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Auto and allo-immunity are common observations Human proteins can be immunogenic in humans. (e.g. recombinant insulin, EPO and Factor VIII) Human antibodies can be immunogenic in humans (anti-idiotype and anti-allotype) and this applies to chimeric, humanised and fully human antibodies. Y ZtB         ) !l Good News  i Auto and allo-immunity are common observations but these immune reponses can be modified and regulated. Human antibodies can be immunogenic in humans but this immunogenicity varies from antibody to antibody for complex reasons, and is probably more dependent on the mode of action, and not just the way they were made (i.e. chimeric, humanised or fully human). ijt   3  W     "mAntigenicity and Immunogenicity4     Antigenicity is simply an ability of a molecule to be recognised by a pre-existing T-cell receptor (TCR) or a B-cell receptor (antibody) But once an antigen is recognised by a receptor it can either be immunogenic or tolerogenic. The same antigen can sometimes induce tolerance and sometimes provoke an immune response depending upon factors such as mode of administration and uptake by and co-stimulation of antigen presenting cells (APCs).\Z  !|N        c#nImmunogenicity  +Immunogenicity of T-cell dependent antigens relies on presentation by professional APCs (e.g. Dendritic cells). Dendritic cells (and other APCs) acquire antigen through use of innate receptors including complement receptors and Fc receptors, thus allowing recognition and uptake of immune complexes. E           U  F $ogAntibody selection and design   The choice of antibody constant region is largely dictated by functional requirements of the antibody. But what about the V-regions ?  hd%pf&q'rj(s-x*u.yWhat determines immunogenicity?&   iClassical Self vs non-Self (Peter Medawar) Aquired neonatal tolerance to antigens. Danger Hypothesis (Polly Matzinger) Cell killing (inappropriate, non-apoptotic) Inflammation (cytokine release) Pattern recognition (Charles Janeway) Innate receptors for infectious pathogens Complement activation and fixation of C3 (Fearon) ( Fc receptors for immune complexes)+($L& (LT    '        :   k  V    ! /zThe effect of aglycosylation on the immunogenicity of a humanised therapeutic CD3 monoclonal antibody Routledge et al 1995 Transplantation 60, 847-853 g1Z    5   ( 0{The effect of aglycosylation on the immunogenicity of a humanised therapeutic CD3 monoclonal antibody Routledge et al 1995 Transplantation 60, 847-853 g1Z    5   ( 1|jElimination of the immunogenicity of therapeutic antibodies. Gilliland et al 1999 J.Immunol 162, 3663-3671"k=.@  1    Took CAMPATH antibody and mutated a key residue in the CDR region so as to prevent cell binding to CD52. 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SB  s *޽h ? ̙3380___PPT10.N   0(   B  s *޽h ? ̙3380___PPT10.NEi 0p (  pr p S G@  r p S TH`` `   p ZA? 1?"6?@`NNN?N CK p s 8A?igrotxs"*?@NNN?N` P  p s 8A?igrotys"*?@NNN?N` `  H p 0޽h ? ̙33y___PPT10Y+D=' = @B +  `@(  @r @ S Xlj    @ xA? ?npo000000Picture 4"<?@@`NNN?NwH @ 0޽h ? ̙33___PPT10i.s|P9+D=' = @B +  @8(  8r 8 S l    8 rA? ?npo000002Picture 6"<?@@`NNN?NJH 8 0޽h ? ̙33___PPT10i.n"+D=' = @B +  H(  Hr H S @׳l    H rA? ?npo000004Picture 4"<?@@`NNN?NM7:H H 0޽h ? ̙33___PPT10i.s0bP+D=' = @B +  P(  Pr P S 0ܳl    P rA? ?npo000006Picture 4"<?@@`NNN?N*H P 0޽h ? ̙33___PPT10i.sPZ+D=' = @B +  h(  hr h S @l    h rA? ?npo000007Picture 4"<?@@`NNN?NBH h 0޽h ? ̙33___PPT10i.s0'{+D=' = @B +  X(  Xr X S l    X rA? ?npo000009Picture 4"<?@@`NNN?N]qH X 0޽h ? ̙33___PPT10i.sg+D=' = @B +  `(  `r ` S l    ` rA.? ?npo00000bPicture 4"<?@@`NNN?N 6H ` 0޽h ? ̙33___PPT10i.spp+D=' = @B +   p(  pr p S l    p rA/? ?npo00000dPicture 4"<?@@`NNN?N*H p 0޽h ? ̙33___PPT10i.s+D=' = @B +_ ~`x(  x x rA0? ?npo000010Picture 3"<?@@`NNN?NT&ZH x 0޽h ? ̙33y___PPT10Y+D=' = @B + `t(  x  c $ j)     ZA? 1?"6?@`NNN?N  ZA? 1?"6?@`NNN?N O$  s 8A?igrotxs"*?@NNN?N` P   s 8A?igrotys"*?@NNN?N` `  H  0޽h ? ̙33y___PPT10Y+D=' = @B +}\ 5 [[ [(  I  Zgֳgֳ? Effector functions of human IgG* &4    hh88  Z|gֳgֳ?  LIgG1    Zgֳgֳ?  LIgG2    Zgֳgֳ? LIgG3    Z gֳgֳ?} LIgG4  X  0?X  0?X  0? X  0? X  0? x X  0?x X  0? OX  0?OXX  0?X&^  61?)*X  0?/X  0?X  0?X  0?X  0? X  0?x X  0?OX^  61?)*X  0?  Z)gֳgֳ?&T ]Complement activation  X  0?X  0? X  0? x X  0?x X  0? OX  0?OXX ! 0?X&^ " 61?)*X # 0?/X $ 0?X % 0?X & 0? X ' 0?x X ( 0?OX^ ) 61?)*X * 0? + Z1gֳgֳ? YClassical pathway   , ZP6gֳgֳ?)  K+++   - ZX;gֳgֳ?u Q I+   . Zd=gֳgֳ? K+++   / ZHBgֳgֳ?" K-  X 0 0?X 1 0? X 2 0?x X 3 0?OX^ 4 61?)*X 5 0? 6 ZFgֳgֳ?y) [Alternative pathway   7 ZpJgֳgֳ? w  K-   8 ZxOgֳgֳ?yu Q I+   9 ZQgֳgֳ?L% K-   : ZhVgֳgֳ?" K-  X ; 0?qX < 0? qX = 0?x qX > 0?OXq^ ? 61?)*mX @ 0?qX A 0?qIX B 0?q IX C 0?qx IX D 0?qOXI^ E 61?u)*EX F 0?qI G Z\gֳgֳ?1&OH  mFc receptor recognition  X H 0?I! X I 0?I ! X J 0?Ix ! X K 0?IOX! ^ L 61?M)* X M 0?I!  N Zbgֳgֳ? +  XFc   O Zggֳgֳ? g-  Kg   P Zhkgֳgֳ? )+  JRI   Q Zjgֳgֳ? )  K+++   R Zrgֳgֳ? u N-  K-   S Z vgֳgֳ?   K+++   T Ztgֳgֳ? ,  J++  X U 0?!  X V 0?!  X W 0?! x  X X 0?! OX ^ Y 61?% )* X Z 0?!  X [ 0?  X \ 0? X ] 0? x X ^ 0? OX ^ _ 61? )* X ` 0?   a Zgֳgֳ?   XFc   b Zgֳgֳ? g  Kg   c Z8gֳgֳ? Q  b RIIa, 131R/R     d Z\gֳgֳ? c  J++   e Zgֳgֳ? u N  K-   f Zgֳgֳ? U  J++   g Z̒gֳgֳ? "  K-  X h 0?  X i 0? X j 0? x X k 0? OX ^ l 61? )* X m 0?   n Zgֳgֳ?   XFc   o ZTgֳgֳ? g  Kg   p Zgֳgֳ? e  b RIIa, 131H/H     q Zgֳgֳ? z  I+   r Zgֳgֳ? u Q  I+   s Z3gֳgֳ? U  J++   t ZLgֳgֳ? "  K-  X u 0?  X v 0? X w 0? x X x 0? OX ^ y 61? )* X z 0?   { ZHgֳgֳ?   XFc   | ZĻgֳgֳ? g  Kg   } Zgֳgֳ?   ZRIIb   ~ Z$gֳgֳ? c  J++    Z4gֳgֳ? u N  K-    Zlgֳgֳ? U  J++    Z@gֳgֳ? "  I+  X  0?  X  0? X  0? x X  0? OX ^  61? )* X  0?  X  0? ]X  0? ]X  0? x ]X  0? OX]^  61? )*YX  0? ]  ZLgֳgֳ?Qh XFc    Zgֳgֳ?Rgi Kg    Zgֳgֳ?Qh LRIII    Z@gֳgֳ?F z ] I+    Zgֳgֳ?Q .h J+/    ZLgֳgֳ?R i K-    Zgֳgֳ?FL(] I+    ZTgֳgֳ?Qh J+/    Zgֳgֳ?R|Ui K-  X  0?]@X  0?@HX  0?@HX  0?@ HX  0?] @X  0?@ HX  0?@ x HX  0?]x @X  0?@x HX  0?@ OHX  0?]OX@X  0?@OXHX  0?@X&H^  61?a)*<^  61?D)*DX  0?@/HX  0?]@X  0?@HX  0?@HH  0޽h ? ̙33y___PPT10Y+D=' = @B +_ ~@(    rA2? ?npo000011Picture 2"<?@@`NNN?NPaH  0޽h ? ̙33y___PPT10Y+D=' = @B +  v(  r  S w<L     rA3? ?npo000014Picture 3"<?@@`NNN?N `b   rA4? ?npo000016Picture 4"<?