Immunomodulatory drugs

  1. BCG (ImmuCyst)
    • Adjuvant - live attenuated bacillus calmette-guerin
    • surface antigens interact directly with PAMPs on APCs to increase APC activity
    • useful in some cancer therapies (bladder cancer)
    • direct activation of leukocytes (principally macrophages) can produce a systemic inflammatory response and septic shock
    • BCG related to pathogen that causes TB - will test + for TB test if used BCG
  2. interleukin-2 (IL-2, Aldesleukin, Proleukin)
    • cytokine
    • increase proliferation of activated T cells, production of IFN-γ, and cytotoxic killer cell activity
    • treatment of metastatic melanoma and renal cell carcinoma
    • assoc. with serious cap. leak syndrome, hypotension, and reduced organ perfusion. Can be fatal
  3. IFN-γ (Actimmune)
    • cytokine - interferons
    • stimulates cell mediated cytotoxic immune response
    • used to treat severe recurrent infections
  4. ipilimumab (Yervoy)
    • immune checkpoint inhibitor: fully human antibody to CTLA-4
    • experimentally shown to promote regression of a variety of tumor types
    • approved in 2011 for treatment of metastatic melanoma
    • can cause severe and fatal immune-mediated rxns caused by T-cell activation and proliferation (enterocolitis, dermatitis, neuropathy, endocrinopathy, hepatitis)
    • runs can occur weeks to months after treatment
    • requires permanent discontinued treatment and high dose corticosteroid treatment to suppress immune-mediated rxns
  5. nivolumab (Opdivo) and pembrolizumab (Keytruda)
    • immune checkpoint inhibitor - fully human antibody to PD-1
    • experimentally shown to promote regression of a variety of tumor types
    • increased survival rates compared to conventional chemotherapy for melanoma or non-small cell lung cancer (approved for both)
    • assoc. with severe immune-mediated colitis, hepatitis, nephritis, pneumonitis, and thyroid disfunction
    • combination drug synergistically increases tumor regression and survival in melanoma clinical trials
  6. cyclophosphamide (Cytoxan)
    • immunosuppressive - crosslinks DNA and kills proliferating cells, preventing expansion of antigen-specific lymphocytes
    • used in many auto-immune diseases and bone marrow transplants
    • adverse effects: myelosuppression, nausea, vomiting, infertility
  7. azathioprine (Imuran)
    • immunosuppressive - metabolized to 6-mercaptopurine and further metabolized to 6-thioguanine
    • products inhibit purine synthesis and become incorporated into DNA as thio-guanine nucleotides (causes DNA damage)
    • inactivated by xanthine oxidase (decreased when combined with allopurinol)
    • uses: renal and other tissue transplantation, some auto-immune disorders (lupus, RA)
    • adverse effects: myelosuppression, nausea, vomiting
  8. mycophenolate mofetil (Cell-Cept)
    • hydrolyzed to mycophenolic acid
    • inhibits inosine monophosphate dehydrogenase, preventing purine synthesis
    • used for solid organ transplant as an alternative to cyclosporine, and some auto-immune diseases
    • adverse effets: myelosuppression, nausea, vomiting
  9. methotrexate
    • inhibits DHFR - direct inhibition and accumulated inhibitory intermediates prevent synthesis of thymidine and purine nucleotides
    • used as drug of choice in RA, some auto-immune diseases
    • adverse effects: nausea, mucosal ulcers, modest hepatotoxicity, myelosuppression
  10. leflunomide (Arava)
    • metabolized to A77-1726 (active form)
    • inhibits dihydroorotate dehydrogenase, leading to decreased pyrimidine synthesis
    • A77-1726 is subject to enterohepatic recirculation and has a half-life of 19 days
    • used for RA and some autoimmune diseases
    • adverse effects: diarrhea, modest hepatotoxicity, myelosuppression
  11. prednisone
    • glucocorticosteroid - combined immuno-suppresive and anti-inflammatory effect (focus now on immunosuppressive)
    • affect gene txn as ligands for glucocorticoid receptors
    • primary immunosuppressive effect is in inhibition of cytokine (IL-2, IFN-γ) gene expression from antigen-activated T cells
    • orally available for systemic immunosuppression and reduced inflammation - can apply topically for localized effects and inhaled as aerosol for asthma therapy
    • first line immunosuppressant for solid organ and hematopoietic stem cell transplant
    • useful in management of various immune-based disorders (certain autoimmune diseases, asthma, allergic rxns, systemic inflammation)
    • adverse effects (generally with >2 weeks daily systemic administration): Cushing's syndrome effects, glucose intolerance, hypertension and fluid retention, osteoporosis, adrenal suppression, GI disturbances, ocular disturbance, psychiatric disturbances
