1. Tocilizumab Robert A. Montgomery, M.D., D.Phil. Professor of Surgery
Director of the NYU Langone Transplant Institute

2. Scope of the Problem Sensitization to HLA molecules limits access to
transplantation for about 30,000 patients on the kidney
waiting list
The post-transplant presence of DSA is perhaps
the most significant contributor to premature graft loss
Acute AMR further accelerates the the rate and
speed of graft loss
Strategies to prevent or treat chronic microcirculation
injury and transplant glomerulopathy from DSA remains
an important unmet need

3. Need for Efficacious Therapies
Standard of care therapy (plasmapheresis and IVIg)
can effectively ameliorate antibody mediated injury
especially when the AMR is early and associated with
acute renal dysfunction
Many drugs with autoimmune and oncologic
indications have been repurposed to treat or prevent
AMR because of attractive mechanisms of action
These add-on therapies may enhance the efficacy
of SOC treatments and the search for more effective
therapeutic agents continues

4. Therapies and Intervention For HLA DSA
The Tackle Box
Standard of Care (SOC)
Add-ons to SOC
Plasmapheresis
Immunoabsorption
IVIg (high or low dose)
Steroids, ATG, Bela
[Rituximab]
Splenectomy
Anti-CD20
Complement Inhibitors
(eculizumab and C1INH)
Proteosomal Inhibitors
Anti-BAFF/BLyS
IdeS
Anti-IL-6R

5. IL-6 IL-6 : B-cell stimulatory factor-2 Is a Pleiotropic Cytokine
IL-6 Levels increase in Major Depressive Disorder (MDD) , Alzheimer’s Disease and schizophrenia.
Neuron
IL-6
Stimulate B- cells to Increase antibody production
Increase plasmablast
Decrease Treg differentiation
Enhances Th17 and Tfh cells
Immune cells
Skin
IL-6
Increase Keratinocytes
Increase dermal fibroblast collagen
Liver
Increase CRP, decrease albumin & transferrin
Increase Serum Amyloid A
Increase Fibrinogen
Increase Hepcidin
IL-6
Cardiac
Increase VEGF to increase angiogenesis
Increase cardiovascular disease
Increases mesangial cell proliferation, critical to
ANCA vasculitis. Proximal tubular cells express
IL-6 with injury.
Kidney
IL-6
Increase osteoclast differentiation
Increase angiogenesis
Increase platelet
Bone Marrow
Synovial Fibroblast
Dysregulation of IL-6-type cytokine
signaling contributes to the onset and
maintenance of multiple diseases and cancers

6. Tocilizumab Humanized monoclonal antibody against the Interleukin-6
receptor (IL-6R)
Its delivered by monthly infusion or subcutaneous injection
Used for rheumatoid arthritis, systemic juvenile arthritis, and
Castleman’s disease. In Phase II/III trials for GVHD.
Very limited experience in solid organ transplantation
For naïve B-cells, IL-6 promotes activation and differentiation
into plasmablasts and plasma cells
IL-6 may also be important for the maintenance of:
survival milieu in the long-lived plasma cell niche
Germinal center and Tfh/B-cell interactions

7. IL-6 Producing Plasmablast
Figure 3a
IL-6 Drives B-cell Activation & Differentiation to Antibody Producing Plasma Cells
CD4+ Tfh
CXCR5+
Bcl-6+
Naïve B-cell
Donor Specific Antibodies
Plasma Cell
IL-6
IL-21 +
IL-6 Producing Plasmablast
Germinal Center

8. Pathogenesis of the Humoral Immune Response1
HLA antibody
Plasmablasts
Plasma cells
Clonal
expansion
Complement
Activation
Tocilizumab
Tfh cell
AMR: Pathogenesis of the Immune Response
Regina, do we need all of the little y-looking images? We are going to need to condense this down. Do you know where this comes from? I added the title. I’ll have studio redraw if we determine we are keeping this. Do we need a reference at all? I can’t find a definition for LLPC. I removed some of the Ys at the top. Please look at the original and let me know if this works.
Naïve and
Memory B cells
Tocilizumab
LLPC
Bone marrow
Coagulative
necrosis
1. Modified Montgomery et al. Seminars in Immunology :

9. Figure 5

10. Kim et al Transplantation 2014
Anti-IL-6R Inhibits Plasma Cell IgG Production and Anti-HLA-A2 Antibody
Anti-HLA-A2
Anti-HLA-A2
Kim et al Transplantation 2014

11. Vo et al. Transplantation. 2015; 99:2356.

12. Tocilizumab Protocol for Patients Unresponsive to IVIg/Rituxumab

13. Fate of Patients Enrolled
The mean time to transplant from first DES was 25 ± 10.5 months but after TCZ was 8.1 ± 5.4 months.
No ABMR was seen on protocol biopsies performed at 6 months from all transplanted patients.
Vo et al. Transplantation. 2015; 99:2356.

14. Serum IL-6 and IL-6R Levels Increase On Tocilizumab
Vo et al. Transplantation. 2015; 99:2356.

15. Fate of Immuno-dominant DSAs
Vo et al. Transplantation. 2015; 99:2356.

16. Tocilizumab Treatment of Chronic ABMR & TG: Treatment Protocol
75 Patients with Chronic Active ABMR +/- Transplant Glomerulopathy (TG)
39 Patients Treated with IVIG + Rituximab +/- PLEX
(SOC)
37 Patients who failed IVIG + Rituximab + PLEX
Rx with Tocilizumab 8mg/kg monthly 6-18M
Patients followed for up to 5 years post-treatment with assessments
Shin & Toyoda, ATC, Abstract C9 2016

17. Allograft Survival Since Initial Biopsy: TCZ v. SOC

18. Allograft Survival Since Biopsy in Patients with TG

19. Patient Survival Since Biopsy: TCZ v. SOC

20. GFR Values for TCZ Treated Patients
GFR ml/min
Tocilizumab 4-8mg/kg monthly x 6M or more

21. Effect of 6M Tocilizumab Therapy on IgG Subclasses in Patients with ABMR & TG
IgG Levels (mg/dl)
Shin & Toyoda, ATC, Abstract C9 2016

22. Mean Immunodominant DSA Values for TCZ Treated Patients
RIS*
p =
Tocilizumab 4-8mg/kg monthly x 6M or more
*Relative Intensity Scale (RIS) [0 points = No DSA; 2 points = <5000MFI {weak}; 5 points = ,000 MFI {moderate}; 10 points = >10,000MFI {strong}].

23. Conclusions Tocilizumab (anti-IL-6R mAB) has an attractive mechanism
of action for desensitization and treatment of AMR
In two small uncontrolled clinical trials appears to have a
good safety profile in patients pre and post-transplant
The drug may show promise as an add-on therapy to SOC for
patients recalcitrant to desensitization with the Cedars protocol
It may also be one of the first drugs to extend the half-life of
grafts chronically injured by persistent DSA