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Dr Angeline Goh Senior Consultant
National University Centre for Organ Transplantation
Biologics in Transplantation
National University Centre for Organ Transplantation
Objectives
1. Definition of Biologics
2. Definition of Transplantation
3. The Immune System
4. Types of Immunosuppression
5. Biologics as Immunosuppressants
Definition of Biologics
• Drug(s) which modifies a biological response, and is created by a biologic process, rather than being chemically synthesized.
• Block the activity of biologic mediators of the immune response
• Nomenclature – Monoclonal Antibodies (mAb): generic name ending in “-mab” – Antecedents: “u” (-umab) indicates a human Ab “xi”(-ximab) indicates a “chimeric” Ab
• Fusion proteins – fusion of a receptor to the Fc part of the human immunologlobulin G1 (IgG1): generic name ending in “-cept”
Definition of Biologics
• Usually produced by recombinant DNA technology – ie. Development of recombinant DNA molecules by genetic
engineering to unite genetic material from multiple sources, to create sequences that would not otherwise be found in biological organisms.
– Recombinant DNA = chimeric DNA
• DNA molecules from all organisms share the same chemical structure; they differ only in the sequence of the nucleotides.
• When DNA from a foreign source is linked to host sequences that can drive DNA replication & then introduced into a host organism, the foreign DNA is replicated along with the host DNA.
• Eg. Insulin – human insulin DNA is placed into the DNA of a second organism e.g. pig, which becomes an insulin-producing ‘factory’.
Definition of Transplantation
• Process of taking an organ or living tissue and implanting it in another part of the body or in another body. – Autograft
The Immune System
— Allograft
The Allo-Immune Response
The Afferent Response
Antigen Presentation: Direct vs. Indirect Allorecognition
T-cell Receptor (Signal 1) & its Co-stimulatory molecules (Signal 2)
Antigen Signal Transduction
Cytokine Synthesis
Cytokine Signal Transduction (Signal 3)
Lymphocyte proliferation (Clonal expansion)
The Efferent Response
Types of Immunosuppression
Desensitization Induction / Maintenance
Treatment / prophylaxis of primary
disease recurrence
Treatment of steroid-
resistant or Ab-mediated
rejection
Days or weeks Days, months, or years
Kidney Transplant
• Mainstay of immunosuppressive drugs:
Biologics in Transplantation – WHY?
SIDE EFFFECTS • Cardiovascular – Hypertension;
Hypercholesterolemia
• Glucose intolerance
• Neurotoxicity – Tremor; Headache; Insomnia; Paraesthesia
• Nephrotoxicity – perhaps long-term dose and level-related
• Hepatotoxicity
• Physical – Gingival Hypertrophy; Hirsutism (CSA); Alopecia (TAC)
SIDE EFFFECTS • Cardiovascular - Hyperlipidemia,
hypertension • Glucose intolerance • Physical: Acne, cushingoid
facies, hirsutism, weight gain • Others: Mood disorder,
cataracts, osteoporosis, growth retardation in children
Steroids Calcineurin Inhibitors (CNI)
• Attempts at CNI-sparing regimens have been met with allograft failure.
• Need a therapy that would be effective in preventing acute rejection without the adverse effects of the CNIs or long-term high dose steroids.
• With increased understanding of the roles of target cells and that of their cell surface proteins & receptors, it became clear that a biologic agent might selectively target an antigenic ligand to inhibit a single pathway or cell type, leaving other targets unaffected and thus avoiding adverse effects.
• Aimed at depleting specific cell subpopulations or blocking circulating alloantibody responses or the complement system.
Biologics in Transplantation – WHY?
Biologics in Transplantation – WHEN & WHAT?
