A Phase I/II Trial to Evaluate the Safety and Tolerability of Clazakizumab (Anti-IL-6 Monoclonal) As an Agent to Eliminate Donor Specific HLA Antibodies and Improve Outcomes of Patients With Chronic & Active Antibody-Mediated Rejection Post-Kidney Transplantation
Phase: PHASE1
Conditions: Antibody-mediated Rejection, Kidney Transplant; Complications, Transplant Glomerulopathy, Transplant Glomerulopathy - Late Form, Transplant Glomerulopathy - Early Form, Kidney Transplant Rejection
Sponsor: Stanley Jordan, MD

P a g e 1   
 
P R O T O C OL  
S T U D Y TI TL E:  
A P h as e I/II Tri al t o Ev al u at e t h e S af ety a n d T ol er a bility of Cl az a kiz u m a b ® ( A nti -IL-6 m o n ocl o n al ) As a n 
A g e nt t o Eli mi n at e D o n or S p ecific HL A A nti b o di es ( D S As) a n d I m pr o v e O utc o m es of P ati e nts wit h 
C hr o nic & Activ e A nti b o dy -M e di at e d R ej ecti o n (c A B M R) P ost -Ki d n e y Tr a ns pl a nt ati o n  
 
St u dy Dr u g  
Cl az a kiz u m a b  (A nti -IL-6 m o n o cl o n al) 
 
S u p p ort Pr ovi d e d By  
C SL B e hri n g L.L. C.  
1 0 2 0 First Av e n u e  
P A 1 9 4 0 6  Ki n g of Pr ussi a  
U nit e d St at es  
    
S p o ns or I nv esti g at or  
N a m e:  St a nl e y C. J or d a n, M. D.  
I nstit uti o n/ Or g a niz ati o n: C e d ars-Si n ai M e dic al C e nt er  
A d dr ess: 8 9 0 0 B ev erly Bl v d.  
L. A., C A. 9 0 0 4 8 
P h o n e: 3 1 0 -4 2 3 -8 2 8 2  
F ax: 3 1 0 -4 2 3 -8 2 0 8  
E m ail: sj or d a n @cs hs. or g 
N C T: N C T 0 3 3 8 0 3 7 7  
F D A I N D: 1 3 4 7 3 3  
 
C o -I nv esti g at or(s) a n d R es e arc h C o or di n at ors 
As hl e y V o, P h ar m. D.  
Dir ect or, Tr a ns pl a nt I m m u n ot h er a py Pr o gr a m  
I nstit uti o n/ Or g a niz ati o n: C e d ars-Si n ai M e dic al C e nt er  
A d dr ess: 8 9 0 0 B ev erly Bl v d.  
L. A., C A. 9 0 0 4 8 
P h o n e: 3 1 0 -4 2 3 -2 6 4 1  
 
N ori A m m er m a n, P h ar m D  
8 9 0 0 B ev erl y Bl v d. L. A., C A. 9 0 0 4 8 
P h o n e: 3 1 0 -2 4 8 -8 1 8 6  
 
C o or di n ati n g I nstit uti o n  
C e d ars -Si n ai M e dic al C e nt er  
8 7 0 0 B ev erl y Bl v d., L. A., C A. 9 0 0 4 8  
 
V ersi o n 9 . 0  
D ec e m b er 1 4, 2 0 2 2  
 
 

 
 
P a g e 2   
 
 
A b br e vi ati o ns  
A b br e vi ati o n  
D escri pti o n  
A b br e vi ati o n  
D escri pti o n  
A B M R  
A nti b o dy m e di at e d r ej ecti o n  
S A E  
S eri o us a dv ers e ev e nts  
PL E X  
Pl as m a p h er esis  
L F T 
Liv er f u ncti o n t est 
c A B M R  
C hr o nic activ e A B M R  
4 W  
4 w e eks  
T G  
Tr a ns pl a nt gl o m er ul o p at hy  
e G F R  
Esti m at e d Gl o m er ul ar filtr ati o n r at e  
D e K A F  
D et eri or ati o n i n Ki d n ey All o gr aft F u ncti o n ( D e K A F)  
ELI S A  
E nz y m e li n k e d i m m u n os or bti o n ass a y  
C 4 d  
C o m pl e m e nt -4 d pr ot ei n  
P C Rs  
P oly m er as e c h ai n r e acti o n  
D S As  
D o n or s p ecific a nti b o dy  
E B V  
E pst ei n b arr vir us  
HL A  
H u m a n l e u k ocyt e a nti g e n  
C M V  
C yt o m e g al ovir us  
F D A 
F o o d & Dr u g A d mi nistr ati o n  
B K V  
P oly o m a B K vir us  
IL-6  
I nt erl e u ki n-6  
C G 3  
C hr o nic gl o m er ulitis l ev el 3 (s ev er e)  
IL-6 R  
I nt erl e u ki n-6 R ec e pt or  
H B V  
H e p atitis B vir us  
A nti -IL-6 R  
A nti -i nt erl u e ki n-6 R ec e pt or  
H C V  
H e p atitis C vir us  
T r eg 
T -r e g ul at ory c ells 
RI B A  
R ec o m bi n a nt i m m u n o bl ot ass a y  
T f h 
T -f ollic ul ar c ells 
T B  
T u b erc ul osis  
I g G  
I m m u n o gl o b uli n 
W B C  
W hit e bl o o d c ell  
d n D S A  
D e n ov o D S A  
H g b  
H e m o gl o bi n  
SL E  
S yst e mic l u p us eryt h e m at os us  
S G O T  
S er u m gl ut a mic ox al o ac etic tr a ns a mi n as e  
I g A  
I m m u n o gl o b uli n A 
S G P T  
S er u m gl ut a mic -pyr uvic tr a ns a mi n as e  
C TL A 4 -I g 
C yt ot oxic T -ly m p h ocyt e-ass oc at e d pr ot ei n 4  
P TL D  
P ost -tr a ns pl a nt ly m p h o pr olif er ativ e dis or d er 
T h 1 7  
T -h el p er ty p e 1 7  
P ML  
Pr o gr essiv e M ultif oc al L e u k o e nc e p h al o p at hy  
IL-2 1  
I nt erl e u ki n 2 1 
D E S  
D es e nsitiz ati o n  
m M R 1 6 -1  
M o us e niz e d r at - a nti -m o us e IL -6 r ec e pt or m o n ocl o n al 
a nti b o dy  
A Es  
A dv ers e ev e nts  
I g M 
I m m u n ol o g u bli n M 
J C  
P oly o m a J C vir us  
B M  
B o n e m arr o w  
I V 
I ntr av e n o us 
G V H D  
Gr aft v ers us h ost dis e as e  
E X P  
Ex piry d at e  
R A  
R h u e m at oi d art hritis  
T N F  
T u m or n ecr osis f act or  
C X C R 5  
C h e m oki n e r ec e pt or ty p e 5  
UL N  
U p p er li mit of n or m al  
N H P  
N o n -h u m a n pri m at e  
L DL 
L o w d e nsity li p o pr ot ei n  
M M F  
Myc o p h e n ol at e m of etil  
C D  
Cr o h n’s dis e as e  
A T G  
A nti -t hy m ocyt e gl o b uli n 
M T X  
M et h otr ex at e  
S O C 
St a n d ar d of c ar e  
GI  
G astr oi nt esti n al  
D S A +  
D o n or s p ecific a nti b o dy p ositiv e  
m A bs  
M o n ocl o n al a nti b o di es  
D S A - 
D o n or s p ecific a nti b o dy n e g ativ e  
 
 
I VI G 
I ntr a v e n o us I m m u n o gl o b uli n 
 
 
S Q/ S C  
S u bc ut a n e o us  
 
 
C D C  
C o m pl e m e nt d e p e n d e nt cyt ot oxicity  
 
 
C NI  
C alci n e uri n i n hi bit ors  
 
 
A R  
Ac ut e r ej ecti o n  
 
 
A M R  
A nti b o dy m e di at e d r ej ecti o n  
 
 
C M R  
C ell m e di at e d r ej ecti o n  
 
 
s C R 
S er u ms cr e ati ni n e  
 
 
IL-1 0  
I nt erl e u ki n -1 0  
 
 
IL-1 7 a  
I nt erl e u ki n-1 7 a  
 
 
I F Nγ 
I nt erf er o n g a m m a  
 
 
C 1 q  
C o m pl e m e nt 1 q pr ot ei n  
 
 
HL Ai  
H u m a n l e u k ocyt e a nti g e n i nc o m p ati bl e  
 
 
I g G 1 
H u m a niz e d i m m u n ogl o b uli n G 1 a nti b o dy  
 
 
p M  
Pic o m ol ar  
 
 
sIL-6 R  
S ol u bl e i nt erl e u ki n 6 r ec e pt or  
 
 
S T A T 3 
Si g n al tr a ns d uc er a n d activ at or of tr a nscri pti o n 3  
 
 
C R P  
c-r e activ e pr ot ei n 
 
 
Ps A  
Ps ori atic art hritis  
 
 
P K   
P h ar m ac oki n etic  
 
 
P D  
P h ar m ac o dy n a mic  
 
 
p S T A T 3  
P h os p h oryl at e d Si g n al tr a ns d uc er a n d activ at or of 
tr a nscri pti o n 3 
 
 
n M  
N a n m ol ar  
 
 
e P P N D  
E n h a nc e d pr e - a n d p ost -n at al d ev el o p m e nt  
 
 
 
 
 

 
 
P a g e 3   
T a bl e of C o nt e nts  
S ecti o n  
D escri pti o n  
P a g e  
1  
B ack gr o u n d & R ati o n al e  
4  
Fi g ur e 1 A & B 
O utc o m es of p ati e nts wit h c A B M R a n d T G  
5  
1. 1  
IL-6/IL -6 R I n hi biti o n: A n I m p ort a nt N e w T h er a p e utic O pti o n f or Pr ev e nti o n & Tr e at m e nt of 
A B M R  
5  
Fi g ur e 2  
Circ ul ati n g Pl as m a bl ast Pr o d uc e C o pi o us A m o u nts of IL -6 w hic h Activ at es Tf h diff er e nti ati o n  
7  
Fi g ur e 3  
T ociliz u m a b Tr e at m e nt I n d uc es T r eg c ells i n R A p ati e nts  
7  
1. 2  
Ex p eri e nc e wit h A nti -IL 6 R i n a M o us e M o d el of All os e nsitiz ati o n  
7  
Fi g ur e 4 A & 4 B 
M o us e niz e d A nti -IL-6 R A nti b o dy i n a M o us e M o d el of All o -s e nsitiz ati o n 
8  
Fi g ur e 5  
A nti -IL 6 R Tr e at m e nt R e d uc es Tf h f or m ati o n a n d I n d uc es T-r e gs i n M o us e M o d el of 
All os e nsitiz ati o n  
9  
Fi g ur e 6 A & 6 B 
Fl o w C yt o m etry A n alysis of Bl o o d fr o m N o n h u m a n Pri m at es B ef or e a n d Aft er Tr e at m e nt wit h 
T ociliz u m a b  
9  
1. 3  
T h er a p e utic Us e of T ociliz u m a b f or Pr ev e nti o n of A nti b o d y - M e di at e d I nj ur y i n H u m a ns  
1 0  
Fi g ur e 7 A & 7 B 
O ur T ociliz u m a b Tri al D esi g n a n d I m m u n o d o mi n a nt D S A r es ults  
1 1  
1. 3. 1  
T h e Pr o bl e m: A nti b o dy M e di at e R ej ecti o n  
1 1  
Fi g ur e 8  
P at h o g e nic M ec h a nis ms f or A B M R i n R e n al All o gr af ts 
1 2  
1. 4  
Is T h er e a R ol e f or IL-6 i n M e di ati o n of A B M R  
1 2  
Fi g ur e 9  
S er u m C yt oki n e L ev els i n Ki d n ey Tr a ns pl a nt R eci pi e nts wit h N or m al Gr aft F u ncti o n a n d All o gr aft 
R ej ecti o n  
1 3  
Fi g ur e 1 0 A & 1 0 B  
IL-6 Ex pr essi o n i n Ki d n ey Tiss u e & IL -6 + C ells I ncr e as e i n All o gr afts wit h A B M R 
1 4  
1. 4. 1  
I m p act of D S As o n L o n g-T er m All o gr aft S urviv al  
1 4  
Fi g ur e 1 1 A & 1 1 B  
I m p act of D S As o n L o n g T er m All o gr aft S urviv al a n d M ec h a nis ms of All o gr aft I nj ury 
1 4  
Fi g ur e 1 2 A & 1 2 B,  
C e d ars -Si n ai L o n g -t er m O utc o m es 
 
1 6  
T a bl e 1  
T a bl e 1: C h ar act eristics pr e dis p osi n g t o A B M R  
1 7  
1. 4. 2  
Pr eli mi n ary D at a o n Us e of T ociliz u m a b f or Tr e at m e nt of A B M R i n H u m a ns  
1 8  
Fi g ur e 1 3 A -E  
O utc o m es of T ociliz u m a b P ati e nts Tr e at e d f or c A B M R a n d T G  
1 9  
2  
Cl az a kiz u m a b ( a nti -IL 6) as a P ot e nti al A g e nt t o Tr e at c A B M R a n d T G  
1 9  
3  
Pri m ary O bj ectiv es  
2 2  
3. 1  
M aj or S ec o n d ary O bj ectiv es  
2 2  
3. 2  
I ncl usi o n Crit eri a 
2 2  
3. 3  
Excl usi o n Crit eri a  
2 2  
4  
St u dy D esi g n & M et h o ds  
2 3  
Fi g ur e 1 4  
Cl az a kiz u m a b D osi n g Pr ot oc ol f or c A B M R + T G  
2 5  
4. 1  
St u dy A n alysis  
2 5  
4. 2  
D efi ni n g A B M R  
2 5  
4. 3  
Tr e at m e nt of All o gr aft R ej ecti o n E pis o d es D uri n g t h e St u dy  
2 5  
4. 4  
M o nit ori n g f or A E/ S A Es P ost -Tr a ns pl a nt i n H S P ati e nts  
2 6  
Fi g ur e 1 5 A & 1 5 B  
Pr o p orti o n of Ki d n ey Tr a ns pl a nt R eci pi e nts w h o D ev el o p e d I nf ecti o ns P ost -Tr a ns pl a nt  
2 6  
Fi g ur e 1 6  
Vir al P C R P ositivity f or C M V, E B V, a n d P oly o m a B K Vir us i n D es e nsitiz e d vs St a n d ar d Ki d n ey 
R eci pi e nts  
2 7  
4. 5  
S af ety R e p orti n g of A dv ers e E v e nts  
2 7  
4. 5. 1  
R e p orti n g of S eri o us A dv ers e E v e nts Ass oci at e d wit h Cl az a kiz u m a b  
2 8  
4. 6  
I nf ecti o n Pr o p h yl axis Pr ot oc ols a n d Vir al M o nit ori n g P ost-Tr a ns pl a nt  
3 1  
5  
D osi n g of Cl az a kiz u m a b  
3 1  
5. 1  
St or a g e a n d H a n dli n g  
3 2  
5. 1. 1  
Cl az a kiz u m a b Ov er d os a g e  
3 2  
5. 2  
D os e M o dific ati o n/ T oxicity M a n a g e m e nt  
3 2  
5. 3  
A dv ers e Dr u g R e acti o ns  
3 2  
T a bl e 2  
N e utr o p e ni a Ris k Miti g ati o n  
3 0  
T a bl e 3  
T hr o m b ocyt o p e ni a Ris k Miti g ati o n  
3 4  
T a bl e 4  
El ev at e d Liv er E nz y m es a n d H e p atic Ev e nts  
3 4  
6  
T h er a py St o p pi n g P oi nts  
3 7  
7  
St atistic al A n alysis  
3 7  
8  
R ef er e nc es  
3 9  
A p p e n dix A  
A B M R Visit Sc h e d ul e  
4 2  
A p p e n dix B  
S e n d o ut L a bs  
4 3  
A p p e n dix C  
D S M B C h art er  
4 3  
A p p e n dix D  
S af ety R e p orti n g F or ms  
4 3  

 
 
P a g e 4   
 
1. 0 B ac k gr o u n d & R ati o n al e  
A nti b o dy -m e di at e d r ej ecti o n ( A B M R) is a u ni q u e, si g nific a nt a n d oft e n s e v er e f or m of all o gr aft r ej ecti o n. A B M R is 
c h ar act eriz e d by s e v er al p at h ol o gic v ari a nts t h at ar e oft e n r esist a nt t o tr e at m e nt wit h st a n d ar d i m m u n os u p pr essi v e 
m e dic ati o ns. Si g nific a nt a d v a nc es h a v e occ urr e d i n o ur a bilit y t o pr e dict p ati e nts at ris k f or a n d t o di a g n os e A B M R 1, 2.  
T h e p at h o p hysi ol o gy of A B M R s u g g ests a pri m e r ol e f or a nti b o di es, B -c ells a n d pl as m a c ells. As a r es ult, I VI G, rit uxi m a b, 
a n d/ or pl as m a p h er esis ( PL E X) h av e b e e n l ev er a g e d f or t h e tr e at m e nt of ac ut e A B M R 3- 7.  D es pit e t h e s ucc ess of t h es e 
t h er a pi es, p ost-tr a ns pl a nt A B M R, c hr o nic activ e A B M R (c A B M R), a n d tr a ns pl a nt gl o m er ul o p at hy ( T G) r e m ai n si g nific a nt 
pr o bl e ms t h at ar e o ft e n u nr es p o nsiv e t o c urr e nt t h er a pi es4. D at a fr o m t h e D et eri or ati o n i n Ki d n ey All o gr aft F u ncti o n 
( D e K A F) st u dy s h o w t h at m ost gr aft l oss es i n t h e c urr e nt er a of i m m u n os u p pr essi o n h a v e evi d e nc e of c A B M R wit h 
p ositiv e C 4 d st ai ni n g 2, 8. It is esti m at e d t h at 5, 0 0 0 r e n al all o gr afts ar e l ost e ac h y e ar i n t h e U S, pri m arily fr o m c A B M R a n d 
T G 9. T h e c urr e nt tr e at m e nt p ar a di g ms r el y o n r e d ucti o n of a nti b o dy l e v els t o pr e v e nt A B M R. T his r ais es t h e i m p ort anc e 
of m ai nt ai ni n g i m m u n os u p pr essi o n a n d i nv esti g ati n g n o v el m et h o ds t o pr ev e nt a n d tr e at A B M R/c A B M R t h at dir ectly 
a d dr ess t h e r e d ucti o n of d o n or s p ecific a nti b o di es ( D S As ) a n d a nti b o dy pr o d uci n g c ells.  
 
A B M R is fr e q u e ntly s e e n i n p ati e nts r ec eivi n g i n a d e q u at e i m m u n os u p pr essi o n or w h o ar e n o nc o m pli a nt wit h a nti -
r ej ecti o n m e dic ati o ns a n d t h os e w h o r ec ei v e h u m a n le u k ocyt e a nti g e n ( HL A) -i nc o m p ati bl e tr a ns pl a nts.  I n a d diti o n, T G 
is a k n o w n c o ns e q u e nc e of p ersist e nt D S A p ositivity w hic h r a pi dl y dissi p at es all o gr aft f u ncti o n, r es ulti n g i n gr aft f ail ur e 
a n d r et ur n t o di al ysis wit h att e n d a nt e m oti o n al c o ns e q u e nc es f or t h e p ati e nts a n d fi n a nci al c o ns e q u e nc es f or t h e h e alt h 
c ar e syst e m 1 0 -1 4. N o c urr e nt t h er a py is F D A a p pr ov e d a n d p ati e nts ar e oft e n tr e at e d wit h c o m bi n ati o n t h er a pi es t h at 
m a k e a n al ysis of  effic ac y diffic ult. T h us, t h er e is a l ar g e u n m et cli nic al n e e d. T o t his e n d, it is i m p er ativ e t h at n ov el 
t h er a pi es t o pr e v e nt i m m u n ol o gic i nj ury t o t h e micr ocirc ul ati o n b e d e v el o p e d a n d st u di e d i n p ati e nts wit h c A B M R a n d 
T G. 
 
I nt erl e u ki n-6 is a k e y c yt oki n e w hic h r e g ul at es i nfl a m m ati o n a n d t h e d ev el o p m e nt, m at ur ati o n, a n d activ ati o n of T -c ells, 
B- c ells a n d pl as m a c ells 1 5.  Exc essiv e IL-6 pr o d ucti o n h as b e e n li n k e d t o a n u m b er of h u m a n dis e as es c h ar act eriz e d b y 
u nr e g ul at e d a nti b o dy pr o d ucti o n a n d a ut oi m m u nity 1 5, 1 6.  W e h a v e s h o w n IL-6/IL -6 R i nt er acti o ns ar e critic al f or 
all o a nti b o dy g e n er ati o n i n a n a ni m al m o d el of all oi m m u nit y 1 7. Bl ock a d e of t h es e i nt er acti o ns wit h a n a nti-IL-6 R 
m o n ocl o n al r es ults i n si g nific a nt r e d ucti o ns of all o a nti b o di es, a nti b o dy pr o d ucti o n by s pl e nic a n d b o n e m arr o w pl as m a 
c ells, dir ect i n hi biti o n of pl as m a c ell a nti -HL A a nti b o dy pr o d ucti o n a n d i n d ucti o n of T r e g c ells wit h i n hi biti o n of T-f ollic ul ar 
( Tf h) c ells. T h us, IL-6 s h a p es T -c ell i m m u nit y a n d is a p o w erf ul sti m ul a nt f or p at h o g e nic I g G pr o d ucti o n 1 8, 1 9. 
 
T his r ais es t h e i m p ort a nc e of m ai nt ai ni n g i m m u n os u p pr essi o n a n d i nv esti g ati n g n o v el m et h o ds t o pr ev e n t a n d tr e at 
a nti b o dy -m e di at e d i nj ur y  t h at dir ectly a d dr ess t h e r e d ucti o n of D S As a n d a nti b o dy pr o d uci n g c ells. 
 
 
B as e d o n t h es e o bs erv ati o ns, w e f e el t h er e is a l ar g e u n m et cli nic al n e e d f or n e w t h er a pi es t o pr ev e nt a n d tr e at A B M R.  
T his is als o tr u e f or cA B M R a n d T G  t h at ar e n o w l e a di n g c a us es of c hr o nic all o gr aft f ail ur e. D es pit e o ur b est eff orts, w e 
still a ntici p at e a n A B M R r at e of a p pr oxi m at el y 2 5-4 0 % i n d es e nsitiz e d p ati e nts.  Fr o m o ur ex p eri e nc e, 8 0 % of t h es e 
e pis o d es occ ur i n t h e first 1 -3 m o nt hs p os t-tr a ns pl a nt a n d c a n si g nific a ntl y i m p act l o n g-t er m p ati e nt a n d gr aft s ur viv al. 
C urr e nt esti m at es of d e n ov o D S A ( d n D S A) i n d uc e d A B M R s u g g est a p pr oxi m at ely 3 0 % of ki d n e y tr a ns pl a nt p ati e nts ar e 
at ris k f or d e v el o p m e nt of A B M R, c A B M R a n d T G. T h us t h e sc o p e of a nti b o dy -i n d uc e d i nj ur y i n t h e tr a ns pl a nt p o p ul ati o n 
is si g nific a nt a n d gr o wi n g9.  
 
