Updates in immunosuppression Dr Sara Assadiasl MD Ph
- Slides: 36
Updates in immunosuppression Dr. Sara Assadiasl MD. Ph. D. of immunology Assistant professor Molecular immunology research center Tehran university of medical sciences
Immunosuppression • • T cell inhibition B cell inhibition Complement inhibition Cytokine inhibition Blocking cell adhesion Immunoglobulins Anti‐metabolites and Cytotoxic agents
Monoclonal antibodies • The Latin root word cept means “taken. ” A combining form for a drug formed when a receptor is fused to the Fc portion of an immunoglobulin G molecule (decoy receptor) • The suffix "nib" nib indicates a small‐molecule inhibitor ("nib" is verbal shorthand for "inhibit") of kinase enzymes. More specifically, "tinib" is used for tyrosine kinase inhibitors, "anib" for angiogenesis inhibitors, and rafenib for rapidly accelerated fibrosarcoma (RAF) kinase inhibitors
Engineered antibodies
List of FDA approved monoclonal antibodies • • • • abciximab (Reopro) adalimumab (Humira, Amjevita) alefacept (Amevive) alemtuzumab (Campath) basiliximab (Simulect) belimumab (Benlysta) bezlotoxumab (Zinplava) canakinumab (Ilaris) certolizumab pegol (Cimzia) cetuximab (Erbitux) daclizumab (Zenapax, Zinbryta) denosumab (Prolia, Xgeva) efalizumab (Raptiva) golimumab (Simponi, Simponi Aria) inflectra (Remicade) • • • • ipilimumab (Yervoy) ixekizumab (Taltz) natalizumab (Tysabri) nivolumab (Opdivo) olaratumab (Lartruvo) omalizumab (Xolair) palivizumab (Synagis) panitumumab (Vectibix) pembrolizumab (Keytruda) rituximab (Rituxan) tocilizumab (Actemra) trastuzumab (Herceptin) secukinumab (Cosentyx) ustekinumab (Stelara)
T cell inhibition 1. TCR inhibition (Anti‐CD 3 m. Ab): Muromonab-CD 3, Otelixizumab, Foralumab 2. Calcineurin Inhibitors: Cyclosporine, Tacrolimus and Voclosporin 3. Co‐stimulation Blockade by CD 80/86: CD 28 Targeting: Abatacept and Belatacept 4. Co‐stimulation Blockade by CD 154: CD 40 Targeting (Anti‐CD 40 m. Ab): Bleselumab, Dacetuzumab 5. Protein kinase C inhibitors: Sotrastaurin
TCR inhibition (Anti-CD 3 m. Abs)
TCR inhibition (Anti-CD 3 m. Abs) • OKT 3 is no longer in production because of significant side effects related to the mitogenicity associated with its murine source • Otelixizumab is a chimeric monoclonal antibody that targets the epsilon (ε)‐chain of the CD 3 TCR that has been developed with the aim of short therapeutic courses capable of inducing a remission of T 1 DM • Foralumab (TZLS‐ 0401; NI‐ 0401) is a fully human monoclonal antibody that binds to the ε chain of the CD 3/TCR • Visilizumab
Cyclosporine, Tacrolimus
Voclosporin (ISA 247) • Treatment of psoriasis, prevention of organ rejection, management of autoimmune diseases • Three times as potent as cyclosporine in vitro • In single‐dose and multiple‐dose, with dosages to 4. 5 mg/kg/day • The most commonly reported adverse events: headache, hypertension, upper respiratory tract infection, and diarrhea; renal function was little affected
Co-stimulation Blockade • • • CD 40 L (CD 154) present on activated T cells is also present on platelets, and agents binding this cell surface molecule led to an increase in thrombotic events Bleselumab (ASKP 1240; Astellas) a fully‐human anti‐CD 40 monoclonal recombinant Ig. G 4, Under study in phase 2 clinical trials in kidney transplantation Dacetuzumab (SGN‐ 40 or hu. S 2 C 6)
Co-stimulation Blockade • Belatacept (NULOJIX) is a selective co‐stimulation blocker that improves long‐term outcomes in kidney‐ transplant recipients by providing effective immunosuppression without the toxic effects of calcineurin inhibitors • Abatacept (ORENCIA) is a prescription medication for moderate to severe Adult Rheumatoid Arthritis, Juvenile Idiopathic Arthritis, and Adult Psoriatic Arthritis
Protein kinase C inhibitors (Sotrastaurin) • • • Protein kinases are important in the activation of NF‐k. B Sotrastaurin blocks early T‐cell activation through a calcineurin‐independent mechanism Further development of sotrastaurin for the prevention of acute rejection in kidney transplant recipients has been halted following the results of a phase II randomized controlled study. In patients who also received basiliximab, everolimus and prednisone, use of sotrastaurin was associated with a higher incidence of efficacy failure (a composite of acute rejection, graft loss, death, or loss to follow‐up) at 12 months than was use of cyclosporine A. All deaths and graft losses occurred in patients treated with sotrastaurin.