Desensitization: IVIg*
Rituximab* Bortezomib*
Induction / Maintenance:
Basiliximab Thymoglobulin Alemtuzumab*
Belatacept*
Treatment / prophylaxis of
primary disease recurrence: Rituximab*
Eculizumab*
Treatment of steroid-resistant or Ab-mediated
rejection: Thymoglobulin
IVIg* Rituximab*
Eculizumab* Bortezomib*
Days or weeks Days, months, or years
*Off-label or under investigation
Kidney Transplant
Biologics in Desensitization
• Sensitizing events: Blood transfusion, pregnancy, transplantation
• Desensitization: Reduce titre of preformed anti-HLA Abs
• Options for desensitization: – Plasmapheresis (PP) / Immunoadsorption (IA) – IVIg: Anti-inflammatory modulator – Rituximab: Anti CD-20 – Bortezomib: Proteosome inhibitor – Eculizumab
Immunomodulatory & Anti-inflammatory actions of IVIg
16
Time in Days -30 0 -1 -16
IVIg 2g/kg
IVIg 2g/kg Tplt
IVIg 2g/kg Rituxmab
1g
IVIg 2g/kg
10 to 14
- Vo et al. Transplantation 2010
Biologics in Desensitization – Example 1
Deceased Donor
PP/IVIg 100mg/kg
PP/IVIg 100mg/kg
17
PP/IVIg 100mg/kg
-4 -3 -1 1 -2 3
Rituximab 375mg/m2
Time in Days
PP/IVIg 100mg/kg
MMF 1g BD
PP/IVIg 100mg/kg
Splenectomy
0
PP/IVIg 100mg/kg
XM-
Tplt
Immunosuppression Induction: Thymoglobulin
Maintenance: Tac + MMF + Pred
- Gloor et al. Am J Transpl 2003
2 4
Biologics in Desensitization – Example 2
Living Donor
Biologics in Desensitization
• Encouraging short-term results • Long-term efficacy questionable
– 1- & 5-year graft survival rate significantly inferior in patients who underwent desensitization protocol ie. high to very high immunological risk vs. no desensitization ie. low to moderate immunological risk
• Overall risk of graft loss significantly higher in desensitized patients (HR 2.6, p=0.04)
Hariran A et al. Positive crossmatch living donor kidney transplantation: longer-term outcome. Am J Transplant 2009; 9:536-542.
XM+ve
XM-ve
Why desensitize them?
Recipients of high or very high immunological risk transplants ESRD patients on waiting list OR received deceased donor transplant ESRD patients on transplant waiting list
Orandi BJ et al. Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors. NEJM 2016; 374: 940-50.
Biologics in Induction Immunosuppression
• Induction immunosuppressants: – Decrease the risk of hyperacute rejection in the immediate post-
op period, thereby increasing allograft survival – Decrease occurrence of Delayed Graft Function, thereby reducing
rejection & increasing allograft survival
• With biologics: – Enhance strength of initial triple immunosuppression – Allow use of CNI & steroids at lower doses
Biologics in Induction Immunosuppression
• Lymphocyte depletion – Polyclonal anti-lymphocyte Ab e.g. ATG, Thymoglobulin (from
rabbit) – Monoclonal Abs
• Target T lymphocytes e.g. Alemtuzumab • Target B lymphocytes e.g. Rituximab
• Modulation of specific receptors e.g. Anti-CD3 (OKT3)
• Blocking of receptors / ligands – Anti-CD25 (IL2 Receptor) Abs e.g. Basiliximab, Daclizumab – B7 mediated co-stimulation e.g. Belatacept
Biologics in Induction Immunosuppression
Biologics in Induction Immunosuppression
2006 OPTN/SRTR Annual Report Chapter IV
Biologics in Induction Immunosuppression
SRTR 2017
Polyclonal Ab - Thymoglobulin
• T cell depletion in blood & peripheral lymphoid tissues
• Interference with leukocyte-and-endothelium interaction
• Apoptosis in all B cell lineages
• Induction of Tregs
– Minimize allorecognition & homing
– Reduce incidence of Delayed Graft Function
– Prevention of activation of alloreactive B cells & reduces alloreactive plasma cells
– Immunological quiescence
Lymphocyte-Depleting Antibodies
• Bind to a variety of human lymphocyte receptors.
• Macrophages bind to the Ab-lymphocyte complex & remove lymphocytes by opsonization. Apoptosis & complement-dependent cell-mediated lysis are other mechanisms of T cell depletion.
• Thus lymphocytes get depleted, resulting in profound immunosuppression.
• Other effects: hypersensitivity reactions
Monoclonal Antibodies
Biologics in Induction Immunosuppression
HARMONY TRIAL Lancet 2016; 388:3006-16
HARMONY Trial – Induction Immunosuppression
• First multi-centre RCT to show that rapid steroid withdrawal can be safely done without compromising efficacy with a Tac and MMF based regimen.
