Treatment of Chronic Antibody
Mediated Rejection
Robert A. Montgomery MD, DPhil
Professor of Surgery
Director of the NYU Langone Transplant Institute
Disclosures:
Served on Advisory Boards for Genentech
Scientific/ROCHE, True North/iPierian, Alexion,
Novartis, and Hansa Medical
Received consulting fees from OrbidMed,
GuidePoint Global, Sucampo, Astellas,and Shire
Received research grants from Immune Tolerance
Network, ViroPharma,Hansa, and Alexion.
I have been involved in clinical trial design for some
of the off label drugs I will be discussing.
Objectives
• To understand the phenotypes and natural
history of untreated chronic AMR and its effect
on graft survival.
• To gain an appreciation for treatment
modalities that have a mechanism of action
that might prove effective for reversing chronic
AMR or prolonging allograft half-life.
1
De Novo HLA DSA is Common and Leads to Graft
Failure1
Years post-transplant
1Mao,
et al. Am J Transplant. 2007 Apr;7(4):864-71.
Development of De Novo HLA DSA is
Associated With Allograft Loss1
Graft survival of patients with de novo DSA versus those without
1Wiebe
C et al. Am J Transplant. 2012;12:1157-1167.
AMR Is Associated With A Poor Outcome1
1Lefaucheur
C et al. J Am Soc Nephrol. 2010.21:1398-1406.
2
Chronic AMR may result form De Novo DSA
formation, incomplete elimination of DSA following
Acute AMR, or persistence of preformed DSA after
Desensitization
Effectiveness of therapy may depend upon:
• Target
• Strength
• Timing
• Ability of DSA to Bind Complement
• Ability of DSA to Produce Microcirculation Inflammation
• Presence of Renal Dysfunction
DSA Fate By Specificity After Plasmapheresis1
Specific
Eliminated Persistent
cI
74%
26%
cII (DR, DQ)
56%
44%
DR51, 52, 53
20%
0%
100%
Isoagglutinins
1Zachary,
80%
et al. Transplantation. 2003 Nov 27;76(10):1519-25.
Allograft Survival Is Lower With
Class II DSA1
1Bentall
et al. AJT 2013; 13:76
3
The Significance of AMR Varies By The Antibody’s Ability To
Bind Complement: Outcomes of C4d+ vs. C4d- AMR1
1Orandi
B et al. Am J Transplant. 2016; 16:213.
However, Antibodies That Do Not Bind Complement
Can Have Clinical Significance 1
Specificity/sensitivity/positive predictive and negative
predictive values for C4d
Sensitivity = 0.69
Specificity = 0.83
PPV = 0.93
NPV = 0.44
C4d+ (n = 90)
Protocol biopsies
KTRs with
at 3-mo and 1-y
preformed
post-transplant
DSA (n = 80)
(n = 157)
C4d- (n = 67)
Microvascular
inflammation +
(n = 84)
Microvascular
inflammation –
(n = 6)
Microvascular
inflammation +
(n = 37)
Microvascular
inflammation –
(n = 30)
NPV: negative predictive value; PPV: positive predictive value.
1. Loupy A et al. Am J Transplant. 2011;11:652-660.
Post Treatment DSA and C1q: Is There Both A
Quantitative and Qualitative Difference in DSA1
DSA+/C1q+ = Higher risk of graft loss
1Loupy
et al. NEJM 2013; 369:1215
4
SOC PP/IVIg Treatment Protocol Is Effective
Therapy for Acute AMR but has Limited Success
with Chronic AMR1
Anti-CD20
PP: single plasma volume exchange
IVIG: 100 mg/kg following each PP
treatment (CMV hyperimmune
globulin)
Steroid bolus
or
α-thymocyte globulin
PP/IVIg
PP/IVIg
PP/IVIg
PP/IVIg
PP/IVIg
2
4
6
8
AMR
diagnosis
1Montgomery
et al. Transplantation. 2000; 70(6):887-95.
Rituximab as Add-On Therapy to SOC did not Show
Improved Outcomes for Acute AMR Compared to SOC
Alone in a Multi-Center Double-Blind Randomized trial1
° end pt: Day 12 < 30% Creatinine
1
(n=19) Placebo
ABMR
<1 year (Bx)
+ IVIG + PE + Steroids 57.4%
(n=19) Rituximab + IVIG + PE + Steroids 52.6%
p = NS
1Sautenet
et al., Transplantation 2016; 100:391
Bortezomib Add-On to PP/IVIg Treatment Protocol
Anti-CD20
PP: single plasma volume exchange
IVIG: 100 mg/kg following each PP
treatment (CMV hyperimmune
globulin)
Steroid bolus
or
α-thymocyte globulin
PP/IVIg
AMR
diagnosis
1
Repeat cycle every 21 days
PP/IVIg
PP/IVIg
PP/IVIg
2
4
6
PP/IVIg PP/IVIg
8
11
Bortezomib (1.5 mg/m 2)
Bortezomib (1.5 mg/m 2)
Bortezomib (1.5 mg/m 2)
Bortezomib (1.5 mg/m 2)
5
Poor Responce to Bortezomib as Add-On to SOC for
Chronic AMR1
1Alachkar
et al. Transplantation; 97:1240.
