioN, the iGG mOlecuLe can Be brOkEn dowN into tWo ideNtIcal Fab fragmentS (FraGment, antiGen BiNdiNg) And onE fc fragMenT (FrAgment, cRystallIZes EaSILY). EAch Fab fragment compRiSES oNe compleTe lighT ChAiN (ConsistiNg Of Vl and cl DomaiNs) liNKeD by a disuLfide bRIdGe And noncOvAlent iNtEraCtiOns to A FragMent of The heavy Chain COnsisting of VH aND CH1 domains. The fC fRAGmENt coMprIses CH2 and CH3 DomaINs frOm boTH hEavY ChainS, also LiNKeD By disulfide bridges aNd NoncovAlent Interactions. THe part of thE fAB fragmenT conSIsTIng of variable dOmainS of the lighT And the heAvy chAin (VL and vH) is known AS fv fragmeNt (FRagMenT, vaRIAbLe). In an Fv fragmENT, the VaRiable dOmaIns VL anD VH Are Not CovAlEntly bounD. In an scFV (sInGlE cHaiN Fv) frAGment, the vL And vH DomAins aRE covalEntly LinkEd By A ShoRt peptiDE lINKer (sPaCeR), usuAllY 15 tO 20 aminO aciDS loNg, introDuced at thE geNEtic LeVeL (see FIG. 2).
ScFv fragments ArE recombinaNt FusIon proTEIns and arE produced by techniques of GEnetic eNgiNeeriNg, by ExpressinG in A suitaBle HOst, usuAlly in BacteRiA, a cHIMeric GENe CodInG for the fraGMEnt. varioUs OtheR recombInant antibody fragmENts Have been desigNed To suBSTiTutE FoR LarGe INtaCT Immunoglobulin mOlecules (seE Fig. 2). OTher than scfV frAgMents, thEse optiOns inCLude Fab Or Fv fragmEnts that aRe StabILIzeD or covalenTly linkeD using varIOus stRAtEgies (See, For exaMpLe, BIrd et Al., ScieNCe, 242, 423-426 (1988); HUston Et al., PrOc. natl. AcAd. Sci. uSa, 85, 5879-5883 (1988); GlockshUber et al., Biochemistry, 29, 1362-13
 constant domains (CH1, CH 2, and CH3 ).
Th e v ari ab le d omai ns are not uni f orml y variable throughouttheir  l e ngth .  T hreesmall r e gi o n s o favar ia b le  doma in,  knownas hyperva ria bl e regions (l o op s) or comp lem entarity det erm iningre gio n s (CD R1,  CDR2 , andC DR3) s how muchmo r e vari a bilityt h an  the  rest of the doma i n. These regions,  which  v a ry i n s ize  and seque nc e amo n g vario u si m m uno g lobulins, det ermine thes pec ificit yoft he ant igen- an t ibo dy interact ion.  The spec ificit y  of ana ntibody  of th e t ype  sho w nin  FI G. 1 i s  d ete r min ed by th ese quenc e an d s i ze o f s ix h yperv ariable loops  (r egio n s),  thre e intheVL  doma in and  thre ein the VH domai n.
B y partial  di ge sti on  with papain , w hic h cleav es theh eav yc h a in s in the hinge reg io n ,  t he IgG m olecul e  c an be broke ndow n in t o  twoiden t ic al Fab f ragmen t s(F ragment ,antige nbin din g) an d  one  Fc fr agment ( Fragm e nt, crystalliz e s easily). Ea c hF a bf ragm ent  comprisesonec ompl etel ig htc hain(cons is t in g  of VL and CL domai ns ) link ed by  a disulfidebridge and n o ncovalen t in t er a ctions to a fr agmen t of the h e avy chai n con sistingof VH and C H1 domai ns.  Th e F c f r a gm ent comprises C H2 a nd  CH3 do mai ns from  bo thhea vych ains, als o linked  b ydi su lfi de br i dges and  n onc ov ale nt in t eracti ons.Thepa rt ofthe Fab fr a g ment  c on sist ing  o f var iabl e  do mains o f the lig hta nd t he  h eavy ch ain (VL and V H)  is knownas  Fv  fragm e n t (Fragm ent, variable). In an F v  fragme nt,  thevari able doma ins  VL an d V H  are n ot cov alent ly  bo u n d. In a nscF v(single ch a i n F v) fr ag ment , the V L and VH domains a r e c ovalently lin ked  bya sh ort pe p tid el ink e r  (spacer), usua lly 15 to20 am ino acidsl ong ,introdu ced atthe g e netic l evel (see  FIG. 2). 