T cell inhibition
B cell inhibition 1. Anti‐CD 20 Targeting: Rituximab (Mab. Thera), Ocrelizumab, Ofatumumab, and Veltuzumab 2. Targeting B Cell Differentiation: Belimumab and Atacicept 3. Anti‐CD 22 Targeting: Epratuzumab 4. Plasma Cell Targeting: Bortezomib (Velcade)
Anti-CD 20 Targeting • The chimeric nature of Rituximab leads to side effects attributable to cytokine release, such as fever, bronchospasm, and hypotension • Agents that are humanized (Ocrelizumab) Ocrelizumab or fully humanized (Ofatumumab) Ofatumumab were developed to minimize these untoward infusion reactions • Ocrelizumab development in RA has been discontinued because of an increased risk of serious infections • All anti‐CD 20 therapy carries a risk of hepatitis B reactivation in patients positive for hepatitis B surface antigen or hepatitis B core antibody
Targeting B Cell Differentiation • Belimumab is a humanized anti‐BAFF/Bly. S m. Ab that interferes with ligand/receptor binding and inhibits B cells maturation and survival
Targeting B Cell Differentiation • Atacicept acts as a “decoy receptor” for BAFF and APRIL by binding soluble APRIL, soluble BAFF and membrane‐bound BAFF
Anti-CD 22 Targeting (Epratuzumab) • • Expression of CD 22 is restricted to B cells • The functional consequences of Epratuzumab binding to CD 22 include diminished B‐cell proliferation, effects on adhesion molecule expression, and B‐ cell migration, as well as reduced production of pro‐inflammatory cytokines, such as IL‐ 6 and TNF CD 22 is expressed on immature B cells, certain memory B cells and germinal center B cells, highly expressed on naive B cells, but is lost on plasmablasts and plasma cells
Plasma Cell Targeting • • Bortezomib is a proteasome inhibitor • Inhibition of the proteasome leads to inhibition of cell cycling and induction of apoptosis • Side effects of peripheral neuropathy, cytopenias, and gastrointestinal effects occur in a dose‐ dependent fashion Proteasome is critical to the function of highly metabolic cells, such as plasma cells, to regulate the degradation of proteins
B cell inhibition
Complement inhibition • • Eculizumab is a humanized m. Ab to C 5 Tesidolumab (LFG‐ 316) is a human Ig. G 1 monoclonal antibody directed against C 5
Cytokine inhibition 1. Nonspecific cytokine inhibition: Corticosteroids 2. Janus Kinase Inhibition (Tofacitinib, Baricitinib, Ruxolitinib and Ibrutinib) 3. Targeting TNF‐α (adalimumab, infliximab, etanercept) 4. IL‐ 1 Inhibition (Anikinra, Rilonacept, and Canakinumab) 5. IL‐ 2 Receptor Antagonist (Basiliximab (Simulect) and Daclizumab) 6. IL‐ 6 Inhibition (Tocilizumab) 7. IL‐ 12 inhibition (Ustekinumab) 8. IL‐ 17 Inhibition (Secukinumab)
Corticosteroids • • Depletion of T cells because of IL‐ 2 inhibition • • Eosinophil apoptosis (directly or by IL‐ 5 inhibition) • Neutrophil migration to sites of inflammation is impaired • B cells are not significantly inhibited by corticosteroids, with only mild decreases in Ig production Inhibition of Th 1 differentiation, differentiation and induction of apoptosis Macrophage dysfunction because of inhibition of IL‐ 1 and TNF‐a
