Immunosuppressive drugs

Philip F. Halloran:N Engl J Med 2004;351:2715-29

three-signal model of alloimmune responses

Philip F. Halloran:N Engl J Med 2004;351:2715-29

Classification of Immunosuppressive TherapiesUsed in Organ Transplantation

• Glucocorticoids• Small-molecule drugs

– Immunophilin-binding drugs• Calcineurin inhibitors

– Cyclophilin-binding drugs: cyclosporine,ISA(TX)247– FKBP12-binding drugs: tacrolimus,modified release tacrolimus

• Target-of-rapamycin inhibitors: sirolimus,everolimus

– Inhibitors of nucleotide synthesis• Purine synthesis (IMPDH) inhibitors

– Mycophenolate mofetil– Enteric-coated mycophenolic acid– Mizoribine

• Pyrimidine synthesis (DHODH) inhibitors– Leflunomide– FK778

– Antimetabolites: azathioprine– Sphingosine-1-phosphate–receptor antagonists:Fingolimod

• Protein drugs– Depleting antibodies (against T cells, B cells, or both)

• Polyclonal antibody: horse or rabbit antithymocyte globulin• Mouse monoclonal anti-CD3 antibody (muromonab-CD3)• Humanized monoclonal anti-CD52 antibody (alemtuzumab)• B-cell–depleting monoclonal anti-CD20 antibody (rituximab)

– Nondepleting antibodies and fusion proteins• Humanized or chimeric monoclonal anti-CD25 antibody

(daclizumab, basiliximab)• Fusion protein with natural binding properties:CTLA-4–Ig

Belatacept

– Intravenous immune globulin

Cyclosporine

• Neoral : oral formulation of cyclosporine that immediately forms a microemulsion in an aqueous environment

• Description– 11-amino-acid cyclic peptide fromTolypocladium

inflatum • Mechanism

– Binds to cyclophilin; complex inhibits calcineurin phosphatase and T-cell activation

Cyclosporine

• Prescribed for– Kidney, liver, heart organ transplantation used in

combination with azathioprine and corticosteroids– Rheumatoid Arthritis used in combination with

methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone

– Psosiasis nonimmunocompromised patients with severe (i.e.,extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (eg., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated

Cyclosporine

• Side effect– Nephrotoxicity, hemolytic–uremic syndrome,

hypertension, neurotoxicity, gum hyperplasia, skin changes, hirsutism, post-transplantation diabetes mellitus, hyperlipidemia; trough monitoring or checking levels two hours after administration required

ISA 247

• More potent and less toxic than cyclosporin• Clinical development for the treatment of

psoriasis (phase III) and prevention of organ rejection after transplantation (phase II)

Tacrolimus (FK506)

• Prescribed for– Liver, kidney– Heart transplant (prograft+azathripine+MMF)– second-line therapy for the short-term and non-continuous chronic

treatment of moderate to severe atopic dermatitis• Side effect

– Effects similar to those of cyclosporine but with a lower incidence of hypertension, hyperlipidemia, skin changes, hirsutism, and gum hyperplasia and a higher incidence of post-transplantation diabetes mellitus and neurotoxicity; trough monitoring required

– Seizures, Lymphomas, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, Bullous impetigo, osteomyelitis, septicemia, Rosacea

Tacrolimus (FK506)

• Prograf capsule, injection and Protopic ointment

• Description– Macrolide antibiotic from Streptomyces

tsukubaensis• Mechanism

– Binds to FKBP12; complex inhibits calcineurin phosphatase and T-cell activation

– reduces T-cell and IL-2 activity

J Am Soc Nephrol 10: 1366–1380, 1999

Tacrolimus (FK506)

N =1645 renal transplant,standard-dose cyclosporine, MMFand corticosteroidsDaclizumab induction,MMF, and corticosteroids, low dose sirolimusDaclizumab induction,MMF, and corticosteroids, low dose cyclosporinDaclizumab induction,MMF, and corticosteroids, low dose tacrolimus

Pimecrolimus

• Elidel – cream 1%• Description

– ascomycin macrolactam derivative• Mechanism

– Binds to macrophilin-12 and inhibits calcineurin– Inhibits T-cell activation by inhibiting the synthesis and release of

cytokines from T-cells– Prevents the release of inflammatory cytokines and mediators from

mast cells– Similar mode of action to tacrolimus but is more selective

• no effect on dendritic (Langerhans) cells• lower permeation through the skin than topical steroids or topical tacrolimus

Pimecrolimus

• Prescribed for– second-line therapy for the short- term and non-

continuous chronic treatment of mild to moderate atopic dermatitis

– not indicated for use in children less than 2 years of age • Side effect

– impetigo, skin infection , superinfection (infected atopic dermatitis)

– Anaphylactic reactions, ocular irritation – Lymphomas, basal cell carcinoma, malignant melanoma,

squamous cell carcinoma

Sirolimus

• Rapamycin• Description

– Triene macrolide antibiotic from Streptomyces hygroscopicus from Easter Island (Rapa Nui)

