Recent Advances in Immunopharmacology               Dr Aaditya
Immumopharmacology                               Modulating          Evaluating      Recent     Understanding             ...
THE NORMAL IMMUNE RESPONSE05/11/2011     Dr Aaditya       3
ImmunityAbility to resist almost all types of organisms or  toxins that tends to damage the tissues or  organ.            ...
05/11/2011   Dr Aaditya   5
T- Cell Activation                                  Signal II- ligation of co-                                  stimulator...
T- Cell Activation• Negative feed-back loop  T-lymphocyte –  associated antigen 4 (CTLA-4)• Following binding of CD28 wit...
IPILIMUMAB• Recombinant humanized antibody that binds  CTLA- 4 and prevents its association with CD  80, 86.• So, the acti...
ABATACEPT• Recombinant fusion protein composed of the  extracellular domain of cytotoxic T-  lymphocyte-associated antigen...
05/11/2011   Dr Aaditya   10
RECENT EVALUATION TECHNIQUES05/11/2011      Dr Aaditya        11
Anti Inflammatory                              ModelsReceptor binding    activity                                         ...
Immuno-modulatory                                           Activity                                           AutoimmuneP...
MARKERS USED IN   IMMUNOPHARMACOLOGY05/11/2011   Dr Aaditya   14
Traditional markers•   Total leukocyte count•   Differential count•   Neutrophil/Lymphocyte Ratio•   T-cell CD4+/CD8+ Rati...
Newer markers of immune response• Plasma Cytokine levels      – In fever, shock  TNF, INF-γ, IL-1,2,6,10• The soluble rec...
AGENTS MODIFYING THE IMMUNE   RESPONSE05/11/2011     Dr Aaditya        17
GLUCOCORTICOIDS• First hormonal agents recognized as having  lympholytic properties• Reduces the size and lymphoid content...
IMMUNOPHILIN LIGANDS• Cyclosporine  – Peptide antibiotic  early stage in the antigen receptor-      induced differentiati...
IMMUNOPHILIN LIGANDS• Tacrolimus  – It is not chemically related to cyclosporine, but their    mechanisms of action are si...
PROLIFERATION SIGNAL INHIBITOR• Sirolimus (Rapamycin):  – Binds to FK-506 binding protein 12  – It blocks molecular target...
ADR• Glucocorticoids:   – Iatrogenic Cushings Syndrome, Adrenal Suppression, Peptic     Ulcers, Bacterial And Mycotic Infe...
MYCOPHENOLATE MOFETIL• It inhibits T- and B-lymphocyte responses, including  mitogen and mixed lymphocyte responses,  prob...
THALIDOMIDE• It has significant immunomodulatory actions and is  currently studied for over 40 different illnesses• Curren...
IMiDs• Immunomodulatory derivatives of thalidomide• Lenalidomide is an IMiD that in animal and in vitro   studies has been...
Immunostimulants• Immunostimulants are substances that modulate the  immune system by stimulating the function of one or m...
Recent advances in                Immunostimulants• Auto immune diseases:  – Traditionally only immunodepressents were use...
ANTIBODIES IN CLINICAL USE05/11/2011       Dr Aaditya     28
POLYCLONAL ANTIBODIES• Antilymphocyte antibodies (ALG)• Antithymocyte antibodies(ATG)• Immune globulin Intravenous (IGIV)•...
ATG AND ALG• Obtained by immunization of large animals  such as horses with human lymphoid cells• They lead to destruction...
IGIV• Nonspecific polyclonal human  immunoglobulin• Prepared from pools of healthy donors• Leads to reduction in helper T ...
HYPERIMMUNE Ig• IGIV prepared from pools of selected human  and animal donors• High titers of antibodies against a particu...
OTHER PUTATIVE APPLICATIONS• Blocking the action of cell surface receptors• Receptor binding and antagonism• Induction of ...
MONOCLONAL ANTIBODIES (mAb)• Antibodies produced from single clone of B  cells• More selective and specific• Less toxic• C...
FIRSTMONOCLONALANTIBODY•Was produced byKöhler and Milsteinin 1975•Technique wassomatic cellhybridization•Nobel prize in198...
05/11/2011   Dr Aaditya   36
LIMITATIONS• Human immune response – HAMA• Gradually reducing efficacy• Renal damage• Weak interactions between mouse anti...
SOLUTION• Chimeric antibodies (-ximabs) – Variable  region of mouse antibody with constant  region of human antibody      ...
HUMANMONOCLONAL ANTIBODIESTransgenic mice   Eg. IpilimumabPhage displaylibraries   Eg. AdalimumabLimitation – Lack ofspeci...
MUROMONAB-CD3• Murine monoclonal antibody  Directed  against the CD3 molecule on the surface of  human thymocytes and mat...
ANTIBODIES AGAINST TUMOURS05/11/2011     Dr Aaditya       41
Antitumor MABs• Alemtuzumab is a humanized IgG1 with a kappa chain that  binds to CD52 found on normal and malignant B and...
Antitumor MABs• Cetuximab is a human-mouse chimeric monoclonal  antibody that targets epidermal growth factor receptor  (E...
Antitumor MABs• Rituximab: Chimeric murine-human monoclonal IgG1  (human Fc) that binds to the CD20 molecule on normal and...
MABs Used to Deliver Isotopes to              Tumours• Arcitumomab is a murine F(ab’)2 fragment from an anti-  carcinoembr...
MABs Used to Deliver Isotopes to             Tumours• Ibritumomab tiuxetan is an anti-CD20 murine monoclonal  antibody lab...
MABs Used to Deliver Isotopes to             Tumours• Tositumomab is an anti-CD20 monoclonal antibody and is  complexed wi...
