B.28 Flashcards
Immunopharmacology III
Blocking T cell surface molecules involved in signaling of immunoglobulins: ATG (antithymocyte-globulin)
Antibodies against B cells: Rituximab
Antibodies against adhesion molecules/cytokines:
- Anti TNFα: Infliximab, Adalimumab
- Anti-IL-1β: Canakinumab
- Anti-IL6R: Tocilizumab
- Anti-IL-17: Secukinumab
- Anti-IL-23: Ustekinumab
- Anti-α4-integrin: Natalizumab
- Anti-IL-13R: Dupilumab
- CTLA4 activator: Abatacept
ATG (antithymocyte-globulin), ALG (Anti-lymphocyte-globulin)
MOA: They are isolated from blood of rabbits or horses immunized by human lymphocytes or thymocytes→ it kills and blocks the lymphocytes/thymocytes in the body;
IND: most effective agents against acute graft rejection after transplantation (used if possibility of rejection is high), in BM transplantation the pretreatment of the graft by ALG reduces the GVH disease;
SEs: Dyspnea, Serum disease / anaphylaxis, fever, GI disturbances
Rituximab, Ocrelizumab
MOA: Bind CD20 on both normal and malignant B-cells → reduce B-cell count for several months (after 1 treatment they reduce it dramatically) through complement and cell (macrophages, neutrophil and NK)-mediated pathway. They are also able to induce apoptosis;
IND: Rituximab was developed for malignant B-cell lymphomas and CLL, in RA it’s given periodically (2 doses in 2 weeks and after 6 months of break), it’s also registered for vasculitis diseases, Wegener’s granulomatosis, microscopic polyanfiitis, off lable-therapy resistant autoimmune diseases and organ transplantation, Ocrelizumab can be used for MS;
SEs: infusion-reactions (steroid, paracetamol and antihistamines prophylaxis are needed), Neutropenia (→infections, fever, can be countered with G-CSF Filgrastim), GI disturbances, Hypotension
Infliximab, Adalimumab
MOA: Infliximab- Chimeric Anti-TNFα Ab, Adalimumab-Human Anti-TNFα Ab;
Kinetics: Infliximab- i.v once in 2 months, Biosimilars are available. Adalimumab- s.c. adm once/2weeks;
IND: RA (mostly in comb. with MTX), JIA, Bechterew’s disease (ankylosing spondylitis), Psoriasis, IBDs;
SEs: risk of infections (TB, opportunistic infections, activation of latent viral hepatitis), injection sites and infusion reactions, allergy;
Extra: Neutralizing Ab formation is possible (more common with infliximab)
Tocilizumab
MOA: Anti-IL-6R Ab (→block the receptor, not the cytokine itself!);
IND: RA, JIA;
Kinetics: monthly i.v.;
SEs: neutropenia, increased lipid level,risk of infections (TB, opportunistic infections, activation of latent viral hepatitis), injection sites and infusion reactions, allergy
Ustekinumab
MOA: Anti-IL-12/13 Ab (→ it binds to the common p40 subunit of IL-12 and IL-23 →preventing the activation of the proinflammatory lymphocytes TH1 cells and TH17 cells respectively);
IND: Psoriasis (plaqe psoriasis, arthritis psoriatica), Crohn’s disease;
SEs: infections
Natalizumab
MOA: it inhibits the docking and extravasation of T-cells through α4β1-VCAM-1 interaction in CNS and α4β7-MadCAM-1 in GIT;
IND: multiple sclerosis;
SEs: Fever, Nausea, Infections, Progressive multifocal leukoencephalopathia (it can activate with a 1:1000 possibility polyomavirus JC→leading to PML)
Dupilumab
MOA: Anti-IL-4αR and IL-13R Ab (→it blocks also TH2 mediated immunreaction);
IND: Eosinophilic asthma, atopic dermatitis;
SEs: Local reactions, Oral herpes, Conjunctivitis, Ab formation
Abatacept
MOA: It blocks the interaction of the co-stimulator CD28 with CD80/86 by binding to CD80/86 (CD80/86 - CTLA4 interaction is inhibitory on lymphocytes);
IND: RA, JIA (with uveitis), Psoriatic arthritis;
SEs: Headache, Infections, (neutralizing) Ab production
Biosimilar
Biopharmaceutical drus designed to have active properties similar to those of a drug that has previously been licensed
Neutralizing antibody
type of Ab that can specifically recognize and bind to a virus or other pathogen, preventing it from infecting cells or causing disease. They neutralize the biological activity of the pathogen, often by blocking its entry into a cells or preventing it from replicating. Neutralizing Abs are produced by the immune system in response to exposure to a pathogen or through vaccination.
