Clinical trial NCT03380377
Conditions: Antibody-mediated Rejection Kidney Transplant; Complications Transplant Glomerulopathy Transplant Glomerulopathy - Late Form Transplant Glomerulopathy - Early Form Kidney Transplant Rejection
Keywords: kidney transplant Chronic antibody mediated rejection donor specific antibody
Sponsor: Stanley Jordan, MD
Start date: 2018-02-21; Completion date: 2024-04-16
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Antibody mediated rejection (ABMR) is a unique, significant and often severe form of allograft rejection. This single center, phase I/II, open label single-arm exploratory study focuses on enrolling ten patients with biopsy proven chronic antibody medicated rejection and/or donor specific antibody present at time of biopsy. Patients who qualify will be receiving clazakizumab (anti-IL6 monoclonal antibody) monthly x six doses. A protocol biopsy will be performed at 6 months and if improvement is seen, patients will continue another six doses for up to 12 months. For those completing 12 doses, there will be a 12 month protocol biopsy. For those who only received six doses, the next and last study visit will be at 12 months from enrollment. Total study duration is 12 months.

Detailed description:
This is a single center, Phase I/II, open label single-arm exploratory study. The trial will primarily examine the safety and tolerability of clazakizumab given after the diagnosis of cABMR in 10 subjects (15-75yrs) who exhibit DSAs to their donor. Patients entered will also have been diagnosed with cABMR + TG post-transplant based on Banff 2015 criteria. Patients are required to have a eGFR \> 30 mL/min/1.73m2 as calculated by the MDRD equation (Schwartz equation will be used to estimate CrCl for patients under 18 years of age) at entry. All patients will be recruited from the renal transplant program at Cedars-Sinai Medical Center. Once cABMR is diagnosed, donor-specific anti-HLA antibodies will be assessed (DSA) which are associated with cABMR and/or graft loss. DSA will be detected using solid phase assay systems currently utilized at the Cedars-Sinai Medical Center HLA Laboratory (Dr. Xiaohai Zhang Director, Phone: 310-423-4979)41. These anti-HLA antibodies may result naturally or from previous pregnancy, transfusions, or prior transplants. Patients treated with clazakizumab for cABMR will have labs for DSAs, and other monitoring labs as well as immunologic studies as outlined. In addition to the standard post-transplant immunosuppressive protocol, patients with cABMR will receive clazakizumab 25mg SC given every 4 weeks (30 days) for a total of 6 doses. If no safety/tolerability/efficacy issues are observed after the initial dose, patients will continue the protocol as outlined. A protocol biopsy will be performed after the 6th and after the 12th doses of clazakizumab to assess the allograft for evidence of cABMR/ABMR, including C4d staining and TG using Banff 2015 criteria14. Banff scoring will be compared between the index and protocol biopsy after cessation of therapy. Patients who have evidence of persistent allograft dysfunction may have non-protocol biopsies for cause. After completion of the clazakizumab therapy, patients will be followed up to assess allograft function and ABMR episodes as well as DSAs. The protocol is summarized in figure 14 below. Monitoring of Treg, Th17, Tfh and plasmablast as well as IL-6, and CRP levels will be performed in the Transplant Immunology Lab at Cedars-Sinai Medical Center at select time points (Dr. Mieko Toyoda Director, Phone: 310-423-8282). confirmation) they will continue monthly clazakizumab for an additional 6 months and will have a second biopsy at 12 month protocol. Immunologic and viral monitoring labs will be performed as indicated.

The subjects will be followed to determine if the use of clazakizumab for treatment of cABMR in this high-risk transplant population is safe and without infectious risks. In addition, the investigators will determine the effects of clazakizumab treatment on renal biopsy assessments performed at 6 months. Assessments of renal function, donor specific antibody, and Banff 2015 biopsy scores will be evaluated at that time. If improvement or stabilization observed, clazakizumab will be resumed monthly x 6 doses (starting day 180 to day 330) and last study visit will be day 365 with biopsy. Study investigators will assess the transplanted patients to determine the number who sustain a viable and functioning kidney allograft as well. In the event a patient does not show improvement after receiving 6 doses of clazakizumab, no further treatment will be given and the patient will return at Day 365 for a final study visit. All subjects will be evaluated on an intent-to-treat basis. The subject accrual rate will be limited to no more than 1-2 subjects per month in the initial three months to assure safety to all subjects. Repeat laboratories will be performed at the completion of clazakizumab therapy to determine effect on levels and correlation with any potential events.

Long term dosing option at conclusion of 12 months (after Study Day 365 visit) will be available for those patients who complete the 12 month protocol. Patients may continue to receive clazakizumab 25 mg subQ every 8 weeks long term, per PI discretion.

Arms: arm 1: All ten patients will be receiving clazakizumab (Anti-IL-6 Monoclonal) monthly for six months. Then patients will be scheduled for six month protocol biopsy. If biopsy and all clinical labs show benefit or stability (up to PI discretion), patients will continue receiving clazakizumab monthly for another six months. All patients completing twelve doses of clazakizumab will be scheduled for a twelve month protocol biopsy and last study visit. If at the 6 month protocol biopsy, no improvement was seen, PI will have patient come for their last study visit on month 12 post enrollment.
Interventions: intervention 1: Clazakizumab
Intervention descriptions: intervention 1: Clazakizumab 25 mg subcutaneous monthly x 6 doses (or max of 12 doses) will be given to patients who are enrolled in this clinical trial.

Protocol documents:
Prot_000.pdf: 
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