R ec e nt d at a i n dic at e t h at l o n g -t er m o utc o m es of p ati e nts wit h c A B M R a n d T G ar e v er y p o or2 0, 2 1. R e dfi el d et al ev al u at e d 
gr aft s urviv al i n 1 2 3 p ati e nts wit h c A B M R. O nc e c A B M R w as di a g n os e d, 7 6 p ati e nts l ost t h eir all o gr afts wit h a m e di a n 
gr aft s urviv al of 1. 9 y e ars 2 0. I n a d diti o n, t h e gr aft s ur viv als at 2 y e ars f or p ati e nts wit h c A B M R wit h o ut tr e at m e nt w as 
~ 2 0 % 2 0, 2 1.  D at a fr o m t his st u dy is s h o w n i n Fi g ur e 1 A & B b el o w:  
 
 
Fi g ur e 1 A   
  
  
  
 
Fi g ur e 1 B  

 
 
P a g e 5   
 
 
 
1. 1  IL-6/IL -6 R I n hi biti o n : A n I m p ort a nt N e w T h era p e utic O pti o n f or Pr ev e nti o n & Tr e at m e nt of A B M R  
 
I nt erl e u ki n-6 is a n i m p ort a nt m e di at or of i nfl a m m ati o n  a n d t h e d ev el o p m e nt, m at ur ati o n, a n d activ ati o n  of T -c ells, B-c ells 
a n d pl as m a c ells 2 2, 2 3.  Exc essi v e IL - 6 pr o d ucti o n h as b e e n li n k e d t o a n u m b er of h u m a n dis e as es  c h ar act eriz e d by exc essiv e 
a n d u nr e g ul at e d a nti b o dy pr o d ucti o n  a n d a ut oi m m u nit y 1 5, 1 6.  D at a ar e acc u m ul ati n g o n t h e i m p ort a nc e of i n hi biti n g IL -
6/IL -6 R i nt er acti o ns i n tr e at m e nt of a ut oi m m u n e dis e a s e a n d tr a ns pl a nt ati o n usi n g t h e a nti-IL-6 R m o n ocl o n al t ociliz u m a b.  
T ociliz u m a b ( Act e mr a ®, R oc h e/ G e n e nt ec h, S o ut h S a n Fr a ncisc o, C A, U S A) is t h e first i n cl ass h u m a niz e d m o n ocl o n al 
ai m e d at t h e IL -6 r ec e pt or (IL -6 R). T ociliz u m a b bi n ds t o b ot h s ol u bl e a n d m e m br a n e b o u n d f or ms of t h e IL -6 R r ec e pt or. 
T ociliz u m a b w as r ec e ntl y a p pr o v e d by t h e F D A f or tr e at m e nt of r h e u m at oi d art hritis a n d j uv e nil e i di o p at hic art hritis. 
Si nc e t h e i ntr o d ucti o n of t h e dr u g, ot h er r e p orts i n dic at e t h at i n hi biti o n of t h e IL -6/IL -6 R p a t h w ay m a y h av e si g nific a nt 
b e n efits i n SL E a n d ot h er v asc ulitic dis or d ers a n d r e d uc es a nti b o dy pr o d uci n g c ells i n tr e at e d p ati e nts. R ec e nt r e p orts 
d e m o nstr at e d a si g nific a nt r e d ucti o n i n a nti -ds -D N A a nti b o di es a n d circ ul ati n g pl as m a c ells i n SL E p ati e nts t r e at e d wit h 
t ociliz u m a b2 4, 2 5.  T ociliz u m a b tr e at m e nt c a n als o r es ult i n a r e d ucti o n of p eri p h er al pr e - a n d p ost -s witc h m e m ory B c ells 
i n r h e u m at oi d art hritis p ati e nts. T h es e p ati e nts als o s h o w e d si g nific a nt r e d ucti o ns i n I g G + a n d I g A + B c ells a n d r e d ucti o n 
i n s er u m l e v els of I g G a n d I g A. T h us, B-c ell hy p er-r e acti vit y is si g nific a ntly i m p act e d i n h u m a ns tr e at e d wit h t ociliz u m a b 
2 4 . 
R e p orts h av e s h o w n t h at t ociliz u m a b als o r e d uc es  a nti b o dy -pr o d uci n g c ells, di mi nis h es i nfl a m m at ory m ar k ers,  a n d 
i m pr ov es cli nic al sy m pt o m at ol o gy i n a n u m b er of ot h er a ut oi m m u n e dis e as es 1 5, 1 6, 2 6, 2 7. R ec e nt cli nic al o bs erv ati o ns a n d 
a ni m al m o d els h av e  s h o w n t h at IL-6 m ay b e i m p ort a nt i n m e di ati o n of all o gr aft  r ej ecti o n. IL-6 pr o d ucti o n i ncr e as es i n 
m o us e all o gr afts  u n d e r g oi n g r ej ecti o n a n d is r es p o nsi bl e f or all o g e n eic T-c ell i nfiltr ati o n2 2. I n a d diti o n, IL-6 d efic i e nc y, i n 
c o m bi n ati o n wit h c osti m ul at ory p at h w ay bl oc k a g e by C TL A 4 -I g i n d uc es gr aft acc e pt a nc e2 8. It is acc e pt e d t h at IL- 6 dri v es 
C D 4 T -c ells t o w ar d T-h el p er t y p e 1 7 ( T h 1 7) p h e n ot y p e  w hil e n e g ati n g r e g ul at or y T -c ell diff er e nti ati o n 1 5, 2 4. N e utr aliz ati o n 
of IL -6 r e d uc es all o gr aft r ej ecti o n by all o wi n g  e m er g e nc e of r e g ul at or y T c ells ( Tr e g)2 2. R ec e nt e vi d e nc e als o i n dic at es t h at 
IL-6 tri g g ers IL -2 1 pr o d ucti o n by f ollic ul ar T -h el p er c ells ( Tf h) dri vi n g B c ell m at ur ati o n t o pl as m a c ells d uri n g a nti b o dy 
r es p o ns es2 9, 3 0. A nti- IL-6 R a nti b o di es h av e  s h o w n si g nific a nt r e d ucti o n i n gr aft-v ers us -h ost dis e as e a n d  all o gr aft r ej ecti o n 
i n a ni m al m o d els ass oci at e d wit h i ncr e as e d Tr e g diff er e nti ati o n 3 1, 3 2. W e h a v e pr evi o usly r e p ort e d o n t h e utilit y of a  
m o us e niz e d r at - a nti -m o us e IL -6 r ec e pt or m o n ocl o n al a nti b o dy  (cl o n e m M R 1 6-1) i n a m o us e m o d el of HL A. A 2 
Fi g ur e 1 A & B: O ut c o m e s of p ati e nt s wit h c A B M R a n d T G ar e s h o w n. Fi g ur e 1 A s h o w s o ut c o m e s f or all 1 2 3 
p ati e nt s. B y 1. 9 y e ar s p o st -c A B M R di a g n o si s, ~ 5 0 % of gr aft s w er e l o st. Fi g ur e 1 B s h o w s t h at c urr e nt 
t h er a pi e s u si n g I VI G + st er oi d s +/- rit u xi m a b ar e a s s o ciat e d wit h i m pr o v e d o ut c o m e s at 2 y e ar s ( ~ 5 0 % 
s ur vi v al) c o m p ar e d t o 2 0 % wit h n o tr e at m e nt. T h e s e d at a i n di c at e t h e p o or pr o g n o si s s e e n wit h c A B M R 
+ T G t h at c urr e ntl y h a s n o g o o d t h er a pi e s.  

 
 
P a g e 6   
s e nsitiz ati o n 2 2. T h e st u dy f o u n d t h at a nti- IL-6 R tr e at m e nt  att e n u at es d e n ov o D S A, i ncl u di n g b ot h i m m u n o gl o b uli n  (I g) M 
a n d I g G r es p o ns es. W e d esi g n e d ex p eri m e nts t o i nv esti g at e  t h e a bility of a nti-IL-6 R t o m o dif y a nti b o dy r ec all  r es p o ns es t o 
all o a nti g e n w hic h mi mics t h e m ost r el ev a nt  cli nic al sc e n ari o of hi g hl y s e nsitiz e d p ati e n ts. W e hy p ot h esiz e t h at a nti- IL-6 R 
s u p pr ess es d o n or-s p ecific I g G r es p o ns e by bl ocki n g IL -6 si g n ali n g i n pl as m a c ells, w hic h is critic al f o r t er mi n al 
diff er e nti ati o n of m e m ory B c ells t o pl as m a bl asts a n d  f or s urvi v al of l o n g-li v e d pl as m a c ells i n t h e b o n e m arr o w ( B M)2 9. 
R ec e nt d at a 2 9 als o s u g g ests t h at IL -6 pr o d ucti o n by a nti g e n -acti v at e d pl as m a bl ast is r es p o nsi bl e f or T f h c ell d ev el o p m e nt 
a n d g er mi n al c e nt er f or m ati o n. T his d at a w as o bt ai n e d i n h u m a ns.  I n d e e d, w h e n p ati e nts wit h r h e u m at oi d art hritis w er e 
ex a mi n e d, circ ul ati n g T f h a n d pl as m a bl ast n u m b ers w er e el ev at e d i n p ati e nts  wit h acti v e dis e as e. Tr e at m e nt wit h 
t ociliz u m a b si g nific a ntl y r e d uc e d T f h c ell n u m b ers, IL-2 1 pr o d ucti o n by T f h a n d circ ul ati n g pl as m a bl ast ( s e e Fi g ur e 2). Ot h er 
r ec e nt d at a als o s h o w t h at t ociliz u m a b i n d uc es si g nific a nt i ncr e as es i n T r e g c ells i n p ati e nts wit h r h e u m at oi d art hritis. T his 
als o c orr e l at e d wit h r es p o ns es t o t h er a py 3 0. T h es e fi n di n gs h a v e  p ot e nti all y i m p ort a nt i m plic at i o ns i n pr ev e nti o n a n d 
tr e at m e nt of all o gr aft r ej ecti o n i n h u m a ns. 
C urr e ntl y, t h er e ar e t w o tri als of t ociliz u m a b f or G V H D i n h u m a ns. I n a d diti o n, w e h a v e c o m pl et e d  a tri al of t ociliz u m a b 
as a d es e nsitiz ati o n a g e nt f or H S p ati e nts a w aiti n g r e n al tr a ns pl a nt ati o n a n d w h o h a d f ail e d d es e nsitiz ati o n wit h I VI g + 
rit uxi m a b. T his st u dy is a P h as e I/II st u dy ( N C T 0 1 5 9 4 4 2 4) t h at is o p e n l a b el. D at a o n t his tri al w er e r ec e ntl y r e p ort e d3 3. I n 
t his tri al, w e f o u n d th at t ociliz u m a b i m pr o v e d r e n al tr a ns pl a nt r at es i n p ati e nts w h o h a d f ail e d d es e nsitiz ati o n wit h I VI G 
+ rit uxi m a b +/ - pl as m a  exc h a n g e ( PL E X). D o n or s p ecific a nti b o di es ( D S As) t h at w er e r esist a nt t o ot h er t h er a pi es w er e 
si g nific a ntl y r e d uc e d wit h t h er a py a n d n o n e of t h e tr a ns pl a nt e d p ati e nts s h o w e d a nti b o dy m e di at e d r ej ecti o n p ost 
tr a ns pl a nt.  
Fi g ur e  2: Circ ul ati n g Pl as m a bl ast Pr o d uc e C o pi o us A m o u nts of IL-6 w hic h Activ at es T f h Diff er e nti ati o n  
 
Fi g ur e 2: T h e fi g ur e s h o ws t h at h e alt hy i n di vi d u als h av e l o w l ev els of circ ul ati n g Tf h c ells, b ut R A p ati e nts ex pr ess hi g h er 
l e v els wit h dis e as e. Tr e at m e nt wit h t ociliz u m a b r es ults i n a dr a m atic r e d ucti o n i n Tf h c ells, IL-2 1 pr o d ucti o n by T f h c ells 
a n d circ ul ati n g pl as m a bl ast.  T h e a ut h ors c o ncl u d e t h at i n hi biti o n o f IL-6/Il -6 R i nt er acti o ns will li k ely r e d uc e T f h 
f or m ati o n a n d r e d uc e g er mi n al c e nt er f or m ati o n wit h s u bs e q u e nt r e d ucti o ns i n p at h o g e nic a nti b o dy pr o d ucti o n. T h e 
a ut h ors als o d e m o nstr at e d t h at circ ul ati n g pl as m a bl ast pr o d uc e d c o pi o us a m o u nts of IL -6 a n d w a s li k ely r es p o nsi bl e f or 
a d diti o n al T f h c ell activ ati o n a n d g er mi n al c e nt er f or m ati o n. Tr e at m e nt wit h t ociliz u m a b r es ult e d i n a dr a m atic r e d ucti o n 
i n circ ul ati n g pl as m a bl ast a n d IL-6 pr o d ucti o n 2 9.  
Fi g ur e 3: T ociliz u m a b tr e at m e nt i n d uc es T r e g c ells i n R A p ati e nts a n d is ass oci at e d wit h r e missi o n  of acti v e dis e as e. N ot e, 
T r e g c ells aris e aft er s ev er al m o nt hs of t h er a py.  

 
 
P a g e 7   
 
 
1. 2  Ex p eri e nc e wit h A nti -IL-6 R i n a M o us e M o d el of All o -S e nsitiz ati o n.  
 
R ec e nt d at a fr o m o ur gr o u p 2 2 i nv esti g at e d t h e a bilit y of a nti-IL-6 R t o m o dif y i m m u n e r es p o ns es t o HL A -2 tr a ns g e nic s ki n 
gr afts. W e i nv esti g at e d t h e a bilit y t o m o dif y circ ul ati n g a nti -HL A -A 2 a nti b o dy l e v els ( D S A), pl as m a c ell r es p o ns es i n t h e 
b o n e m arr o w a n d s pl e e n of s e nsitiz e d a ni m a ls a n d t h e a bilit y t o m o dify T-c ell s u bs ets. T h e d at a ar e s h o w n b el o w: 
  
Fi g ur e 4 A & 4 B: T his fi g ur e s h o ws d at a fr o m o ur gr o u p usi n g a m o us e niz e d a nit -IL-6 R a nti b o dy i n a m o us e m o d el of all o -
s e nsitiz ati o n 2 2. Bri efl y, aft er s e nsitiz ati o n, w e c a n d et ect a nti-HL A -A 2 a nti b o di es i n s er a of a ni m als. A nti -IL-6 R 
si g nific a ntl y r e d uc es circ ul ati n g l e v els of a nti-HL A -A 2 a nti b o di es. I n a d diti o n, as s h o w n h er e, t h er e is a si g nific a nt 
r e d ucti o n of a nti b o dy pr o d uci n g pl as m a c ells is ol at e d fr o m t h e b o n e m arr o w a n d s pl e e ns of s e nsitiz e d a ni m als ( 4A). 
M or e i m p ort a ntl y, pl as m a c ells pr o d uci n g a nti -HL A -A 2 a nti b o dy i n t h e b o n e m arr o w ar e i n hi bit e d by a nti -IL-6 t h er a py 
( 4B). A d diti o n of a nti -IL-6 tr e at m e nt of c o n diti o n e d m e di a of b o n e m arr o w pl as m a c ells fr o m u ntr e at e d s e nsitiz e d 
a ni m als als o si g nific a ntly r e d uc e d a nti -HL A -A 2 a nti b o dy pr o d ucti o n.  
 
S u bs e q u e nt s t u di es s u g g est t h at a nti-IL-6 R tr e at m e nt is m or e eff ecti v e t h a n a m o us e a nti -m o us e a nti -C D 2 0 i n r e d uci n g 
r e b o u n d a nti-HL A -A 2 a nti b o di es aft er r e -ex p os ur e t o HL A -A 2 + s ki n gr afts 9 0 d ays aft er 1 st ex p os ur e. T his si m ul at es t h e 
s e nsitiz ati o n sit u ati o n w e s e e n i n h u m a ns w h o h a v e hi g hl y all o-r e activ e T & B-c ells at t h e ti m e t h ey pr es e nt f or 
d es e nsitiz ati o n.  

 
 
P a g e 8   
  
 
 
 
Fi g ur e 5: T his fi g ur e s h o ws t h at i n a d diti o n t o t h e a bilit y of a nti -IL-6 R tr e at m e nt t o r e d uc e pl as m a c ell  I g G a n d a nti-HL A -
A 2 pr o d ucti o n , t h er e ar e si g nific a nt alt er ati o ns i n t h e c ell ul ar c o m p art m e nts as w ell. First, a nti-IL- 6R tr e at m e nt of 
s e nsitiz e d a ni m als is ass oci at e d wit h a d evi ati o n of T-c ell s u bs ets t o a T r e g pr ofil e. T his is ass oci at e d wit h a si g nifi c a nt 
r e d ucti o n i n t h e Tf h m ark ers (IL -2 1 a n d C X C R 5 ). T his d at a s u g g ests t h at a nti-IL-6 R t h er a py m o difi es T -c ell r es p o ns es t o 
all o -a nti g e ns r es ulti n g i n a di mi n uti o n of i nfl a m m at ory T -c ell r es p o ns es a n d li k ely r e d ucti o n i n T f h i n d uc e d g er mi n al 
c e nt er f or m ati o n2 2.  
 
Fi g ur e 5  

 
 
P a g e 9   
 
 
 
I n a d diti o n, r ec e nt d at a fr o m a n o n-h u m a n pri m at e ( N H P) m o d el of l u n g tr a ns pl a nt ati o n s u g g ests t h at t ociliz u m a b is 
critic al f or l o n g-t er m r ej ecti o n-fr e e s ur viv al. T ociliz u m a b tr e at m e nt w as ass oci at e d wit h a n i ncr e as e i n Tr e g c ells a n d 
i n hi biti o n of D S A g e ner ati o n p ost -tr a ns pl a nt3 4. Of i nt er est i n t his m o d el is t h e i m p ort a nc e of T-c ell d e pl eti o n at 
tr a ns pl a nt t o m axi miz e t h e i n d ucti o n of Tr e gs by t ociliz u m a b. T his is als o si mil ar t o t h e pr ot oc ol w e us e d p ost -tr a ns pl a nt 
i n o ur hi g hl y-HL A s e nsitiz e d p ati e nts r ec eivi n g d es e nsitiz ati o n wit h I VI G + t ociliz u m a b w h er e w e s a w r a pi d r e d ucti o ns of 
D S As a n d n o evi d e nc e of A B M R o n pr ot oc ol bi o psi es p erf or m e d at 6 m o nt hs 3 5. D at a ar e s h o w n i n Fi g ur e 6 A & 6 B b el o w.  
 
 

 
 
P a g e 1 0   
 
Fi g ur e 6 A & 6 B: Fi g ur e 6 A s h o ws t h e fl o w c yt o m etr y a n al ysis of bl o o d fr o m n o n h u m a n pri m at es b ef or e a n d aft er 
tr e at m e nt wit h t ociliz u m a b. Bri efl y, t ociliz u m a b tr e at m e nt r es ults i n a dr a m atic i ncr e as e i n T r e g c ells i n t h e circ ul ati o n of 
t he N H P a ni m als. Fi g ur e 6 B s h o ws t h e r es ults of l u n g tr a ns pl a nt ati o n i n N H P w h o r ec eiv e d st a n d ar d tr e at m e nt wit h 
t acr oli m us + st er oi ds + M M F  ( S O C), A T G + S O C a n d A T G + t ociliz u m a b + S O C. Bri efl y, a ni m als tr e at e d wit h S O C h a d all 
l ost t h eir gr afts by 1 0 0 d ays wit h 2 0 % s urvi v al at 6 0 d a ys. All a ni m als w er e als o D S A +. T h os e r ec ei vi n g A T G + S O C h a d 
6 0 % s urviv al at 1 2 0 d a ys a n d w er e als o D S A +. H o w ev er, t h os e t h at r ec ei v e d A T G + t ociliz u m a b + S O C h a d 1 0 0 % s urvi v al 
at 1 2 0 + d a ys a n d w er e D S A -. W e als o k n o w fr o m t his u n p u blis h e d d at a t h at t h e a ni m als r ec eivi n g b ot h A T G + 
t ociliz u m a b h a d si g nific a ntly gr e at er i ncr e as es i n Tr e g c ells c o m p ar e d t o  us e of eit h er a g e nt al o n e. T h us t h e i ncr e as e i n 
T r e g is li k el y r es p o nsi bl e f or t h e i m pr ov e d gr aft s ur viv al a n d l ac k of D S A d ev el o p m e nt p ost-tr a ns pl a nt. 
 
1. 3   T h er a p e utic Us e of T ociliz u m a b  f or Pr e v e nti o n of A nti b o dy- M e di at e d I nj ur y  i n H u m a ns 
 
As m e nti o n e d a b ov e, all o a nti b o di es ar e a m aj or d et err e nt t o acc ess t o a n d s ucc ess of lif e -s avi n g or g a n tr a ns pl a nts. 
D es pit e a dv a nc e m e nts i n d es e nsitiz ati o n, d esi g ni n g effici e nt a n d eff ectiv e m e a ns of r e m ov al of p at h o g e nic HL A 
a nti b o di es r e m ai ns a si g nific a nt m e dic al c h all e n g e.  Pr eli mi n ary d at a s u g g ests t h at t ociliz u m a b ex hi bits a br o a d r a n g e of 
i m m u n o m o d ul at or y acti o ns t h at c o ul d a d dr ess t h e all o-a nti b o dy r es p o ns e t o all o gr afts t h at ar e s o d estr uctiv e.  
 
W e r ec e ntly c o m pl et e d a tri al ass essi n g t h e a bility of t ociliz u m a b  t o m o dif y all o a nti b o dy r es p o ns es a n d i m pr o v e 
tr a ns pl a nt r at es i n hi g hl y -HL A s e nsitiz e d p ati e nts wit h e n d -st a g e r e n al dis e as e ( E S R D) w h o h a d f aile d d es e nsitiz ati o n 
wit h I VI G + rit uxi m a b +/ - PL E X 3 3. D at a fr o m t his st u dy ar e s h o w n b el o w i n Fi g ur e 7 A & 7B. 
 
T his fi g ur e s u m m ariz es d at a fr o m a r ec e ntl y c o m pl et e d o p e n l a b el e d P h as e I/II cli nic al tri al of t ociliz u m a b i n hi g hl y-HL A 
s e nsitiz e d p ati e nts a w aiti n g ki d n e y tr a ns pl a nts. All p ati e nts h a d h a d pr e vi o us r e n al tr a ns pl a nts a n d w er e r esist a nt t o 
d es e nsitiz ati o n  wit h I VI G + rit uxi m a b +/ - PL E X. T e n p ati e nts w er e e nt er e d a n d six tr a ns pl a nt e d d uri n g t h e st u dy. T w o of 
t h e n o n-tr a ns pl a nt e d p ati e nts w er e wit h dr a w n fr o m t h e st u dy d u e t o n o n-c o m pli a nc e wit h t h e pr ot oc ol. T h us, six of 
ei g ht p ati e nts r e m ai ni n g i n t h e st u dy  r ec ei v e d tr a ns pl a nts.  T h e fi g ur es a b o v e s h o w t h e c o urs e of D S As b ef or e t h er a py 
wit h t ociliz u m a b, at tr a ns pl a nt a n d 1 2 m o nt hs l at er. As c a n b e s e e n, si g nific a nt r e d ucti o ns i n i m m u n o d o mi n a nt D S As 
w as s e e n i n all tr a ns pl a nt e d p ati e nts. T his w as m ost si g n ific a nt at 1 2 M p ost-tr a ns pl a nt. It is i m p ort a nt t o n ot e t h at all 
p ati e nts r ec eiv e d a n a d diti o n al 6 m o nt hl y d os es of t ociliz u m a b aft er tr a ns pl a nt. Pr ot oc ol bi o psi es at 6 M s h o w e d n o 
e vi d e nc e of r ej ecti o n i n a ny p ati e nt. T h e pr ot oc ol d esi g n a n d r es ults ar e s h o w n b el o w: 

 
 
P a g e 1 1   
 
Fi g ur e 7 A & 7 B:  O ur ori gi n al tri al d esi g n f or d es e nsitiz ati o n of hi g hl y -HL A s e nsitiz e d E S R D p ati e nts usi n g t ociliz u m a b is 
s h o w n. Bri efl y, p ati e nts e nt er e d i nt o t his st u dy r ec eiv e d d es e nsitiz ati o n wit h I VI G + t ociliz u m a b f or u p t o 6 m o nt hs. I f 
r e n al tr a ns pl a nt ati o n w as acc o m plis h e d, p ati e nts r ec eiv e d a n a d diti o n al 6 M of t ociliz u m a b aft er initi al i n d ucti o n wit h 
al e mt uz u m a b  3 0 m g/ S Q a n d I VI G p ost -tr a ns pl a nt. D S As a n d ot h er i m m u n e p ar a m et ers w er e m e as ur e d. I m p ort a ntly, 
D S As pr es e nt pr e -tr a ns pl a nt w er e r e d uc e d by t ociliz u m a b + I VI G tr e at m e nt. P ost-tr a ns pl a nt t ociliz u m a b r es ult e d i n a 
m ar k e d r e d ucti o n i n D S As t h at w er e a n alyz e d  at 6 M a n d 1 2 M p ost -tr a ns pl a nt ( Fi g ur e 7 B). Bi o psi es p erf or m e d at 6 M 
p ost -tr a ns pl a nt s h o w e d n o p ati e nts h a d A B M R, T G or c A B M R. T h es e r es ults ar e si mil ar t o t h at r e p ort e d i n t h e N H P 
m o d els a b o v e si nc e T -c ell d e pl eti o n + t ociliz u m a b + S O C w as us e d p ost -tr a nspl a nt.  
 