PML
Progressive myeloid leukoencephalopathy→ a demyelinating disease of the CNS
Main groups of immunosuppressive drugs
- Cytotoxic agents
- Inhibitors of cytokine production or action
- Inhibitors of cytokine gene expression
- Immunosuppressive Abs:
- Blocking T cell surface molecules involved in signaling of imuunoglobulins
- Antibodies against T cells
- Antibodies against B cells
- Antibodies against adhesion molecules/cytokines::4 groups - Non-specific immunosuppresants
- Interferons
- Immunostimulants
Nomenclature of Antibodies
Mouse: -omab (e.g. Muromab)
Chimera: -ximab (e.g. Infliximab)
Humanized: -zumab (e.g. Palivizumab)
Human: -mumab (e.g. Panitumumab)
- Other non-specific immunosuppressants:
Cloroquine, Hydroxychloroquine
MOA: ↑lysosomal pH in macrophages (→inhibiting the presentation of antigens), block autophagy and formation of proinflammatory mediators;
Kinetics: good absorption, T1/2 up to 40 days, hepatic metabolism;
IND: RA (in combo or monotherapy in mild cases), SLE, DLE, Sjorgen’s syndrome;
SEs: skin exanthemas, stomachache, nausea, vomiting, myopathy, nightmares, maculadegeneration and cornea discoloration
- Interferons
Type I IFNs (IFN-α, IFN-β)
MOA: type I IFNs are part of the innate immune system. They use common receptors, and could also have immunosuppressive functions;
IND: IFN-α subtypes for viral infections and tumor therapy, IFN-β1a and IFN-β1b for remitting-relapsing MS (x3/week s.c), IFN-γ for chronic granulomatosis;
SEs: flu-like symptoms (fever, fatigue, muscle pain etc), BM suppression, GI disorders, liver and kidney dysfunction, CNS problems etc.
- Immunostimulants:
Levamisole
IND: immunostimulants are applicable during infections, immunodeficiencies and cancers;
MOA: restores depressed immune function of B and T cells, monocytes and macrophages;
SEs: agranulocytosis
*High dose Immunoglobulin mix (IVIG)
MOA: Isolated from blood of healthy donors;
Kinetics: adm. i.v;
IND: Treatment of Ig deficiencies, can be used as immune modulator (to neutralize super-antigens and autoantibodies, to block Fc-Rs of macrophages, to inhibit the complement and immuncomplex mediated tissue destruction), idiopathic thrombocytic purpura, Kawasaki-syndrome, Guillan-Barre syndrome, Polymyositis, Vasculitis, SLE;
SEs: allergic reactions (→anaphylaxis)
*Belimumab
MOA: Ab against B-lymphocyte-stimulator protein (BLyS, BAFF)→ it inhibits the survival of autoreactive B cells and their differentiation into plasmocytes, it normalizes low complement in SLE;
IND: SLE;
SEs: fever, Leukocytopenia, Migraine, Arthralgy
*Secukinumab
MOA: Anti IL-17 mAb(→blocks the pro-inflammatory cytokine IL-17 produced by TH17 cells);
IND: Psoriasis (plaque psoriasis and arthritis psoriatica), Bechterew’s disease;
SEs: infections (respiratory), allergy (rhinitis)
CAPS
are a group of rare autoinflammatory diseases caused by mutations in the NLRP3 gene. they typically present in childhood. the symptoms are recurrent episodes of fever, rash, joint pain and other signs of inflammation
Why are monoclonal Antibodies administered parenterally?
They are all proteins, if they would be administered p.o they would be destroyed by the gastric acids in the GIT