  12. cyclosporine (Sandimmune)
    • calcineurin inhibitor
    • can be effective without other immunosuppressants, but often combined with other agents
    • forms a complex with the immunophilin cyclophilin
    • commonly useful in kidney, liver, and cardiac transplants
    • can be useful in a variety of autoimmune disorders (RA) and may have applications in some inflammatory diseases (IBD, asthma)
    • adverse effects: nephrotoxicity, HTN, hyperglycemia, liver dysfunction, increased cancer incidence documented although probably no greater than other immunosuppressants
  13. tacrolimus (Program, FK506)
    • calcineurin inhibitor
    • can be effective without other immunosuppressants, but often combined with other agents
    • forms a complex with the immunophilin FKBP12
    • commonly useful in kidney, liver, and cardiac transplants
    • can be useful in a variety of autoimmune disorders (RA) and may have applications in some inflammatory diseases (IBD, asthma)
    • adverse effects: nephrotoxicity, HTN, hyperglycemia, liver dysfunction, increased cancer incidence documented although probably no greater than other immunosuppressants
    • 10-100x more potent than cyclosporine
  14. sirolimus (Rapamune, rapamycin) and everolimus (Afinitor)
    • mTOR inhibitor
    • can be used alone or in combination therapies to preserve solid organ transplants
    • forms a complex with FKBP12
    • may be useful in steroid-resistant GVHD in hematopoietic stem cell transplants
    • antagonizes tacrolimus effects, but synergies with cyclosporine
    • Adverse effects: myelosuppression, hyperlipidemia, hypertension, edema, hepatotoxicity
    • everolimus more commonly used in cancer chemotherapy
  15. Rh(D) immune globulin (BayRho-D, WinRho SDF)
    • antibody for RH hemolytic disease
    • Rh negative mothers can be sensitized to foreign D antigen of an Rh+ fetus. Subsequent pregnancies, maternal antibodies against Rh+ cells can transfer to the fetus leading to hemolytic disease
    • concentrated solution of human IgG with a high titer of Rh(D) antibodies. 
    • prevents initiation of a maternal immune response to fetal Rh(D) antigen
    • mechanism is mediated by opsonization and clearance of fetal Rh+ cells before an effective immune response can develop
  16. belatacept (Nulojix)
    • fusion protein of a high-affinity B7 ligand (CTLA4) with an IgG Fc domain
    • second generation version of abatacept, with higher affinity for B7
    • approved for kidney transplants
    • prevents B7 (on APC) interacting with CD28 (TCell), causes T cells to become anergic, which prevents proliferation, cytokine production, and causes the TCell to die
    • Adverse effects: anemia, neutropenia, peripheral edema, increase risk of infection and malignancy, post transplant lymphoproliferative disorder (possibly higher frequency than other immunosuppressive agents, contraindicated in EBV-negative patients)
    • Effect: comparable to calcineurin inhibitors in preventing transplant rejection
  17. anti-T cell globulin (ATG)
    • Immune-depleting agent
    • product of repeated injection of human T cells into animals. Purified serum IgG
    • blocks T cell surface receptors and opsonizes T cells
    • Adverse effects: cytokine release syndrome (fever, chills, headache, nausea, malaise, etc) which is reduced with acetaminophen and antihistamine, serum sickness, anaphylaxis potential (mostly on repeated use)
    • effect: produces prolonged T cell depletion (more than a year), but potential for late rejection as lymphoid system recovers
  18. alemtuzumab (Campath)
    • immune-depleting agent
    • humanized anti-CD52 antibody
    • CD52: surface protein expressed on T and B cells, monocytes, macrophages, and NK cells
    • mechanism: depletes a broad variety of cells involved in adaptive and innate immune rxns
    • adverse effects: myelosuppression, flu-like symptoms
    • effect: produces prolonged depletion of T cell and other cells of the immune system (up to a year)
  19. basiliximab (Simulect)
    • immune-depleting agent
    • humanized anti-IL-2 receptor (anti-CD25) antibody
    • mechanism: blocks and opsonizes α-chain of IL2 receptor (CD25) that is present on ACTIVATED T cells
    • adverse effects: well tolerated
    • effect: depletes only antigen-activated T cells, moderate effect compared to ATG
    • may be more appropriate for patients with low to moderate risk of rejection
    • reduced immune-depletion is assoc with a reduced incidence of infection (particularly chronic CMV) and malignancy
Author
jboi
ID
319360
Card Set
Immunomodulatory drugs
Description
MOHD3
Updated