@@`NNN?N 1 PH  0޽h ? ̙33y___PPT10Y+D=' = @B +_ ~ (    rA5? ?npo000017Picture 2"<?@@`NNN?NxH  0޽h ? ̙33y___PPT10Y+D=' = @B +_ ~`(    rA6? ?npo00001aPicture 2"<?@@`NNN?N?hH  0޽h ? ̙33y___PPT10Y+D=' = @B +_ ~p(    rA7? ?npo00001cPicture 2"<?@@`NNN?NP \H  0޽h ? ̙33y___PPT10Y+D=' = @B +  (  x  c $? `l@  ?    s 8A ?igfcrns"*?@NNN?Np0/ 5  Z? xaxa 1?"p   ?Interaction with FcRn and with Protein A through similar region@@&  + 7  Z? xaxa 1?" P  1FcRn is important for IgG half-life and transport224      rA8? ?npo00001ePicture 6"<?@@`NNN?N 2 H  0޽h ? ̙33y___PPT10Y+D=' = @B +  5    % (  V 0  Group 20   A9? ?npo00001fObject 3"<?@@`NNN?N    A:? ?npo000020Object 4"<?@@`NNN?N Pyl  <1?*   `"? gֳgֳ?0 ,Transferring motifs between human subclasses--$ - HH     `)? gֳgֳ?NI [ Db mutation    l  <1? |     `<.? gֳgֳ?N P  [ Dc mutation        `2? gֳgֳ?v) i Da mutation     r"   BGf 31?4r"   BGf 31?4r"   BGf 31?d,LTH  0޽h ? ̙33y___PPT10Y+D=' = @B +H 5 [S(  '  Z,>? gֳgֳ?` P 5Residues at key positions in mutated constant regions66$ 6 hh88   A;? ?npo000021Object 3"<?@@`NNN?NP0  ZA? 1?"6?@`NNN?N  ZA? 1?"6?@`NNN?N=H  0޽h ? ̙33y___PPT10Y+D=' = @B + 5  (   F l#<  #l<  ZK? xaxa?l# nSummary of terminology$    ZR? gֳgֳ?;H ZMutant residues    ZhV? gֳgֳ?\ MD     Z Z? gֳgֳ?A5Z Ka     Z]? gֳgֳ?" S fResidues 327, 330, 331 of IgG4    Za? gֳgֳ?_  MD      Z,\? gֳgֳ?AC]  Kb      Zc? gֳgֳ?" EV  l$Lower hinge of IgG2; omitting Gly236%% %    Z g? gֳgֳ? r  MD      Zo? gֳgֳ?A 'p  Kc      Zdn? gֳgֳ?"$ k  m%Lower hinge of IgG2; including Gly236&& & L  Zdw? gֳgֳ?l < & Armour et al. Eur J Imm 1999; 0'@       ZP|? gֳgֳ? 5 J29    Z? gֳgֳ??4 L: 2613    ZA? 1?"6?@`NNN?N  ZA? 1?"6?@`NNN?N=H  0޽h ? ̙33y___PPT10Y+D=' = @B +' NF(    rA<? ?npo000022Picture 2"<?@@`NNN?N[  ZA? 1?"6?@`NNN?N=H  0޽h ? ̙33y___PPT10Y+D=' = @B + J(    S xaxaA=? 1?npo000025Object 2"<?@@`NNN?N9FH  0޽h ? ̙33y___PPT10Y+D=' = @B +' NF(    rA>? ?npo000026Picture 2"<?@@`NNN?NK  ZA? 1?"6?@`NNN?N=H  0޽h ? ̙33y___PPT10Y+D=' = @B +' NF(    rA?? ?npo000028Picture 2"<?@@`NNN?NK  ZA? 1?"6?@`NNN?N=H  0޽h ? ̙33y___PPT10Y+D=' = @B + J(    S xaxaA@? 1?npo00002bObject 2"<?@@`NNN?N PH  0޽h ? ̙33y___PPT10Y+D=' = @B + 5 n(  c  Z0? gֳgֳ?HP` ;Test systems: antibodies with CD52 and a-RhD specificities8<($$$&*   HH  )  T? gֳgֳ?  Short, GPI-anchored glycoprotein Found on T cells and some B cells, granulocytes and eosinophils About 45 x 104 molecules/cell Good target for CDC and ADCC Humanised variable domains of CAMPATH-1 antibody used Range of antibodies with same variable domains already existed4%03xo &V      T~? gֳgֳ?0  NCD52(2    ZA? 1?"6?@`NNN?N Ps{ H  0޽h ? ̙33y___PPT10Y+D=' = @B +7 5 JB(  c  Zt? gֳgֳ?H` ;Test systems: antibodies with CD52 and a-RhD specificities8<(&&&&*   HH  n  T? gֳgֳ?P Protein complex on erythrocyte membrane 1 - 3 x 104 molecules/cell Provides opportunities for use of agglutination and rosetting assays Target for ADCC Used variable domains of Fog-1, a human IgG isolated from hyperimmunised, RhD- blood donorJ%03x2   tw   @         T? gֳgֳ?  ua-RhD&&     ZA? 1?"6?@`NNN?NP P H  0޽h ? ̙33y___PPT10Y+D=' = @B + 5 +#@**(    B C+ DEF? * * @C   B C+ DEF1? * * @C^B  61?B^B  61?B@B^B  61?& @& ^B  61? @ ^B  61? @ ^B   61? @ ^B   61?@^B   61?@^B   61?s@s^B   61?T@T^B  61?8@8^B  61?@^B  61?BB^B  61?$B^B  61?$B^B  61?$OOB^B  61?$B^B  61?$VVB^B  61?$B^B  61?$B^B  61?$DDB^B  61?$B^B  61?$B^B  61?$  B^B  61?$ B^B  61?$| | B^B  61?$ B^B  61?$M M B^B   61?$ B^B ! 61?$ B^B " 61?$  B^B # 61?$P P B^B $ 61?$ B^B % 61?$B^B & 61?$B^B ' 61?$B^B ( 61?$B^B ) 61?$44B^B * 61?$zzB^B + 61?$B^B , 61?$B^B - 61?g^B . 61?g^B / 61?P P g^B 0 61?g 1  B CwDE F(1? L%t%u%_ v@= ^B 2 61?G^B 3 61?GgG^B 4 61?]$$^B 5 61?]I]^B 6 61? :^B 7 61? ^B 8 61?a a T^B 9 61?@ ^B : 61? ;^B ; 61? " ^B < 61? ^B = 61? z ^B > 61? 77 ^B ? 61? \ ^B @ 61? < ^B A 61?  ^B B 61?E^B C 61?EgE^B D 61?$$y^B E 61?yIy^B F 61?: ^B G 61? ^B H 61?Ta a ^B I 61?@ ^B J 61?; ^B K 61? " ^B L 61? ^B M 61? z ^B N 61? 77 ^B O 61? \ ^B P 61?< Z ^B Q 61?Z Z  R  B C7DE F(1? Le% _6@( _ ^B S 61? ( ^B T 61? g ^B U 61?\ $$ ^B V 61?\ I\ ^B W 61?  ^B X 61? ^B Y 61? a a  ^B Z 61? @ ^B [ 61? 9 ^B \ 61? "  ^B ] 61?& H ^B ^ 61?& z& ^B _ 61?V 77^ ^B ` 61?V \V ^B a 61?" @ ^B b 61?" " ^B c 61?( J ^B d 61?J gJ ^B e 61? $$ ^B f 61? I ^B g 61? 9 ^B h 61?9 9 ^B i 61? a a K ^B j 61?K @ K ^B k 61?9 e ^B l 61?e " e ^B m 61?H e ^B n 61?e ze ^B o 61?^ 77e ^B p 61?e \e ^B q 61?@ ^ ^B r 61?^ ^  s  B CjDE F(1? LGR@%a^_i^@ 6  t  B CuDE F(1? L<K%at_pi@ E  u  B CfDE F(1? L%O%Za_eK@ _  v  B CuDE F(1? LDbS%bp_^t@ [  w  B CDE F(1? L%a_@p? ^B x 61?!_^B y 61?!g!^B z 61?$$^B { 61?I^B | 61?c ^B } 61?c c^B ~ 61?a a ^B  61?@ ^B  61?b ^B  61?b " b ^B  61?S | ^B  61?S zS ^B  61? 77& ^B  61? \ ^B  61? - ^B  61?  ^B  61?_^B  61?g^B  61?$$^B  61?I^B  61? ^B  61? ^B  61?a a ^B  61?@ ^B  61? ! ^B  61?! " ! ^B  61?|  ^B  61? z ^B  61?& 77^ ^B  61?^ \^ ^B  61?- b ^B  61?b b    B CDE F(1? L %_@^ u    B C=DE F(1? L%)<_4@" _    B CODE F(1? L)GC%NN_4;@ j    B C.DE F(1? L%--%) _@O } ^2  61?k^2  61?A ^2  61? [^2  61?2D  u^2  61?  ]^2  61?~ ^2  61? U ^2  61? ^ ^  61?$ k, ^  61? E ^  61?  ^  61? D # ^  61?5  = ^  61?D ~L ^  61?Z Xb ^  61?= E d  <1? k d  <1? A5 d  <1? @ d  <1? D  - d  <1?  O d  <1? ~K d  <1? UV d  <1? K ^  61? k ^  61? A ^  61? - ^  61? D  < ^  61?  R ^  61?" ~e ^  61? Ua ^  61? Z   C BBCKDEF1?AJJ @ g   C BCCKDEF1?!BJJ! @ F   C BDCLDEF1?!CKK! @ E   C BDCLDEF1?!CKK! @" @ n   C BDCLDEF1?!CKK! @- y   C BDCLDEF1?!CKK! @5 z   C BDCKDEF1?!CJJ! @9 Z   C BCCLDEF1?!BKK! @ j   C BBCLDEF1?AKK @ g   C BCCLDEF1?!BKK! @ FP   C BDCLDEF1?!CKK! @" n   C BDCLDEF1?!CKK! @ @ _   C BDCLDEF1?!CKK! @" n   C BDCLDEF1?!CKK! @1 z}   C BDCLDEF1?!CKK! @ Zj   C BCCLDEF1?!BKK! @5  ^2  61?>k^2  61?A^2  61? 7^2  61?D  #^2  61?  ^2  61?[ ~ ^2  61? UG ^2  61? O ^  61?Z kb ^  61?f En ^  61?q y ^  61?i D q ^  61?i  q ^  61?b ~j ^  61?^ Xf ^  61?^ f ^2  61? kG ^2  61? AD ^2  61? D ^2  61? D  R ^2  61?*  m ^2  61?= ~ ^2  61?5 Ux ^2  61? ^ d  <1? k< d  <1?" Ae d  <1?@ d  <1?= D   d  <1?H  d  <1?H ~ d  <1?. Up d  <1?5 x ^  61?9 k| ^  61?S A ^  61?Z ^  61?Z D  ^  61?W  ^  61?9 ~| ^  61?. Up ^  61?5 x   Zx,S gֳgֳ? $ J-5    Z<1S gֳgֳ? I  I0    Z(5S gֳgֳ? I`  I5    Z9S gֳgֳ? D  J10    Z6S gֳgֳ?d $  J15    Z8@S gֳgֳ?H   J20    ZCS gֳgֳ?(  J25    ZDBS gֳgֳ?   J30    ZJS gֳgֳ?  J35    ZLNS gֳgֳ?  