 
1. 3. 1 T h e Pr o bl e m: A nti b o dy M e di at e d R ej ecti o n  
 
D S As ( A nti -HL A a nti b o di es) h a v e  a str o n g  a n d u ni v ers all y d el et eri o us i m p act o n m e di ati o n of all o gr aft i nj ury a n d l oss. 
As d e pict e d i n Fi g ur e 8 b el o w, pr e -f or m e d or d e n o v o D S As acti v at e c o m pl e m e nt, i n d uc e e n d ot h eli al c ell pr olif er ati o n 
a nti g e ns a n d m e di a t e A D C C r es ulti n g i n a pr o gr essi o n of all o gr aft dysf u ncti o n  a n d l oss. M or e t h a n 5 0 0 0 r e n al all o gr afts 
ar e l ost e ac h y e ar i n t h e U.S., a p pr oxi m at ely 7 5 -8 0 % t o a nti b o dy m e di at e d i nj ur y 9, 3 6.  T h us, u n d erst a n di n g t h e 
p at h o p hysi ol o gy of A B M R a n d B -c ell acti v ati o n ar e critic al t o i m pr ovi n g t h e l o n g e vity of existi n g all o gr afts a n d 
d e v el o p m e nt of s ucc essf ul str at e gi es f or d es e nsitiz ati o n t o pr ev e nt A B M R. Wit h t his u n d erst a n di n g, n e w dr u gs c a n b e 
d e v el o p e d t o a d dr ess r el e v a nt p at h w a ys. C urr e ntly, t h er e ar e n o a p pr ov e d dr u gs f or pr ev e nti o n or tr e at m e nt of A B M R. 
T his r e pr es e nts o n e of m ost pr essi n g u n m et n e e ds i n tr a ns pl a nt m e dici n e.  
 
I ncr e as e d IL-6 Pr o d ucti o n  

 
 
P a g e 1 2   
Fi g ur e 8. T his fi g ur e s h o ws t h e r el e v a nt p at h o g e nic m ec h a nis ms r es p o nsi bl e f or A B M R i n r e n al all o gr afts. First a n d m ost 
d o mi n a nt is C D C w h er e D S A -
m e di at e d c o m pl e m e nt 
acti v ati o n i niti at es a n 
i nfl a m m at ory c asc a d e t h at 
r es ults i n s e v er e i nj ury t o t h e 
all o gr af t e n d ot h eli u m. A D C C 
m e di at e d by N K c ells, 
m acr o p h a g es, a n d P M Ns als o 
c a us es s e v er e i nj ury t o t h e 
all o gr aft 1. I n a d diti o n, D S As c a n 
acti v at e e n d ot h eli al c ell IL -6 
tr a nscri pti o n wit h o ut A D C C or 
C D C t hr o u g h dir ect i nt er acti o ns 
wit h HL A m ol ec ul e s o n 
e n d ot h eli al c ells.  
 
 
1. 4 Is T h er e a R ol e f or IL -6 i n 
M e di ati o n of A B M R  
 
W e h av e p erf or m e d ext e nsi v e 
i nv esti g ati o ns i nt o t h e r ol e of IL-
6 ov er ex pr essi o n i n t h e m e di ati o n of A B M R. O ur first st u di es h a v e c e nt er e d o n m e as ur e m e nt of s er u m cyt o ki n e l e v els i n 
p eri p h er al bl o o d of E S R D p ati e nts a w aiti n g ki d n ey tr a ns pl a nt. T his d at a is n ot y et p u blis h e d b ut is s h o w n b el o w.   
 
 

 
 
P a g e 1 3   
 
Fi g ur e 9: T his fi g ur e s h o ws t h e r el ati o ns hi p of s er u m cyt oki n es m e as ur e d at v ari o us ti m es p ost -tr a ns pl a nt. Bri efl y, i n 
p a n el A, s er u m cyt o ki n es ar e s h o w n f or p ati e nts w h o h a d f or c a us e bi o psi es ( bl u e) vs. t h os e w h o di d n ot h a v e bi o psi es. 
As c a n b e s e e n, t h e IL -6 l e v els ar e q uit e l o w i n p ati e nts wit h q ui esc e nt all o gr afts. H o w ev er i n P a n el B, p ati e nts wit h 
A B M R s h o w si g nific a nt el ev ati o ns of IL -6 s er u m l e v els i n c o nc ert wit h A B M R o ns et. T h e X axis s h o ws ti m e b ef or e, at a n d 
aft er bi o psi es. IL -6 l e v els a p p e ar t o di mi nis h wit h tr e at m e nt of A B M R. P a n el C s h o ws c yt oki n e l ev els i n p ati e nts w h o h a d 
bi o psi es t h at di d n ot s h o w all o gr aft r ej ecti o n. T h es e d at a s u g g est t h at el ev ati o ns of s er u m IL -6 l e v els c o ul d b e us e d as a n 
e arl y m ar k er f or all o gr aft dysf u ncti o n m e di at e d by a nti b o dy i nj ur y.  
 
W e n ext e n d e av or e d t o d et er mi n e if IL -6 is ex pr ess e d i n t h e bi o psi es of p ati e nts u n d er g oi n g all o gr aft r ej ecti o n. T o 
acc o m plis h t his, w e ex a mi n e d r e n al bi o ps y m at eri al fr o m p ati e nts wit h n or m al ki d n e ys, p ati e nts wit h c ell ul ar r ej ecti o n 
a n d p ati e nts wit h A B M R. S ecti o ns w er e st ai n e d wit h a nti -s er a dir ect e d at IL -6 a n d e v al u at e d  by m or p h o m etric sc a n ni n g 
micr osc o py.  T h e d at a ar e s h o w n b el o w.  Bri efly, o ur i nv esti g ati o ns s h o w e d t h at t h e n u m b er of IL -6 + c ells w er e 
si g nific a ntl y i ncr e as e d i n bi o psi es d e m o nstr ati n g A B M R. T his s u g g ests a p ossi bl e r ol e f or IL -6/IL -6 R i nt er acti o ns i n 
m e di ati n g A B M R a n d e n h a nc e d D S A pr o d ucti o n. Al o n g wit h t h e d at a pr e s e nt e d a b o v e w hic h d e m o nstr at es el ev at e d 
l e v els of IL-6 i n t h e s er a of p ati e nts wit h A B M R t h es e fi n di n gs s u g g est t h e p ossi bilit y of IL -6 bl oc k a d e as a p ot e nti all y 
i m p ort a nt t h er a py i n m a n a g e m e nt of A B M R a n d p ossi bl y c A B M R a n d T G. 
 
Fi g ur e 1 0 A.   
  
  
  
 
Fi g ur e 1 0 B.  
 
 
Fi g ur e 1 0 A & 1 0 B: Fi g ur e 1 0 A s h o ws r e pr es e nt ativ e st ai ni n g of n or m al ki d n e y tiss u e, tiss u e fr o m a p ati e nt wit h c ell ul ar 
r ej ecti o n a n d a bi o ps y fr o m a p ati e nt wit h a nti b o dy-m e di at e d r ej ecti o n. I n t his i nst a nc e, t h er e ar e n u m er o us IL -6 + c ells 
i n t h e bi o psy of A B M R c o m p ar e d wit h C M R a n d n or m al tiss u e. Fi g ur e 1 0 B s h o ws d at a fr o m a l ar g er a n alysis of A B M R 
bi o psi es c o m p ar e d t o ot h er di a g n os es. Usi n g m or p h o m etric sc a n ni n g a n al ysis, w e w er e a bl e t o s h o w a si g nific a nt 
i ncr e as e i n IL-6 ex pr essi o n i n bi o psi es w it h A B M R. T h es e d at a s u g g est t h at IL-6 mi g ht pl a y a n i m p ort a nt r ol e i n a nti b o dy -
m e di at e d i nj ur y t o all o gr afts.  
 
1. 4. 1 I m p act of D S As o n L o n g -T er m All o gr aft S ur vi v al  
 
D at a s h o w n i n t h e c o m p osit e gr a p hs b el o w s h o w t h e i m p act of D S As, es p eci ally C 1 q + or c o m pl e m e nt activ ati n g D S As o n 
l o n g-t er m gr aft s urviv al. T his i m p ort a nt p a p er fr o m t h e Fr e nc h gr o u p c o difi e d t h e i m p ort a nc e of C 1 q + D S As i n m e di ati n g 
t h e m or e s ev er e f or ms of A B M R a n d c A B M R. A n ot h er i m p ort a nt f act or s h o w n i n fi g ur e 1 1B is t h e i m p act of D S As o n 
a cc el er ati n g at h er oscl er otic c h a n g es i n t h e all o gr aft w hic h q uic k e ns d e mis e. T his m a y als o b e r el at e d t o IL -6 i n d ucti o n i n 
e n d ot h eli al c ells by D S As t h at r es ults i n o blit er ativ e v asc ul o p at hy as w as pr evi o usl y r e p ort e d 3 7.  T h us, a nti b o dy -t ar g et e d 
t h er a pi es w o ul d b e of i m p ort a nc e i n mi ni mizi n g t h es e m a nif est ati o ns of D S A i nj ur y. 
 

 
 
P a g e 1 4   
Fi g ur e 1 1 A   
  
 
Fi g ur e 1 1 B 
 
 
Fi g ur e 1 1 A & 1 1 B: Fi g ur e 1 1 A s h o ws t h e i m p act of D S As o n l o n g t er m all o gr aft s ur vi v al i n p ati e nts tr a ns pl a nt e d i n 
Fr a nc e 3 8. T h es e i nv esti g at ors s h o w e d t h at D S As h a v e a n e g ati v e i m p act o n l o n g-t er m gr aft s urvi v al, b ut w h e n s e gr e g at e d 
by a bilit y t o activ at e c o m pl e m e nt ( C 1 q + D S As), t h e i m p act w as si g nific a ntl y m a g nifi e d. I n f act, t h os e w h o d ev el o p e d 
C 1 q + D S As p ost -tr a ns pl a nt h as a 1 2f ol d gr e at er ris k f or all o gr aft l oss t h a n C 1 q- D S A p ati e nts. Fi g ur e 1 1 B s h o ws t h e 
m ec h a nis ms of all o a nti b o dy i nj ur y t o gr afts w hi c h i ncl u d e c o m pl e m e nt activ ati o n e n d ot h eli al i nj ur y t hr o u g h dir ect 
acti o ns of all o a nti b o dy o n E N D A Ts a n d A D C C as w ell as i n d ucti o n of acc el er at e d at h er oscl er osis i n all o gr afts 9. 
 
Cl e arl y, t h e m ost i m p ort a nt w ay t o a p pr o ac h a nti b o dy m e di at e d all o gr aft i nj ur y is t hr o u g h t h e d ev el o p m e nt of a nti b o dy -
t ar g et e d t h er a pi es. T his w oul d a d dr ess all p at h o g e nic m ec h a nis m ass oci at e d wit h all o a nti b o dy a n d all o w gr afts t o 
c o nti n u e f u ncti o ni n g f or m uc h l o n g er p eri o ds of ti m e. T his w o ul d i m pr ov e t h e l e n gt h a n d q u alit y of lif e of all o gr aft 
r eci pi e nts a n d r e d uc e c osts t o t h e h e alt h c ar e syst e m. 
 
Fi g ur e 1 2 A & 1 2 B b el o w s h o w d at a fr o m o ur c e nt er o n t h e l o n g -t er m o utc o m es i n p ati e nts w h o ex p eri e nc e d A B M R aft er 
d es e nsitiz ati o n v. t h os e w h o di d n ot.  
 
Fi g ur e 1 2 A: Fi g ur e 1 2 B:  
 
Fi g ur e 1 2 A & 1 2 B. W e r etr os p ecti v ely r e vi e w e d t h e o utc o m es of 2 2 6 p ati e nts w h o u n d er w e nt d es e nsitiz ati o n wit h I VI G 
+ Rit uxi m a b +/ - PL E X at C e d ars -Si n ai M e dic al C e nt er. P ati e nts w er e divi d e d i nt o t w o gr o u ps. Gr o u p 1 h a d n o A B M R 
( 8 0 %) w hil e Gr o u p 2 ex p eri e nce d A B M R ( 2 0 %). As c a n b e s e e n i n Fi g ur e 1 2 A, t h e l o n g -t er m o utc o m es i n H S p ati e nts w h o 
ar e A B M R + ar e si g nific a ntly w ors e t h a n t h os e w h o w er e A B M R -.  I n f act, d at a f or t h e 5 y e ar o utc o m es of Gr o u p 1 ar e 
si mil ar t o n o n-s e nsitiz e d p ati e nts i n t h e U N O S d at a b as e.  T his s u g g est pr e v e nti o n of A B M R is critic al f or a n exc ell e nt 
l o n g-t er m o utc o m e of all o gr afts. Ass ess m e nt of f act ors ass oci at e d wit h ris k f or A B M R s h o w e d t h at r e-tr a ns pl a nt ati o n, 
f e m al e g e n d er, E S R D c a us e d by gl o m er ul o n e p hritis a n d pr es e nc e of str o n g er cl ass I a n d cl ass II D S As at ti m e of 
tr a ns pl a nt w er e m ost i m p ort a nt. ( T a bl e 1). Fi g ur e 1 2 B s h o ws t h e diffic ulty i n tr e ati n g A B M R aft er tr a ns pl a nt i n H S 

 
 
P a g e 1 5   
P ati e nts. P ati e nts w er e tr e at e d wit h I VI G + rit uxi m a b or I VI G + rit uxi m a b + PL E X. T h os e tr e at e d wit h I V I G + rit uxi m a b di d 
b ett er, b ut t his lik el y r efl ects a s el ecti o n bi as as m or e s e v er e c as es w er e tr e at e d wit h PL E X.  Cl e arl y, t h e m ost i m p ort a nt 
t hi n g w e c a n acc o m plis h is t o d ev el o p n e w str at e gi es t o pr ev e nt A B M R alt o g et h er t o all o w t h e l o n g t er m b e n efits of 
tr a ns pl a nt ati o n t o b e m a nif est i n t h es e p ati e nts.  I n a d diti o n, t his d at a p oi nts o ut t h at c urr e nt tr e at m e nts f or s e v er e, 
e arl y o ns et A B M R wit h r a pi d r e d ucti o n i n r e n al f u ncti o n, r e pr es e nts a n u n m et m e dic al n e e d as l o n g -t er m o utc o m es f or 
gr aft  s urviv al ar e p o or a n d, p ati e nt s ur viv al aft er gr aft f ail ur e fr o m A B M R is si g nific a ntl y w ors e t h a n t h os e w h o 
r es p o n d e d t o tr e at m e nt3 9. 
 
 
1. 4. 2 Pr eli mi n ary D at a o n Us e of T ociliz u m a b  f or Tr e at m e nt of A B M R i n H u m a ns 
 
B as e d o n t h e pr eli mi n ary i nv esti g ati o ns i n a ni m al m o d els a n d h u m a ns, w e b e g a n tr e ati n g p ati e nts wit h A B M R w h o h a d 
f ail e d tr e at m e nt of I VI G + rit uxi m a b +/- PL E X. I n A pril 2 0 1 1, w e tr e at e d o ur 1 st p ati e nt w h o h a d o ns et of s ev er e A B M R 
p ost -tr a nspl a nt t h at w as u nr es p o nsi v e t o tr e at m e nt wit h PL E X + I VI G ( S O C). T h e p ati e nt r ec eiv e d t ociliz u m a b 8 m g/ k g 
i niti all y, t h e n m o nt hl y X 4 m or e d os es a n d h a d a c o m pl et e r ec ov ery wit h S Cr 1. 3 m g/ dl n o w n e arl y  6 y e ars o n. Si nc e t his 
i niti al p ati e nt, w e h a v e tr e at e d 3 6  p a ti e nts wit h c hr o nic, activ e A B M (cA B M R) a n d T G . T h es e p ati e nts h av e a v ery b a d 
pr o g n osis, wit h ~ 5 0 % gr aft l oss by 2 y e ars p ost -bi o ps y. I n 2 0 1 1, w e b e g a n tr e at m e nt of p ati e nts wit h c A B M R a n d T G 
usi n g m o nt hly t ociliz u m a b  at 8 m g/k g. Tr e at m e nt w as c arri e d o ut f or 6 -2 4 m o nt hs. P ati e nts w er e m o nit or e d f or D S As, 
gr aft/ p ati e nt s urviv al a n d m ai nt e n a nc e of r e n al f u ncti o n.  O utc o m es w er e  c o m p ar e d t o 3 9 p ati e nts wit h si mil ar bi o ps y 
fi n di n gs w h o w er e tr e at e d wit h st a n d ar d -of -c ar e (I VI g + rit uxi m a b + PL E X) D at a f or t h es e p ati e nts is s h o w i n Fi g ur e 1 3  
b el o w. Bri efl y, tr e at m e nt wit h t ociliz u m a b w as ass oci at e d wit h a si g nific a nt i m pr ov e m e nt i n p ati e nt a n d gr aft s ur vi v al of 
t h e e ns ui n g 6 y e ars. P ati e nts i n t h e c AB M R + T G gr o u p h a d a gr aft s urvi v al at 6 y e ars of 8 2 % v.  2 0 % f or t h e S O C gr o u p 

 
 
P a g e 1 6   
( Fi g ur e 1 3C). I n a d diti o n t o t h e i m pr ov e d o utc o m es, p ati e nts tr e at e d wit h t ociliz u m a b als o s h o w e d st a biliz ati o n of r e n al 
f u ncti o n, r e d uc e d D S As a n d i m pr ov e m e nt i n bi o psy p ar a m eters of cA B M R o n e y e ar aft er i niti atl o n of t ociliz u m a b 
t h er apy 4 0. D at a f or t h es e p ati e nts c o m par e d wit h S O C ar e s h o w n i n Fi g 1 3 A- E b el o w. Bri efl y, o utc o m es f or all 
t ociliz u m a b p ati e nts, i ncl u di n g gr aft s ur vi v al at 6 y e ars ( 1 3 A), gr aft s ur vi v al f or t h os e wit h T G ( 1 3B), gr aft s urvi v al f or 
p ati e nts w h o l ost t h eir gr aft m or e t h a n 3 m o nt hs p ost -bi o ps y a n d p ati e nt s urvi v al all s h o w si g nific a nt i m pr ov e m e nt i n 
t h os e tr e at e d wit h t ociliz u m a b c o m p ar e d t o S O C. Fi g ur e 1 3E s h o ws t h at bi o psi es p erf or m e d i n 9 p ati e nts 1 y e ar aft er 
i niti ati o n of t ociliz u m a b t h er a py s h o w e d si g nific a nt i m pr ov e m e nt i n C 4 D + sc or es a n d g + ptc sc or es.  
 
 
 
 
 
 
 
 
Fi g ur e 1 3 A- E: T his fi g ur e s h o ws t h e o utc o m es of p ati e nts tr e at e d wit h t ociliz u m a b f or cA B M R a n d T G ar e s h o w n a n d 
d escri b e d a b o v e. 3 6 p ati e nts w er e tr e at e d wit h t ociliz u m a b m o nt hly f or 6 -2 5 m o nt hs a n d 3 9 p ati e nts r ec eiv e d st a n d ar d 
of c ar e ( S O C) tr e at m e nt (I VI G + rit uxi m a b +/ - PL E X) a n d c o nstit ut e t h e r etr os p ectiv e c o h ort. T ociliz u m a b  p ati e nts h a v e 
b e e n f oll o w e d f or u p t o 6 y e ars. T h er e ar e n o w 5 4 p ati e nts i n t his c o h ort. T his d at a s u p p orts t h e i d e a t h at i nt err u pti o n 
of t h e IL -6/IL -6 R si g n ali n g p at h w a y m ay b e i m p ort a n t i n tr e ati n g p ati e nts wit h s e v er e cA B M R a n d T G m e di at e d by HL A 
a nti b o di es. I n a d diti o n, w e s e e a n i m p ort a nt r e d ucti o n of D S As o v er ti m e t h at w o ul d i n dic at e a p ot e nti al b e n efit i n 
d es e nsitiz ati o n tr e at m e nts . Fi g ur e 1 3 A s h o ws t h e gr aft s ur vi v al of all p ati e nts fr o m i n d ex bi o psy. T ociliz u m a b  p ati e nts 
h av e s u p eri or gr aft s urvi v al. I n 1 3 B, w e s e e t h e s ur viv al of p ati e nts wit h T G w h er e 8 2 % of t ociliz u m a b tr e at e d p ati e nts’ 
gr aft w er e f u ncti o ni n g at 6 y e ars. Fi g ur e 1 3 C s h o ws t h e gr aft s urvi v al f or p ati e nts w h o l ost t h eir gr afts > 3 M aft er i n d ex 
bi o ps y a n d fi g ur e 1 3 D s h o ws a n e ar si g nific a nt b e n efit i n i ncr e asi n g p ati e nt s urviv al.  I n fi g ur e 1 3 E, 9 p ati e nts wh o 
r ec eiv e d t ociliz u m a b at i n d ex bi o psy a n d h a d r e p e at bi o psi es at 1 y e ar ar e s h o w n. W e c o m p ar e d sc or es f or i nfl a m m ati o n 
a n d c hr o nicity. Bri efly, t ociliz u m a b p ati e nts s h o w e d r e d ucti o ns i n C 4 d + st ai ni n g a n d g + ptc sc or es, f e at ur es w hic h ar e 
c o m m o nl y ass oci at e d wit h a w ors e pr o g n osis.  
 
2. 0 Cl az akiz u m a b ( a nti -IL-6) as a P ot e nti al A g e nt t o Tr e at c A B M R a n d T G  
 
Cl az a kiz u m a b ( C SL B e hri n g LL C ., Ki n g of Pr ussi a, P A ) is a h u m a niz e d m o n ocl o n al a nti b o dy ai m e d at t h e cyt o ki n e IL -6 
li g a n d. Cl az a kiz u m a b h as b e e n ev al u at e d ext e nsiv el y i n p ati e nts wit h r h e u m at oi d art hritis, b ut h as n ot y et b e e n 
a p pr o v e d by t h e F D A f or a ny c o n diti o n. Si nc e t h e i ntr o d ucti o n of IL -6/IL -6 R bl ocki n g dr u gs, r e p orts i n dic at e t h at 
i n hi biti o n of t h e IL-6/IL -6 R p at h w a y m ay h av e si g nific a nt b e n efits i n SL E a n d ot h er v asc ulitic dis or d ers a n d r e d uc es 
a nti b o dy pr o d uci n g c ells i n tr e at e d p ati e nts. T h er e is c urr e ntl y n o i nf or m ati o n f or Cl az a kiz u m a b i n H S p ati e nts a w aiti n g 
i nc o m p ati bl e ( HL Ai) tr a ns pl a nts or f or tr e at m e nt of a nti b o dy-m e di at e d r ej ecti o n.  