Janus Kinase Inhibition • An inhibitor of Janus kinase, Tofacitinib inhibits cytokine receptor signaling from a number of cytokines, including IL‐ 2, ‐ 4, ‐ 7, ‐ 9, ‐ 15, and ‐ 21 • Its development as an alternative for CNI in kidney transplantation was halted after a phase 2 b trial showed similar rejection rates, better GFR, lower rates of post‐transplant diabetes, and higher rates of cytomegalovirus and BK virus infection and post‐transplant lymphoproliferative disease
Targeting TNF-α • Infliximab, Adalimumab, Golimumab, and Certolizumab are m. Abs to TNF‐a that differ in the degree of chimerism and route of administration (intravenous versus subcutaneous) • • Etanercept is a TNFR fusion protein bound to Ig. G Increased risk of intracellular pathogens, such as Tuberculosis, Coccidiomycosis, and Cryptococcus
IL-2 Receptor Antagonist • Humanized antibodies to the α‐subunit of the IL‐ 2 receptor (Basiliximab and Daclizumab) limit proliferation of activated T cells and have been approved for the prevention of acute rejection in kidney transplantation
IL-1 Inhibition • • • Anakinra (an IL‐ 1 receptor antagonist) Rilonacept (a soluble decoy receptor) Canakinumab (an anti–IL‐ 1 b m. Ab)
IL-17 inhibition • • Secukinumab a human anti–IL‐ 17 A m. Ab has been developed for clinical use Vunakizumab (SHR‐ 1314) is an investigational, humanized monoclonal antibody targeting IL‐ 17 A Perakizumab (INN) Humanized Anti‐IL‐ 17 A Ig. G 1‐kappa antibody Ixekizumab (Taltz) is a humanized immunoglobulin G subclass 4 (Ig. G 4) monoclonal antibody against IL‐ 17 A
IL-6 Inhibition (Tocilizumab) • IL‐ 6 is expressed in response to inflammatory stimuli and contributes to CD 8 T and B cell differentiation, and activation of hepatic acute‐phase response • • • Increased circulating IL‐ 6 has been associated with mortality in AKI, ESRD and rejection in recipients of kidney transplants Clinical trials on safety and effect on donor‐specific anti‐HLA antibodies Used in managing cytokine storm
IL-12 inhibition • Ustekinumab is a human Ig G 1 kappa monoclonal antibody directed against IL‐ 12 and IL‐ 23
Cell Adhesion inhibition 1. Fingolimod (FTY 720) is a sphingosine 1‐phosphate (S 1 P) receptor modulator 2. Efalizumab is a humanized m. Ab to leukocyte function–associated antigen‐ 1 (LFA‐ 1) 3. Natalizumab, a humanized m. Ab against the adhesion molecule α‐ 4 integrin 4. Vedolizumab is humanized Ig. G 1 against the human lymphocyte α 4β 7 integrin
Cell Adhesion inhibition • • Fingolimod prevents lymphocyte migration from lymph node to the vasculature Prolonged QT interval, bradycardia (by S 1 P receptor binding on cardiomyocytes) and macular edema are the most reported side effects
Cell Adhesion inhibition • Efalizumab prevents lymphocyte activation and cell migration from the vasculature into tissues • Effective in psoriasis, islet and kidney transplant, withdrawn from USA market after high rates of post‐ transplant lymphoproliferative disease and brain infections
Cell Adhesion inhibition • Natalizumab and Vedolizumab block lymphocyte migration from vasculature to tissue (high infection rates)
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