J40    ZLS gֳgֳ? q J45    ZUS gֳgֳ?N K0.1    ZXS gֳgֳ?U S I1    ZWS gֳgֳ? S J10    Z$`S gֳgֳ?KS K100    ZcS gֳgֳ?){  b antibody, (     Z0hS gֳgֳ?',  Km    ZkS gֳgֳ?)w  Lg/ml     `   ZԎS gֳgֳ?  lG1D ac6  dB  <1?  ^2  61? =x   Z4S gֳgֳ?s G  JG2  dB  <1?  ^  61? =|   ZS gֳgֳ?H z  kG2D a6  dB  <1?x x ^2   61?W =x  ! Z4S gֳgֳ?   JG4  dB " <1?F F d # <1?$ =xg  $ ZS gֳgֳ?   kG4D b6  dB % <1?  ^ & 61? =x1  ' Z4S gֳgֳ? z}  kG4D c6   ( Z8S gֳgֳ?/c b CAMPATH-1 (    ) ZS gֳgֳ? R antibodies    * ZS gֳgֳ?*]4 .Complement-mediated lysis of mononuclear cells//#&   H  0޽h ? ̙33y___PPT10Y+D=' = @B +3 5 22PeeD2(    BIC DEF?HH  @g8y   BIC DEF1?HH  @g8y^B  61?gx^B  61?xx^B  61?  ^B  61?s s ^B  61?  ^B   61?mm^B   61?^B   61?gg^B   61?x7x^B   61?[x^B  61?[x^B  61?[x^B  61?[ggx^B  61?[x^B  61?[kkx^B  61?[x^B  61?[""x^B  61?[oox^B  61?[x^B  61?[n n x^B  61?[r r x^B  61?[) ) x^B  61?[ x^B  61?[- - x^B  61?[ x^B  61?[ x^B  61?[22x^B  61?[ttx^B   61?[00x^B ! 61?[44x^B " 61?[x^B # 61?[{{x^B $ 61?[x^B % 61?[TTx^B & 61?[x^B ' 61?[x^B ( 61?[77x^B ) 61?T^B * 61?T^B + 61?Ttt^B , 61?T77 -  B# CSDE F(1?" Rf O&3@x-@17^B . 61?006^B / 61?U^B 0 61?tt3^B 1 61?S^B 2 61? ^B 3 61? ^B 4 61?v ^B 5 61?v " v ^B 6 61?A A $ ^B 7 61? f ^B 8 61?^B 9 61?d^B : 61?^B ; 61?^B < 61?v^B = 61?v3v^B > 61?600W^B ? 61?WUW^B @ 61?3ttf^B A 61?fSf^B B 61?  P^B C 61?P P^B D 61?  ^B E 61? "  ^B F 61?$ A A ^B G 61? f ^B H 61?t^B I 61?tdt^B J 61?]^B K 61?]]^B L 61?O^B M 61?O3O^2 N 61?NW^2 O 61?WS^2 P 61? +^2 Q 61?  ^2 R 61? $ _ E ^2 S 61?h2^2 T 61?"^2 U 61?+ V ZTS gֳgֳ? J-5   W ZS gֳgֳ? &Y  I0   X Z@S gֳgֳ? &  I5   Y ZS gֳgֳ? S  J10   Z ZS gֳgֳ? J15   [ ZLS gֳgֳ?M J20   \ ZS gֳgֳ? J25   ] ZLS gֳgֳ?C I1   ^ ZXS gֳgֳ?<  J10   _ ZS gֳgֳ?  K100   ` ZDU gֳgֳ? L1000   a Z\U gֳgֳ?`D 4 yG2Da concentration,6   b Z< U gֳgֳ?f : \ m*   c ZU gֳgֳ?`2 4 Lg/ml   d  ``U gֳgֳ?r  ]% specific Cr release   e ZU gֳgֳ?0@? TComplement-mediated lysis with CAMPATH-1 G1(6.3 mg/ml), inhibited by CAMPATH-1 G2Da dU0$$ $$$&  < hh88H  0޽h ? ̙33y___PPT10Y+D=' = @B +n  5  y `  (  y  ZU gֳgֳ?0P` OBinding to the FcgRI-bearing cell line, B2KA, measured by fluorescence staining8P$$>$&  < hh88    AA? ?npo00002cObject 3"<?@@`NNN?N0` _  ZP7U gֳgֳ?aq hG2f  hh88  ZBU gֳgֳ?ag5  G1Db6333  hh88  ZXOU gֳgֳ?   G1Dc6333  hh88  ZPU gֳgֳ?  hG4  hh88  ZaU gֳgֳ? | G1Da6333  hh88   Z|eU gֳgֳ?_ 3  hG13  hh88    TX^U gֳgֳ? "CAMPATH-1H antibodies at 100 mg/ml,# # hh88H  0޽h ? ̙33y___PPT10Y+D=' = @B +mv 5 uxupu(    Bq CB DEF?p p A A @U    Bq CB DEF1?p p A A @U ^B  61?UU ^B  61? 4u ^B  61? 4u ^B  61? 4u ^B  61?q 4uq ^B   61?H 4uH ^B   61?4u^B   61?4u^B   61?4u^B   61?4u^B  61? U ^B  61? UU ^B  61? ## ^B  61?  ^B  61?  ^B  61? 55 ^B  61? mm ^B  61?  ^B  61?  ^B  61?  ^B  61?  ^B  61?  ^B  61? NN ^B  61?  ^B  61?  ^B  61?  ^B  61? II ^B  61? qq ^B   61?  ^B ! 61?  ^B " 61? ^B # 61? ^B $ 61? Q Q ^B % 61? ^B & 61? ^B ' 61? ^B ( 61? # # ^B ) 61? G G ^B * 61? d d ^B + 61? 5 5 ^B , 61? ^B - 61?   ^B . 61? E E ^B / 61? | | ^B 0 61? ^B 1 61? ^B 2 61? ^B 3 61?  ^B 4 61?  ^B 5 61? ]] ^B 6 61?  ^B 7 61?  ^B 8 61? ++ ^B 9 61? YY ^B : 61?  ^B ; 61?  ^B < 61?  ^B = 61? UU ^B > 61?  ^B ? 61?  ^B @ 61? d d ^B A 61?  ^B B 61?  * C  B CDE,F41? A fi"emJ@Z * D  B CEDE,F41? 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R i  s *?g T ^B j  61?h U m ^B k  61? m ^B l @ 61? U m ^B m  61?h m R n  s *?? x ^B o  61?@ Z ^B p  61?Z u ^B q @ 61?Z u ^B r  61?@ Z R s  s *?* 1fd ^B t  61?+ 3KF ^B u  61?F Kc` ^B v @ 61?F 3K` ^B w  61?+ KcF R x  s *?~  ^B y  61?  ^B z  61?  ^B { @ 61?  ^B |  61?  R2 }  s *1?  R2 ~  s *1? 9 R2   s *1?B n R2   s *1?  R2   s *1? Y R2   s *1? R2   s *1?7_<R2   s *1?5   C B1C6DEF1?05 @   C B1C5DEF1?04 @ >   C B1C5DEF1?04 @ {B    C B1C5DEF1?04 @      C B1C6DEF1?05 @ U    C B1C5DEF1?04 @    C B1C6DEF1?05 @: 3dp    C B2C5DEF1?14 @ J ^   61?^   61?^   61?   5^   61?{Y ^   61? -^   61?h7_^   61?   ZRZ gֳgֳ? & g0  hh88   Z$\Z gֳgֳ?~ >  h40  hh88   ZeZ gֳgֳ?   h80  hh88   ZdoZ gֳgֳ? M  i120  hh88   ZyZ gֳgֳ? i160  hh88   ZZ gֳgֳ?] i200  hh88   ZDZ gֳgֳ?$ i240  hh88   ZZ gֳgֳ?3S g0  hh88   ZZ gֳgֳ?.S h10  hh88   Z$Z gֳgֳ? S i100  hh88   ZIJZ gֳgֳ?zS j1000  hh88E   ZpZ gֳgֳ? o G2Da concentration, mg/mlT  hh88#    `Z gֳgֳ?j  % chemiluminescence&   hh88R   s *?Z dB   <1?22^2   61?AiI   ZhZ gֳgֳ? hG1  hh88dB   <1?   C B1C5DEF1?04 @=n   ZZ gֳgֳ?P $ tanti-D serum A  hh88dB   <1?jjR   s *1?TAi   Z`Z gֳgֳ? tanti-D serum B  hh88dB   <1?     C B1C5DEF1?044 @=n"    ZlZ gֳgֳ?]  tanti-D serum C  hh88dB   <1?  R   s *? <p ^B   61? =U ^B   61? Um ^B  @ 61? =U ^B   61? Um    Z\ gֳgֳ?&    tanti-D serum D  hh88dB   <1?@ @ R2   s *1?) AiV    Z\ gֳgֳ?   tanti-D serum E  hh88dB   <1?     C B1C5DEF1?04 @ =n    Z\ gֳgֳ?^ A2  tanti-C+D serum  hh88dB   <1?x x ^   61?b Ai    Zx$\ gֳgֳ?   r anti-K serum   hh88dB   <)?''dB   <)?dB   <)?^^M^B   61?i^B   61?ii^B   61?  ^B   61?x x ^B   61?  ^B   61?^B   61?^B   61?^B   61?^B   61?Ri^B   61?HH   0޽h ? ̙33y___PPT10Y+D=' = @B + 5 !(  m  Z\-\ gֳgֳ? GBinding to the cell line 3T6 + FcgRIIa 131R, measured by flow cytometry8H!$$&$@        BC DEF? @p\   BC DEF1? @p\^B  61?pp^B  61?I^B  61?k Ik ^B  61?V IV ^B   61?@ I@ ^B   61?* I* ^B   61? I ^B   61?I^B   61?I^B  61?I^B  61?I^B  61?p[^B  61?fpp^B  61?f^B  61?f^B  61?foo^B  61?f^B  61?fNN^B  61?f^B  61?f^B  61?f..^B  61?fii^B  61?f^B  61?f ^B  61?fh h ^B  61?f ^B  61?fG G ^B   61?f ^B ! 61?f ^B " 61?f( ( ^B # 61?fb b ^B $ 61?f ^B % 61?f^B & 61?faa^B ' 61?f^B ( 61?f@@^B ) 61?f^B * 61?f^B + 61?f!!^B , 61?f[[^B - 61?]pp^B . 61?]ii^B / 61?]b b ^B 0 61?][[ 1  B| C=DE F(1?{ |<@4\q  2  B| CDE F(1?{ J|D@\   3  BCDEF$1?}9W{@- _\   4  BCdDEF$1?}Acc@V _\   5  BCDEF$1?}D@ _\   6  BC)DEF$1?}(@ _\  7  B| CLDE F(1?{ |;K@~ \  8  B| C3DE F(1?{ \|;*2@~ \   9  BCDEF$1?}9  @ _\   :  BCtDEF$1?}Rcs@V _\   ;  BCDEF$1?}3~@* _\  <  B| CDE F(1?{ |**g@ \   =  BCYDEF$1?}&GX@ _\ ^2 > 61? EqH^2 ? 61?^2 @ 61? Fs ^2 A 61?  ^2 B 61? I u ^2 C 61? ^2 D 61?4 Hu[ ^2 E 61?]  ^ F 61?Es^ G 61?  ^ H 61?N FtO ^ I 61? ^ J 61?e I v g ^ K 61?  ^ L 61?p Hvq ^ M 61?  X N 01? EqA X O 01?R z X P 01? Fs X Q 01?p X R 01? I u X S 01? X T 01? Hu ^ U 61?B Eqj ^ V 61?R z ^ W 61? Fs/ ^ X 61?] ^ Y 61? I u ^ Z 61? ^ [ 61? Hu  \ C B5C1DEF1?400 @ Av  ] C B6C0DEF1?5// @   ^ C B6C1DEF1?500 @ Bx  _ C B6C0DEF1?5// @0 `  ` C B5C1DEF1?400 @ E z  a C B5C1DEF1?400 @  b C B6C1DEF1?500 @ Dz  c C B5C1DEF1?400 @ Av  d C B6C1DEF1?500 @   e C B6C1DEF1?500 @ BxJ  f C B6C1DEF1?500 @l  g C B5C1DEF1?400 @ E z  h C B5C1DEF1?400 @  i C B6C1DEF1?500 @ Dz ^2 j 61?j Eq ^2 k 61?  ^2 l 61?R Fsz ^2 m 61?  ^2 n 61?I I u q ^2 o 61? ^2 p 61? Hu ^2 q 61?  ^ r 61?~ Es ^ s 61?  ^ t 61? Ft ^ u 61? ^ v 61?G I v H ^ w 61? ^ x 61? Hv ^ y 61?  ^2 z 61? Eq ^2 { 61?  ^2 | 61? Fs ^2 } 61?4 [ ^2 ~ 61?p I u ^2  61? ^2  61? Hu X  01?B Eqj X  01?R z X  01? Fs/ X  01?] X  01? I u X  01? X  01? Hu ^  61? Eq> ^  61?  ^  61?I Fsq ^  61? ^  61? I u ^  61? ^  61? Hu R  s *? @y8 ^B  61? [[ ^B  61? [[5 ^B @ 61? A[ ^B  61? [u R  s *? H ^B  61? - ^B  61?- E ^B @ 61?- - ^B  61?- - R  s *?. Azc ^B  61?/ \\G ^B  61?G \\_ ^B @ 61?G B\G ^B  61?G \wG R  s *? ^B  61? ^B  61? ^B @ 61? ^B  61? R  s *?. C } c ^B  61?0 _ _ G ^B  61?G _ _ _ ^B @ 61?G E _ G ^B  61?G _ y G R  s *?k ^B  61?l ^B  61? ^B @ 61? ^B  61? R  s *? C} ^B  61? __ ^B  61? __ ^B @ 61? D_ ^B  61? _y R  s *?  ^B  61?  ^B  61?  ^B @ 61?  ^B  61?  X  0?i @y ^B  61?k A[ ^B  61? [u ^B @ 61? A[ ^B  61?k [u X  0?  ^B  61?  ^B  61?  ^B @ 61?  ^B  61?  X  0?D Azx ^B  61?E B\] ^B  61?] \wu ^B @ 61?] B\u ^B  61?E \w] X  0?k ^B  61?l ^B  61? ^B @ 61? ^B  61?l X  0? C } ^B  61? E _ ^B  61? _ y ^B @ 61? E _ ^B  61? _ y X  0? ^B  61? ^B  61? ^B @ 61? ^B  61? X  0? C} ^B  61? D_ ^B  61? _y ^B @ 61? D_ ^B  61? _y   Z,\ gֳgֳ?!\@ J10    Z\\ gֳgֳ? \@  J20    Z\ gֳgֳ? \@  J30    Zh\ gֳgֳ? \@  J40    Z\ gֳgֳ? \@  J50    Z$\ gֳgֳ?\@v  J60    Zl\ gֳgֳ?\@a J70    Z$\ gֳgֳ?\@K J80    Z0\ gֳgֳ?v\@6 J90    Z\ gֳgֳ?`9  K100    Zl\ gֳgֳ? K0.1    ZH\ gֳgֳ? I1    Zl\ gֳgֳ?  J10    ZȦ\ gֳgֳ? K100     Zȭ\ gֳgֳ?X1 , antibody concentration, mg/ml6     `\ gֳgֳ?4j>d  Ymean fluorescence  R  s *?[RdB  <1?)~O)^2  61?=  ZP\ gֳgֳ?+( JG1  dB  <1?~O^  61?  Z\ gֳgֳ?r32 jG1Da6  dB  <1?x~OxX  01?d  Z\ gֳgֳ?3 jG1Db6  dB  <1? ~O ^  61? 4  Z\ gֳgֳ?3 jG1Dc6  dB  <1?~O  C B5C1DEF1?400 @  Zd\ gֳgֳ?h3(  kG1Dab6  dB  <1?n ~On   C B5C0DEF1?4// @W    Z\ gֳgֳ? 3  kG1Dac6  dB  <1? ~O ^2  61? *   ZX\ gֳgֳ? +(o  JG2  dB  <1? ~O ^  61?    Zx\ gֳgֳ?^ 3  jG2Da6  dB  <1?e ~Oe ^2  61?Q y   Z\ gֳgֳ? +(  JG4  dB  <1? ~O X  01?    Zt\ gֳgֳ? 3m  jG4Db6  dB   <1? ~O ^   61?     Z\ gֳgֳ?T 3  jG4Dc6  ^B   61?[ ~O[ R   s *?B v ^B  61?C [ ^B  61?[ s ^B @ 61?[ [ ^B  61?[ [   ZT\ gֳgֳ? 3  jG1Dg6  ^B  61?~OX  0? ^B  61? ^B  61?^B @ 61?^B  61?   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TfB 0 61?uuT 1  Bq CDE F(1?p Qf * Z@5v  2  Bq CDE F(1?p fb %Z@vi  3  BCDEF$1?d YZ@_ vi  4  BCDEF$1?d bZ@_ vi  5  BCDEF$1?d IZZ@_ vi  6  BCcDEF$1?rd ,Z=b@_ vi  7  Bq CDE F(1?p f: ZC@5v  8  Bq CDE F(1?p "f eZ@FvD  9  BCDEF$1?d  JZ[@_ vi  :  BCoDEF$1?d  [Znn@_ vW  ;  BCDEF$1?Qd Z@_B vW  <  Bq CDE F(1?p $fX Z@; vW  =  BCDEF$1?dA kZ@_ vz f2 > 61?_Kf2 ? 61?3f2 @ 61? p f2 A 61?U ! f2 B 61? I ' u f2 C 61? , W f2 D 61?I u f2 E 61? 3 f F 61?_f G 61? 4 f H 61?   f I 61?U f J 61? ( f K 61?  f L 61?IB vD f M 61?g i ` N 01?_m  ` O 01? 3 ` P 01? } ` Q 01?U ` R 01?  ' 3 ` S 01? . Y ` T 01?IR u~ f U 61?_  f V 61?G 3r f W 61? f X 61?U  f Y 61?  ' H f Z 61? . Y f [ 61?IR u~  \ C B5C5DEF1?444 @[   ] C B5C5DEF1?444 @ 8  ^ C B5C4DEF1?433 @ ^  _ C B5C5DEF1?444 @Q  ` C B5C5DEF1?444 @  , M  a C B6C4DEF1?533 @ * ^  b C B5C5DEF1?444 @EN z  c C B5C4DEF1?433 @[   d C B5C4DEF1?433 @^ 8  e C B5C5DEF1?444 @  f C B5C4DEF1?433 @Q #  g C B5C5DEF1?444 @  , M  h C B6C4DEF1?533 @ * ^  i C B5C5DEF1?444 @EN z f2 j 61?_Kf2 k 61?3f2 l 61? 0 \f2 m 61?U Y f2 n 61? ' f2 o 61? f2 p 61?Ib u f2 q 61?  f r 61?_EGf s 61?8 4: f t 61? g i f u 61?U ^ ` f v 61? # ( % f w 61? f x 61?I v f y 61?B D f2 z 61?_  f2 { 61?b 3 f2 | 61? f2 } 61?U  f2 ~ 61?  ' H f2  61? . Y f2  61?IR u~ `  01?_  `  01?b 3 `  01? `  01?U  `  01? . ' Y `  01? @ k `  01?I@ uk f  61?_, W f  61?} 3 f  61?  f  61?U  3 f  61? . ' Y f  61? @ k f  61?I@ uk Z  s *?Z X fB  61?u! u; fB  61?u; uU fB B 61?[; u; fB  61?u; ; Z  s *?D ;| fB  61?E _ fB  61?_ y fB B 61?_ _ fB  61?_ 7_ Z  s *? B fB  61? $ fB  61? $ > fB B 61? $ $ fB  61? $ $ Z  s *?O x fB  61?k y k fB  61?k k fB B 61?Q k fB  61?k Z  s *? / fB  61?  fB  61?  fB B 61?  fB  61? + Z  s *?  P fB  61?  2 fB  61? 2 L fB B 61? 2 2 fB  61? 2 2 Z  s *?D( }a fB  61?_* _C fB  61?_C _] fB B 61?EC _C fB  61?_C yC Z  s *?; #s fB  61?< V fB  61?V o fB B 61?V V fB  61?V V `  0?Z  fB  61?[ u fB  61?u  fB B 61?[ u fB  61?u  `  0?x ; fB  61?y  fB  61? 7 fB B 61?  fB  61?y 7 `  0? & fB  61?  fB  61?  " fB B 61?  " fB  61?  `  0?O  P fB  61?Q  k 2 fB  61?k 2 L fB B 61?Q 2 k L fB  61?k  2 `  0? ; / s fB  61? <  V fB  61? V + o fB B 61? V  o fB  61? < + V `  0? M fB  61? N h fB  61? h fB B 61? h fB  61? N h `  0?D^ } fB  61?E` _y fB  61?_y y fB B 61?Ey _ fB  61?_` yy   ZpN^ gֳgֳ?  J10    ZQ^ gֳgֳ? f  J20    ZV^ gֳgֳ?y 9  J30    ZU^ gֳgֳ?N   J40    Z]^ gֳgֳ?#   J50    ZY^ gֳgֳ? J60    Z_^ gֳgֳ? J70    Zg^ gֳgֳ?^ J80    Z0f^ gֳgֳ?s3 J90    Z,j^ gֳgֳ?H K0.1    ZPr^ gֳgֳ?(H I1    Zm^ gֳgֳ? g H J10    Zw^ gֳgֳ?H K100    Z\t^ gֳgֳ?O # antibody concentration, mg/ml6      `h^ gֳgֳ?Z  tmean f luorescence&    N y  ylB  <1?##f2  61?d 8  Z^ gֳgֳ? JG1  lB  <1?f  61?d  Z^ gֳgֳ?{:; jG1Da6  lB  <1?`  01?dv  Z^ gֳgֳ?/@ jG1Db6  lB  <1?@@f  61?d*U  Z̖^ gֳgֳ?: jG1Dc6  lB  <1?  C B5C5DEF1?444 @`   Z^ gֳgֳ?rX  kG1Dab6  lB  <1?    C B5C4DEF1?433 @`    Z^ gֳgֳ?L k  kG1Dac6  lB  <1?] ] f2  61?dG r   Z^ gֳgֳ?   JG2  lB  <1?  f  61?d    Z^ gֳgֳ? :u  jG2Da6  lB  <1?  f2  61?d    Z,^ gֳgֳ?i )  JG4  lB  <1?z z `  01?dd    ZP^ gֳgֳ? @  jG4Db6  lB  <1?. . f   61?d D    Z^ gֳgֳ? :  jG4Dc6  fB   61?  Z   s *?_ fB   61?z z fB  61?z z fB B 61?` z fB  61?z    Zx^ gֳgֳ? @F jG1Dg6  fB  61?`  0?_|fB  61?`}zfB  61?zfB B 61?`zfB  61?z}  Z^ gֳgֳ?:y ^IgA1,k(    TT^ gֳgֳ? VFog-1 antibodies 2  H  0޽h ? ̙33y___PPT10Y+D=' = @B +Ҕ 5 ݓu(  =F ~   ~ X  Z(^ gֳgֳ?~ DBinding to the cell line 3T6 + FcgRIIb1*, measured by flow cytometry8E!$$#$&;      B6C` DEF?55_ _ @'   B6C` DEF1?55_ _ @'fB  61?&fB  61?&&fB  61?F F fB   61?f f fB   61?fB   61?fB   61?fB   61?&&fB  61? &fB  61? &fB  61? &fB  61? &fB  61? &fB  61?^ ^&fB  61? &fB  61? &fB  61?3 3&fB  61?j j&fB  61? &fB  61?  &fB  61?D D &fB  61?  &fB  61?  &fB  61?j j &fB  61?  &fB  61?  &fB   61?' ' &fB ! 61?  &fB " 61?i i&fB # 61? &fB $ 61?v v&fB % 61? &fB & 61?( (&fB ' 61?n n&fB ( 61? &fB ) 61? &fB * 61?JfB + 61?jjJfB , 61?' ' JfB - 61?J .  B CDE F(1? "H^m}@  /  B CzDE F(1? "Hm?y@@  0  BC'DEF$1?"gTHn&@T   1  BCJDEF$1?"tkH$n8I@T   2  BCDEF$1?"CzH`n@TY   3  BCDEF$1?"xHNn@T   4  B CRDE F(1? "vIH mKQ@  5  B CDDE F(1? B"Hm)C@  6  B CDE F(1? L" HYm@  7  BCDEF$1?"