• Potentially improving safety profile and reducing new-onset diabetes after transplant.
Immunological low risk cohort, Tac and MMF based IS regimen
Basiliximab Induction with or without rapid
steroid tapering
Rabbit ATG Induction with rapid steroid
tapering
• Classically, rabbit Anti-Thymocyte Globulin (ATG) is considered to have a greater immunosuppressive effect by direct depletion of immunocompetent cell populations and is preferred in immunologically high-risk populations.
• This study findings suggests that both Basiliximab and Rabbit ATG are equipotent in preventing biopsy-proven acute rejection.
• May be related to low immunological risk cohort of patients.
HARMONY Trial – Induction Immunosuppression
Polyclonal and Monoclonal Abs for Induction Therapy in Kidney Transplant Recipients (review)3 • ATG reduces acute rejection by 33%, but has uncertain effects on
death, graft survival, malignancy and NODAT; and increases CMV infection, thrombocytopenia & leukopenia.
• Without ATG induction → 45% acute rejection risk – NNT = 7, to prevent 1 having rejection – For every 12 patients given ATG induction, 1 would experience
CMV disease
• Steroid minimization: – Alemtuzumab prevents acute rejection at 1 year compared to
ATG. – NNT = 11, to prevent 1 having rejection
• Overall, ATG & Alemtuzumab decrease acute rejection at a cost of increased CMV disease while patient-centred outcomes (reduced death or lower toxicity) do not appear to be improved.
Biologics in Maintenance Immunosuppression
• Belatacept (T-cell co-stimulation blocker)
• Fusion protein composed of the Fc fragment of human IgG1 linked to the extracellular domain of cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), selectively inhibits T-cell activation through co-stimulation blockade.
• Potential for maintaining graft survival similar to strategies of global T-cell depletion without added consequences of over-immunosuppression and adverse cardiovascular and metabolic effects.
BENEFIT Trial4
• Phase III BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) trial – 1-year study – Assess more (MI) or less intensive (LI) regimen of Belatacept vs.
Cyclosporine A in adult ECD kidney transplant recipients.
• Primary objective: assess each belatacept-based regimen compared with CyA-based regimen on 3 primary outcomes at 12 months: 1. Renal function 2. Composite of graft & patient survival 3. Acute rejection rate by 12 months
BENEFIT Trial - Design Belatacept MI, n=225
0-3 Months 10mg/kg Days 1,5
Weeks 2,4,6,8,10,12
4-6 Months 10mg/kg
Weeks 16,20,24
7-12 months 5mg/kg
every 4 weeks
Belatacept LI, n=230
0-1 Month 10mg/kg Days 1,5
Weeks 2,4
2-3 Months 10mg/kg
Weeks 8,12
3-12 months 5mg/kg
every 4 weeks
CsA, n=231
Initial daily dose 4-10mg/kg
0-1 Month Aim trough 150-200
ng/ml
2-12 Month Aim trough 100-250
ng/ml
Completed 12 months n=173
Completed 12 months n=181
Completed 12 months n=173
Completed 84 months n=153
Completed 84 months n=163
Completed 84 months n=131
BENEFIT Trial – Change in GFR over 1 year
BENEFIT Trial – Change in GFR over 7 years5
BENEFIT Trial – Patient & Graft Survival over 7 years
BENEFIT Trial – 7 year data: secondary outcomes
BENEFIT Trial – final conclusions
• Patients assigned to the Belatacept arms had a 43% reduction in death or graft loss over 7 years, compared to those on Cyclosporine.
• Clinically & statistically significant improvements in renal function observed in patients on Belatacept as compared with Cyclosporine at earlier time points were sustained at 7 years, despite a higher rate of early acute rejection.
• Long-term safety profile of Belatacept comparable to Cyclosporine, EXCEPT for higher incidence of post-transplant lymphoproliferative disorder in first 24 months.
• Preserves renal function via mechanisms that need further elucidation beyond increased compliance with monthly injections.
Biologics in Treatment of Acute Rejection
• About 10-35% of all kidney transplant recipients will experience 1 episode of acute rejection (AR) in the 1st year.