 
 
P a g e 1 7   
Cl az a kiz u m a b is a g e n etic all y e n gi n e er e d h u m a niz e d i m m u n o gl o b uli n G 1 (I g G 1) a nti b o dy t h at bi n ds t o h u m a n IL -6 wit h 
a n affi nit y of 4 p M. Usi n g m ulti pl e ass a ys f or si g n ali n g a n d c ell ul ar f u ncti o ns i n r es p o ns e t o IL-6 al o n e (t o m e as ur e 
cl assic al si g n ali n g) a n d a c o m bi n ati o n of IL -6 a n d sIL -6 R (t o m e as ur e tr a ns -si g n ali n g), it w as d e m o nstr at e d t h at 
cl az a kiz u m a b is a p ot e nt a n d f ull a nt a g o nist of IL - 6-i n d uc e d si g n ali n g as m e as ur e d by p h os p h or yl ati o n of si g n al 
tr a ns d uc er a n d activ at or of tr a nscri pti o n 3 ( S T A T 3), as w ell as c ell ul ar f u ncti o ns s uc h as c ell pr olif er ati o n, diff er e nti ati on, 
activ ati o n, B -c ell pr o d ucti o n of i m m u n o gl o b uli ns, a n d h e p at ocyt e pr o d ucti o n of ac ut e p h as e pr ot ei ns ( C -r e acti v e pr ot ei n 
[C R P] a n d fi bri n o g e n). I n a d diti o n, cl az a kiz u m a b is s h o w n t o b e a c o m p etitiv e a nt a g o nist of IL - 6-i n d uc e d c ell 
pr olif er ati o n. T his i n  vitr o p h ar m ac ol o gic al pr ofil e s u p p orts t h e p ot e nti al of cl az akiz u m a b t o i m p act m ulti pl e i m m u n e 
a n d n o n -i m m u n e c ell ul ar pr oc ess es t h at ar e c e ntr al t o dis e as e p at h o g e n esis, a n d t h us, t o off er a n e w t h er a p e utic 
m o d alit y i n t h e tr e at m e nt of a ut oi m m u n e dis e as es a n d ot h er IL -6 m e di at e d dis e as es.  
T h e cl az a kiz u m a b d ev el o p m e nt pr o gr a m i ncl u d es a c o m pr e h e nsi v e n o ncli nic al d e v el o p m e nt pr o gr a m a n d cli nic al st u di es 
c o n d uct e d i n h e alt hy s u bj ects a n d i n s u bj ects wit h R A, ps ori atic art hritis ( Ps A), Cr o h n’s dis e as e, gr aft -v ers us -h ost dis e as e 
( G V H D), a n d o nc ol o gy. T o d at e, n o st u di es wit h cl az akiz u m a b h a v e b e e n c o n d uct e d i n s u bj ects wit h hi g hl y s e nsitiz e d 
p ati e nts u n d er g oi n g r e n al tr a ns pl a nt, alt h o u g h s u p p orti n g s af ety d at a ar e av ail a bl e fr o m t h e pr evi o us cli nic al st u di es.  
N o ncli nic al St u di es  
A c o m pr e h e nsiv e n o ncli nic al d e v el o p m e nt pr o gr a m h as b e e n c o m pl et e d. Cl az a kiz u m a b w as s h o w n t o b e a p ot e n t 
i n hi bit or of IL- 6-i n d uc e d ac ut e p h as e pr ot ei ns. I n p h ar m ac o ki n etic ( P K)/ p h ar m ac o dy n a mic ( P D) st u di es, a si n gl e d os e of 
cl az a kiz u m a b r es ult e d i n f ull i n hi biti o n of IL -6 activity as m e as ur e d by t h e i n hi biti o n of IL - 6-i n d uc e d p h os p h or yl at e d 
S T A T 3 ( p S T A T 3) a ctivity i n w h ol e bl o o d tr e at e d ex viv o wit h IL -6. T h e r es ults of t his f u ncti o n al P D ass ay c orr el at e d wit h 
dr u g ex p os ur es w h er e f ull i n hi biti o n of p S T A T 3 activit y w as o bs erv e d w h e n dr u g l e v els exc e e d e d 5 0  n g/ mL 
( a p pr oxi m at ely 0. 3 n M). I n a tiss u e cr oss-r e acti vity st u dy, tiss u e bi n di n g of cl az akiz u m a b w as o bs er v e d i n m ulti pl e 
tiss u es i n b ot h h u m a n a n d c y n o m ol g us m o n k e y, w as g e n er all y c yt o pl as mic i n n at ur e, a n d w as c o nsist e nt wit h t h e k n o w n 
ex pr essi o n of IL -6 by c ells a n d tiss u es. R es ults fr o m b ot h si n gl e - a n d  r e p e at-d os e n o ncli nic al t oxic ol o gy st u di es of u p t o 6 
m o nt hs i n cy n o m ol g us m o n k e ys  d e m o nstr at e d a n acc e pt a bl e s af ety pr ofil e f or cl az a kiz u m a b.  I n a pr eli mi n ary e n h a nc e d 
pr e - a n d p ost -n at al d ev el o p m e nt ( e P P N D) st u dy c o n d uct e d i n cy n o m ol g us m o n k e ys, a n i ncr e as e i n t h e n u m b er of 
m o nk e ys wit h r et e nti o n of t h e pl ac e nt a at p art uriti o n w as o bs erv e d at cl az a kiz u m a b d os es of 3 m g/k g ( n = 2) a n d 3 0 
m g/k g ( n = 3), c orr es p o n di n g t o d os es 1 1 a n d 1 1 0 ti m es t h e pl a n n e d h u m a n d os e of 5 0 m g. T h er e w er e n o ot h er s af ety 
fi n di n gs of cli nic al c o nc er n.  
Cli nic al st u di es  
Cli nic al st u di es h av e b e e n c o n d uct e d i n h e alt hy s u bj ects a n d i n t h e f oll o wi n g p ati e nt p o p ul ati o ns: R A, Ps A, C D, gr aft -
v ers us -h ost dis e as e ( G V H D), a n d o nc ol o gy. T h es e cli nic al st u di es i ncl u d e a t ot al of 1, 2 2 3 s u bj ects,  of w hic h 8 8 8 s u bj ects 
w er e ex p os e d t o cl az a kiz u m a b wit h d os es r a n gi n g fr o m 1 m g t o 6 4 0 m g gi v e n by eit h er i ntr a v e n o us (I V) or s u bc ut a n e o us 
( S C) i nj ecti o n f or u p t o 4 8 w e eks.  
Cli nic al P h ar m ac ol o gy  
F oll o wi n g t h e a d mi nistr ati o n of cl az akiz u m a b as a 1 -h o ur I V i nf usi o n, t h e P K of cl az a kiz u m a b w er e li n e ar o v er t h e d os e 
r a n g es of 3 0 m g t o 6 4 0 m g i n h e alt hy s u bj ects a n d 8 0 m g t o 3 2 0 m g i n s u bj ects wit h R A as i n dic at e d by c o nsist e nt 
cl e ar a nc e at t h es e d os e l ev els. T h e T -h alf of cl az a kiz u m a b at all d os es w as v ery si mil ar i n h e alt hy m al e s u bj ects a n d i n 
s u bj ects wit h R A a n d w as c o nsist e nt wit h t h at ex p ect e d f or a h u m a niz e d I g G 1 a nti b o dy. Acr oss t h e d os es st u di e d, t h e 
m e a n T -h alf of cl az a kiz u m a b r a n g e d fr o m 1 9. 5 t o 3 1. 0 d a ys i n h e alt hy m al e s u bj ects a n d fr o m 2 6. 4 t o 3 0. 9 d ays i n 
s u bj ects wit h R A. T h e T-h alf of cl az a kiz u m a b aft er S C a d mi nistr ati o n i n h e alt hy m al e s u bj ects w as si mil ar t o t h e I V 
a d mi nistr ati o n. I n a P h as e 1 st u dy c o m p ari n g I V a n d S C d osi n g i n h e alt hy m al e s u bj ects, t h e m e a n T -h alf of cl az a kiz u m a b 

 
 
P a g e 1 8   
w as 3 0. 7  d a ys aft er a si n gl e I V d os e a n d ,  3 1. 1 t o 3 3. 6 d a ys aft er S C a d mi nistr ati o n. T h e bi o av ail a bility of cl az a kiz u m a b 
aft er S C a d mi nistr ati o n w as 6 0 % of t h e I V f or m ul ati o n. As ex p ect e d, C m ax w as l o w er a n d T m ax w as l o n g er f or t h e S C 
a d mi nistr ati o n r el ativ e t o I V a d mi nistr ati o n.  
P o p ul ati o n P K a n alysis of t h e d at a fr o m cli nic al st u di es i n R A, Ps A a n d h e alt hy s u bj ects h av e i n dic at e d t h at b o dy w ei g ht 
aff ects t h e P K of cl az a kiz u m a b s uc h t h at b ot h cl e ar a nc e a n d c e ntr al v ol u m e of distri b uti o n i ncr e as e wit h i ncr e asi n g b o dy 
w ei g ht. T h er ef or e, h e a vi er s u bj ects will h a v e l o w er dr u g ex p os ur e c o m p ar e d wit h l ess h e av y s u bj ects.  
Cli nic al Effic acy a n d S af et y St u di es  
Effic ac y a n d s af et y d at a f or cl az a kiz u m a b is a v ail a bl e fr o m cli nic al st u di es c o n d uct e d i n R A, Ps A, a n d o nc ol o gy. S t u di es 
c o n d uct e d i n G V R D a n d Cr o h n’s dis e as e w er e pr e m at ur el y t er mi n at e d d u e t o s af et y c o nc er ns a n d t h er ef or e n o effic acy 
c o ncl usi o ns ar e av ail a bl e f or t h es e st u di es. 
I n P h as e 2 st u di es i n R A a n d Ps A, d os es fr o m 5 m g S C o nc e e v er y 4 w e e ks ( Q 4 W) u p t o 3 2 0 m g I V o nc e e v er y 8 w e eks 
w er e si g nific a ntl y eff ecti v e wit h cli nic al r es p o ns e evi d e nt as e arly as 1 2  w e eks p ost tr e at m e nt.  O n e st u dy i n R A als o 
d e m o nstr at e d t h at t h e effic ac y of cl az a kiz u m a b is c o m p ar a bl e or m ay b e b ett er t h a n t h e st a n d ar d of c ar e tr e at m e nt 
( a d ali m u m a b + m et hr otr ex at e ( M T X)) i n R A. 
Effic ac y wit h cl az a kiz u m a b w as n ot s h o w n i n t h e 2 P h as e 2 st u di es i n o nc ol o gy ( h e a d a n d n ec k c a nc er a n d n o n -s m all c ell 
l u n g c a nc er). 
T w o st u di es w er e t er mi n at e d pr e m at ur ely d u e t o s af et y c o nc er ns. A P h as e 2 st u dy i n Cr o h n’s w as t er mi n at e d e arl y 
b ec a us e of GI p erf or ati o n i n 3 s u bj ects w h o h a d r ec eiv e d cl az akiz u m a b a n d t his i n dic ati o n is n o l o n g er b ei n g st u di e d. 
Alt h o u g h t h es e s u bj ects h a d m ulti pl e c o nf o u n di n g m e dic al iss u es, a n d t h e dis e as e its elf h as a n i n h er e nt ris k of m uc os al 
p erf or ati o n, g astr oi nt esti n al p erf or ati o ns w er e als o o bs er v e d d uri n g t h e cli nic al st u di es wit h t ociliz u m a b i n p ati e nts wit h 
R A. G astr oi nt esti n al p erf or ati o n is a r ec o g niz e d risk of a nti -IL-6 m A bs. Aft er o nl y 3 s u bj ects w er e e nr oll e d, a st u dy i n 
s u bj ects wit h G V H D w as als o pr e m at ur el y t er mi n at e d d u e t o 2 s u bj ects ex p eri e nci n g si mil ar s eri o us a dv ers e e v e nts 
( S A Es) (i. e., ac ut e r e n al f ail ur e) w hic h l e d t o d e at h. B ot h s u bj ects h a d s ev er e G V H D dis e as e at t h e ti m e of d e at h. 
O v er all, t h e s af ety fi n di n gs fr o m t h e cli nic al st u di es c o n d uct e d wit h cl az a kiz u m a b t o d at e ar e c o nsist e nt wit h t h e k n o w n 
eff ects of bl ocki n g t h e IL -6 p at h w a y (s e e Act e mr a ® pr escri bi n g i nf or m ati o n]). I d e ntifi e d ris ks ass oci at e d wit h 
cl az a kiz u m a b a d mi nistr ati o n i ncl u d e t h e f oll o wi n g:  i nf ecti o ns, li v er f u ncti o n t est (L F T) a b n or m aliti es, c h a n g es i n 
h e m at ol o gy p ar a m et ers (i. e., n e utr o p e ni a a n d t hr o m b oc yt o p e ni a), dysli pi d e mi a (i. e., hy p erc h ol est er ol e mi a a n d 
hy p ertri gl yc eri d e mi a), a n d g astr oi nt esti n al p erf or ati o ns .  
F or f urt h er d et ails r e g ar di n g cli nic al st u di es wit h cl az akiz u m a b, pl e as e c o ns ult t h e I nv esti g at or’s Br oc h ur e.  
  
3. 0  Pri m ar y O bj ectiv es  
 
T his st u dy will b e a n o p e n l a b el d esi g n t o ass ess t h e s af et y a n d effic acy of cl az akiz u m a b 2 5 m g S C giv e n e v er y 4 w e eks 
(3 0 d a ys ) f or a t ot al of 6 d os es in eli mi n ati n g D S As  a n d st a bilizi n g cli nic al f e at ur es of c A B M R  i n p ati e nts w h o  h a v e bi o ps y 
pr o v e n s ev er e cA B M R + T G . If i m pr o v e m e nts ar e s e e n i n p at h ol o gic f e at ur es of a nti b o dy m e di at e d r ej ecti o n fr o m t his 
bi o ps y c o m p ar e d t o i n d ex bi o ps y, w e will off er p ati e nts t h e o p p ort u nit y t o c o nti n u e cl az a kiz u m a b a d mi nistr ati o ns 
m o nt hl y f or a n a d dit i o n al 6 m o nt hs. A o n e y e ar bi o psy will  t h e n b e p erf or m e d at t h e e n d of t h e st u dy.  S af ety 
d et er mi n ati o ns will b e ai m e d at ass ess m e nts of a ny si d e eff ects ass oci at e d wit h cl az a kiz u m a b a d mi nistr ati o n a n d ris k f or 
i nf ecti o us c o m plic ati o ns ass oci at e d wit h cl az a kiz u m a b t h er a py. Li mit e d effic acy d et er mi n ati o ns will i ncl u d e ass ess m e nt 

 
 
P a g e 1 9   
of c o m p osit e s urr o g at e e n d p oi nts i ncl u di n g p ati e nt a n d gr aft s ur viv al, st a biliz ati o n of t h e cli nic al f e at ur es of  cA B M R 
( e G F R, S Cr) aft er cl az a kiz u m a b tr e at m e nt, a n d s af et y t hr o u g h o ut st u dy d ur ati o n.   
 
L o n g t er m pri m ar y o bj ecti v es i ncl u d e: 
1.  ass ess t h e s af ety a n d effic acy of cl az akiz u m a b 1 2. 5 m g or 2 5 m g S C giv e n ev ery 4 -8 w e eks i n eli mi n ati n g DS As a n d 
st a bilizi n g cli nic al f e at ur es of c A B M R i n p ati e nts w h o h av e bi o psy pr ov e n s ev er e c A B M R + T G  
2.  ass ess c o m p osit e s urr o g at e e n d p oi nts i ncl u di n g p ati e nt a n d gr aft s urviv al, st a biliz ati o n of t h e cli nic al f e at ur es of 
c A B M R ( e G F R, S Cr) aft er cl az akiz u m a b tr e at m e nt, a n d s af ety t hr o u g h o ut st u dy d ur ati o n  
 
3 . 1 M aj or S ec o n d ar y O bj ecti v es  
  
I n a d diti o n t o o ur eff orts t o d et er mi n e if cl az a kiz u m a b tr e at m e nt c a n si g nific a ntly r e d uc e or eli mi n at e t h e s ev erit y of 
cA B M R e pis o d es a n d m o dif y p at h ol o gic f e at ur es ( B a nff 2 0 1 5 ) at t h e e n d of 6 m o nt hs of cl az a kiz u m a b t h era py, w e will 
ass ess all o gr aft f u ncti o n u p t o 6- 1 2 M p ost -tr a ns pl a nt, d et er mi n e r e n al f u ncti o n usi n g S Cr, M D R D G F R ( Sc h w artz 
e q u ati o n will b e us e d t o esti m at e Cr Cl f or p ati e nts u n d er 1 8 y e ars of a g e)  c alc ul ati o ns a n d D S A l ev els.  A pr ot oc ol bi o ps y 
will b e p erf or m e d at 6 M p ost -cl az a kiz u m a b t h er a py a n d 1 2 M (f or p ati e nts w h o r ec ei v e 1 2 d os es of cl az a kiz u m a b). W e 
will als o r ec or d a ny l at e cA B M R e pis o d es aft er cl az a kiz u m a b t h er a py. I n a d diti o n, s ev er al i m m u n ol o gic d et er mi n ati o ns 
will b e ass ess e d at ti m e p oi nts b ef or e a n d aft er i niti ati o n of cl az a kiz u m a b t h er a py. T h es e i ncl u d e t h e f oll o wi n g: 
 Ass ess m e nt of T r e g c ells ( C D 4 +, C D 2 5 +, F ox P 3 + C D 1 2 7 di m) 
 Ass ess m e nt of T f h c ells ( C D 4 +,I C O S +, C X C R 5 +, IL-2 1 +)  
 Ass ess m e nt of circ ul ati n g pl as m a bl ast ( C D 1 9 +, C D 3 8 +, C D 2 7 +, IL -6 +)  
 Ass ess m e nt of C R P, IL -6 l ev els a n d Q u a ntit ati v e i m m u n o gl o b uli ns by ELI S A pr e - a n d p ost -tr e at m e nt f or c A B M R 
 Vir al P C R m o nit ori n g by c e nt er pr ot oc ol f or E B V, C M V a n d P ol y o m a B K  
 
T his st u dy pr ot oc ol is s h o w n i n Fi g ur e  1 4. T h es e s ec o n d ar y e n d p oi nts will h el p us u n d erst a n d t h e bi ol o gy of all oi m m u n e 
r es p o ns es t o all o gr afts a n d t o d et er mi n e t h e a bilit y a n d m ec h a nis ms of cl az a kiz u m a b’s b e n efici al eff ects. W e will als o 
m o nit or vir al P C Rs as p er st a n d ar d -of -c ar e.   L o n g t er m s ec o n d ar y o bj ecti v es i ncl u d e:  
1.  d et er mi n e r e n al f u ncti o n usi n g S Cr, e G F R  
2.  D S A l ev els  
3.  A pr ot oc ol bi o psy will b e p erf or m e d at 1 2 M, 2 4 M p ost -cl az akiz u m a b L T E.  
4.  r ec or d a ny l at e c A B M R e pis o d es aft er cl az akiz u m a b t h er a py. 
5.  Ass ess m e nt of C R P a n d I g G  
6.  Vir al P C R m o nit ori n g by c e nt er pr ot oc ol f or E B V, C M V a n d P oly o m a B K  
 
3. 2  I ncl usi o n Crit eri a 
 
 A g e 1 5- 7 5  y e ars at t h e ti m e of scr e e ni n g.  
 Bi o ps y pr ov e n cA B M R wit h T G o n  bi o psy  as d efi n e d by B a nff 2 0 1 5 a n d D S A + at ti m e of bi o ps y  
 S u bj ect/ P ar e nt/ G u ar di a n m ust b e a bl e t o u n d erst a n d a n d pr o vi d e i nf or m e d c o ns e nt.  
 P n e u m oc occ al v acci n at e d  
 N e g ativ e t u b erc uli n p p d r es ult or n e g ati v e Q u a ntif er o n T B g ol d  
3. 3  Excl usi o n Crit eri a  
 
 M ulti -or g a n tr a ns pl a nt ( e. g. ki d n e y a n d p a ncr e as)  
 e G F R < 3 0 mL/ mi n/ 1. 7 3 m
2  
 A dv a nc e d Tr a ns pl a nt Gl o m er ul o p at hy ( C G 3)  or a dv a nc e d I F T A (ct or ci sc or es ≥3)  
 Pr evi o us all er gic r e acti o ns t o m o n ocl o n al a nti b o di es.  
 L act ati n g or pr e g n a nt f e m al es. 

 
 
P a g e 2 0   
 W o m e n of c hil d -b e ari n g a g e a n d m al e p art n ers of w o m e n of c hil d -b e ari n g a g e w h o ar e n ot willi n g or a bl e t o 
pr actic e F D A -a p pr ov e d f or ms of c o ntr ac e pti o n  d uri n g st u dy a n d f or 5 m o nt hs aft er l ast d os e . 
 HI V -p ositiv e s u bj ects.  
 S u bj ects w h o t est p ositiv e f or H B V by H B V e A g/ D N A or H C V i nf ect i o n [ p ositi v e A nti-H C V ( EI A) a n d c o nfir m at ory 
H C V RI B A].  
 S u bj ects wit h l at e nt or acti v e T B.  S u bj ects m ust h av e n e g ati v e Q u a ntif er o n T B g ol d t est r es ult.   
 R ec e nt r eci pi e nts of a ny lic e ns e d or i nv esti g ati o n al liv e att e n u at e d v acci n e(s) wit hi n t w o m o nt hs of t h e 
scr e e ni n g visit (i ncl u di n g b ut n ot li mit e d t o a ny of t h e f oll o wi n g: 
o  A d e n o vir us [ A d e n ovir us v acci n e li v e or al ty p e 7]  
o  V aric ell a [ V ariv ax]  
o  H e p atitis A [ V A Q T A]  
o  R ot avir us [ R ot as hi el d]  
o  Y ell o w f ev er [ Y - F-V ax]  
o  M e asl es a n d m u m ps [ M e asl es a n d m u m ps vir us v acci n e li v e]  
o  M e asl es, m u m ps, a n d r u b ell a v acci n e [ M - M- R-II] 
o  S a bi n or al p oli o v acci n e  
o  R a bi es v acci n es [I M O V A X R a bi es I. D., R a b Av ert])  
 A si g nific a ntl y a b n or m al g e n er al s er u m scr e e ni n g l a b r es ult d efi n e d as a W B C < 3. 0 X 1 0 3/ ml, a H g b < 8. 0 g/ dL, a 
pl at el et c o u nt < 1 0 0 X 1 0 3/ ml, a n S G O T or S G P T  > 3 X u p p er li mit  n or m al  
 I n divi d u als d e e m e d u n a bl e t o c o m pl y wit h t h e pr ot oc ol. 
 S u bj ects wit h activ e C M V or E B V i nf ecti o n as d efi n e d by C M V -s p ecific s er ol o gy (I g G or I g M) a n d c o nfir m e d by 
q u a ntit ativ e P C R wit h or wit h o ut a c o m p ati bl e ill n ess  (Q u a ntit ativ e P C R c ut off d efi n e d as h a vi n g > 5 0 c o pi es of 
C M V or E B V D N A/ P C R)  
 Us e of i nv esti g ati o n al a g e nts wit hi n 4 w e eks of p artici p ati o n.  
 Hist or y or activ e I nfl a m m at or y B o w el Dis e as e or Di v ertic ul ar Dis e as e or g astr oi nt esti n al p erf or ati o n  
 R ec e nt i nf ecti o n ( wit hi n p ast 6 w e e ks of scr e e ni n g) r e q uiri n g a ny a nti bi otic us e ( or al, p ar e nt er al or t o pic al).  
 Pr es e nt or pr evi o us ( wit hi n 5 y e ars) m ali g n a nc y exc e pt f or b as al c ell c arci n o m a, f ull y excis e d s q u a m o us c ell 
c arci n o m a of t h e s ki n or n o n-r ec urr e nt ( wit hi n 5 y e ars) c ervic al c arci n o m a-i n-sit u. 
4. St u dy D esi g n & M et h o ds  
 
B ac k gr o u n d: T his is a si n gl e c e nt er, P h as e I/II, o p e n l a b el si n gl e-ar m ex pl or at ory st u dy.  T h e tri al will pri m arily ex a mi n e 
t h e s af et y a n d t ol er a bilit y of cl az a kiz u m a b  giv e n aft er t h e di a g n osis of cA B M R  i n 1 0 s u bj ects ( 15- 7 5yrs)  w h o ex hi bit 
D S As t o t h eir d o n or. P ati e nts e nt er e d will als o h a v e b e e n di a g n os e d wit h c A B M R + T G p ost -tr a ns pl a nt b as e d o n B a nff 
2 0 1 5 crit eri a. P ati e nts ar e r e q uir e d t o h a v e a e G F R > 3 0  mL/ mi n/ 1. 7 3 m
2 as c alc ul at e d by t h e M D R D e q u ati o n ( Sc h w artz 
e q u ati o n will b e us e d t o esti m at e Cr Cl f or p ati e nts u n d er 1 8 y e ars of a g e) at e ntry.  All p ati e nts will b e  r ecr uit e d fr o m t h e 
r e n al tr a ns pl a nt pr o gr a m at C e d ars -Si n ai M e dic al C e nt er. O nc e cA B M R is di a g n os e d,  d o n or -s p ecific a nti-HL A a nti b o di es 
will b e ass ess e d ( D S A) w hic h ar e ass oci at e d wit h cA B M R a n d/ or gr aft l oss. D S A will b e d et ect e d usi n g s oli d p h as e ass ay 
s yst e ms c urr e ntly utiliz e d at t h e C e d ars-Si n ai M e dic al C e nt er HL A L a b or at ory ( Dr. Xi a o h ai Z h a n g  Dir ect or , P h o n e: 3 1 0-
4 2 3 -4 9 7 9) 4 1. T h es e a nti-HL A a nti b o di es m ay r es ult n at ur all y or fr o m pr e vi o us pr e g n a nc y, tr a nsf usi o ns, or pri or 
tr a ns pl a nts. P ati e nts tr e at e d wit h cl az a kiz u m a b f or cA B M R will h a v e l a bs f or D S As, a n d ot h er m o nit ori n g l a bs as w ell as 
i m m u n ol o gic st u di es as o utli n e d ( S e e St u dy  Pr ot oc ol i n A p p e n dix A). I n a d diti o n t o t h e st a n d ar d p ost -tr a ns pl a nt 
i m m u n os u p pr essiv e pr ot oc ol, p ati e nts wit h cA B M R will r ec eiv e cl az a kiz u m a b 2 5 m g S C gi v e n e v er y 4 w e e ks ( 3 0 d a ys ) f or 
a t ot al of 6 d os es . If n o s af et y/t ol er a bility/ effic acy iss u es ar e o bs erv e d aft er t h e i niti al d os e,  p ati e nts will c o nti n u e t h e 
pr ot oc ol as o utli n e d  (s e e Ap p e n dix A).   A pr ot oc ol bi o ps y will b e p erf or m e d aft er t h e 6 t h a n d aft er t h e  1 2 t h d os e s  of 
cl az a kiz u m a b ( as m e nti o n e d b ef or e) t o ass ess t h e all o gr aft f or evi d e nc e of cA B M R / A B M R, i ncl u di n g C 4 d st ai ni n g a n d T G 
usi n g B a nff 2 0 1 5 crit eri a 1 4.  B a nff sc ori n g will b e c o m p ar e d b et w e e n t h e i n d ex a n d pr ot oc ol bi o psy aft er c ess ati o n of 
t h er a py. P ati e nts w h o h av e e vi d e nc e of p ersist e nt all o gr aft dysf u ncti o n m a y h a v e n o n -pr ot oc ol bi o psi es f or c a us e. Aft er 
c o m pl eti o n of t h e cl az a kiz u m a b t h er a py, p ati e nts will b e f oll o w e d u p t o ass ess all o gr aft f u ncti o n a n d A B M R e pis o d es as 
w ell as D S As.  T h e pr o t oc ol is s u m m ariz e d i n fi g ur e 1 4 b el o w.  M o nit ori n g of T
r e g, Th 1 7, Tf h a n d pl as m a bl ast as w ell as IL -6 

 
 
P a g e 2 1   
a n d C R P l e v el will b e p erf or m e d  i n t h e Tr a ns pl a nt I m m u n ol o gy L a b at C e d ars-Si n ai M e dic al C e nt er at s el ect ti m e p oi nts 
( Dr. Mi e k o T oy od a Dir ect or, P h o n e: 3 1 0 -4 2 3 -8 2 8 2 ).  
 