• Mechanism– Binds to FKBP12; complex inhibits target of

rapamycin and interleukin- 2–driven T-cell proliferation

– arresting the cell cycle in the G1 phase

Sirolimus

• Prescribed for– Renal transplant

• Side effect– Hyperlipidemia, increased toxicity of calcineurin

inhibitors, thrombocytopenia, delayed wound healing, delayed graft function, mouth ulcers, pneumonitis, interstitial lung disease; lipid monitoring required; recipients whose risk of rejection is low to moderate can stop cyclosporine treatment two to four months after transplantation

Everolimus

• Certican : Derivative of Rapamycin• Mechanism

– Works similarly to Rapamycin as an mTOR (mammalian target of rapamycin) inhibitor

– lead to a hyper-activation of the kinase AKT via inhibition on the mTORC1 negative feedback loop while not inhibiting the mTORC2 positive feedback to AKT.

– This AKT elevation can lead to longer survival in some cell types• Prescribed for

– Heart transplant reduce chronic allograft vasculopathy Howard J. Eisen: N Engl J Med 2003;349:847-58

– Advance renal cancer– Vascular stent

Azathioprine

• Imuran: immunosuppressive antimetabolite, is available in tablet form for oral administration and 100-mg vials for intravenous injection

• Description– Prodrug that releases 6-mercaptopurine – the first immunosuppressive agent to achieve widespread use in organ

transplantation• Mechanism

– Purine synthesis inhibitor, inhibiting the proliferation of cells, especially leukocyte

– Converts 6-mercaptopurine to tissue inhibitor of metalloproteinase, which is converted to thioguanine nucleotides that interfere with DNA synthesis; thioguanine derivatives may inhibit purine synthesis

– prevents mitosis and proliferation of rapidly dividing cells, such as activated B and T lymphocytes

• Azathioprine is metabolized to 6-mercaptopurine (6-MP), which is either inactivated by two enzymes, thiopurine s-methyltransferase (TPMT) and xanthine oxidase (XO), or is further metabolized to thioinosine monophosphate (TIMP).

• Genetic polymorphism involving the inactivating enzyme TPMT• Allopurinol inhibits XO, elevate azathioprine bioavailability by fivefold

Azathioprine

• Prescribed for – FDA :

• Renal Homotransplantation: Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables.

• Rheumatoid Arthritis: treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms

• Juvenile Rheumatoid Arthritis

– Non-FDA : Multiple Sclerosis, Crohn's disease, myasthenia gravis, chronic ulcerative colitis, and autoimmune hepatitis

• Side effect– Leukopenia, bone marrow depression, macrocytosis, liver toxicity

(uncommon); blood-count monitoring required

Mycophenolate mofetil

• Cellcept oral and injection• Myfortic : mycophenolate sodium• Description

– Mycophenolic acid from penicillium molds• Mechanism

– Inhibits synthesis of inosine monophosphate dehydrogenase (IMPDH); blocks purine synthesis, preventing proliferation of T and B cells

Mycophenolate mofetil

• Prescribed for • Renal, liver and cardiac transplant• Lupus nephritis

• Side effect– GI symptoms (mainly diarrhea), neutropenia, mild anemia;

blood-level monitoring not required but may improve efficacy; absorption reduced by cyclosporine

– lymphomas and other malignancies, particularly of the skin – Infection, CMV– Progressive Multifocal Leukoencephalopathy (PML)

Mizoribine

• Bredinin• Description

– isolated from the mould Eupenicillium brefeldianum

• Mechanism– Mizoribine monophosphate (MZP) is the active

metabolite– Inhibitor of IMP dehydrogenase (IMPDH)

Leflunomide

• Arava oral administration as tablets containing 10, 20, or 100 mg

• Description– pyrimidine synthesis inhibitor

• Mechanism– Dihydroorotate dehydrogenase inhibitor– antiproliferative activity– Several in vivo and in vitro experimental models

have demonstrated an anti-inflammatory effect

Leflunomide

Leflunomide

• Prescribed for – RA: reduction in signs and symptoms, and inhibition of structural

damage and improvement in physical function (loading dose of 100 mg per day for three days only was used

followed by 20 mg per day )Aspirin, NSAIDS and/or low dose corticosteroids may be continued during treatment with ARAVA

Psoriatic arthritis, AS• Side effect

– diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash – high BP, chest pain and abnormal heartbeats– increase the risk to patients of infections

FK778

• malononitrilamides• Description

– active derivative of leflunomide• Mechanism

– Inhibits pyrimidine synthesis, blocking proliferation of T and B cells

• Side effect– Anemia; other effects not known; in phase 2 trials

kidney transplant

Fingolimod

• FTY720• Description

– Sphingosine-like derivative of myriocin from ascomycete fungus

• Mechanism– Works as an antagonist for sphingosine-1-

phosphate receptors on lymphocytes, enhancing homing to lymphoid tissues and preventing egress, causing lymphopenia