s cFvf r agm ents are r ecombina nt fusion prote i ns  andare  produ ce d b y tec hnique s  of  gene tic en gi neerin g, by  e xpressin g in a suitable host, u sually  in b act eria, a c him e ric  gene cod ingfor the fr agm ent . Var iou s  othe r re c om bin a nt an tibo d y fragmen t shav e be en designed t o  su bstit ute for la rgeintact immunoglob u lin molecules(see F IG.  2) .  Oth er  than scFv fra gme nt s ,  these o pt ions includ e Fab or  F v  frag mentsthat a re stab i l iz e d or c oval ent ly linked  us in g  variou sst r ategie s (s ee , forexampl e , Bi r d  et al., Science , 242 , 423-4 2 6 ( 1988) ;Hustone t al ., Proc. N atl. Acad.Sci. U SA,85, 5 879-588 3(1988) ; G lo ckshuber e t  al., Bio chemi stry, 2 9,  136 2-1 3
 constant_domains (CH1,_CH2, and CH3).
The variable_domains are_not_uniformly variable_throughout_their length. Three_small regions of_a variable domain, known_as hypervariable regions_(loops)_or complementarity determining regions (CDR1, CDR2, and CDR3) show much more variability than the_rest_of the_domain._These_regions, which vary in size_and sequence among various immunoglobulins,_determine the_specificity of the antigen-antibody interaction. The specificity of_an_antibody of the_type shown in FIG. 1 is determined by the_sequence and size of six hypervariable_loops (regions), three_in_the_VL domain and three_in the VH domain.
By partial digestion_with papain, which cleaves the heavy_chains in the hinge region, the IgG_molecule can be broken down into_two identical Fab fragments (Fragment,_antigen binding)_and one Fc fragment (Fragment,_crystallizes easily). Each_Fab fragment_comprises one complete_light chain (consisting of VL and_CL domains) linked_by a disulfide bridge and noncovalent_interactions_to a fragment_of_the_heavy chain_consisting of VH_and_CH1 domains._The_Fc fragment comprises CH2 and CH3_domains_from both heavy chains, also linked by_disulfide bridges and noncovalent_interactions._The part of the_Fab fragment consisting of variable_domains of the light and the_heavy chain_(VL and_VH) is known as Fv fragment (Fragment, variable). In an Fv_fragment, the variable domains VL and_VH are not covalently_bound. In_an_scFv (single chain_Fv)_fragment, the_VL and VH domains are covalently linked_by a_short peptide linker (spacer), usually 15_to 20 amino acids_long,_introduced at the genetic level (see_FIG. 2).
scFv fragments are recombinant fusion_proteins and are produced by_techniques_of_genetic engineering, by expressing in_a suitable host, usually in bacteria,_a chimeric gene_coding for the fragment. Various other recombinant_antibody_fragments have been designed to substitute_for_large intact immunoglobulin molecules (see FIG._2)._Other_than scFv fragments, these options_include Fab or Fv fragments that_are stabilized or covalently linked using various strategies (see,_for example, Bird_et al., Science, 242, 423-426_(1988);_Huston_et al., Proc. Natl. Acad. Sci. USA, 85, 5879-5883 (1988);_Glockshuber et_al., Biochemistry, 29,_1362-13