%Hnn@T   8  BCfDEF$1?"HMn`e@T   9  BCDEF$1?"4Hn@T   :  BCDEF$1?"XvHn@TK  f2 ; 61?f2 < 61?`f2 = 61? q  f2 > 61?  f2 ? 61? B F k f2 @ 61? # f2 A 61?>a j f2 B 61?  f C 61??Gf D 61?`f E 61? ! f F 61? ' / f G 61? V G ^ f H 61?  f I 61?>~ l f J 61?  ` K 01?  ` L 01?` B ` M 01?  . ` N 01? t ` O 01? F ` P 01? ` Q 01?> jf R 61?  f S 61?` , f T 61? # f U 61? t f V 61? F f W 61? f X 61?> j Y C B6C3DEF1?522 @@ s  Z C B6C3DEF1?522 @\   [ C B6C2DEF1?511 @ %  \ C B6C3DEF1?522 @ > q  ] C B6C3DEF1?522 @ K  ^ C B6C2DEF1?511 @  _ C B5C3DEF1?422 @: o ` C B6C3DEF1?522 @ #  a C B6C3DEF1?522 @\h   b C B6C2DEF1?511 @ %  c C B6C3DEF1?522 @ > q  d C B6C3DEF1?522 @ K  e C B6C2DEF1?511 @  f C B5C3DEF1?422 @: of2 g 61?uf2 h 61?`D n f2 i 61?  f2 j 61? f2 k 61? M F v f2 l 61? f2 m 61?> j f2 n 61?  f o 61?f p 61?`  f q 61? ! f r 61? f s 61? 3 G ; f t 61? f u 61?> l f v 61?  f2 w 61?f2 x 61?` < f2 y 61?  f2 z 61? f2 { 61? F f2 | 61?  H f2 } 61?>| j f2 ~ 61?  `  01?  `  01?` B `  01?  `  01? a `  01? F `  01? `  01?> jf  61?l  f  61?`h  f  61? + T f  61? | f  61? F f  61? f  61?> j Z  s *?  fB  61?  fB  61?  fB B 61?  fB  61?  Z  s *?[  fB  61?v v fB  61?v v fB B 61?\ v fB  61?v  Z  s *?  (P fB  61?  4 fB  61? 4 L fB B 61? 4 4 fB  61? 4 $4 Z  s *? o fB  61? p fB  61? fB B 61? fB  61? Z  s *? N fB  61?/ / fB  61?/ / fB B 61? / fB  61?/ J Z  s *? fB  61? fB  61? fB B 61? fB  61? Z  s *?8 rfB  61?T T fB  61?T T fB B 61?: T fB  61?T n `  0?1 h fB  61?2 K fB  61?K d fB B 61?K d fB  61?2 K `  0?[  fB  61?\ v fB  61?v  fB B 61?\ v fB  61?v  `  0? ( fB  61?  fB  61?  $ fB B 61?  fB  61?  $ `  0? fB  61? fB  61? fB B 61? fB  61? `  0? N fB  61? / fB  61?/ J fB B 61? / fB  61?/ J `  0? fB  61? fB  61? fB B 61? fB  61? `  0?8 rfB  61?: T fB  61?T nfB B 61?: TfB  61?T n   Z` gֳgֳ? | J10    Z4` gֳgֳ? |  J60    Z` gֳgֳ?Y u  K110    Z@` gֳgֳ?Y(u K160    Z` gֳgֳ?YHu K210    Z"` gֳgֳ?Yhu( K260    Z<` gֳgֳ?&w&7 K0.1    Z,&` gֳgֳ?w7 I1    Z)` gֳgֳ? w 7 J10    Z,-` gֳgֳ?Kwg7 K100    Z0` gֳgֳ?6  antibody concentration, mg/ml6     `$:` gֳgֳ?&hV  Ymean fluorescence  jN o  oZ  s *?o N ]  ]lB  <1?]A/Af2  61?,U  Zx>` gֳgֳ? JG1  lB  <1?]/f  61?  ZB` gֳgֳ?P jG1Da6  lB  <1?]/`  01?  ZxH` gֳgֳ?= jG1Db6  lB  <1?]J/Jf  61?5_  Z N` gֳgֳ? jG1Dc6  lB  <1?]/  C B6C2DEF1?511 @   ZS` gֳgֳ?Y  kG1Dab6  lB  <1?] /   C B6C3DEF1?522 @    Z4Y` gֳgֳ?F   kG1Dac6  lB  <1?]S /S f2  61?> h   Z^` gֳgֳ?   JG2  lB  <1?] / f  61?    Z[` gֳgֳ? b  jG2Da6  lB  <1?] / f2  61?    Zg` gֳgֳ?O   JG4  lB  <1?]\ /\ `  01?G q   ZXa` gֳgֳ?   jG4Db6  lB  <1?] / f  61?    Zlj` gֳgֳ? k  jG4Dc6  fB  61?] / Z  s *?  fB  61?  fB  61?  fB B 61?  fB  61?     Zw` gֳgֳ?Y  jG1Dg6  fB   61?]e/e`   0?KfB   61?LefB   61?e~fB B 61?e~fB  61?Le  Zl}` gֳgֳ? ^IgA1,k(    T܁` gֳgֳ? VFog-1 antibodies 2  H  0޽h ? ̙33y___PPT10Y+D=' = @B +D 5 CCQQ$C(  \AF 0  08  Z` gֳgֳ?0p $Binding to different forms of FcgRII8% $$$&     Z` gֳgֳ?; [/ `antibody constant region     ` ` gֳgֳ?X,  `percentage of G1 binding    T` gֳgֳ? h0% = binding of IgA1,k" 2    BC DEF? @mR    BC DEF1? @mR    C B^C?DEF1?]]>> @[R    C B`CgDEF1?__ff @aR    C B_CDEF1?^^ @Z R    C B_CDEF1?^^ @O^ R    C B_CWDEF1?^^VV @ T R   C B_CDEF1?^^ @ R   C B_CDEF1?^^ @C R   C B_C=DEF1?^^<< @  GR   C B_CDEF1?^^ @ R   C B_CDEF1?^^ @6k R   C B_CDEF1?^^ @6 ;R   C B`CDEF1?__ @ R   C B`C?DEF1?__>> @R   C B_CDEF1?^^ @` R   C B_CDEF1?^^ @ eR   C B^CeDEF1?]]dd @ R   C B`CDEF1?__ @S A R   C B_C2DEF1?^^11 @ Y R   C B]C DEF1?\\  @ C R   C B`CDEF1?__ @FR   C B_CEDEF1?^^DD @ LR   C B_C6DEF1?^^55 @ R   C B^CDEF1?]] @ @R    C B_C?DEF1?^^>> @vR  ! C B^CDEF1?]] @R  " C B_CDEF1?^^ @dA R  # C B`CDEF1?__ @ e jR  $ C B_CDEF1?^^ @  R  % C B_CDEF1?^^ @X R  & C B`CZDEF1?__YY @ ] R  ' C B_CDEF1?^^ @R  ( C B_CDEF1?^^ @KR  ) C B_CDEF1?^^ @ QR  * C B_CXDEF1?^^WW @ R  + C B_CLDEF1?^^KK @? R fB , 61?mQ fB - 61?Q 5Q fB . 61? 5 fB / 61? 5 fB 0 61?_5_fB 1 61?5fB 2 61?5fB 3 61?m5mfB 4 61?Q Q  5 Z` gֳgֳ?[   I0   6 Z` gֳgֳ?&J   J20   7 Z` gֳgֳ?& d  J40   8 Z` gֳgֳ?&  J60   9 Z<` gֳgֳ?&X  J80   : Zв` gֳgֳ? r K100   ; Z̶` gֳgֳ?   K120   <  `` gֳgֳ? W JG1   =  ` ` gֳgֳ?<  jG1Da6   >  `x` gֳgֳ?  jG1Db6   ?  `` gֳgֳ? I jG1Dc6   @  `X` gֳgֳ?1 2 kG1Dab6   A  `\` gֳgֳ? 3 kG1Dac6   B  ``` gֳgֳ?v 6  JG2   C  `` gֳgֳ?#  jG2Da6   D  `P` gֳgֳ?  JG4   E  `d` gֳgֳ?r 2 jG4Db6   F  `` gֳgֳ?  jG4Dc6   G  `D` gֳgֳ?  jG1Dg6  ` H 0?]` I 01?q J Z` gֳgֳ?U:<  FcgRIIa 131R6    ` K 01?qy L Zb gֳgֳ?#B   FcgRIIa 131H6    ` M 01?qF N Zb gֳgֳ?n } FcgRIIb1*D   lB O <1?>L L  P ZA? 1?"6?@`NNN?N`= Q ZA? 1?"6?@`NNN?NH  0޽h ? ̙33y___PPT10Y+D=' = @B +T 5 SS 8S(      Zb gֳgֳ?l n$Activity of Fog-1 antibodies in ADCC%%( %    BC Cn DEF?B B m m @K    BC Cn DEF1?B B m m @K^B   61?^B   61?"^B   61? " ^B   61? " ^B   61? " ^B   61?"^B   61?"^B   61?"^B   61?"^B   61?J^B   61?n^B   61?n^B   61?n44^B   61?n^B   61?n^B   61?n^B   61?n^B   61?n??^B   61?n__^B   61?n}}^B   61?n99^B   61?n^B   61?n^B   61?n33^B   61?nee^B   61?n^B   61?n^B   61?n^B !  61?n^B "  61?n ^B #  61?n  ^B $  61?nj j ^B %  61?n ^B &  61?n ^B '  61?n  ^B (  61?n& & ^B )  61?nE E ^B *  61?nd d ^B +  61?n ^B ,  61?n ^B -  61?n ^B .  61?n  ^B /  61?nL L ^B 0  61?nv v ^B 1  61?n ^B 2  61?n ^B 3  61?n ^B 4  61?n^B 5  61?n^B 6  61?nQQ^B 7  61?n^B 8  61?n^B 9  61?n^B :  61?n^B ;  61?n..^B <  61?nJJ^B =  61?g^B >  61?g}}^B ?  61?g^B @  61?gd d ^B A  61?g ^B B  61?gJJ C   BCDE F(1?XN^r)o@(8 D   BC_DE F(1?N[::Lt^,M^@ ^  E   BCDE F(1?[H t,@   F   BC{DE F(1?Z)Yztf,_v@ R  G   BC#DE F(1?R[Et,"@ c  H   BCVDE F(1?[:;Ut1,G/@  ^2 I  61?iA^2 J  61?= k ^2 K  61?^ # ^2 L  61? ^2 M  61?n ^2 N  61?W^2 O  61?<^2 P  61?O Q  C B6C9DEF1?588 @ Bx  R  C B7C9DEF1?688 @  M  S  C B8C:DEF1?799 @   T  C B6C:DEF1?599 @  U  C B6C;DEF1?5:: @ Z   V  C B7C9DEF1?688 @ /f!  W  C B8C:DEF1?799 @   X  C B6C9DEF1?588 @ ! ^2 Y  61? t ^2 Z  61? H v  ^2 [  61? . N ^2 \  61?   ^2 ]  61?| ^2 ^  61? a ^2 _  61? G ^2 `  61?  ^ a  61? :j ^ b  61?  = ^ c  61? ^ d  61? ^ e  61? S  ^ f  61? 'W ^ g  61?  ^ h  61?  ^2 i  61? KxD ^2 j  61?  L  ^2 k  61?  6 ^2 l  61? ^2 m  61? d ^2 n  61?t 8f ^2 o  61?  ^2 p  61?  X q  01? t X r  01? H v X s  01? .  X t  01?   X u  01? 2 X v  01? a X w  01? G% X x  01?   y  Z,9b gֳgֳ? M-20    z  Z\>b gֳgֳ? EO  K0    {  Z=b gֳgֳ?$   L20    |  Zh@b gֳgֳ? T  L40    }  ZCb gֳgֳ?