 
 
Fi g ur e 1 4: T his fi g ur e s h o ws t h e pr ot oc ol d esi g n e d t o i nv esti g at e t h e s af et y a n d effic ac y of cl az a kiz u m a b i n tr e ati n g 
c A B M R + T G. T h e st u dy is o p e n l a b el, si n gl e c e nt er o n e -ar m st u dy t h at will e nt er p ati e nts di a g n os e d wit h c A B M R + T G by 
r e n al bi o psy a n d w h o h av e e G F R of > 3 0cc/ mi n at ti m e of di a g n osis. E nt er e d p ati e nts will rec eiv e cl az a kiz u m a b 2 5 m g 
e v ery 4 w e eks ( 3 0 d a ys ) f or a t ot al of 6 d os es.  If p ati e nts s h o w i m pr ov e m e nt (i e: e G F R/ D S A/ bi o psy/ PI c o nfir m ati o n) t h e y 
will c o nti n u e m o nt hly cl az akiz u m a b f or a n a d diti o n a l 6 m o nt hs a n d will h a v e a s ec o n d bi o psy at 1 2 m o nt h pr ot oc ol.  
I m m u n ol o gic a n d vir al m o nit ori n g l a bs will b e p erf or m e d as i n dic at e d.  F or t h os e c o nti n ui n g i n t h e l o n g t er m ext e nsi o n, 
t h e d a y 3 6 5 visit will b e f oll o w e d by visits ev ery  4- 8 w e e ks . 
T h e  s u bj ects will b e f oll o w e d t o d et er mi n e if t h e us e of cl az a kiz u m a b f or tr e at m e nt of cA B M R i n t hi s hi g h-ris k tr a ns pl a nt 
p o p ul ati o n is s af e a n d wit h o ut i nf ecti o us ris ks. I n a d diti o n , w e will d et er mi n e t h e eff ects of cl az a kiz u m a b tr e at m e nt o n 
r e n al bi o psy ass ess m e nts p erf or m e d at 6 m o nt hs. A ss ess m e nts of r e n al f u ncti o n, d o n or s p ecific a nti b o dy, a n d B a nff 
2 0 1 5  bi o ps y sc or es will b e e v al u at e d at t h at ti m e. If i m pr ov e m e nt or st a biliz ati o n o bs erv e d, cl az a kiz u m a b will b e 
r es u m e d m o nt hly x 6 d os es (st arti n g d ay 1 8 0 t o d a y 3 3 0) a n d l ast st u dy visit will b e d a y 3 6 5 wit h bi o ps y  f or t h os e w h o 
ar e n ot c o nti n ui n g t o t h e l o n g t er m ext e nsi o n . F or t h os e c o nti n ui n g i n t h e l o n g t er m ext e nsi o n, t h e d a y 3 6 5 visit will b e 
f oll o w e d by visits  e v er y  4- 8 w e e ks , p er t h e sc h e d ul e i n A p p e n dix E .  W e will ass ess t h e tr a ns pl a nt e d p ati e nts t o 
d et er mi n e t h e n u m b er w h o s ust ai n a vi a bl e a n d f u ncti o ni n g ki d n e y all o gr aft as w ell .  I n t h e ev e nt a p ati e nt d o es n ot 
s h o w i m pr o v e m e nt aft er r ec eivi n g 6 d os es of cl az a kiz u m a b, n o f urt h er tr e at m e nt will b e gi v e n a n d t h e p ati e nt will 
r et ur n at D ay 3 6 5 f or a fi n al st u dy visit. All s u bj ects will b e ev al u at e d o n a n i nt e nt-t o-tr e at b asis.  T h e s ubj ect accr u al r at e 
will b e li mit e d  t o 2 p ati e nts f or t h e i niti al d osi n g a p p oi nt m e nt. O nc e t h e first 2 p ati e nts h av e r ec eiv e d t h eir first 
i nj ecti o n, 2-4 p ati e nts m a y b e scr e e n e d p er m o nt h u ntil all 1 0 p ati e nts ar e e nr oll e d.  R e p e at l a b or at ori es will b e 
p erf o r m e d at t h e c o m pl eti o n of cl az a kiz u m a b t h er a py t o d et er mi n e eff ect o n l ev els a n d c orr el ati o n wit h a ny p ot e nti al 
e v e nts. A d et ail e d a n alysis of t h e st u dy is disc uss e d b el o w.  
A l o n g t er m d osi n g o pti o n at c o ncl usi o n of 1 2 m o nt hs ( aft er St u dy D a y 3 6 5 visit) F o r t h os e p ati e nts w h o c o m pl et e t h e 1 2 
m o nt h pr ot oc ol, p ati e nts m a y c o nti n u e t o r ec eiv e cl az a kiz u m a b 1 2. 5 m g or 2 5 m g s u b Q , d os e d ev ery 4 - 8 w e e ks  l o n g 
t er m, p er PI discr eti o n. Pl e as e s e e A p p e n dix E f or l o n g t er m visit sc h e d ul e. Bi o psi es d uri n g t h e l o n g t er m ext e nsi o n will 

 
 
P a g e 2 2   
b e c o n d uct e d at 1 2 m o nt hs p er PI discr eti o n or f or c a us e (s us p ect e d r ej ecti o n).  T h e l o n g t er m ext e nsi o n of t his st u dy is 
pl a n n e d as a n o n g oi n g pr ot oc ol, wit h p ati e nts t o c o nti n u e i n t h e L T E if a p pr ov e d o n a n a n n u al b asis by PI a n d C SL 
B e hr i n g.  P artici p a nts i n t h e L T E c o m p o n e nt of t h e st u dy will b e r e m o v e d if it is d et er mi n e d t h at t h er e is n o l o n g er a 
cli nic al b e n efit of t h er a py or if t h er e is a n o bs erv e d iss u e wit h s af ety. T h e L T E will b e all o w e d u ntil cl az a kiz u m a b is F D A 
a p pr o v e d i n t h e U S or if t h e st u dy is t er mi n at e d. T h e o bj ectiv es f or t h e L T E ar e i ncl u d e d i n S ecti o ns 3 a n d 3. 1.  P hysic al 
ex a ms d uri n g t h e L T E will occ ur i n p ers o n or vi a Vi d e o Visit, as p er S O C pr ot oc ol.  
 
4. 1  St u dy A n al ysis  
  
T his si n gl e -c e nt er, si n gl e-ar m, P h as e I/II, tri al is d esi g n e d t o ex a mi n e t h e s af ety, t ol er a bility a n d li mit e d effic ac y of 
h u m a n cl az a kiz u m a b (2 5 m g  S C Q 4 W ) giv e n as p er pr ot oc ol ( A p p e n dix A) i n 1 0 s u bj ects  w h o ar e D S A +  a n d h a v e bi o ps y 
pr o v e n cA B M R  + T G . P ati e nts c o nsi d er e d f or t his st u dy m a y h av e  b e e n tr e at e d wit h  hi g h -d os e I VI G + rit uxi m a b a n d/ or 
pl as m a p h er esis 3, 6, 7  I n a d diti o n, s o m e p ati e nts wit h e arl y, s ev er e A B M R m ay h a v e b e e n tr e at e d wit h Ec uliz u m a b4 2. 
 
4. 2  D efi ni n g A B M R   
 
F or p ur p os es of t his i nv esti g ati o n, a nti b o dy -m e di at e d r ej ecti o n ( A B M R) is d efi n e d as f oll o ws:  
 
 D et eri or ati o n of all o gr aft f u ncti o n i n a tr a ns pl a nt r eci pi e nt m e as ur e d by  e G F R  ( d efi n e d as a e G F R > 
3 0cc/ mi n  r e d ucti o n fr o m b as eli n e).    
 Ass oci ati o n wit h t h e pr es e nc e of D S A ( us u all y i ncr e asi n g i n str e n gt h) m e as ur e d by l u mi n ex t ec h ni q u es.  
 Bi o ps y e vi d e nc e of c A B M R a n d T G by bi o ps y by B a nff 2 0 1 5 crit eri a.  
 
4. 3 Tr e at m e nt of All o gr aft R ej ecti o n E pis o d es  D uri n g t h e St u dy  
 
Bi o ps y- pr o v e n r ej ecti o n e pis o d es  t h at occ ur d uri n g t h e st u dy ar e tr e at e d wit h “ p uls e” m et hyl pr e d nis ol o n e 
( 1 0 m g/k g/ d ay, m ax 1 0 0 0 m g f or > 1 0 0 k g f or 3 d ays) a n d a nti -t hy m oc yt e gl o b uli n ( 1. 5 m g/ k g d ail y X 4) f or c ell-m e di at e d 
r ej ecti o n e pis o d es t h at ar e u nr es p o nsi v e t o p uls e st er oi ds. P ati e nts  ex p eri e nci n g r ec urr e nt A B M R  e pis o d es aft er st u dy 
dr u g tr e at m e nt, will i niti ally r ec ei v e p uls e m et hyl pr e d nis ol o n e ( 1 0 m g/k g/ d a y, m ax 1 0 0 0 m g f or > 1 0 0 k g) I V d ail y x 3 d os es 
t h e n, d e p e n di n g o n s ev erity, I VI G 1 0 % s ol uti o n 2 g m/k g ( m ax 1 4 0 g f or > 7 0 k g) I V X 1  d os e  f oll o w e d by rit uxi m a b 
( 3 7 5 m g/ m 2 r o u n d e d t o t h e n e ar est 1 0 0 m g) I V X 1  d os e  t hr e e t o fi v e d a ys aft er l ast I VI G d os e. I n c as es w h er e ra pi d 
d et eri or ati o n of all o gr aft f u ncti o n is s e e n a n d/ or t hr o m b otic micr o a n gi o p at h y di a g n os e d , t h e p ati e nt will r ec ei v e pl as m a 
exc h a n g e X  3-5 s essi o ns f oll o w e d by a nti -C 5 ( Ec uliz u m a b ®) I V w e ekl y X 4 w e e ks ( 1 2 0 0 m g w e e k # 1 f oll o w e d by 9 0 0 m g/ 
w e ekl y f or 3 a d diti o n al w e e ks).  Effic acy of t h er a py will b e ass ess e d by d et er mi ni n g r e n al f u ncti o n i m pr o v e m e nt, 
m o nit ori n g D S A r es p o ns es a n d r e p e at all o gr aft bi o psi es, if n e e d e d.  
 
4. 4  M o nit ori n g f or A E/ S A Es P ost -Tr a ns pl a nt i n H S P ati e nts   
 
A dv ers e ev e nts ( A Es) a n d s eri o us a dv ers e ev e nts will b e m o nit or e d p ost -A B M R tr e at m e nt wit h cl az akiz u m a b. T h es e 
i ncl u d e c ar ef ul att e nti o n t o i nf ecti o us c o m plic ati o ns p ot e nti all y ass oci at e d wit h cl az a kiz u m a b t h er a py.  
 
I nf ecti o us c o m plic ati o ns ass oci at e d wit h I VI G + rit uxi m a b d es e nsitiz ati o n a n d al e mt uz u m a b i n d ucti o n t h er a py f oll o w e d 
by m ai nt e n a nc e t h er a py wit h t acr oli m us, M M F a n d pr e d nis o n e h av e b e e n ass ess e d by o ur gr o u p. Bri efl y, w e ev al u at e d 
1 7 0 p ati e nts w h o w er e d es e nsitiz e d wit h I VI G + rit uxi m a b f oll o w e d by al e mt uz u m a b i n d ucti o n a n d m ai nt e n a nc e t h er a py 
wit h t acr oli m us, M M F a n d st er oi ds. T his w as c o m p ar e d t o a c o nc o mit a nt gr o u p of n o n -s e nsitiz e d, l o w-ris k tr a ns pl a nts 
( N = 1 9 1) w h o di d n ot r ec ei v e I VI G, rit uxi m a b or al emt uz u m a b (i n d ucti o n wit h IL -2 R bl ock ers). A c ar ef ul a n al ysis of all 
i nf ecti o ns a n d s eri o us i nf ecti o ns t h at occ urr e d ov er t h e n ext 4 y e ars w as c o m pil e d a n d is s h o w n i n Fi g ur e 1 5 A & 1 5 B .  
Bri efl y, t h es e d at a s h o w t h at t h e us e of t his d es e nsitiz ati o n pr ot oc ol f oll o w e d wit h al e mt uz u m a b i n d ucti o n d o es n ot 
i ncr e as e t h e risk f or c o m m o n or s eri o us i nf ecti o ns p ost-tr a ns pl a nt c o m p ar e d t o a l o w ris k gr o u p of p ati e nts. S eri o us 
i nf ecti o ns w er e d efi n e d as a ny vir al i nf ecti o n a n d f u n g al or b act eri al i nf ecti o ns r e q uiri n g i. v. a nti bi otics or 

 
 
P a g e 2 3   
h os pit aliz ati o ns 4 1. T h us ris k f or i nf ecti o ns i n t h e st u dy gr o u p (cl az a kiz u m a b) aft er A B M R tr e at m e nt will lik ely b e si mil ar 
a n d c o m p ar a bl e t o n o n -s e nsitiz e d p ati e nts.  All p ati e nts e nt er e d i nt o t his st u dy ar e r e q uir e d t o b e v acci n at e d f or 
Str e pt oc occ us p n e u m o ni a e .  
 
1 5 A & 1 5 B : T his fi g ur e s h o ws t h e pr o p orti o n of ki d n ey tr a ns pl a nt r eci pi e nts w h o d e v el o p e d i nf ecti o ns ( all i nf ecti o ns 1 5 A , 
or s eri o us i nf ecti o ns 1 5 B ) p ost-tr a ns pl a nt. P ati e nts w er e i n t h e l o w-ris k gr o u p ( n o n-Rit ux # 1 9 1) w h o di d n ot r ec eiv e 
I VI G/rit ux or al e mt uz u m a b or ( Rit ux # 1 7 1) w h o r ec ei v e d d es e nsitiz ati o n wit h rit uxi m a b, I VI G f oll o w e d by 
tr a ns pl a nt ati o n. F oll o w u p f or u p t o 4 5 m o nt hs s h o ws t h at i nf ecti o n r at es ar e si mil ar. T h e c o m m o n est i nf ecti o n w as 
uri n ar y tr act i nf ecti o n i n b ot h gr o u ps. T h e i nci d e nc e of C M V w as g r e at er i n t h e n o n-Rit ux gr o u p w hil e t h er e w er e m or e 
B K i nf ecti o ns i n t h e Rit ux gr o u p. N o p ati e nts i n t h e Rit ux gr o u p d ev el o p e d P TL D or P ML w hil e 2 p ati e nts i n t h e n o n -Rit ux 
gr o u p d e v el o p e d P TL D 4 3.  
 
M or e r ec e nt s af ety d at a o n vir al i nf ecti o ns i n m or e t h a n 4 0 0 hi g hl y HL A s e nsitiz e d p ati e nts tr e at e d wit h I VI G + rit uxi m a b 
a n d C a m p at h -1 H i n d ucti o n t h er a py  w er e c o m p ar e d t o ~ 6 0 0 p ati e nts w h o w er e n o n -s e nsitiz e d a n d di d n ot r ec eiv e 
d es e nsitiz ati o n. T h e d at a ar e s h o w n b el o w:  
 
 
 

 
 
P a g e 2 4   
Fi g ur e 1 6 : T h e d at a s h o w n a b o v e  s h o w t h e vir al P C R p ositivit y f or C M V, E B V a n d p ol y m a B K vir us i n 4 0 0 d es e nsitiz e d 
p ati e nts c o m p ar e d wit h 6 0 0 st a n d ar d ki d n e y tr a ns pl a nt r eci pi e nts. Of i nt er est ar e t h e si g nific a ntl y l o w er i nci d e nc e of 
E B V a n d C M V vir e mi a i n d es e nsitiz e d i n di vi d u als c o m p ar e d wit h n or m al n o n -s e nsitiz e d tr a ns pl a nt r eci pi e nts. N o 
diff er e nc es w er e s e e n b et w e e n t h e hi g hl y -HL A s e nsitiz e d p ati e nts a n d n o n -s e nsitiz e d p ati e nts i n i nci d e nc e of B K 
vir e mi a. T h us, n o si g nific a nt ris k f or vir e mi a is s e e n, i n f act, t h er e a p p e ars t o b e a b e n efic al eff ect of D E S o n r e d uci n g 
i nci d e nc e of C M V a n d E B V vir e mi a.  
 
4. 5  S af et y R e p orti n g of A dv ers e E v e nts  
S af et y R e p orti n g of A dv ers e E v e nts  
Ass ess m e nt of S af ety  
S p ecific ati o n of S af ety V ari a bl es  
S af et y ass ess m e nts will c o nsist of m o nit ori n g a n d r e p orti n g all a dv ers e ev e nts ( A Es) a n d s eri o us a dv ers e ev e nts ( S A Es) , 
all e v e nts of d e at h, a n d a ny st u dy s p ecific iss u e of c o nc er n.  
A dv ers e E v e nts  
A n A E is a ny u nf av or a bl e a n d u ni nt e n d e d si g n, s y m pt o m, or dis e as e t e m p or ally ass oci at e d wit h t h e us e of a n 
i nv esti gati o n al m e dici n al pr o d uct (I M P) or ot h er pr ot oc ol -i m p os e d i nt er v e nti o n, r e g ar dl ess of attri b uti o n. 
T his i ncl u d es t h e f oll o wi n g:  
•  
A Es n ot pr evi o usly o bs erv e d i n t h e s u bj ect t h at e m er g e d uri n g t h e pr ot oc ol -s p ecifi e d A E r e p orti n g p eri o d, 
i ncl u di n g si g ns or s y m pt o ms ass oci at e d wit h Cl az a kiz u m a b i nf usi o n t h at w er e n ot pr es e nt pri or t o t h e A E 
r e p orti n g p eri o d. 
•  
C o m plic ati o ns t h at occ ur as a r es ult of pr ot oc ol -m a n d at e d i nt erv e nti o ns ( e. g., r e n al pr ot oc ol bi o psy).  
•  
If a p plic a bl e, A Es t h at occ ur pri or t o assi g n m e nt of st u dy tr e at m e nt ass oci at e d wit h m e dic ati o n w as h o ut, n o 
tr e at m e nt r u n-i n, or ot h er pr ot oc ol-m a n d at e d i nt erv e nti o n.  
•  
Pr e existi n g m e dic al c o n diti o ns ( ot h er t h a n t h e c o n diti o n b ei n g st u di e d) j u d g e d by t h e i nv esti g at or t o h av e 
w ors e n e d i n s e v erit y or fr e q u e nc y or c h a n g e d i n c h ar act er d uri n g t h e pr ot oc ol -s p ecifi e d A E r e p orti n g p eri o d. 
S eri o us A dv ers e Ev e nts  
A n A E s h o ul d b e cl assifi e d as a n S A E if t h e f oll o wi n g crit eri a ar e m et:  
•  
It r es ults i n d e at h (i. e., t h e A E act u all y c a us es or l e a ds t o d e at h). 
•  
It is lif e t hr e at e ni n g (i. e., t h e A E, i n t h e vi e w of t h e i nv esti g at or, pl ac es t h e s u bj ect at i m m e di at e ris k of d e at h. It 
d o es n ot i ncl u d e a n A E t h at, h a d it occ urr e d i n a m or e s e v er e f or m, mi g ht h av e c a us e d d e at h.).  
•  
It r e q uir es or pr ol o n gs i n p ati e nt h os pit aliz ati o n. 
•  
It r es ults i n p ersist e nt or si g nific a nt dis a bilit y/i nc a p acit y (i. e., t h e A E r es ults i n s u bst a nti al disr u pti o n of t h e 
s u bj ect’s a bility t o c o n d uct n or m al lif e f u ncti o ns). 
•  
It r es ults i n a c o n g e nit al a n o m al y/ birt h d ef ect i n a n e o n at e/i nf a nt b or n t o a m ot h er ex p os e d t o t h e I M P. 
•  
It is c o nsi d er e d a si g nific a nt m e dic al ev e nt by t h e i nv esti g at or b as e d o n m e dic al j u d g m e nt ( e. g., m ay j e o p ar diz e 
t h e s u bj ect or m a y r e q uir e m e dic al/s ur gic al i nt er v e nti o n t o pr ev e nt o n e of t h e o utc o m es list e d a b ov e). 
M et h o ds a n d Ti mi n g f or Ass essi n g A N D R ec or di n g S af et y v ari a bl es  
T h e i nv esti g at or is r es p o nsi bl e f or e ns uri n g t h at all A Es a n d S A Es t h at ar e o bs erv e d or r e p ort e d d uri n g t h e st u dy, ar e 
c oll ect e d a n d r e p ort e d t o t h e F D A, a p pr o pri at e I R B(s), a n d C SL B e hri n g LL C . i n acc or d a nc e wit h C F R 3 1 2. 3 2 (I N D S af ety 
R e p orts).  