Fingolimod

• Prescribed for– Renal transplant– Multiple sclerosis : reduced the number of lesions detected

on MRI and clinical disease activity (Ludwig Kappos N Engl J Med 2006;355:1124-40)

• Side effect– Reversible first-dose bradycardia, potentiated by general

anesthetics and beta-blockers; nausea, vomiting, diarrhea, increased liver-enzyme

– infections, skin cancer and, recently, a case of haemorrhaging focal encephalitis

Muromonab-CD3

• Orthoclone OKT3• Description

– Murine monoclonal antibody against CD3 component of T-cell–receptor signal-transduction complex

• Mechanism– monoclonal IgG2a antibody– binds to the T cell receptor-CD3-complex (specifically the CD3 epsilon

chain) on the surface of circulating T cells, interfering with the receptor-antigen-interaction

– resulting in a transient activation of T cells, release of cytokines, and blocking of T-cell proliferation and differentiation

– T-cell function usually returns to normal within approximately 48 hours of discontinuation of therapy

Muromonab-CD3

• Prescribed for– Renal, heart and liver transplant

• Side effect– Severe cytokine-release syndrome, pulmonary

edema, acute renal failure, gastrointestinal disturbances, changes in central nervous system

– pyrexia myalgia, nausea and diarrhoea

Alemtuzumab

• Campath• Description

– Humanized monoclonal antibody against CD52, a 25-to-29-kD membrane protein

• Mechanism– Binds to CD52 on all B and T cells, most

monocytes, macrophages, and natural killer cells, causing cell lysis and prolonged depletion

Alemtuzumab

• Prescribed for– CLL, CTCL and T cell lymphoma

• Side effect– hypotension, rigors, fever, shortness of breath,

bronchospasm, chills, and/or rash

Rituximab

• Rituxan, MabThera• Description

– Chimeric monoclonal antibody against membrane-spanning four-domain protein CD20

• Mechanism– Binds to CD20 on B cells and mediates B-cell lysis

Rituximab

• Prescribed for– Lymphoma, leukemia– RA with MTX– Renal transplant (especially useful in transplants

involving incompatible blood groups)– Off label – MS, SLE, autoimmune hemolytic anemia

• Side effect– Infusion reactions, hypersensitivity reactions– Infection : HBV, PML– Tumor Lysis Syndrome (TLS) in ARF

Daclizumab

• Zenapax• Description

– Humanized monoclonal antibody against CD25 (interleukin-2– receptor α chain)

• Mechanism– Binds to and blocks the interleukin-2– receptor α chain

(CD25 antigen) binds with high-affinity to the Tac subunit of the high-affinity IL-2 receptor complex and inhibits IL-2 binding

– on activated T cells, depleting them and inhibiting interleukin-2–induced T-cell activation

Daclizumab

• Prescribed for• Renal, cardiac transplant• MS

• Side effect– Hypersensitivity reactions (uncommon)– gastrointestinal disorders – does not appear to increase the incidence of

opportunistic infections or malignancies

Belatacept

• Description– Protein combining B7-binding portion of CTLA-4

with IgG Fc region• Mechaniasm

– Binds to B7 on T cells, preventing CD28 signaling and signal 2

• Prescribed for– Renal transplant

• Orencia• second-generation belatacept• Prescribed for

– Renal transplant– RA, UC, lupus nephritis

Abatacept

CP-690,550

• JAK3 inhibitor• Phase II treatment RA• Phase II renal transplant

Polyclonal antibody

• Antithymocyte globulin-equine (Atgam®), Antithymocyte globulin-rabbit (RATG, Thymoglobulin®)

• Description– Polyclonal antibodies are directed against

lymphocyte antigens, directed against multiple epitopes

Polyclonal antibody

• Mechanism– agents contain antibodies specific for many

common T cell antigens including CD2, CD3, CD4, CD8, CD11a, CD18

– effectively depletes T-cell concentration in the body through complement-dependent cytolysis and cell mediated opsonization

– following with T cell clearance from the circulation by the reticuloendothelial system

Polyclonal antibody

• Side effect– Leukopenia – serum sickness (cross-reactivity with other tissue antigens) – adversely affects the ability of the patient to make antibodies

against foreign protein – thrombocytopenia – pruritis – fever – arthralgias – opportunistic infections – malignancies

Immunosuppressive drugs used to treat transplant rejectionCalcineurin inhibitors

Ciclosporin Tacrolimus mTOR inhibitors Sirolimus Everolimus Anti-proliferatives Azathioprine Mycophenolic acid Corticosteroids Prednisolone Hydrocortisone Antibodies Monoclonal anti-IL-2Rα receptor antibodies

Basiliximab Daclizumab

Polyclonal anti-T-cell antibodies Anti-thymocyte globulin (ATG)

• The IL-2 receptor antagonist daclizumab is approved for use in what condition? (A) Asthma (B) Hypereosinophilia

(C) Renal transplant (D) Non-Hodgkin’s lymphoma

Cyclosporine modulates calcium dependent T cell activation by inhibiting (A) Cadherin (B) Calnexin (C) Calcineurin (D) Calreticulin