+ L60    ~  Z$Lb gֳgֳ?Z L80      ZlOb gֳgֳ?0 M100      Z$Sb gֳgֳ?_ M120      Z0Nb gֳgֳ?O M0.1      ZYb gֳgֳ?)O K1      Zl]b gֳgֳ?b O L10      ZH\b gֳgֳ? O M100      Zldb gֳgֳ?: O N1000      Z_b gֳgֳ?O O10000       Zfb gֳgֳ?:n  antibody concentration, ng/ml&       `hob gֳgֳ?xL  m % RBC lysis &   < F `*    `* Z   s *?`* lB   <1?kkf2   61?%SR   Ztb gֳgֳ? JG1  lB   <1?   C B6C:DEF1?599 @!W7   Zxb gֳgֳ?|s G1D ab6&   lB   <1?f2   61?%R   Z~b gֳgֳ?L  JG2  lB   <1?w w f   61?%u S}    Zpb gֳgֳ?<  kG2D a6  lB   <1?$ $ f2   61?% R<    ZԈb gֳgֳ? |  JG4  lB   <1?  `   01?% R    Zb gֳgֳ?V C*  kG4D b6  H   0޽h ? ̙33y___PPT10Y+D=' = @B +gV 5 zUrU$ U(  $5 $ ZĔb gֳgֳ?~` EInhibition by Fog-1 antibodies of ADCC due to Fog-1 IgG1 (at 2ng/ml)FF$ F HH   $ Z- ;~ ^O@ G  $  B?CDEF$1?>  k_@N/  $  B?CDEF$1?>l ~ ^N@f   $  B@CZDEF$1??Y * Z x_0@_   $  B@C4DEF$1??h 3  _i@   !$  B?CRDEF$1?>Q :~ ^W@   "$  B>CPDEF$1?=O E~ X._[E@2  #$  B?CBDEF$1?>A ~ Q5^Z@G  $$  B?CJDEF$1?>6 I k_]@_  %$  B?CGDEF$1?>F ~ 9_S@`G &$ C B,C)DEF1?+(( @%N '$ C B+C)DEF1?*(( @2Y[ ($ C B-C*DEF1?,)) @ %  )$ C B,C+DEF1?+** @  *$ C B-C)DEF1?,(( @9 f 8 +$ C B,C*DEF1?+)) @Fp ,$ C B.C)DEF1?-(( @yX -$ 01??X .$ 01?Np4X /$ 01?M n X 0$ 01? X 1$ 01?. R X 2$ 01?X 3$ 01?=o_^ 4$ 61? > ^ 5$ 61?U ]v ^ 6$ 61?   ^ 7$ 61?x ^ 8$ 61?= a ^ 9$ 61?^ :$ 61?}  ;$ C B+C)DEF1?*(( @Js <$ C B-C)DEF1?,(( @tE =$ C B+C*DEF1?*)) @L @v  >$ C B-C*DEF1?,)) @   ?$ C B+C*DEF1?*)) @iV  @$ C B,C*DEF1?+)) @!!K A$ C B,C*DEF1?+)) @^ B$ 61?  ^ C$ 61? x ^ D$ 61? < ^ E$ 61? ^ F$ 61?Z } ^ G$ 61?HQ^ H$ 61?^2 I$ 61?  ^2 J$ 61? ] ^2 K$ 61?   ^2 L$ 61?{ ^2 M$ 61?= a :^2 N$ 61?]}^2 O$ 61?}^ P$ 61?09^ Q$ 61?(k0^ R$ 61?; 0C ^ S$ 61? ^ T$ 61?K p ^ U$ 61?=F^ V$ 61?)1^2 W$ 61?6V^2 X$ 61? ]^2 Y$ 61?   ^2 Z$ 61?F g ^2 [$ 61?+= a K^2 \$ 61?^2 ]$ 61?O}pX ^$ 01?<^X _$ 01?NNpnX `$ 01? . X a$ 01?  X b$ 01?q. R X c$ 01?&X d$ 01?ao^ e$ 61?6V^ f$ 61? -O^ g$ 61?* J ^ h$ 61?m  ^ i$ 61? 0 ^ j$ 61?^ k$ 61?CMrc l$ Zb gֳgֳ?: I0   m$ Z$b gֳgֳ?   I5   n$ Zb gֳgֳ?   J10   o$ Z0b gֳgֳ?   J15   p$ Zb gֳgֳ?   J20   q$ Zb gֳgֳ?a  J25   r$ Z4b gֳgֳ?A J30   s$ Zb gֳgֳ?a! J35   t$ Zb gֳgֳ?D J40   u$ Zb gֳgֳ?% J45   v$ Z4b gֳgֳ?um N0.0001   w$ Zb gֳgֳ?Dm M0.001   x$ Z4b gֳgֳ?m L0.01   y$ Zb gֳgֳ?3 3 m K0.1   z$ Zb gֳgֳ? a m I1   {$ Zd gֳgֳ? m J10   |$ Z d gֳgֳ?Fbm K100   }$ Zd gֳgֳ?m L1000   ~$ Z d gֳgֳ?am M10000   $ Z d gֳgֳ?   [G1D(   $ ZXd gֳgֳ?   J a   $ Z|d gֳgֳ?j OQ  ZG1  xx $ Z d gֳgֳ?j Q  KD   $ Z%d gֳgֳ?q !X  J c   $ Z'd gֳgֳ? m JG2   $ Z,d gֳgֳ?Gl KD   $ Z*d gֳgֳ?\l J a   $ Z\3d gֳgֳ?L 3 JG2  ^B $@ 61?  Pt $ T87d gֳgֳ? 4 <G1Db, G1Dab, G1Dac, G4, G4Db, G4Dc= 2$ =  $ ZAd gֳgֳ?  E{  H $ 0޽h ? ̙33y___PPT10Y+D=' = @B + 5 ("(  ( ( ZFd gֳgֳ?@~ hSummary of antibody activities(   (  AB? ?npo00002eObject 3"<?@@`NNN?N(dB ( <8c?", ( ZA? 1?"6?@`NNN?N ( ZA? 1?"6?@`NNN?N=H ( 0޽h ? ̙33y___PPT10Y+D=' = @B + 5 ,Q(  ,Z , ZVd gֳgֳ?`x0 PEffect of mutations cannot always be predicted from wildtype antibody activitiesQQ$&4   HH   , TdYd gֳgֳ?pF 3Complement lysis: IgG2 activity is only ~3-fold lower than that of IgG1 but placing IgG2 residues in IgG1 (Db, Dc) eliminates lysis. FcgRIIa 131H binding: IgG1 and IgG2 show equal binding but G1Db and G1Dc activities are 30-fold lower. IgG1 binding may depend heavily on the mutated regions. Other subclasses may have additional sites of interaction with the effector molecules. nFTn3n8 #t   q        H , 0޽h ? ̙33y___PPT10Y+D=' = @B + 5  0T(  0/ 0 Zwd gֳgֳ?Hx( Db and Dc mutantsH$$$ $  HH  q 0 T yd gֳgֳ?HH\ {The 3 pairs of Db and Dc mutants show reduced activity in all functions assayed but the residual levels of activity differ:B|xe | N 0 T`d gֳgֳ?` 8Db slightly more active in FcgRIIa 131H and 131R bindingH90<2&    0 Td gֳgֳ?`*  3YDc more active in FcgRI binding, monocyte activation FcgRIIIb NA1and NA2 binding and ADCC\Zn ""Z         W 0 TDd gֳgֳ? x sThese mutants differ only by -/+ G236. This must affect the ability of the FcR to accommodate the IgG2 lower hinge.txt&K  & H 0 0޽h ? ̙33y___PPT10Y+D=' = @B +   @xr(  xr x S 0d l  d   x c t0e0eA     ? A@  A5% 8c8c     ?A)BCD|E||Slide03c " ?@  `    @ABC DEEFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `abN E5%  N E5%  N F   5%    !"?N@ABC DEFFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `ab+ d H x 0޽h ? ̙33___PPT10i.w+D=' = @B +}  $(  r  S d l  d  r  S \d  d  H  0޽h ? ̙33___PPT10i.*+D=' = @B +   0(  x  c $ةd l  d  x  c $d  d  H  0޽h ? ̙33___PPT10i.*+D=' = @B +}  0$(  r  S d l  d  r  S ̳d zY d  H  0޽h ? ̙33___PPT10i.*s+D=' = @B +o ~0(    rAC? ?npo00002fPicture 4"<?@@`NNN?NTX!H  0޽h ? ̙33___PPT10i.O)@z֨+D=' = @B +}  @$(  r  S d l  d  r  S d ' d  H  0޽h ? ̙33___PPT10i.*0S+D=' = @B + /'P(  o   fDd xaxa 1?" Benjamin,R.J., Cobbold,S.P., Clark,M.R., & Waldmann,H. (1986) J. Exp. Med. 163, 1539-1552. Tolerance to rat monoclonal antibodies: implications for serotherapy Observation Relatively easy to tolerise mice, with de-aggregated human immunoglobulin or with rat immunoglobulin, despite large differences in the constant region sequences between mouse, human and rat. However in mice which are tolerant of soluble rat IgG2b, administration of antibodies which bind to mouse cell surface antigens provokes a strong anti-idiotype response. Explanation Is this a function of the inherent immunogenicity of immune complexes? Aggregated antibody is more likely to activate complement and to bind to low affinity Fc receptors.  7e l     '9   "=<m ZZZ@ @ @@!$@&(*-@/1  Zd xaxa 1?"T x0Induction of tolerance to therapeutic antibodies11 1 H  0޽h ? ̙33___PPT10i.*:;+D=' = @B + *(  x  c $d ,7W d  r  S \d `  d  H  0޽h ? ̙33___PPT10i.|)+D=' = @B +E \T (    X7&"A? ?Slide03"6?@`NNN?NZ   Z|l xaxa 1?"q ^The V-region Mythology     Z l xaxa 1?"WV  gChimaeric 65% Human ?       fd xaxa 1?"y 5  YHumanised 95% Human ?    Zxl xaxa 1?"  L This commercial marketing mythology is based on an assumption that mouse and human antibody sequences are unique. However a study of the Kabat database shows that there is high sequence homology for antibodies from different species.&  \ H  0޽h ? ̙33___PPT10i.|)Щ+D=' = @B +{ P"(    ~ADH ? ?npo000032Picture 4"<?@@`NNN?NH  0޽h ? ̙33___PPT10i.R)pt+D=' = @B + p.(    rAE? ?npo000033Picture 4"<?@@`NNN?N{    f5l xaxa 1?" |*Kabat database variability of VH sequences++ &    f:l xaxa 1?"   LHuman VH       f=l xaxa 1?" C LMouse VH    H  0޽h ? ̙33___PPT10i.