 
 
P a g e 2 5   
A dv ers e E v e nt R e p orti n g P eri o d  
T h e st u dy p eri o d d uri n g w hic h all A Es a n d S A Es m ust b e r e p ort e d b e gi ns aft er i nf or m e d c o ns e nt is o bt ai n e d a n d 
i niti ati o n of st u dy tr e at m e nt a n d e n ds 1 5 0 d a ys aft er t h e l ast d os e of st u dy dr u g 
4. 5. 1  
R e p orti n g of S eri o us A dv ers e Ev e nts Ass oci at e d wit h Cl az a kiz u m a b  
A ny S eri o us A dv ers e E v e nt ( S A E)/ S eri o us A dv ers e R e acti o n ( S A R)/ S p eci al Sit u ati o n  ( d efi n e d i n t h e C SL N ov ati o n 
A gr e e m e nt)  t h at occ urs d uri n g t h e c o urs e of t h e S T U D Y a n d is ass oci at e d wit h t h e us e of a C SL B st u dy dr u g m ust b e 
f or w ar d e d wit hi n o n e ( 1) w or ki n g d a y  fr o m D at e of First R ec ei pt t o C SL B by e-m ail or f ax (s e e T a bl e ) irr es p ecti v e of 
w h et h er it is ass ess e d t o b e r el at e d t o t his pr o d uct.  
T h e exc h a n g e of a ll S A E/ S A R/ A R c as e r e p ort i nf or m ati o n s h all b e i n E n glis h l a n g u a g e by usi n g a C as e R e p ort F or m a gr e e d 
o n by C SL B .  
C SL B s h all ack n o wl e d g e r ec ei pt wit hi n t w o ( 2) w or ki n g d a ys. S h o ul d t h e I N S TI T U TI O N n ot r ec ei v e a c o nfir m ati o n of t h e 
c as e r ec ei pt wit hi n t h e t w o ( 2) w or ki n g d a ys, t h e I N S TI T U TI O N s h all r e q u est c o nfir m ati o n t h at t h e r e p ort h as r e ac h e d 
C SL B.  
T h e I N S TI T U TI O N s h o ul d c o o p er at e wit h C SL B a n d pr ovi d e missi n g i nf or m ati o n i n a ti m ely m a n n er as w ell as r es p o ns es 
t o q u eri es u ntil t h e ev e nt h as r es ol v e d, or, i n c as e of p er m a n e nt i m p air m e nt, u ntil st a biliz e d.  F oll o w -u p i nf or m ati o n 
o bt ai n e d by t h e I N S TI T U TI O N s h o ul d b e h a n dl e d acc or di n gl y, a n d f or w ar d e d as p er t h e ti m eli n es st at e d a b ov e.  
C o nt act f or E xc h a n g e of S A E/ S A R/ A R r es p. S U S A R/ Pr e g n a nc y/ S p eci al Sit u ati o n I nf or m ati o n: 
N a m e  
H el e n S b orli ni ( C as e R e p orts)  
S a m a nt h a G a n ( A E -R ec o ncili ati o n)  
Titl e  
C as e M a n a g e m e nt T e a m L e a d, C SL B -G C S P Ki n g of Pr ussi a U S  
I C S R C o m pli a nc e a n d R ec o ncili ati o n L e a d, C SL B-G C S P P ar kvill e A U  
e- m ail  
A E r e p orti n g: a dv ers e. e v e nts. gl o b al @ C SL B e hri n g.c o m  
Gl o b al A E r ec o ncili ati o n e m ail:  
Gl o b al. R ec o ncili ati o n @csl.c o m. a u  
F ax  
+ 1 6 1 0 -8 7 8 -4 4 8 7  
C o nt act f or o t h er S af et y Iss u es r e g ar di n g t h e P R O D U C T: 
N a m e  
D a vi d G a o  
Titl e  
Dir ect or, Cli nic al S af et y P hysici a n , I m m u n ol o gy 
Gl o b al Cli nic al S af ety a n d P h ar m ac o vi gil a nc e  
e- m ail  
Z hi y o n g. G a o @csl b e hri n g.c o m   
P h o n e  
+ 1 6 1 0 -2 9 0 -7 6 5 9  (f or A E R e p orti n g o nl y) 
 
C o nt act f or St u d y R e p ort distri b uti o n (r ef er t o s ecti o n 1. 3):  e m ail s u bj ect ' R e p ort fr o m Cl az a kiz u m a b II T , pl e as e 
distri b ut e t o r es p o nsi bl e G SL / C S S a n d C M' 

 
 
P a g e 2 6   
N a m e  
S af et y Sci e nc e & Si g n al M a n a g e m e nt  
e- m ail  
R D G C S P S af ety Sci e nc es Si g n al M a n a g e m e nt @csl b e hri n g.c o m  
 
S A E R e p orti n g  
C o nt act I nf or m ati o n  
St u dy C o or di n ati o n C e nt er/ Pri nci p al 
I nv esti g at or: St a nl ey C. J or d a n, M. D. 
T el:  
3 1 0 -4 2 3 -2 6 4 1  
F ax:  
3 1 0 -4 2 3 -6 3 6 9  
I R B C o nt act i nf or m ati o n a n d f ax # 
K er e n D u n n  
C e d ars -Si n ai M e dic al C e nt er  
Dir ect or, R es e arc h C o m pli a nc e  
T el: 3 1 0 -4 2 3 -3 7 8 3  
F ax: 3 1 0 -4 2 3 -4 1 9 5  
 
A N D:  
M e d W atc h 3 5 0 0 A R e p orti n g G ui d eli n es:  
I n a d diti o n t o c o m pl eti n g a p pr o pri at e p ati e nt d e m o gr a p hic a n d s us p ect m e dic ati o n i nf or m ati o n, t h e r e p ort s h o ul d 
i ncl u d e t h e f oll o wi n g i nf or m ati o n wit hi n t h e E v e nt D escri pti o n (s ecti o n 5) of t h e M e d W atc h 3 5 0 0 A f or m: 
•  
Tr e at m e nt r e gi m e n ( d osi n g fr e q u e nc y, c o m bi n ati o n t h er a py)  
•  
Pr ot oc ol d escri pti o n ( a n d n u m b er, if assi g n e d)  
•  
D escri pti o n of e v e nt, s e v erit y, tr e at m e nt, a n d o utc o m e if k n o w n  
•  
S u p p ortiv e l a b or at ory r es ults a n d di a g n ostics  
•  
I nv esti g at or’s ass ess m e nt of t h e r el ati o ns hi p of t h e a dv ers e ev e nt t o e ac h i nv esti g ati o n al pr o d uct a n d s us p ect 
m e dic ati o n  
F oll o w -u p i nf or m ati o n:   
A d diti o n al i nf or m ati o n m ay b e a d d e d t o a pr evi o usl y s u b mitt e d r e p ort by a ny of t h e f oll o wi n g m et h o ds:  
•  
A d di n g t o t h e ori gi n al M e d W atc h 3 5 0 0 A r e p ort a n d s u b mitti n g it as f oll o w-u p  
•  
A d di n g s u p pl e m e nt al s u m m ar y i nf or m ati o n a n d s u b mitti n g it as f oll o w -u p wit h t h e ori gi n al M e d W atc h 3 5 0 0 A f or m .  
•  
S u m m arizi n g n e w i nf or m ati o n a n d f axi n g it wit h a c o v er l ett er i ncl u di n g s u bj ect i d e ntifi ers (i. e. D. O. B. i niti al, s u bj ect 
n u m b er), pr ot oc ol d escri pti o n a n d n u m b er, if assi g n e d, s us p ect dr u g, bri ef a dv ers e ev e nt d escri pti o n, a n d n ot ati o n 
t h at a d diti o n al or f oll o w-u p  i nf or m ati o n is b ei n g s u b mitt e d ( T h e p ati e nt i d e ntifi ers ar e i m p orta nt s o t h at t h e n e w 
i nf or m ati o n is a d d e d t o t h e c orr ect i niti al r e p ort) 
 
Occ asi o n all y C SL B e hri n g  m a y c o nt act t h e r e p ort er f or a d diti o n al i nf or m ati o n, cl arific ati o n, or c urr e nt st at us of t h e 
s u bj ect f or w h o m a n d a dv ers e ev e nt w as r e p ort e d.  F or q u esti o ns re g ar di n g S A E r e p orti n g, y o u m ay c o nt act t h e C SL 
B e hri n g  Dr u g S af et y r e pr es e nt ati v e n ot e d a b ov e.  
W it h c o m pl eti o n of t h e S T U D Y, t h e I N S TI T U TI O N s h all pr o vi d e t o C SL B vi a e m ail or f ax (s e e A P P E N DI X 0 1) t h e 
fi n al/cli nic al st u dy r e p ort wit hi n t hr e e m o nt hs aft er c o m pl eti o n of St u dy c o n d uct or t er mi n ati o n of t his a gr e e m e nt .. A ny 

 
 
P a g e 2 7   
i nt eri m r e p ort is t o b e pr o vi d e d by t h e I N S TI T U TI O N h as t o b e f or w ar d e d o n a bi -a n n u al b asis . 
I n a d diti o n, t h e I N S TI T U TI O N s h all pr o vi d e a li n e listi n g/t a bl e i ncl u di n g t h e c a us alit y ass ess m e nt f or e ac h 
S A E/ S A R/ A R/ A E/ S p eci al Sit u ati o n wit hi n fi v e ( 5) w or ki n g d a ys aft er cl os ur e of t h e d at a b as e. T h e P A R TI E S will a gr e e o n 
t h e ev e nt-l e v el d et ail pri or t o f or w ar di n g t o C SL B. 
St u dy Dr u g R el ati o ns hi p:  
T h e i nv esti g at or will d et er mi n e w hic h ev e nts ar e ass oci at e d wit h t h e us e of t h e st u dy dr u gs.  T h e c a us ality ass ess m e nt is 
t h e d et er mi n ati o n of w h et h er t h er e exists a r e as o n a bl e p ossi bility t h at t h e St u dy tr e at m e nt c a us e d or c o ntri b ut e d t o a n 
a dv ers e ev e nt:  
•  
N ot r el at e d:  T e m p or al r el ati o ns hi p t o St u dy tr e at m e nt a d mi nistr ati o n is missi n g or i m pl a usi bl e, or t h er e is evi d e nc e 
of a n ot h er c a us e.  
•  
P ossi bl y r el at e d:  R e as o n a bl e ti m e s e q u e nc e t o a d mi nistr ati o n of St u dy tr e at m e nt, b ut t h e e v e nt c o ul d als o b e 
ex pl ai n e d b y c o nc urr e nt dis e as e of ot h er dr u gs or c h e mic als.  I nf or m ati o n o n dr u g wit h dr a w al m ay b e l ac ki n g or 
u ncl e ar.  
•  
D efi nit ely r el at e d : Pl a usi bl e ti m e r el ati o ns hi p t o St u dy tr e at m e nt a d mi nistr ati o n; ev e nt c a n n ot b e ex pl ai n e d by 
c o nc urr e nt dis e as e or ot h er dr u gs or c h e mic als.  T h e r es p o ns e t o wit h dr a w al of t h e dr u g ( d ec h all e n g e) s h o ul d b e 
cli nic all y pl a usi bl e.  T h e e v e nt m ust b e d efi niti v e p h ar m ac ol o gic all y or p h e n o m e n ol o gic ally, usi n g a s atisf act or y r e -
c h all e n g e pr oc e d ur e if n ec ess ar y. 
4. 5. 2  
 
Pr e g n a nc y R e p o rti n g 
 
S h o ul d a p ati e nt or f e m al e p art n er of a m al e u n d er tr e at m e nt wit h a C SL B pr o d uct b ec o m e pr e g n a nt d uri n g t h e c o urs e 
of t h e S T U D Y, t his i nf or m ati o n m ust b e f or w ar d e d t o CSL B wit hi n t e n ( 1 0) c al e n d ar d a ys. T h e I N S TI T U TI O N s h all f oll o w-
u p u ntil o utc o m e of pr e g n a nc y is k n o w n a n d p ot e nti al s af et y c o nc er ns h av e b e e n cl arifi e d. As s o o n as o utc o m e of 
pr e g n a nc y is av ail a bl e t o t h e I N S TI T U TI O N t his i nf or m ati o n h as t o b e pr o vi d e d t o C SL B wit hi n o n e ( 1) w or ki n g d a y.  
 I n c as e of a pr e g n a nc y i n t h e f e m al e p art n er of a m al e s u bj ect, t h e I nv esti g at or s h o ul d o bt ai n i nf or m e d c o ns e nt of t h e 
pr e g n a nt p art n er pri or t o m o nit ori n g of t h e pr e g n a nc y.  
 
4. 6  I nf ecti o n Pr o p hyl axis Pr ot oc ols a n d Vir al M o nit ori n g P ost-Tr a ns pl a nt  
All st u dy p ati e nts, r e g ar dl ess of t h eir c yt o m e g al o vir us ( C M V) st at us, r ec ei v e I V g a ncicl o vir w hil e i n p ati e nts a n d 
v al g a ncicl ovir as o ut p ati e nts f or 6 m o nt hs p ost ki d n e y tr a ns pl a nt, wit h d os e a dj ust m e nts f or r e n al f u ncti o n. F u n g al 
pr o p hyl axis w as acc o m plis h e d wit h fl uc o n az ol e 1 0 0 m g d ail y f or 1 m o nt h p ost tr a ns pl a nt. P n e u m oc ystis jir o v ecii 
p n e u m o ni a a n d b act eri al pr o p hyl axis is acc o m plis h e d wit h tri m et h o pri m 8 0 m g a n d s ulf a m et h ox az ol e 4 0 0 m g d ail y f or 
1 2 m o nt hs p ost tr a ns pl a nt.  N o a d diti o n al pr o p hyl axis will b e n e e d e d f or p ati e nts w h o ar e e nr oll e d  i n t his tri al m or e t h a n 
o n e y e ar fr o m tr a ns pl a nt.  
Vir al p ol y m er as e c h ai n r e acti o n ass a ys f or C M V, E pst ei n B arr vir us, P arv o vir us B -1 9, P ol y o m a vir us B K a n d J C will b e 
p erf or m e d o n st u dy p ati e nts m o nt hly f or 6 m o nt hs p ost -tr a ns pl a nt ati o n. M et h o d ol o gi es us e d f or m o nit ori n g vir al 
r e plic ati o n h av e b e e n d escri b e d pr e vi o usl y 2 5. 

 
 
P a g e 2 8   
5  
D osi n g of Cl az akiz u m a b   
F or a nti b o d y m e di at e d r ej ecti o n: Cl az a kiz u m a b will b e a d mi nist er e d at a d os e of  2 5 m g/ S C e v er y 4 w e e ks p ost 
p uls e  m et h yl pr e d nis ol o n e , pl as m a p h er esis, a n d hi g h d os e I VI G. If t h e p ati e nt pr oc e e ds t o t h e L T E, t h e y will 
r ec ei v e cl az a kiz u m a b 1 2. 5 m g or 2 5 m g S C Q 4 W or Q 8 W.  
 
Pr o d uct D escri pti o n, St or a g e a n d A d mi nistr ati o n I nstr ucti o ns  
Cl az a kiz u m a b will b e pr o vi d e d by C SL B e hri n g LL C . 
G e n eric n a m e:  
Cl az a kiz u m a b  
Activ e i n gr e di e nt:  
G e n etic ally e n gi n e er e d h u m a niz e d a nti -IL-6 m A b  
Str e n gt h:  
1 2. 5 m g/ mL (o nc e t h e 2 5 m g/ mL c o nc e ntr ati o n w as n o l o n g er a v ail a bl e ) 
Exci pi e nts:   
L-histi di n e, L -histi di n e m o n o hy dr oc hl ori d e, s or bit ol, p ol ys or b at e -8 0, a n d w at er f or i nj ecti o n 
A p p e ar a nc e:  
Cl e ar t o sli g htly o p a q u e, c ol orl ess t o d ar k y ell o w -c ol or e d s ol uti o n 
D os a g e f or m:  
Si n gl e -d os e vi als ( 2 5 m g/ mL  or 1 2. 5 m g/ mL ) f or i nj ecti o n. 
M a n uf act ur er:  Aji n o m ot o Alt h e a, S a n Di e g o C A  
P at h e o n M a n uf act uri n g S er vic es LL C, Gr e e nvill e, N C  
Cl az a kiz u m a b vi als s h o ul d b e st or e d at ≤-2 0° C ( -4° F)  wit h pr ot ecti o n fr o m li g ht.  
T h e dr u g pr o d uct will b e a d mi nist er e d u n dil ut e d at a c o nc e ntr ati o n of 1 2. 5 m g/ mL .  
Pr e p ar e d s yri n g es m a y b e st or e d f or u p t o 2 4 h o urs i n a r efri g er at or, 2° -8° C ( 3 6° -4 6° F), a n d u p t o 4 h o urs of t h e 2 4 h o urs 
m a y b e at r o o m t e m p er at ur e, 1 5° -2 5° C ( 5 9° -7 7° F). T h e pr e p ar e d syri n g es s h o ul d b e pr ot ect e d fr o m li g ht.  
Pri or t o a d mi nistr ati o n, cl az a kiz u m a b s h o ul d r e ac h r o o m t e m p er at ur e by st ori n g u nr efri g er at e d f or 3 0 t o 6 0 mi n ut es 
b ef or e us e.  
 I P r e q u ests s h o ul d b e s e nt t o: C e ntr al Gr o u p. C T S @ csl b e hri n g. c o m   
5. 1  St or a g e a n d H a n dli n g  
Cl az a kiz u m a b will n ot b e us e d aft er t h e ex pir y d at e ( E X P) s h o w n o n t h e kit or vi al . 
5. 1. 1  
Cl az a kiz u m a b Ov er d os e   
T h er e ar e n o s p ecific a nti d ot es or m e as ur es t o t ak e i n t h e ev e nt of a n o v er d os e of cl az a kiz u m a b i nj ecti o n. S u bj ects 
s h o ul d b e tr e at e d wit h t h e a p pr opri at e s u p p ortiv e c ar e.  
5. 2  D os e M o dific ati o n/ T oxicit y M a n a g e m e nt  
A n u m b er of m e as ur es will b e t a k e n t o e ns ur e t h e s af et y of p ati e nts p artici p ati n g i n t his st u dy.  T h es e m e as ur es will b e 
a d dr ess e d t hr o u g h excl usi o n crit eri a (s e e S ecti o n 4. 2) a n d r o uti n e m o nit o ri n g as f oll o ws:   

 
 
P a g e 2 9   
P ati e nts e nr oll e d i n t his st u dy will b e ev al u at e d cli nic all y a n d wit h st a n d ar d l a b or at or y t ests b ef or e a n d d uri n g t h eir 
p artici p ati o n i n t his st u dy.  S af et y e v al u ati o ns will c o nsist of m e dic al i nt er vi e ws, r ec or di n g of a dv ers e ev e nts, p hy sic al 
ex a mi n ati o ns, bl o o d pr ess ur e, a n d l a b or at ory m e as ur e m e nts.  S u bj ects will b e ev al u at e d f or a dv ers e ev e nts ( all gr a d es), 
s eri o us a dv ers e e v e nts, a n d a dv ers e ev e nts r e q uiri n g st u dy dr u g i nt err u pti o n or disc o nti n u ati o n at e ac h st u dy visit f or 
t h e d ur ati o n of t h eir p artici p ati o n i n t h e st u dy.   
5. 3   A dv ers e Dr u g R e acti o ns  
O p p ort u nistic I nf ecti o ns a n d S eri o us I nf ecti o ns  
P hysici a ns s h o ul d ex ercis e c a uti o n w h e n c o nsi d eri n g t h e us e of c l az akiz u m a b i n p ati e nts wit h a hist ory of r ec urri n g 
i nf ecti o n or wit h u n d erlyi n g c o n diti o ns ( e g, di a b et es) w hic h m ay pr e dis p os e p ati e nts t o i nf ecti o ns. Cl az a kiz u m a b s h o ul d 
n ot b e a d mi nist er e d i n p ati e nts wit h ac tiv e i nf ecti o n. T h e eff ects of cl az a kiz u m a b o n C R P, n e utr o p hils, a n d t h e si g ns a n d 
s y m pt o ms of i nf ecti o n s h o ul d b e c o nsi d er e d w h e n ev al u ati n g a p ati e nt f or a p ot e nti al i nf ecti o n.  
Vi gil a nc e f or ti m el y d et ecti o n of s eri o us i nf ecti o n is r ec o m m e n d e d f or p ati e nts r ec ei vi n g bi ol o gic a g e nts f or tr e at m e nt of 
m o d er at e t o s ev er e R A as si g ns a n d s y m pt o ms of ac ut e i nfl a m m ati o n m a y b e l ess e n e d d u e t o s u p pr essi o n of t h e ac ut e 
p h as e r e acti o n. P ati e nts m ust b e i nstr uct e d t o c o nt act t h eir p hysici a n i m m e di at el y w h e n a ny sy m pt o ms s u g g esti n g 
i nf ecti o n a p p e ar, i n or d er t o ass ur e r a pi d ev al u ati o n a n d a p pr o pri at e tr e at m e nt.  
If a p ati e nt d e v el o ps a s eri o us i nf ecti o n, a d mi nistr ati o n of cl az a kiz u m a b is t o b e i nt err u pt e d u ntil t h e i nf ecti o n is 
c o ntr oll e d. T h e cli nici a n s h o ul d c o nsi d er t h e b e n efit -ris k b ef or e r es u mi n g tr e at m e nt wit h c l az a kiz u m a b. 
 G astr oi nt esti n al P erf or ati o ns   
Ti m ely di a g n osis a n d a p pr o pri at e tr e at m e nt m ay r e d uc e t h e p ot e nti al f or c o m plic ati o ns of div ertic ulitis a n d t h us r e d uc e 
t h e ris k of GI p erf or ati o ns. T h er ef or e, p ati e nts s h o ul d b e m a d e a w ar e of t h e sy m pt o m at ol o gy p ot e nti ally i n dic ati v e of 
div ertic ul ar dis e as e, a n d t h e y s h o ul d b e i nstr uct e d t o al ert t h eir h e alt hc ar e pr o vi d er as s o o n as p ossi bl e if t h es e 
s y m pt o ms aris e. I n p ati e nts wit h a hist or y of sy m pt o m atic di v ertic ul osis, di v ertic ulitis or c hr o nic ulc er ati v e l o w er GI 
dis e as e s uc h as Cr o h n’s dis e as e, ulc er ativ e c olitis or ot h er c hr o nic l o w er GI c o n diti o ns t h at mi g ht pr e dis p os e t o 
p erf or ati o ns, t h e cli nici a n s h o ul d c o nsi d er  t h e b e n efit-ris k b ef or e usi n g cl az a kiz u m a b.  Disc o nti n u ati o n of cl az a kiz u m a b 
is r ec o m m e n d e d f or p ati e nts w h o d ev el o p GI p erf or ati o ns. 
D e m y eli n ati n g Dis or d ers  
T h e i m p act of tr e at m e nt wit h cl az a kiz u m a b o n d e my eli n ati n g dis or d ers is n ot k n o w n; ev e nts w er e r ar ely r e p ort e d.  
P ati e nts s h o ul d b e cl os ely m o nit or e d f or si g ns a n d sy m pt o ms p ot e nti ally i n dic ati v e of c e ntr al d e my eli n ati n g dis or d ers.  
P hysici a ns s h o ul d  ex ercis e c a uti o n i n c o nsi d eri n g t h e us e of cl az kiz u m a b i n p ati e nts wit h pr e -existi n g or r ec e nt o ns et 
d e m y eli n ati n g dis or d ers. Tr e at m e nt wit h cl az akiz u m a b s h o ul d b e i nt err u pt e d d uri n g ass ess m e nt of a p ot e nti al 
d e m y eli n ati o n ev e nt a n d o nl y r es u m e d if t h e b e n efit of c o nti n ui n g st u dy dr u g is f a v or a bl e.   
H e m at ol o gic A b n or m aliti es a n d Bl e e di n g Ev e nts  
D ecr e as es i n n e utr o p hil a n d pl at el et c o u nts h a v e b e e n o bs erv e d f oll o wi n g tr e at m e nt wit h c l az a kiz u m a b i n c o m bi n ati o n 
wit h M T X. I n a d diti o n, t h er e m a y b e a n i ncr e as e d risk of n e utr o p e ni a i n p ati e nts w h o h av e pr e vi o usl y b e e n tr e at e d wit h 
a T N F a nt a g o nist.  

 
 
P a g e 3 0   
F or p ati e nts wit h c o nc o mit a nt m e dic ati o ns ass oci at e d wit h h e m at ol o gic t oxicit y, t h e r e d ucti o n or i nt err u pti o n of t h e 
s us p ect e d m e dic ati o n is r ec o m m e n d e d pri or to m o di fyi n g cl az a kiz u m a b. 
 
T a bl e 2: N e utr o p e ni a Ris k Miti g ati o n  
A N C (c ells/ m m 3) 
Acti o n  
> 1 0 0 0  
M ai nt ai n d os e.  
5 0 0 –  1 0 0 0  
I nt err u pt cl az a kiz u m a b d osi n g. 
W h e n A N C i ncr e as es t o > 1 0 0 0, r es u m e c l az a kiz u m a b 2 5 m g S Q 
m o nt hl y  
< 5 0 0  
Disc o nti n u e cl az akiz u m a b. 
A N C = a bs ol ut e n e utr o p hil c o u nt  
 
T a bl e 3: T hr o m b oc yt o p e ni a Ris k Miti g ati o n  
Pl at el et c o u nt (c ells/ m m 3) 
Acti o n  
> 1 0 0, 0 0 0  
M ai nt ai n d os e.  
5 0, 0 0 0 –  1 0 0, 0 0 0  
I nt err u pt cl az a kiz u m a b d osi n g.  
W h e n pl at el et c o u nt i ncr e as es t o > 1 0 0, 0 0 0, r es u m e 
Cl az a kiz u m a b at 2 5 m g S Q m o nt hl y  
< 5 0, 0 0 0  
Disc o nti n u e cl az akiz u m a b.  
 