Bortezomib Differentially Effects Class I vs. Class
II HLA Antibody1
1Philogene
et al., Transplantation. 2014; 98:660.
Tocilizumab (anti-IL-6R mAb) Treatment for Chronic
AMR and TG: Failed SOC Patients1
75 Patients with
Chronic Active ABMR
+/- Transplant
Glomerulopathy (TG)
39 Patients Treated
with IVIG + Rituximab
+/- PLEX
(SOC)
1Vo
37 Patients who failed
IVIG + Rituximab +
PLEX
Rx with Tocilizumab
8mg/kg monthly 6-18M
AA et al. Transplantation. 99:2356.
6
Tocilizumab vs. SOC in Patients with Established Tg
Classical Complement Pathway in Acute AMR in
Sensitized KTRs1
ECULIZUMABa
a FDA approved for PNH and aHUS.
AMR, antibody-mediated rejection; DAF, decay-accelerating factor; DSAs, donor-specific antibodies,
HLA, human leukocyte antigen; Y-CVF, Yunnan-cobra venom factor..
1Stegall
MD et al. Nat Rev Nephrol. 2012;8:670–678.
AJT (2015) 5:1293-1302
Decreased ABMR 6.7% vs. 43.8% but no effect on TG at 2 years
Transplant Glomerulopathy in Controls versus Eculizumab
3-4 months
1 year
2 years
Eculizumab*
0%
26.7%
45.4%
(0/28)
(8/30)
(10/22)
Control
9.3%
39.5%
63.6%
(4/43)
(15/38)
(21/33)
P-value
0.15
0.31
0.27
*Residual DSA was not removed after the transplant
7
AMR: C1 Esterase Inhibitor Mechanistically
Attractive Due To Proximal Complement Blockade1
FDA approved for HAE: Hereditary Angioedema
C1-INH: C1 esterase inhibitor; FDP: fibrin degradation product; HMWK: high molecular weight
kininogen; IL: interleukin; KK: kallikrein; MASP: MBP-associated serine protease; MBP: mannosebinding protein; TNF: tumor necrosis factor; tPA: tissue plasminogen activator
1Levy
J, O’Donnell P. Expert Opin Investig Drugs. 2006;15:1077-1090.
AMR: Randomized Placebo Controlled C1 INH Trial
Cg on 6 mos. Biopsy1
This study was sponsored by ViroPharma, Inc., a wholly owned subsidiary of Shire, PLC.
CG
CG
CG
mg/dL
CG = chronic glomerulopathy
1Montgomery et
mg/dL
17 mg/dL = 1 U/mL
al. Am J Transplant 2016 Epub.
C1-INH (Berinert) as add on Therapy for Chronic
AMR Unresponsive to SOC1
1Viglietti
et al. Am J Transplant;16:1596
8
MFI (raw)
25000
0
DRB1*10:01,-,-,-,-,-,-,-,-,-,-,-,-,DRB4*01:03,-,-,-,-,-,-,-,-,DRB1*09:02,-,-,-,-,-,-,-,-,-,-,-,-,DRB4*01:01,-,-,-,-,-,-,-,-,DRB1*01:01,-,-,-,-,-,-,-,-,-,-,DRB1*09:01,-,-,-,-,-,-,-,-,-,-,DRB1*01:02,-,-,-,-,-,-,-,-,-,-,DRB1*01:03,-,-,-,-,-,-,-,-,-,-,DRB1*07:01,-,-,-,-,-,-,-,-,-,-,-,-,DRB5*02:02,-,-,-,-,-,-,-,-,DRB1*04:04,-,-,-,-,-,-,-,-,-,-,DRB1*04:01,-,-,-,-,-,-,-,-,-,-,-,-,DRB5*01:01,-,-,-,-,-,-,-,-,DRB1*04:05,-,-,-,-,-,-,-,-,-,-,DRB1*04:02,-,-,-,-,-,-,-,-,-,-,DRB1*04:03,-,-,-,-,-,-,-,-,-,-,DRB1*12:01,-,-,-,-,-,-,-,-,-,-,-,-,DRB3*03:01,-,-,-,-,-,-,-,-,DRB1*12:02,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DQA1*01:03,-,DQB1*06:01,-,-,-,-,-,-,DRB3*01:01,-,-,-,-,-,-,-,-,-,-,-,-,DQA1*01:03,-,DQB1*06:03,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*09:01,-,-,-,-,DQA1*02:01,-,DQB1*03:03,-,-,-,-,-,-,-,-,DQA1*03:02,-,DQB1*03:03,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*17:01,DRB1*14:01,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*01:03,-,DPB1*03:01,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*06:01,-,-,-,-,DQA1*03:02,-,DQB1*03:02,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*14:01,-,-,-,-,-,-,-,-,DPA1*01:05,-,DPB1*03:01,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*03:01,-,-,-,-,DQA1*01:02,-,DQB1*06:09,-,-,-,-,DRB1*14:54,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DQA1*01:02,-,DQB1*06:04,-,-,-,-,-,-,-,-,DQA1*01:01,-,DQB1*06:02,-,-,-,-,-,-,-,-,DQA1*01:02,-,DQB1*06:02,-,-,-,-,-,-,-,-,DQA1*03:01,-,DQB1*03:03,-,-,-,-,-,