*5k+D=' = @B +  *(    rAF? ?npo000036Picture 4"<?@@`NNN?N w    rAG? ?npo000038Picture 5"<?@@`NNN?N/@ y   ZGl xaxa 1?"WIu > H  ZJl xaxa 1?",T0 RAre chimaeric, humanised and fully human antibodies so very different in sequence?SS&   F H  0޽h ? ̙33___PPT10i.|)`{+D=' = @B +o ~(    rAH? ?npo000039Picture 4"<?@@`NNN?NhxH  0޽h ? ̙33___PPT10i.*P~&+D=' = @B +   7(     rAI? ?npo00003bPicture 4"<?@@`NNN?ND( !   fRl xaxa 1?" }7Possible to select alternative V genes for humanisation88 8   Z B  ZZl xaxa 1?" vGorman,S.D., Clark,M.R., Routledge,E.G., Cobbold,S.P. & Waldmann,H. P.N.A.S. 88, 4181-4185 (1991) Reshaping a therapeutic CD4 antibody. Routledge,E., Gorman,S., & Clark,M. in Protein engineering of antibody molecules for prophylactic and therapeutic applications in man. (Ed. Clark,M. ) Pub. Academic Titles, UK (1993) pp. 13-44 Reshaping of antibodies for therapy. &wt              I       k  W    Zfl xaxa 1?"f ^ 0 Gorman et al recognised that homology also extended through the CDR regions not just the framework regions Homology to Kol was increased from 69% to 89% by the humanisation process., &|  < H  0޽h ? ̙33___PPT10i.*{Y+D=' = @B + 3(    rAJ? ?npo00003dPicture 4"<?@@`NNN?Nzq  Z pl xaxa 1?"o }7The same strategy can be applied to almost any V-region88 8 H  0޽h ? ̙33___PPT10i.})9s'+D=' = @B +? >>@"T>(  <  ! #">2 PPP \  ftTl xaxa 1?",  m (100/124) 81%,-` "@ @` [  fll xaxa 1?" , k (23/37) 62%, -` "@ @` Z  fpl xaxa 1?"  k (77/87) 89%, -` "@ @`] Y  fl xaxa 1?"  Fog-1 RhD versus germline0-h",@ @` X  f l xaxa 1?",u   V   @` W  fl xaxa 1?" u ,  V   @` V  fl xaxa 1?" u  V   @`M U  fl xaxa 1?"u  human versus human germline0-h"@ @` T  fl xaxa 1?", u  l (82/119) 69%, -` "@ @` S  fl xaxa 1?" ,u  j (6/32) 19%, -` "@ @` R  fl xaxa 1?" u  k (76/87) 87%, -` "@ @`F Q  fl xaxa 1?" u  OKT3 versus germline0-h" @ @` P  fl xaxa 1?",   l (91/116) 78%, -` "@ @` O  f4 xaxa 1?" ,  k (14/29) 48%, -` "@ @` N  f4 xaxa 1?"  k (77/87) 89%, -` "@ @`\ M  f84 xaxa 1?"  Anti-Tac versus germline0-h",@ @` L  f 4 xaxa 1?",   l (86/121) 71%, -` "@ @` K  f)4 xaxa 1?" ,  j (8/34) 24%, -` "@ @` J  f34 xaxa 1?"  k (78/87) 90%, -` "@ @`L I  f=4 xaxa 1?"  Campath-1H versus germline0-h"@ @` H  fF4 xaxa 1?",  V   @` G  fH4 xaxa 1?" ,  V   @` F  fX4 xaxa 1?"   V   @`[ E  fhc4 xaxa 1?"  humanised versus human germline0 -h"$ @ @` D  fm4 xaxa 1?", l (81/119) 68%, -` "@ @` C  fv4 xaxa 1?" , k (12/32) 38%, -` "@ @` B  f4 xaxa 1?"   k (67/87) 77%, -` "@ @` A  f4 xaxa 1?"  hOKT30-h"@ @` @  fd4 xaxa 1?",  l (81/116) 70%, -` "@ @` ?  f@4 xaxa 1?" , k (14/29) 48%, -` "@ @` >  f4 xaxa 1?"   k (67/87) 77%, -` "@ @`: =  f4 xaxa 1?"   Anti-Tac0 -h"@ @` <  f4 xaxa 1?",9  l (82/121) 68%, -` "@ @` ;  f4 xaxa 1?" 9,  k (14/34) 41%, -` "@ @` :  f<4 xaxa 1?" 9  k (68/87) 78%, -` "@ @` 9  fh4 xaxa 1?"9  n Campath-1G0 -h "@ @` 8  f$4 xaxa 1?",9 V   @` 7  f4 xaxa 1?" ,9 V   @` 6  f@4 xaxa 1?"  9 V   @`X 5  f5 xaxa 1?" 9 murine versus human germline0-h"$@ @` 4  f4 xaxa 1?", kWhole V0-h"@ @` 3  f5 xaxa 1?" , gCDR0-h"@ @` 2  f5 xaxa 1?"   fFR0-h"@ @`$ 1  f$)5 xaxa 1?"  xAntibody comparisons0-h"@ @`B ] Nxaxa1 ?"B ^ Nxaxa1 ?"B _ Nxaxa1 ?"B ` Nxaxa1 ?"B c Nxaxa1 ?"B e Nxaxa1 ?"  B h Nxaxa1 ?"  B k Nxaxa1 ?",,B o Nxaxa1 ?"99B  Nxaxa1 ?"  B  Nxaxa1 ?"B  Nxaxa1 ?"B  Nxaxa1 ?"  B  Nxaxa1 ?"  B  Nxaxa1 ?"  B  Nxaxa1 ?"u u B  Nxaxa1 ?"  > "  f(/5 xaxa 1?" BSequence homologies of some rodent, humanised and human sequences  CAA H  0޽h ? ̙33___PPT10i.*pW+D=' = @B +p oopxo(  m qd  #">2 qd   `l xaxa1?#" ``   e0.689,-`"@ @`   `5 xaxa1?#" ` `  d82 ,-`"@ @`   `|_5 xaxa1?#" `   c119,-`"@ @`   `g5 xaxa1?#" `W    dJH6a,-`"@ @`   `0a5 xaxa1?#" `]  W  cb25,-`"@ @`/   ``{5 xaxa1?#" ` ]   Humanised, -` " @ @`   `t5 xaxa1?#" `   cCD3,-`"@ @`   `p5 xaxa1?#" `q   hOKT30-h"@ @`   `L5 xaxa1?#" ``J   e0.702,-`"@ @`   `5 xaxa1?#" `J `  b85,-`"@ @`   `5 xaxa1?#" `J   c121,-`"@ @`   `ж5 xaxa1?#" `W J   dJH4D,-`"@ @`   `5 xaxa1?#" `] J W   k DP-34_DA-10, -` "@ @`   `d5 xaxa1?#" `J ]   cRat,-`"@ @`   `85 xaxa1?#" `J   dCD52,-`"@ @`   `5 xaxa1?#" `qJ   n Campath-1G0 -h "@ @`   `@5 xaxa1?#" ``x J  e0.710,-`"@ @`   `5 xaxa1?#" `x `J  b86,-`"@ @`   `5 xaxa1?#" `x J  c121,-`"@ @`   `6 xaxa1?#" `W x J  dJH4D,-`"@ @`   `l6 xaxa1?#" `] x W J  m DP-71_3D197D-,-` "@ @`/   `6 xaxa1?#" `x ] J   Humanised, -` " @ @`   `$6 xaxa1?#" `x J  dCD52,-`"@ @`   `P.6 xaxa1?#" `qx J  n Campath-1H0 -h "@ @`   `76 xaxa1?#" ``x  e0.718,-`"@ @`   `@A6 xaxa1?#" ``x  b84,-`"@ @`   ``J6 xaxa1?#" `x  c117,-`"@ @`   `T6 xaxa1?#" `W x  dJH3B,-`"@ @`   `^6 xaxa1?#" `] W x  gVI-4-IB,-`"@ @`   `g6 xaxa1?#" `] x  eMouse,-`"@ @`   `  `(8 xaxa1?"W   dJH4D,-`"@ @`  ?  `8 xaxa1?"] W  d6M27,-`"@ @`  @  `T8 xaxa1?" ]  eMouse,-`"@ @`  A  `p8 xaxa1?"   dCD19,-`"@ @` B  `9 xaxa1?"q   hHD370-h"@ @`  K  `< 9 xaxa1?"`   e0.681,-`"@ @` L  `9 xaxa1?" `  b81,-`"@ @`  M  `"9 xaxa1?"   c119,-`"@ @`  N  `49 xaxa1?"W   dJH6a,-`"@ @` O  `p69 xaxa1?"] W  l DP-7_21-2-.., -` "@ @`  P  `@9 xaxa1?" ]  eMouse,-`"@ @`  Q  `I9 xaxa1?"   cCD3,-`"@ @` R  `S9 xaxa1?"q   hOKT30-h"@ @` S  f^9 xaxa 1?"`0 lHomology0 -h"@ @` T  fh9 xaxa 1?"`0 kMatches0-h"@ @` U  fq9 xaxa 1?"0 jLength0-h"@ @` V  f4{9 xaxa 1?"W 0 fJH0-h"@ @` W  f9 xaxa 1?"] W 0 q Homologous VH0-h "@ @` X  f<9 xaxa 1?"] 0 lV-region0 -h"@ @` Y  f9 xaxa 1?"0 o Specificity0 -h "@ @` Z  f89 xaxa 1?"q0 lAntibody0 -h"@ @`B [ Nxaxa1 ?"qB \ Nxaxa1 ?"qddB ] Nxaxa1 ?"qqdB ^ Nxaxa1 ?"dB _ Nxaxa1 ?"q00B ` Nxaxa1 ?"dB a Nxaxa1 ?"dB b Nxaxa1 ?"] ] dB c Nxaxa1 ?"W W dB d Nxaxa1 ?"dB e Nxaxa1 ?"dB f Nxaxa1 ?"``dB g Nxaxa1 ?"q  B i Nxaxa1 ?"q  B w Hxaxa1 ?"qB  Hxaxa1 ?"qB  Hxaxa1 ?"qB  Hxaxa1 ?"qx x B  Hxaxa1 ?"qJ J B  Hxaxa1 ?"q  B  Hxaxa1 ?"q  { p  fp9 xaxa 1?"  gHomologies for antibody heavy chain V regions compared with human germline sequences Sorted by homology2U0UBH  0޽h ? ̙33___PPT10i.*pd=+D=' = @B +P g_@(  "  Z9 xaxa 1?"Zx DWhat of the Emperor s new clothes?## #   Z9 xaxa 1?"Zv@ Appropriate selection of sequences of antibody Constant and Variable regions is likely to be only one factor controlling the immunogenicity of therapeutic antibodies. However it is the final sequence of the antibodies which matters and not the route by which they were made. For example it is possible to come up with alternative humanised sequences for the same antibody. Similar sequences can often be found for mouse, rat and human variable regions within the databases. Even fully human antibodies may contain unusual motifs or structures as a result of the somatic recombination and junctional diversity combined with somatic hypermutation.Z}     !    