 El e v at e d Liv er E nzy m es a n d H e p atic Ev e nts  
El e v ati o ns i n AL T a n d A S T h a v e b e e n o bs erv e d d uri n g tr e at m e nt wit h t h e st u dy m e dic ati o ns  
T a bl e 4:  
L a b V al u e 
Acti o n  
> 1 t o 3x UL N  
D os e m o dify c o nc o mit a nt tr a ns pl a nt i m m u n os u p pr essi v e dr u gs if 
a p pr o pri at e  
F or p ersist e nt i ncr e as es i n t his r a n g e, i nt err u pt cl az a kiz u m a b u ntil 
AL T/ A S T h a v e n or m aliz e d  

 
 
P a g e 3 1   
R est art wit h 2 5 m g S Q m o nt hl y as cli nic all y a p pr o pri at e 
> 3 t o 5x UL N  
(c o nfir m e d by r e p e at 
t esti n g) 
I nt err u pt cl az a kiz u m a b d osi n g u ntil < 3x UL N a n d f oll o w 
r ec o m m e n d ati o ns a b o v e f or > 1 t o 3x UL N 
F or p ersist e nt i ncr e as es > 3x UL N, disc o nti n u e Cl az a kiz u m a b  
Disc o nti n u e cl az akiz u m a b if t ot al  bilir u bi n > 2 x UL N  
> 5x UL N  
Disc o nti n u e cl az akiz u m a b  
 
C ar di o v asc ul ar Ev e nts a n d El e v at e d Li pi ds  
P ati e nts wit h R A h av e a n i ncr e as e d ris k f or c ar di ov asc ul ar dis or d ers, t h er ef or e, ris k f act ors f or c ar di ov asc ul ar dis e as e 
( e g, hy p ert e nsi o n, hy p erli pi d e mi a) s h o ul d b e m a n a g e d as p art of t h eir st a n d ar d of c ar e.  S e e s ecti o n o n Dr u g 
I nt er acti o ns.   
F or p ati e n ts wit h L DL c h ol est er ol ≥1 6 0 m g/ dL, it is str o n gl y r ec o m m e n d e d t h at i nv esti g at ors a dvis e t h er a p e utic lif estyl e 
c h a n g es t h at m ay i ncl u d e i niti ati o n li pi d-l o w eri n g a g e nts. Li pi d-l o w eri n g a g e nts s h o ul d als o b e c o nsi d er e d f or p ati e nts 
wit h l o w er L DL c h ol est er o l l e v els as p art of t h eir t h er a p e utic lif est yl e c h a n g es d e p e n di n g o n t h eir ov er all risk as d efi n e d 
i n N C E P A T P III or ot h er n ati o n al g ui d eli n es. 
M ali g n a nci es  
T h e i m p act of i m m u n os u p pr essi o n o n t h e d ev el o p m e nt of m ali g n a nci es is n ot k n o w n, h o w e v er a n i ncr e as e d r at e of 
s o m e m ali g n a nci es, n ot a bl y l y m p h o m a, h as b e e n o bs er v e d i n R A p ati e nts. Alt h o u g h n o i m b al a nc e of m ali g n a nci es w as 
o bs erv e d i n cli nic al tri als of c laz a kiz u m a b, m ali g n a nci es h a v e b e e n i d e ntifi e d as a c o nc er n f or ot h er bi ol o gics.  It is 
r ec o g niz e d t h at i de ntific ati o n of s uc h ev e nts i n c l az akiz u m a b-tr e at e d p ati e nts m ay r e q uir e a l o n g er p eri o d of 
s urv eill a nc e.  Cl az a kiz u m a b s h o ul d b e disc o nti n u e d i n p ati e nts wit h m ali g n a nci es ( wit h t h e exc e pti o n of l oc al b as al or 
s q u a m o us c ell c arci n o m a of t h e ski n t h at is c o m pl et ely excis e d wit h fr e e m ar gi ns).  
Hy p ers e nsitivity or A n a p hyl axis:  
A n i nf usi o n/ d os e r e acti o n is d efi n e d as a n a dv ers e e v e nt occ urri n g d uri n g a n d wi t hi n 2 4 h o urs aft er t h e i nf usi on or 
s u bc ut a n e o us i nj ecti o n of cl az a kiz u m a b. T his m ay i ncl u d e hy p ers e nsiti vit y r e acti o ns or a n a p hyl actic r e acti o ns.  
Si g ns of a p ossi bl e hy p ers e nsiti vity r e acti o n i ncl u d e b ut ar e n ot li mit e d t o:  
•  
f e v er, c hills, pr urit us, urtic ari a, a n gi o e d e m a, a n d s ki n r as h. 
•  
c ar di o p ul m o n ar y r e acti o ns, i ncl u di n g c h est p ai n, dys p n e a, hy p ot e nsi o n or hy p ert e nsi o n.  
H e alt hc ar e pr of essi o n als a d mi nist eri n g c l az akiz u m a b  s h o ul d b e tr ai n e d i n t h e a p pr o pri at e a d mi nistr ati v e pr oc e d ur es, 
b e a bl e t o r ec o g niz e t h e s y m pt o ms ass oci at e d wit h p ot e nti al a n a p hyl actic or hy p ers e nsitivit y r e acti o ns, a n d h a v e t h e 
a p pr o pri at e m e dic ati o n a v ail a bl e f or i m m e di at e us e i n c as e of a n a p hyl axis or hy p ers e nsitivit y r e acti o n d uri n g or aft er 

 
 
P a g e 3 2   
a d mi nis tr ati o n of cl az a kiz u m a b.  H e alt hc ar e pr of essi o n als s h o ul d als o i nstr uct p ati e nts t o s e ek m e dic al att e nti o n if t h e y 
ex p eri e nc e sy m pt o ms of a hy p ers e nsitivity r e acti o n o utsi d e of t h e cli nic.  
If a p ati e nt h as sy m pt o ms of a n a p hyl axis or s eri o us hy p ers e nsiti vity, or r e q uir es a n i nt err u pti o n of t h e st u dy dr u g 
b ec a us e of sy m pt o ms of a n a p hyl axis or hy p er s e nsitivity, a d mi nistr ati o n of cl az a kiz u m a b m ust b e disc o nti n u e d 
p er m a n e ntly.  T h e p ati e nt s h o ul d b e tr e at e d acc or di n g t o t h e st a n d ar d of c ar e f or m a n a g e m e nt of t h e  hy p ers e nsiti vit y 
r e acti o n.  A bl o o d sa m pl e f or t h e pr es e nc e of a nti -cl az a kiz u m a b a nti b o di es s h o ul d b e o bt ai n e d. 
Cl az a kiz u m a b s h o ul d n ot b e a d mi nist er e d t o s u bj ects w h o h av e h a d a ny pr evi o us all er gic r e acti o ns t o m o n ocl o n al 
a nti b o di es. T o d at e, n o i nf usi o n r e acti o ns h a v e b e e n ass oci at e d wit h cl az a kiz u m a b a d mi nist er e d by I V i nf usi o n. I nj ecti o n 
sit e r e acti o ns h av e b e e n r e p ort e d wit h S C a d mi nistr ati o n. R e acti o ns h a v e b e e n mil d or m o d er at e a n d h a v e r es olv e d 
wit h o ut tr e at m e nt. B ot h all er gic r e acti o ns a n d i nj ect i o n sit e r e acti o ns s h o ul d b e tr e at e d wit h st a n d ar d of c ar e. S u bj ects 
w h o h av e d e v el o p e d si g nific a nt all er gic r e acti o n t o st u dy dr u gs s h o ul d n ot b e r e -c h all e n g e d. 
Vir al R e activ ati o n  
T h o u g h r ar ely r e p ort e d wit hi n t h e cl az a kiz u m a b pr o gr a m d u e t o excl usi o n cri t eri a at st u dy e ntry, r e activ ati o n of vir al 
a n d ot h er s eri o us i nf ecti o ns ( e. g. E B V or T B) h as b e e n o bs erv e d wit h bi ol o gic t h er a pi es.  
Dr u g I nt er acti o n  
T h e f or m ati o n of C Y P 4 5 0 e nzy m es m a y b e s u p pr ess e d by i ncr e as e d l ev els of c yt oki n es ( e g, IL -6) d uri n g c hr o nic 
i nfl a m m ati o n. T h er ef or e, it is ex p ect e d t h at f or m ol ec ul es t h at a nt a g o niz e c yt o ki n e activit y, s uc h as cl az a kiz u m a b, t h e 
f or m ati o n of C Y P 4 5 0 e nzy m es c o ul d b e n or m aliz e d. W h e n st arti n g or st o p pi n g t h er a py wit h cl az akiz u m a b, p ati e nts 
t a ki n g m e dic ati o ns w hic h ar e i n di vi d u all y d os e-a dj ust e d a n d m et a b oliz e d vi a C Y P 4 5 0, 3 A 4, 1 A 2, or 2 C 9 ( e. g. at orv ast ati n, 
c alci u m c h a n n el bl oc k ers, t h e o p hylli n e, w arf ari n, p h e nyt oi n, c ycl os p ori n e, or b e nz o di az e pi n es) s h o ul d b e m o nit or e d as 
d os es m ay n e e d t o b e a dj ust e d t o m ai nt ai n t h eir t h er a p e utic eff ect. Gi v e n its l o n g eli mi n ati o n h alf -lif e (t 1/ 2), t h e eff ect 
of cl az a kiz u m a b o n C Y P 4 5 0 e nzy m e acti vit y m ay p ersist f or s ev er al w e e ks aft er st o p pi n g t h er a py.  
Pr e g n a nci es a n d W o m e n of C hil d B e ari n g P ot e nti al  
A t ot al of 9 pr e g n a nci es w er e r e p ort e d fr o m t h e cl az a kiz u m a b c o m pl et e d cli nic al st u di es. Ei g ht w er e ex p os e d t o 
cl az a kiz u m a b, a n d 1 t o pl ac e b o. Of t h e 8 pr e g n a nci es t h at w er e ex p os e d t o cl az akiz u m a b, 5 w er e m at er n al ex p os ur e a n d 
3 w er e p at er n al ex p os ur e. Ei g ht pr e g n a nci es occ urr e d i n s u bj ects e nr oll e d i n r h e u m at oi d or ps ori atic art hritis st u di es, 
w h o r ec eiv e d c o nc o mit a nt l o w -d os e M T X w hic h is a k n o w n h u m a n t er at o g e n wit h a n  i ncr e as e d ris k of s p o nt a n e o us 
a b orti o ns, i ntr a ut eri n e gr o wt h r estricti o n, a n d c o n g e ni t al m alf or m ati o ns i n c as e of ex p os ur e d uri n g pr e g n a nc y. 
( htt ps:// w w w. m e dici n es. or g. u k/ e mc/ pr o d uct/ 5 1 1/s m pc) 
 
T h e o utc o m es aft er m at er n al ex p os ur e w er e as f oll o ws:  
1 n or m al n e w b or n, 2 s p o nt a n e o us a b orti o ns, 1 miss e d a b orti o n, a n d 1 i ntr a ut eri n e gr o wt h r et ar d ati o n.  
T h e o utc o m es aft er t h e p at er n al ex p os ur es w er e as f oll o ws:  
1 s p o nt a n e o us a b orti o n, 1 u n k n o w n o utc o m e, a n d 1 b a by b or n wit h M os aic D o w n’s s y n dr o m e.  
 
T h e i nv esti g at or c o nsi d er e d t h at 1 s p o nt a n e o us a b orti o n ( St u dy I M 1 3 3 0 0 1) a n d t h e miss e d a b orti o n ( St u dy I M 1 3 3 0 0 4) 
aft er m at er n al ex p os ur e w er e r el at e d t o cl az a kiz u m a b a n d M T X tr e at m e nt. All ot h er pr e g n a nc y o utc o m es w er e 
c o nsi d er e d as u nr el at e d t o cl az a kiz u m a b. 
 
I n t h e U S g e n er al p o p ul ati o n, t h e esti m at e d b ac k gr o u n d ris k of m aj or birt h d ef ects is 2 % t o 4% a n d t h e r at e of 
misc arri a g e i n cli nic ally r ec o g niz e d pr e g n a nci es is 1 5 % t o 2 0 % ( htt ps:// w w w.f d a. g o v/ m e di a/ 9 0 1 6 0/ d o w nl o a d).  

 
 
P a g e 3 3   
D u e t o t h e c o nf o u n di n g eff ect of M T X tr e at m e nt a n d t h e g e n er al b ack gr o u n d risk of m aj or birt h d ef ects a n d misc arri a g e 
i n cli nic all y r ec o g niz e d pr e g n a nci es, t h e r ol e of cl az a kiz u m a b is u n k n o w n. 
 
I ns uffici e nt d at a is av ail a bl e fr o m pr e g n a nc y ex p os ur e i n cli nic al st u di es t o d at e t o i nf or m o n t h e p ot e nti al h ar m of 
cl az a kiz u m a b us e d uri n g pr e g n a nc y .All s u bj ects of c hil d b e ari n g p ot e nti al b ei n g tr e at e d wit h cl az akiz u m a b ( a n d t h eir 
p art n ers) m ust b e i nf or m e d of t his ris k, a n d us e hi g hly eff ectiv e birt h c o ntr ol. A d mi nistr ati o n of cl az akiz u m a b m a y 
d ecr e as e t h e effic ac y of h or m o n al or al c o ntr ac e pti v e s. 
U n d er n o circ u mst a nc es s h all cl az a kiz u m a b i nj ecti o n b e a d mi nist er e d t o w o m e n k n o w n t o b e pr e g n a nt or l act ati n g.  
6  
T h er a py St o p pi n g P oi nts  
As i n dic at e d pr evi o usl y, t h e st u dy will b e h alt e d a n d r e -e v al u at e d by t h e D at a a n d S af et y M o nit ori n g B o ar d ( D S M B) if 
a n y p ati e nt i n t h e st u dy gr o u p d e v el o ps S A Es or e vi d e nc e of s ev er e i nf usi o n r el at e d or i nf ecti o us c o m plic ati o ns. I n 
a d diti o n t h e st u dy will b e r e e v al u at e d if a p ati e nt d ev el o ps w ors e ni n g A B M R w hil e i n tr e at m e nt, p ossi bly i n dic ati n g l ac k 
of effic ac y of cl az a k iz u m a b (s e e a p p e n dix C).  
7 St atistic al A n alysis  
D u e t o t h e ex pl or at ory n at ur e of t his st u dy t h at i nv ol v es s af et y e n d p oi nts o nly a n d t h e s m all s a m pl e siz e t h at is n ot 
p o w er e d f or effic ac y e n d p oi nts, o ur pri m ar y o bj ectiv e will b e t o ass ess s af ety e n d p oi nts a n d li mit e d effic ac y. M ost 
i m p ort a nt will b e t ol er a bilit y i n t h e E S R D p o p ul ati o n a n d det er mi n ati o n of t h e eff ects of c l az a kiz u m a b tr e at m e nt o n 
circ ul ati n g D S As as w ell as t h e a bilit y t o i m pr o v e o utc o m es of p ati e nts wit h c A B M R a n d T G.  W e will h o w e v er pl a n t o 
ass ess bi o psi es 6 M p ost -tr a ns pl a nt ati o n i n p ati e nts d es e nsitiz e d wit h cl az a kiz u m a b tr e at m e nt t o d et er mi n e if t h er e ar e 
d ur a bl e eff ects i n pr ev e nti o n of A B M R b ot h ac ut e a n d c hr o nic.  

 
 
P a g e 3 4   
8 R ef er e nc es  
 
1.  
C olvi n  R B.  A nti b o dy -m e di at e d  r e n al  all o gr aft  r ej ecti o n:  di a g n osis  a n d  p at h o g e n esis.  J  A m  S oc  N e p hr ol  
2 0 0 7; 1 8: 1 0 4 6 -5 6.  
2.  
Dj a m ali A, K a uf m a n D B, Ellis T M, Z h o n g W, M at as A, S a m a ni e g o M. Di a g n osis a n d m a n a g e m e nt of a nti b o dy -
m e di at e d r ej ecti o n: c urr e nt st at us a n d n ov el a p pr o ac h es. A m J Tr a ns pl a nt 2 0 1 4; 1 4: 2 5 5 -7 1.  
3.  
J or d a n  S C,  Ty a n  D,  St a bl ei n  D,  et  al.  Ev al u ati o n  of  i ntr a v e n o us  i m m u n o gl o b uli n  as  a n  a g e nt  t o  l o w er  
all os e nsitiz ati o n a n d i m pr ov e tr a ns pl a nt ati o n i n hi g hl y s e nsitiz e d a d ult p ati e nts wit h e n d -st a g e r e n al dis e ase: r e p ort of 
t h e NI H I G 0 2 tri al. J A m S oc N e p hr ol 2 0 0 4; 1 5: 3 2 5 6-6 2.  
4.  
M arf o K, L u A, Li n g M, A k ali n E. D es e nsitiz ati o n pr ot oc ols a n d t h eir o utc o m e. Cli n J A m S oc N e p hr ol 2 0 1 1; 6: 9 2 2 -
3 6.  
5.  
M o nt g o m ery R A, L o nz e B E, Ki n g K E, et al. D es e nsitiz ati o n i n HL A -i nc om p ati bl e ki d n e y r eci pi e nts a n d s ur viv al. N 
E n gl J M e d 2 0 1 1; 3 6 5: 3 1 8 -2 6.  
6.  
V o A A, L u k ovsk y M, T oy o d a M, et al. Rit uxi m a b a n d i ntr a v e n o us i m m u n e gl o b uli n f or d es e nsitiz ati o n d uri n g r e n al 
tr a ns pl a nt ati o n. N E n gl J M e d 2 0 0 8; 3 5 9: 2 4 2-5 1.  
7.  
V o A A, P etr ozzi n o J, Y e u n g K, et al. Effic acy, o utc o m es, a n d c ost -eff ectiv e n ess of d es e nsitiz ati o n usi n g I VI G a n d 
rit uxi m a b. Tr a ns pl a nt ati o n 2 0 1 3; 9 5: 8 5 2 -8.  
8.  
S ell ar és J, d e Fr eit as D G, M e n g el M, et al. U n d erst a n di n g t h e c a us es of ki d n ey tr a ns pl a nt f ail ur e: t h e d o mi n a nt 
r ol e of a nti b o dy-m e di at e d r ej ecti o n a n d n o n a d h er e nc e. A m J Tr a ns pl a nt 2 0 1 2; 1 2: 3 8 8 -9 9.  
9.  
L o u py A, Hill G S, J or d a n S C. T h e i m p act of d o n or-s p ecific a nti-HL A a nti b o di es o n l at e ki d n ey all o gr aft f ail ur e. N at 
R e v N e p hr ol 2 0 1 2; 8: 3 4 8 -5 7.  
1 0.  
S ol ez K, C olvi n R B, R ac us e n L C, et al. B a nff ' 0 5 M e eti n g R e p ort: diff er e nti al di a g n osis of c hr o nic all o gr aft i nj ur y a n d 
eli mi n ati o n of c hr o nic all o gr aft n e p hr o p at hy (' C A N'). A m J Tr a ns pl a nt 2 0 0 7; 7: 5 1 8 -2 6.  
1 1.  
Gl o or J, C osi o F, L a g er DJ, St e g all M D. T h e s p ectr u m of a nti b o dy -m e di at e d  r e n al all o gr aft i nj ur y: i m plic ati o ns f or 
tr e at m e nt. A m J Tr a ns pl a nt 2 0 0 8; 8: 1 3 6 7-7 3.  
1 2.  
L ef a uc h e ur C, L o u py A, V er n er e y D, et al. A nti b o dy -m e di at e d v asc ul ar r ej ecti o n of ki d n e y all o gr afts: a p o p ul ati o n -
b as e d st u dy. L a nc et 2 0 1 3; 3 8 1: 3 1 3 -9.  
1 3.  
J or d a n S C, R ei ns m o e n N, P e n g A, et al. A dv a nc es i n di a g n osi n g a n d m a n a gi n g a nti b o dy-m e di at e d r ej ecti o n. P e di atr 
N e p hr ol 2 0 1 0; 2 5: 2 0 3 5 -4 5; q uiz 4 5 -8.  
1 4.  
H a as M, Sis B, R ac us e n L C, et al. B a nff 2 0 1 3 m e eti n g r e p ort: i ncl usi o n of c 4 d -n e g ativ e a nti b o dy -m e di at e d r ej ecti o n 
a n d a nti b o dy -ass oci at e d art eri al l esi o ns. A m J Tr a ns pl a nt 2 0 1 4; 1 4: 2 7 2 -8 3.  
1 5.  
T a n a k a T, Kis hi m ot o T. T h e bi ol o gy a n d m e dic al i m plic ati o ns of i nt erl e u ki n -6. C a nc er I m m u n ol R es 2 0 1 4; 2: 2 8 8 -9 4.  
1 6.  
T a n a k a T, N ar az aki M, Kis hi m ot o T. IL -6 i n i nfl a m m ati o n, i m m u nit y, a n d dis e as e. C ol d S pri n g H ar b P ers p ect Bi ol 
2 0 1 4; 6: a 0 1 6 2 9 5.  
1 7.  
Ki m I, W u G, C h ai N N, Kl ei n A S, J or d a n S. A nti -i nt erl e u ki n 6 r ec e pt or a nti b o di es att e n u at e a nti b o dy r ec all 
r es p o ns es i n a m o us e m o d el of all os e nsitiz ati o n. Tr a ns pl a nt ati o n 2 0 1 4; 9 8: 1 2 6 2-7 0.  
1 8.  
H u nt er C A, J o n es S A. IL -6 as a k eyst o n e c yt oki n e i n h e alt h a n d dis e as e. N at I m m u n ol 2 0 1 5; 1 6: 4 4 8 -5 7.  
1 9.  
J or d a n S C, C h oi J, Ki m I, et al. I nt erl e u ki n 6 (IL-6) a Cyt o ki n e Critic al t o M e di ati o n of I nfl a m m ati o n, A ut oI m m u nit y 
a n d All o gr aft R ej ecti o n: T h er a p e utic I m plic ati o ns of IL -6 R ec e pt or Bl oc k a d e. Tr a ns pl a nt ati o n 2 0 1 6.  
2 0.  
R e dfi el d R R, Ellis T M, Z h o n g W, et al. C urr e nt o utc o m es of c hr o nic acti v e a nti b o dy m e di at e d r ej ecti o n - A l ar g e 
si n gl e c e nt er r etr os p ectiv e r e vi e w usi n g t h e u p d at e d B A N F F 2 0 1 3 crit eri a. H u m I m m u n ol 2 0 1 6; 7 7: 3 4 6 -5 2.  
2 1.  
Wi e b e C, Gi bs o n I W, Bly dt -H a ns e n T D, et al. R at es a n d d et er mi n a nts of pr o gr essi o n t o gr aft f ail ur e i n ki d n e y 
all o gr aft r eci pi e nts wit h d e n o v o d o n or -s p ecific a nti b o dy. A m J Tr a ns pl a nt 2 0 1 5; 1 5: 2 9 2 1-3 0.  
2 2.  
Ki m I, W u G, C h ai  N N, Kl ei n A S, J or d a n S. A nti -I nt erl e u ki n 6 R ec e pt or A nti b o di es Att e n u at e A nti b o dy R ec all 
R es p o ns es i n a M o us e M o d el of All os e nsitiz ati o n. Tr a ns pl a nt ati o n 2 0 1 4.  
2 3.  
W u G, C h ai N, Ki m I, Kl ei n A S, J or d a n S C. M o n ocl o n al a nti -i nt erl e u ki n-6 r ec e pt or a nti b o dy a tt e n u at es d o n or-
s p ecific a nti b o dy r es p o ns es i n a m o us e m o d el of all os e nsitiz ati o n. Tr a ns pl I m m u n ol 2 0 1 3; 2 8: 1 3 8 -4 3.  
2 4.  
S hir ot a Y, Y ar b or o C, Fisc h er R, P h a m T H, Li ps ky P, Ill ei G G. I m p act of a nti -i nt erl e u ki n-6 r ec e pt or bl ock a d e o n 
circ ul ati n g T a n d B c ell s u bs ets i n p ati e nts wit h syst e mic l u p us er yt h e m at os us. A n n R h e u m Dis 2 0 1 3; 7 2: 1 1 8 -2 8.  