-,-,-,DQA1*03:01,-,DQB1*03:02,-,-,-,-,DRB1*14:02,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DQA1*01:01,-,DQB1*05:01,-,-,-,-,-,-,-,-,DQA1*03:03,-,DQB1*04:01,-,-,-,-,-,-,-,-,DQA1*02:01,-,DQB1*03:02,-,-,-,-,-,-,-,-,DQA1*01:01,-,DQB1*03:02,-,-,-,-,-,-,-,-,DQA1*02:01,-,DQB1*04:01,-,-,-,-,-,-,-,-,DQA1*02:01,-,DQB1*04:02,-,-,-,-,-,-,-,-,DQA1*01:02,-,DQB1*05:02,-,-,-,-,-,-,-,-,DQA1*04:01,-,DQB1*04:02,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*01:03,-,DPB1*19:01,DRB1*15:03,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*23:01,-,-,-,-,-,-,-,-,DPA1*01:05,-,DPB1*11:01,-,-,-,-,DQA1*06:01,-,DQB1*03:01,-,-,-,-,DRB1*03:02,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*10:01,DRB1*13:01,-,-,-,-,-,-,-,-,-,-,DRB1*16:02,-,-,-,-,-,-,-,-,-,-,DRB1*15:01,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DQA1*02:01,-,DQB1*03:01,-,-,-,-,DRB1*16:01,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*01:03,-,DPB1*02:01,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*28:01,-,-,-,-,-,-,-,-,DPA1*01:05,-,DPB1*13:01,-,-,DRB3*02:02,-,-,-,-,-,-,-,-,DRB1*15:02,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*01:03,-,DPB1*11:01,-,-,-,-,-,-,-,-,DPA1*01:05,-,DPB1*28:01,DRB1*03:01,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*01:01,-,-,-,-,-,-,-,-,DPA1*01:03,-,DPB1*04:02,-,-,-,-,DQA1*03:01,-,DQB1*03:01,-,-,-,-,-,-,-,-,DQA1*05:05,-,DQB1*03:01,-,-,-,-,-,-,-,-,DQA1*05:03,-,DQB1*03:01,-,-,-,-,DRB1*11:04,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*01:05,-,DPB1*18:01,DRB1*13:03,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*15:01,-,-,-,-,-,-,-,-,DPA1*01:04,-,DPB1*18:01,-,-,-,-,-,-,-,-,DPA1*01:03,-,DPB1*01:01,DRB1*08:01,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*05:01,DRB1*11:01,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*01:03,-,DPB1*04:01,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*18:01,-,-,-,-,DQA1*05:01,-,DQB1*02:01,-,-,-,-,-,-,-,-,DQA1*02:01,-,DQB1*02:02,-,-,-,-,-,-,-,-,DQA1*04:01,-,DQB1*02:01,-,-,-,-,-,-,-,-,-,-,-,-,DPA1*02:01,-,DPB1*13:01,-,-,-,-,DQA1*03:01,-,DQB1*02:01,-,-,-,-,-,-,-,-,DQA1*02:01,-,DQB1*02:01,-,-,-,-,-
IdeS: IgG-degrading enzyme of Streptococcus
pyogenes
Highly specific for human IgG
Glu-Leu-Leu-Gly236↓Gly-Pro
2 hrs
IdeS .24 mg/kg
2 hrs
Tx
Positive Cytotoxic or
Flow XM
4 hrs
*
*Single-cleaved IgG (scIgG)
IdeS Effect on Class II Antibody In A Sensitized
Patient
Placebo
IdeS
P02
20000
15000
10000
5000
Individual HLA (DP, DQ, DR)
Trouble in paradise: IgG rebounds by day 14 and patient
cannot be given more than 2 doses because of antibody formation
HLA Incompatible Donor IdeS Protocol
Solumedrol
500mg/d
IVIg 2 gm/kg
d0
d4
SOC rescue
If needed
- XM
d7
d9
Campath SQ
Anti-CD2
9
Which of the following best describes you?
1. I know there are no effective treatments for chronic
AMR so I just let nature take its course and
begin to plan for the next transplant.
2. When I identify a patient with chronic AMR I increase
maintenance immunosuppression and observe.
3. I aggressively treat chronic AMR when found
on a for cause biopsy.
4. I monitor at risk patients with protocol biopsies
and treat chronic AMR until the microcirculation
inflammation resolves on re-biopsy.
Which of the following is false about the treatment of
chronic AMR
A. Therapies for Acute AMR tend to have
limited efficacy for chronic AMR.
B. Class I non-complement fixing antibodies
are associated with the worst outcomes.
C. DSA that binds C1q leads to a higher rate of
graft loss.
D. Transplant glomerulopathy can result form both
acute and chronic AMR
10