H  0޽h ? ̙33___PPT10i.* +D=' = @B +}  $(  r  S x9 l  9  r  S L9 zt 9  H  0޽h ? ̙33___PPT10i.M<5Y+D=' = @B +A  XP(  r  S ,: l  :  6 t  #"```t :      f : xaxa 1?"P  a+ $   @`     f: xaxa 1?" P  a- $   @`&    f(: xaxa 1?"t  zAglycosyl IgG1     @`    f(: xaxa 1?"P @  c+++ $   @`     f 1: xaxa 1?"@P  a- $   @`   fh3: xaxa 1?"t@  h Human IgG1      @`!   `+: xaxa 1?"P @ {CD3 Transgenic (cell surface)    @`   `L: xaxa 1?"P @ wNormal Mouse (no antigen)    @`   `xG: xaxa 1?"t@ V   @`B  Txaxao ?"tB  Nxaxa1 ?"t@@B  Nxaxa1 ?"t  B  Txaxao ?"tB  Txaxao ?"ttB  Nxaxa1 ?"B  Nxaxa1 ?"P P B  Txaxao ?"H  0޽h ? ̙33___PPT10i.O<p(r+D=' = @B +G   ^V$(  $x $ c $dN: l  :   $ Z`: xaxa 1?"d @(2  $ Zc: xaxa 1?"' @(2  $ Zf: xaxa 1?"{Y >  $ Zi: xaxa 1?"P  nThe human IgG1in the CD3 transgenic mice was able to kill target cells, to activate complement, to bind to FcR and to cause cytokine release. Whereas the aglycosylated antibody was poor in these functions and produced only a weak immune response. Is this a special case or can it be generalised to other antibodies? Is it consistent with the Matzinger  Danger Hypothesis as applied to therapeutic administration of recombinant antibodies? 2Zk  ,      Y H $ 0޽h ? ̙33___PPT10i.O<p(r+D=' = @B +}  ($(  (r ( S Lz: T  :  r ( S  {: t :  H ( 0޽h ? ̙33___PPT10i.R<@+D=' = @B +o ~,(  , , rAC? ?npo00003fPicture 2"<?@@`NNN?NTX!H , 0޽h ? ̙33___PPT10i.O)@z֨+D=' = @B + % (  "  Z: xaxa 1?"ws3 Murine constant regions V-region sequences Human Ig allotypes Unusual glycosylation Method of administration Frequency of administration Dosage of antibody Patients' disease status Patients' immune status Patients' MHC haplotype Specificity of antibody Cell surface or soluble antigen? Formation of immune complexes with antigen Complement activation by antibody Fc receptor binding by antibody Inflammation and cytokine release +           ? S   ft: xaxa 1?" EFactors likely to influence immunogenicity of therapeutic antibodies  FD&   H  0޽h ? ̙33___PPT10i.* 2+D=' = @B + ` k(   "   ZX: xaxa 1?" (Will the idiotype always be immunogenic?))&    >   Zd: xaxa 1?" The idiotype will obviously always be unique and thus antigenic. However it may be possible through mode of use to influence whether this antigenic idiotype is immunogenic or tolerogenic!l* L  Z           ZԦ: xaxa 1?" Y +oTake home message to remember In immunological terms antigenicity is certainly not the same as immunogenicity!XQ @6      H   0޽h ? ̙33___PPT10i.*p+D=' = @B +rH@ QSIT'"x?pg 0\U0,,F w-JTqhY_\P_Ab2e#hknI]s< " %|u+EYQصGer Oh+'0T px    , 8DLNo Slide TitleNBST:\Office97\Templates\LW2.pottԭ.po60vMicrosoft PowerPointham@[@А~o&@I v@hWGSg  )'    """)))UUUMMMBBB999|PP3f333f3333f3ffffff3f̙3ff333f333333333f33333333f33f3ff3f3f3f3333f33̙33333f333333f3333f3ffffff3f33ff3f3f3f3fff3ffffffffff3ffff̙fff3fffff3fff333f3f3ff3ff33f̙̙3̙ff̙̙̙3f̙3f333f3333f3ffffff3f̙3f3f3f333f3333f3ffffff3f̙3f3ffffffffff!___www4'A x(xKʦ """)))UUUMMMBBB999|PP3f3333f333ff3fffff3f3f̙f3333f3333333333f3333333f3f33ff3f3f3f3333f3333333f3̙33333f333ff3ffffff3f33f3ff3f3f3ffff3fffffffff3fffffff3f̙ffff3ff333f3ff33fff33f3ff̙3f3f3333f333ff3fffff̙̙3̙f̙̙̙3f̙3f3f3333f333ff3fffff3f3f̙3ffffffffff!___wwwݼݴܻ⻻ݺܳǡDžݳϼܲϼDžϵ܁Dž۲ǡ⺳ǡ܁ϧl֡ⳳmⵧ݁fE?slDFngEFtRRmϵܳmEFLYRf%RJmF+KgoܲmnnܳⳲۼⵡ۳ǧۺ۳ǡֵ⴬⻺ܬⳬּݼݼ⼺ݵݵ¼ϧϧ»ܳϧϧ¼xxVxxpwwxxxVϘqwwwx5V5V4VVxq֡qwTvTvTwŸVV5V555VVܵvvTwTvvV.54VP4.5.4OwNUⵡNvvwNvNwß/5.5/V.5.4.UNO.օkTNwpvNvNß45455V5V4545455ݧǦvTwvvNvvx5454VVV45.545.VϡpvvwNvTwV545.55V.5.5.54VݵpvNvNvNvwx.5.54V55.5.545VDžpNvNpNvTV45454VVVV45455kvpw55454VUVx45454Vx⻦pvv.5.5.wpq.4.5.VDžǦpNx5.5.UNr4.U.5VkvwV454wwp}xݭDžǦ5545OqqVϡǡp.545NݧV45.wüυw454wϧǡqV4Vq槡x.qݧVUN˜ۻݵϧܻϧܻݵݼݵݵݵ___________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________tt՜.+,0    = On-screen Show !D HTimes New RomanSymbolArialLW2WEngineering Antibodies (1) MSc Programme University of Nottingham 14th February 2005"Antibody based immunotherapeuticsIgG is the preferred classSchematic view of IgG domains$Antibody fragments can also be used1Antibodies can be derived from immunised animalsLThe antibody immune response in-vivo can be T-cell dependent or independentWAntibody fragments can also be selected from in-vitro systems such as phage expressionrCycles of selection and mutation can give an artificial in-vitro immune response based simply on binding affinity Slide 10lThe Selection of IgG Fc Regions for appropriate effector functions: The role of isotypes and polymorphisms Slide 12 Slide 13nUnlike mouse the human IgG subclasses are very similar in sequence but they still have different properties Slide 15 Slide 16 Slide 17The IgG receptor FcRn Slide 19 Slide 20 Slide 21 Slide 22 Slide 23 Slide 24 Slide 25 Slide 26 Slide 27 Slide 28 Slide 29 Slide 30 Slide 31 Slide 32 Slide 33 Slide 34 Slide 35 Slide 36 Slide 37 Slide 38 Slide 39 Slide 40 Slide 41 Slide 42 Slide 436What of the immunogenicity of therapeutic antibodies? Bad News Good News Antigenicity and Immunogenicity Slide 48Immunogenicity Slide 50Antibody selection and design Slide 52 Slide 53 Slide 54 Slide 55 Slide 56 Slide 57 Slide 58 Slide 59 Slide 60 Slide 61 What determines immunogenicity?The effect of aglycosylation on the immunogenicity of a humanised therapeutic CD3 monoclonal antibody Routledge et al 1995 Transplantation 60, 847-853The effect of aglycosylation on the immunogenicity of a humanised therapeutic CD3 monoclonal antibody Routledge et al 1995 Transplantation 60, 847-853kElimination of the immunogenicity of therapeutic antibodies. Gilliland et al 1999 J.Immunol 162, 3663-3671 Slide 66 Slide 67 Slide 68  Fonts UsedDesign Template Slide TitlesD0_: ԭUniversity of Nottingham  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~                           ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~                           ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~                            ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~                            ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~                            ! 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