 
 
P a g e 3 5   
2 5.  
Ill ei G G, S hir ot a Y, Y ar b or o C H, et al. T ociliz u m a b i n syst e mic l u p us er yt h e m at os us: d at a o n s af et y, pr eli mi n ar y 
effic ac y, a n d i m p act o n circ ul ati n g pl as m a c ells fr o m a n o p e n -l a b el p h as e I d os a g e-esc al ati o n st u dy. Art hritis R h e u m 
2 0 1 0; 6 2: 5 4 2 -5 2.  
2 6.  
T a n a k a T, Kis hi m ot o T. T ar g eti n g i nt erl e u ki n -6: all t h e w a y t o tr e at a ut oi m m u n e a n d i nfl a m m at ory dis e as es. I nt J 
Bi ol Sci 2 0 1 2; 8: 1 2 2 7 -3 6.  
2 7.  
K a n g S, T a n a k a T, Kis hi m ot o T. T h er a p e utic us es of a nti -i nt erl e u ki n-6 r ec e pt or a nti b o dy. I nt I m m u n ol 2 0 1 5; 2 7: 2 1 -
9.  
2 8.  
W u G, Ki m I, C h ai N -n, et al. C TL A 4I g Diff er e nti all y S u p pr ess es d e n ov o a n d R ec all All o a nti b o dy R es p o ns es i n a 
M o us e M o d el of HL A. A 2 All os e nsitiz ati o n. W T C 2 0 1 4 A bstr ac t 2 0 1 4. 
2 9.  
C h av el e K M, M erry E, E hr e nst ei n M R. C utti n g e d g e: circ ul ati n g pl as m a bl asts i n d uc e t h e diff er e nti ati o n of h u m a n 
T f ollic ul ar h el p er c ells vi a IL -6 pr o d ucti o n. J I m m u n ol 2 0 1 5; 1 9 4: 2 4 8 2 -5.  
3 0.  
Ki k uc hi  J,  H as hiz u m e  M,  K a n e k o  Y,  Y os hi m ot o  K,  Nis hi n a  N,  T ak e uc hi  T.  P eri p h er al  bl o o d  
C D 4( +) C D 2 5( +) C D 1 2 7(l o w)  r e g ul at or y  T  c ells  ar e  si g nific a ntl y  i ncr e as e d  by  t ociliz u m a b  tr e at m e nt  i n  p ati e nts  wit h  
r h e u m at oi d art hritis: i ncr e as e i n r e g ul at ory T c ells c orr el at es wit h cli nic al r es p o ns e. Art hritis R es Th er 2 0 1 5; 1 7: 1 0.  
3 1.  
T a w ar a  I,  K o y a m a  M,  Li u  C,  et  al.  I nt erl e uki n -6  m o d ul at es  gr aft -v ers us -h ost  r es p o ns es  aft er  ex p eri m e nt al  
all o g e n eic b o n e m arr o w tr a ns pl a nt ati o n. Cli n C a nc er R es 2 0 1 1; 1 7: 7 7 -8 8.  
3 2.  
Z h a o X, B o e nisc h O, Y e u n g M, et al. Critic al r ol e of pr oi nfl a m m at ory c yt oki n e IL -6 i n all o gr aft r ej ecti o n a n d 
t ol er a nc e. A m J Tr a ns pl a nt 2 0 1 2; 1 2: 9 0-1 0 1.  
3 3.  
V o A A, C h oi J, Ki m I, et al. A P h as e I/II Tri al of t h e I nt erl e u ki n -6 R ec e pt or S p ecific H u m a niz e d M o n ocl o n al 
( T ociliz u m a b) + I ntr av e n o us I m m u n o gl o b uli n i n Diffic ult t o D es e nsitiz e P ati e nts. Tr a ns pl a nt ati o n 2 0 1 5. 
3 4.  
A o y a m a A T M, S mit h R -N, et al. N o n -H u m a n Pri m at e L u n g All o gr aft S ur viv al is Pr ol o n g e d by IL -6 I n hi biti o n a n d 
A T G Tr e at m e nt P ossi bl y T hr o u g h Ex p a nsi o n of P eri p h er al R e g ul at ory T C ells. [ A bstr act]. A m J Tr a ns pl a nt 2 0 1 6.  
3 5.  
V o A A, C h oi J, Ki m I, et al. A P h as e I/II Tri al of t h e I nt erl e u ki n -6 R ec e pt or -S p ecific H u m a niz e d M o n ocl o n al 
( T ociliz u m a b) + I ntr a v e n o us I m m u n o gl o b uli n i n Diffic ult t o D es e nsitiz e P ati e nts. Tr a ns pl a nt ati o n 2 0 1 5; 9 9: 2 3 5 6-6 3.  
3 6.  
A u b er t O, L o u py A, Hi d al g o L, et al. A nti b o dy-M e di at e d R ej ecti o n D u e t o Pr e existi n g v ers us D e N o v o D o n or -S p ecific 
A nti b o di es i n Ki d n e y All o gr aft R eci pi e nts. J A m S oc N e p hr ol 2 0 1 7. 
3 7.  
F o g al B, Yi T, W a n g C, et al. N e utr alizi n g IL -6 r e d uc es h u m a n art eri al all o gr aft r ej ecti o n by all o wi n g e m er g e nc e of 
C D 1 6 1 + C D 4 + r e g ul at or y T c ells. J I m m u n ol 2 0 1 1; 1 8 7: 6 2 6 8 -8 0.  
3 8.  
L o u py A, L ef a uc h e ur C, V er n er e y D, et al. C o m pl e m e nt -bi n di n g a nti -HL A a nti b o di es a n d ki d n ey -all o gr aft s urvi v al. 
N E n gl J M e d 2 0 1 3; 3 6 9: 1 2 1 5 -2 6.  
3 9.  
V o A A, Si n h a A, H a as M, et al. F act ors Pr e dicti n g Ris k f or A nti b o dy -M e di at e d R ej ecti o n a n d Gr aft L oss i n Hi g hl y 
H u m a n L e u k oc yt e A nti g e n S e nsitiz e d P ati e nts Tr a ns pl a nt e d Aft er D es e nsitiz ati o n. Tr a ns pl a nt ati o n 2 0 1 5.  
4 0.  
C h oi J, A u b ert O, V o A, et al. Ass ess m e nt of T ociliz u m a b ( A nti -IL-6 R ec e pt or M o n ocl o n al) as a P ot e nti al Tr e at m e nt 
f or C hr o nic A nti b o dy M e di at e d R ej ecti o n a n d Tr a ns pl a nt Gl o m er ul o p at hy i n HL A S e nsitiz e d R e n al All o gr aft R eci pi e nts. A m 
J Tr a ns pl a nt 2 0 1 7. 
4 1.  
R ei ns m o e n NL, L ai C H, V o A, e t al. Acc e pt a bl e d o n or-s p ecific a nti b o dy l ev els all o wi n g f or s ucc essf ul d ec e as e d a n d 
livi n g d o n or ki d n ey tr a ns pl a nt ati o n aft er d es e nsitiz ati o n t h er a py. Tr a ns pl a nt ati o n 2 0 0 8; 8 6: 8 2 0-5.  
4 2.  
St e g all M D, Di w a n T, R a g h a v ai a h S, et al. T er mi n al c o m pl e m e nt i n hi bit i o n d ecr e as es a nti b o dy-m e di at e d r ej ecti o n 
i n s e nsitiz e d r e n al tr a ns pl a nt r eci pi e nts. A m J Tr a ns pl a nt 2 0 1 1; 1 1: 2 4 0 5-1 3.  
4 3.  
K a h w aji J, Si n h a A, T oy o d a M, et al. I nf ecti o us c o m plic ati o ns i n ki d n e y -tr a ns pl a nt r eci pi e nts d es e nsitiz e d wit h 
rit uxi m a b a n d i ntr av e no us i m m u n o gl o b uli n. Cli n J A m S oc N e p hr ol 2 0 1 1; 6: 2 8 9 4 -9 0 0.  

 
 
P a g e 3 6   
A p p e n di x A    St u d y/ Pr ot oc ol: A P h as e I/II Tri al t o E v al u at e t h e S af et y a n d T ol er a bilit y of Cl az a kiz u m a b ® ( A nti-IL-6 m o n ocl o n al) As a n A g e nt t o Eli mi n at e D o n or S p ecific HL A 
A nti b o di es ( D S As) a n d I m pr o v e O utc o m es of P ati e nts wit h C hr o nic & Acti v e A nti b o d y -M e di at e d R ej ect i o n (c A B M R) P ost-Ki d n e y Tr a ns pl a nt ati o n  
* * B as e d o n p ati e nt’s pr ot oc ol bi o ps y r es ults, i m pr o v e m e nt i n G F R, i m pr o v e m e nt i n D S A, a n d/ or PI c o nfir m ati o n, p ati e nt will c o nti n u e a n ot h er six m o nt h  c o urs e of cl az a kiz u m a b. If n o i m pr o v e m e nt is o bs erv e d aft er 
6 m o nt hs of i niti al cl az a kiz u m a b tr e at m e nt, t h e p ati e nt will c o m e b ac k f or l ast st u d y visit D a y 3 6 5 aft er D a y 1 8 0 pr ot oc ol bi o ps y.  All o w +/ - 3 0 d a y f or all p ati e nt ass ess m e nts ass oci at e d wit h t h e D a y 1 8 0 visit  
+   At or wit hi n o n e m o nt h pri or t o scr e e ni n g d at e    &  At or wit hi n t w o m o nt hs pri or t o scr e e ni n g d at e     ^  At or wit hi n  1 m o nt h pri or t o a p p oi nt m e nt       # T h e bi o ps y c a n occ ur -3 0 d a ys  fr o m d a y 1 8 0 b ut a mi ni m u m 
of 2 8 d a ys m ust el a ps e b et w e e n Cl az d os e # 6 a n d d os e # 7       1.  D S A t o b e c oll ect e d pri or t o cl az a kiz u m a b i nf usi o n.   2.  W o m e n of c hil d b e ari n g a g e is b et w e e n 1 2 -5 5 y e ars ol d.    3.  R e vi e w of q u alif yi n g  bi o ps y f or i ncl usi o n 
crit eri a   4. R e vi e w of b as eli n e C NI l e v el    5. D a y 3 6 5 visit m a y b e c o m bi n e d wit h t h e D a y 3 3 0 visit. All s t u d y t ests will b e o bt ai n e d b ut d u plic at e pr oc e d ur es/t ests will b e c oll ect e d o nc e ( d u plic at e it e ms o mitt e d)  
St u d y  visit  
Scr e e ni n g  
(-1 5 d a ys)  
D a y 0  
CL A Z # 1   
D a y 3 0 
± 7 d  
 
D a y 6 0 
± 7 
d a ys  
D a y 9 0 
± 7 
d a ys   
D a y 1 2 0 
± 7 d a ys  
D a y 
1 5 0 ± 
7 d a ys  
D a y 1 8 0 ± 
3 0  d a ys  
Bi o psy # * *  
D a y 2 1 0 
± 7 
d a ys * *  
D a y 2 4 0  
± 7 
d a ys * *  
D a y 
2 7 0  
± 7 
d a ys * *  
D a y 
3 0 0  
± 7 
d a ys * *  
D a y 
3 3 0  
± 7 
d a ys * *  
D a y 
3 6 5 ± 
3 0  
d a ys 5 
 
M e dic al Hist ory  
X  
X  
 
X  
 
 
X  
X  
 
 
 
 
 
X  
C o m pl et e P hysic al Ex a m  
X  
X  
 
X  
 
 
X  
X  
 
 
 
 
 
X  
Vit al si g ns/ w ei g ht  
X  
X  
X  
X  
X  
X  
X  
X  
* * X  
* * X  
* * X  
* * X  
* * X  
X  
1 2 -l e a d E C G ( S O C) + 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
C h est X -R a y ( S O C) +  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
S af ety l a b or at ory t ests  
( C B C wit h diff er e nti al, C M P, U A)+ ^  
X 
 
X 
X 
X 
X 
X 
X 
* * X 
* * X 
* * X 
* * X 
* * X 
X  
R evi e w Hist oric al S er ol o gi es f or HI V, 
H B V, H C V, C M V a n d E B V &  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
E B V, C M V, P B K D N A P C R +  
X  
 
 
 
X  
 
 
X  
 
 
* * X  
 
 
X  
I g G+  
 
X  
 
 
X  
 
 
X  
 
 
 
 
 
X  
C R P +  
 
X  
X  
X  
X  
X  
X  
X  
* * X  
* * X  
* * X  
* * X  
* * X  
X  
D o n or – s p ecific a nti b o di es ( D S A)+  
X  
 
X 1 
X 1 
X 1 
X 1 
X 1 
X 1 
* * X 1 
* * X 1 
* * X 1 
* * X 1 
* * X 1 
X  
C NI L ev els ^  
X 4 
 
X  
X  
X   
X   
X  
X  
* * X  
* * X  
* * X  
* * X  
* * X  
X  
T B t esti n g [ Q u a ntif er o n T B G ol d] +  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
I nf or m e d C o ns e nt   
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ Excl usi o n crit eri a r e vi e w  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Cl az a kiz u m a b i nj ecti o n  
 
X # 1  
X # 2  
X # 3  
X # 4  
X # 5  
X # 6  
* * # 7  
* * # 8  
* * # 9  
* * # 1 0  
* * # 1 1  
* * # 1 2  
 
A nti -cl az a kiz u m a b (A D A ), t ot al IL 6, fr e e 
IL 6, a n d P K( S e nt O ut)  
 
X  
 
 
X  
 
 
X  
 
 
* * X  
 
* * X  
X  
Esti m at e d G F R ( usi n g M D R D e q u ati o n or 
Sc h w artz e q u ati o n will b e us e d t o esti m at e 
Cr Cl f or p ati e nts u n d er 1 8 y e ars of a g e ) 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
Pr e g n a ncy t est (f or W O C P) 2 
X  
X  
X  
X  
X  
X  
X  
X  
* * X  
* * X  
* * X  
* * X  
* * X  
X  
C o nc o mit a nt M e d R evi e w  
X  
X  
X  
X  
X  
X  
X  
X  
* * X  
* * X  
* * X  
* * X  
* * X  
X  
Tr e g c ells ( C D 4 +, C D 2 5 +, F ox P 3 +, C D 1 2 7 +) 
Tf h c ells ( C D 4 +, I C O S +, C X C R 5 +, IL-2 1 +)  
Pl as m a bl ast ( C D 1 9 +, C D 3 8 +, C D 2 7 +), 
 IL-6 +)   Ex os o m es    Micr o p articl es  
 
X  
5 mL gr e e n 
t o p 
3 mL l a v e n d er  
2 mL bl u e t o p 
 
 
X  
 
 
X  
 
 
 
 
 
X  
All o gr aft bi o psy  
X 3 
 
 
 
 
 
 
X  
 
 
 
 
 
X * *  
R evi e w of all o gr aft l oss  
 
 
 
 
 
 
 
X  
 
 
 
 
 
X  
R evi e w of n o n -pr ot oc ol bi o psy r es ults  
 
 
 
 
 
 
 
X  
 
 
 
 
 
X  
A dv ers e E v e nt M o nit ori n g  
 
X  
X  
X  
X  
X  
X  
X  
* * X  
* * X  
* * X  
* * X  
* * X  
X  

 
 
P a g e 3 7   
A p p e n dix B : S e n d  o ut l a bs  
 
L a b 
A d dr ess  
A nti -CL A Z A nti b o d y, P K  
I C O N Bi o a n al ytic al L a b 
8 2 8 2 H als ey R o a d  
W hit es b or o, N Y 1 3 4 9 2  
D o n or s p ecific a nti b o d y  
C e d ars -Si n ai HL A L a b or at or y  
C o m pr e h e nsi v e Tr a ns pl a nt C e nt er  
8 7 2 3 Al d e n Dri v e, S S B 1 9 7  
L os A n g el es, C A 9 0 0 4 8 
Tr a ns pl a nt I m m u n ol o g y L a b  
C e d ars -Si n ai Tr a ns pl a nt I m m u n ol o g y L a b  
8 7 2 3 Al d e n Dri v e, St ev e n S pi el b er g B uil di n g, R o o m 3 3 6  
L os A n g el es, C A 9 0 0 4 8 
R ef er e nc e L a b  
C e d ars -Si n ai M e dic al C e nt er D e pt of P at h ol o g y a n d L a b M e dici n e  
8 7 0 0 B ev erl y Bl v d, R o o m 3 7 1 9  
L os A n g el es, C A 9 0 0 4 8  
 
 
A p p e n dix C: D S M B C h art er & F D A G ui d a nc e f or Cli nic al Tri al S p o ns ors  
      
F D A G ui d a n c e f or 
Cli ni c al Tri al S p o n s o   
 
     
D S M B C h art er 
V 2_ E C 2 7 F e b 2 0 1 7. d o  
 
A p p e n dix D: S af ety R e p orti n g F or ms  
F D A M e d w at c h 
ma n d at or y r e p orti n g.  
 
 
 

 
 
P a g e 3 8   
A p p e n di x E    St u d y/ Pr ot oc ol: A P h as e I/II Tri al t o E v al u at e t h e S af et y a n d T ol er a bilit y of Cl az a kiz u m a b ® ( A nti-IL-6 m o n ocl o n al) As a n A g e nt t o Eli mi n at e D o n or S p ecific HL A 
A nti b o di es ( D S As) a n d I m pr o v e O utc o m es of P ati e nts wit h C hr o nic & Acti v e A nti b o d y -M e di at e d R ej ect i o n (c A B M R) P ost-Ki d n e y Tr a ns pl a nt ati o n  
T h e b el o w sc h e d ul e t o r e p e at a n n u all y ( Visit 1 – 6) p er PI discr eti o n  
  
&  T B t esti n g t o b e  
c o m pl et e d o nc e a y e ar. T B t est will b e c oll ect e d if n ot d o n e i n t h e l ast 2 m o nt hs.   
  ^  At or wit hi n 1 m o nt h pri or t o a p p oi nt m e nt  
1.  D S A t o b e c oll ect e d pri or t o cl az a kiz u m a b i nf usi o n.  
2.  W o m e n of c hil d b e ari n g a g e is b et w e e n 1 2 -5 5 y e ars ol d.  
* At 1 2 M o nt hs P er PI discr eti o n ( a n y ot h er bi o psi es will b e c o n d uct e d f or c a us e)  
% Ti m e d mi ni m u m 4 w e e ks fr o m l ast cl az a kiz u m a b d os e  
# Visit s h o ul d b e c o m bi n e d wit h eit h er visit 1, 2, 3, 5, or  6. D e p e n di n g o n w hic h visit is cl os est t o d a y 3 6 5  
 
 
 
 
 
St u d y  visit  
Visit 1  
F oll o w u p 
y e ar  
D a y 0  
CL A Z # 1 %   
Visit 2  
W e ek 8 -
7 d/ + 
1 0 d a ys  
 
Visit 3  
W e ek 1 6 
-7 d/ + 
1 0 d a ys  
Visit 4  
W e ek 2 4 -
7 d/ + 
1 0 d a ys  
Visit 5  
W e ek 3 2 -
7 d/ + 
1 0 d a ys  
Visit 6  
W e ek 4 0 -
7 d/ + 
1 0 d a ys  
 
D a y 3 6 5 ±  3 0  
d a ys  # 
M e dic al Hist ory  
 
 
 
 
 
 
 
X #  
C o m pl et e P hysic al Ex a m  
 
 
 
 
 
 
 
X #  
Vit al si g ns/ w ei g ht  
X  
X  
X  
X  
X  
X  
 
 
S af ety l a b or at ory t ests  
( C B C wit h diff er e nti al, C M P, U A)^  
X 
X 
X 
X 
X 
X 
 
 
E B V, C M V, P B K D N A P C R ^  
 
 
 
X  
 
 
 
X #  
I g G ^ 
 
 
 
X  
 
 
 
X #  
C R P ^  
 
 
 
X  
 
 
 
X #  
D o n or – s p ecific a nti b o di es ( D S A)^  
 
 
 
 
 
 
 
X #  
C NI L ev els ^  
X  
X  
X  
X   
X  
X  
 
 
T B t esti n g [ Q u a ntif er o n T B G ol d]  
 
 
 
 
 
 
 
X & #  
Cl az a kiz u m a b i nj ecti o n  
X # 1 %  
X # 2  
X # 3  
X # 4  
X # 5  
X # 6  
 
 
 
 
 
 
 
 
 
 
 
Esti m at e d G F R ( usi n g M D R D e q u ati o n or Sc h w artz 
e q u ati o n will b e us e d t o esti m at e Cr Cl f or p ati e nts 
u n d er 1 8 y e ars of a g e)  
X 
X 
X 
X 
X 
X 
 
 
Pr e g n a ncy t est (f or W O C P) 2 
X  
X  
X  
X  
X  
X  
 
 
C o nc o mit a nt M e d R evi e w  
X  
X  
X  
X  
X  
X  
 
 
Ki d n ey Bi o psy  
 
 
 
 
 
 
 
X * #  
R evi e w of all o gr aft l oss  
 
 
 
 
 
 
 
X #  
R evi e w of n o n -pr ot oc ol bi o psy r es ults  
 
 
 
 
 
 
 
X #  
A dv ers e E v e nt M o nit ori n g  
X  
X  
X  
X  
X  
X  
 
 

 
 
P a g e 3 9   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
&  T B t esti n g t o b e c o m pl et e d o nc e a y e ar. T B t est will b e c oll ect e d if n ot d o n e i n t h e l ast 2 m o nt hs.    
 ^  At or wit hi n 1 m o nt h pri or t o a p p oi nt m e nt  
1.  D S A t o b e c oll ect e d pri or t o cl az a kiz u m a b i nf usi o n.  
2.  W o m e n of c hil d b e ari n g a g e is b et w e e n 1 2 -5 5 y e ars ol d.  
* At 1 2 M o nt hs P er PI discr eti o n ( a n y ot h er bi o psi es will b e c o n d uct e d f or c a us e)  
% Ti m e d mi ni m u m 4 w e e ks fr o m l ast cl az a kiz u m a b d os e  
# Visi t s h o ul d b e c o m bi n e d wit h eit h er visit 1, 2, 3, 4 or 5. D e p e n di n g o n w hic h visit is cl os est t o d a y 3 6 5  
 
St u d y  vis it 
Visit 1  
F oll o w u p 
y e ar  
CL A Z # 1 %  
Visit 2  
W e ek 4 
- 2d/ + 
1 0 d a ys  
 
Visit 3  
W e ek 8 
- 2d/ + 
1 0 d a ys  
Visit 4  
W e ek 1 2  
- 2d/ + 
1 0 d a ys  
Visit 5  
W e ek 1 6  
- 2d/ + 
1 0 d a ys  
Visit 6  
W e ek 2 0 
- 2d/ + 
1 0 d a ys  
 
D a y 3 6 5 
± 3 0  
d a ys # 
M e dic al Hist ory  
 
 
 
 
 
 
 
X #  
C o m pl et e P hysic al Ex a m  
 
 
 
 
 
 
 
X #  
Vit al si g ns/ w ei g ht  
X  
X  
X  
X  
X  
X  
 
 
S af ety l a b or at ory t ests  
( C B C wit h diff er e nti al, C M P, U A)^  
X 
X 
X 
X 
X 
X 
 
 
E B V, C M V, P B K D N A P C R ^  
 
 
 
 
 
X  
 
X #  
I g G ^ 
 
 
 
 
 
X  
 
X #  
C R P ^  
 
 
 
 
 
X  
 
X #  
D o n or – s p ecific a nti b o di es ( D S A)^  
 
 
 
 
 
 
 
X #  
C NI L ev els ^  
X  
X  
X  
X   
X  
X  
 
 
T B t esti n g [ Q u a ntif er o n T B G ol d]  
 
 
 
 
 
 
 
X & #  
Cl az a kiz u m a b i nj ecti o n  
X # 1  %  
X # 2  
X # 3  
X # 4  
X # 5  
X # 6  
 
 
 
 
 
 
 
 
 
 
 
Esti m at e d G F R ( usi n g M D R D e q u ati o n or 
Sc h w artz e q u ati o n will b e us e d t o esti m at e 
Cr Cl f or p ati e nts u n d er 1 8 y e ars of a g e)  
X 
X 
X 
X 
X 
X 
 
 
Pr e g n a ncy t est (f or W O C P) 2 
X  
X  
X  
X  
X  
X  
 
 
C o nc o mit a nt M e d R evi e w  
X  
X  
X  
X  
X  
X  
 
 
Ki d n ey Bi o psy  
 
 
 
 
 
 
 
X * #  
R evi e w of all o gr aft l oss  
 
 
 
 
 
 
 
X #  
R evi e w of n o n -pr ot oc ol bi o psy r es ults  
 
 
 
 
 
 
 
X #  
A dv ers e E v e nt M o nit ori n g  
X  
X  
X  
X  
X  
X