• Options for treating AR: – Pulsed steroids – Antibody preparation – Increase maintenance immunosuppression – Combination of the above
Polyclonal and Monoclonal Abs for treating Rejection episodes in Kidney Transplant Recipients (review)6
• Any Ab was better that steroids for reversing the 1st episode of acute cellular rejection & preventing graft loss.
• Subsequent rejection & patient survival – little or no difference between using an Ab of pulse steroids.
• Steroid-resistant acute cellular rejection – little or no difference between different Abs over 12 months; limited data beyond that.
• Acute Ab-mediated rejection – use of Ab therapy did not confer additional benefit in reversing the rejection, death, or graft loss.
• Polyclonal Ab-treated patients were more likely to experience an immediate reaction of fever, chills & malaise than those receiving only steroids.
Biologics in Treatment of Acute Rejection
• Used only in steroid-resistant acute rejection – TCMR: Banff Grade II or higher – ABMR
TCMR • Thymoglobulin – 1.5-3mg/kg x 5-10 doses • Alemtuzumab – single dose IV 30mg
ABMR • Rituximab • Bortezomib • IVIg
Adverse effects of Biologics
• Higher risk of infections – Start antimicrobial prophylaxis (according to centre protocol)
• Higher risk of future malignancies?? – Appropriate cancer screening in all patients who receive biologics
• Adverse effects directly related to cumulative dose given; hence giving an appropriate dose which would give desired outcomes with minimal side effects is important.
Agent Target Mechanism of Action Basiliximab (chimeric monoclonal Ab)
CD25 (IL2 receptor α chain)
Binds to & blocks IL2R on T cells, inhibiting IL2-induced T-cell activation
Rituximab (chimeric monoclonal Ab)
CD20 Binds to CD20 on B cells; mediates B-cell lysis & depletion
Alemtuzumab (humanized monoclonal Ab)
CD52 Binds to CD52 receptor on T & B cells, monocytes, macrophages & NK cells, causing cell lysis & depletion
Eculizumab (recombinant humanized monoclonal Ab)
Complement protein C5 Binds to complement protein C5, inhibiting its cleavage to C5a & C5b, preventing generation of membrane attack complex
Examples – Monoclonal Abs
Agent Indication Duration of effect Basiliximab (chimeric monoclonal Ab)
Induction Up to 56 days (2 doses)
Rituximab (chimeric monoclonal Ab)
Desensitization Up to 12 months (cumulative dose-dependent effect)
Alemtuzumab (humanized monoclonal Ab)
Induction Up to 12 months
Eculizumab (recombinant humanized monoclonal Ab)
Recurrence of aHUS, treatment of Ab-mediated rejection
14 days (after 1 dose)
Examples – Monoclonal Abs
Agent Target Mechanism of Action Thymoglobulin (polyclonal IgG)
T cells, B cells, APC Several receptors present on plasma cells, monocytes, dendritic cells, leucocytes & others
Blocks several T- & B-cell receptors, causing cell dysfunction, lysis & depletion
IVIg (polyclonal human IgG
Circulating alloAbs & B cells
Anti-idiotypic blockade of alloAbs; downregulation of Ab production
Examples – Polyclonal Abs
Agent Indication Duration of effect Thymoglobulin (polyclonal IgG)
Induction, steroid-resistant rejection
Up to 12 months (cumulative dose-dependent effect)
IVIg (polyclonal human IgG
Desensitization ???
Examples – Polyclonal Abs
1. Kumar V. Biologics in Solid Organ Transplantation. Medscape CME Activity, 2012.
2. Grenda R. Biologics in Renal Transplantation. Pediatr Nephrol (2015) 30: 1087-98.
3. Hill P, et al. Polyclonal and Monoclonal Abs for Induction Therapy in Kidney Transplant Recipients. Cochrane Database Syst Rev (2017).
4. Vincenti F, et al. BENEFIT Study. Am J Transpl 2010; 10: 547-57. 5. Vincenti F, et al. Belatacept and Long-term Outcomes in Kidney
Transplantation. NEJM 2016; 374: 333-43. 6. Webster AC, etal. Polyclonal and Monoclonal Abs for treating Rejection
episodes in Kidney Transplant Recipients. Cochrane Database Syst Rev (2017).
Other References