MABs USED AS IMMUNO-SUPPRESSANTSAND ANTI-INFLAMMATORY AGENTS 05/11/2011    Dr Aaditya     48
ANTI-TNF-ALPHA MABS• Blocking TNF-a from binding to TNF receptors on  inflammatory cell surfaces results in suppression of...
ANTI-TNF-ALPHA MABS• Etanercept is a dimeric fusion protein composed of human  IgG1 constant regions (CH2, CH3, and hinge,...
ALEFACEPT• It is an engineered protein consisting of the CD2-  binding portion of leukocyte-function-associated  antigen-3...
BASILIXIMAB• It is a chimeric mouse-human IgG1 that binds to  CD25, the IL-2 receptor alpha chain on activated  lymphocyte...
OMALIZUMAB • It is an anti-IgE recombinant humanized monoclonal     antibody that is approved for the treatment of     all...
FUTURE• Fully humanized monoclonal antibodies    Epilimumab CTLA4 specific    Denosumab RANK ligand specific    Zanolimuma...
Humanized MAbs             Atlizumab                           Pascolizumab             Bapineuzumab                      ...
TGN1412- a disaster• CD28-SuperMAB• It is a humanised monoclonal antibody that not only binds  to, but is a strong agonist...
Interferons in therapy• Have a broad spectrum of antiviral activities as well as  immunomodulating and antiproliferative p...
Interferons in therapy• IFNα2b – Condyloma acuminatum               - Chronic Hepatitis C               - Chronic Hepatiti...
Interleukin 2• Exerts its antitumor effects indirectly through  augmentation of its immune function• High doses can produc...
Interleukin - 11• Interleukin-11 (IL-11) is a cytokine that stimulates  hematopoietic stem cells as well as  megakaryocyte...
GM-CSF (Filgrastim)• GM-CSF was first identified based on its ability to  stimulate the clonal proliferation of myeloid pr...
GM-CSFTherapeutic use Results with rhuGM-CSFFungal infections         Decreases incidence, as an adjuvant with antifungal ...
PegFilgrastim• The addition of a 20 kDa polyethylene glycol moiety to filgrastim   virtually eliminate renal clearance.• ...
PegFilgrastim• Clinical trials are needed to further define the role of pegfil-  grastim with other chemotherapy regimens ...
Technicalities And FormalitiesPatents• The exclusive right of an inventor to manufacture  the product invented by him for ...
Technicalities And FormalitiesLaws and guidelines• Guidelines of  – Source of biological substances (origin of feeder cell...
Technicalities And FormalitiesLaws and guidelines• Laws regarding the research of new drugs due to  patent problems• Laws ...
05/11/2011   Dr Aaditya   68
Mechanism Of Autoimmunity(1) Exposure of self-reactive T lymphocytes to antigens previously    sequestered from the immune...
IMMUNOSUPPRESSIVE                ANTIBODIES• Development of hybridoma technology by  Milstein and Kohler in 1975• Hybridom...
CYTOTOXIC AGENTS• Azathioprine (Antimetabolite) produces  immunosuppression by interfering with purine nucleic acid  metab...
RECENT CYTOTOXIC AGENTS• Ixabepilone  – An analog of epothilone B that blocks tubulin polymerization in a    way similar t...
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Dr aaditya recent advances in immunopharmacology 30 jan10

  1. 1. Recent Advances in Immunopharmacology Dr Aaditya
  2. 2. Immumopharmacology Modulating Evaluating Recent Understanding Rules and immune Immunological markers and Immunology regulations response Agents parameters Humoral Cell mediated Immune immune response response Monoclonal Interleukins &Polyclonal Abs Abs other agents 05/11/2011 Dr Aaditya 2
  3. 3. THE NORMAL IMMUNE RESPONSE05/11/2011 Dr Aaditya 3
  4. 4. ImmunityAbility to resist almost all types of organisms or toxins that tends to damage the tissues or organ. Immunity Innate Acquired Active Passive05/11/2011 Dr Aaditya 4
  5. 5. 05/11/2011 Dr Aaditya 5
  6. 6. T- Cell Activation Signal II- ligation of co- stimulatory molecule CD 40, CD80 with to CD 40L, CD 28 respectively Signal I- MHC binding With TCR05/11/2011 Dr Aaditya 6
  7. 7. T- Cell Activation• Negative feed-back loop  T-lymphocyte – associated antigen 4 (CTLA-4)• Following binding of CD28 with CD80 or CD 86, CTLA-4 is mobilised to cell surface were because of its higher affinity for CD80, 86 it outcompetes or displaces CD 28 and results in suppression of T- cell activation & proliferation05/11/2011 Dr Aaditya 7
  8. 8. IPILIMUMAB• Recombinant humanized antibody that binds CTLA- 4 and prevents its association with CD 80, 86.• So, the activated state of T- cells is sustained• Tried in patients of Malignant Melanoma• Showed objective improvement in some• S/E development of autoimmune toxicity05/11/2011 Dr Aaditya 8
  9. 9. ABATACEPT• Recombinant fusion protein composed of the extracellular domain of cytotoxic T- lymphocyte-associated antigen 4 (CTLA-4) fused to human IgG Fc• This fusion protein blocks activation of T cells by binding to CD80 or 86 so that CD28 on T cells cannot bind and stimulate the T cell and lead to cytokine release• Approved for patients with severe rheumatoid arthritis who have failed other DMARDS05/11/2011 Dr Aaditya 9
  10. 10. 05/11/2011 Dr Aaditya 10
  11. 11. RECENT EVALUATION TECHNIQUES05/11/2011 Dr Aaditya 11
  12. 12. Anti Inflammatory ModelsReceptor binding activity Cytokines Assays of Migration and aggregation Flow cytometry Substance P Polymorphonuclear leukocyte TNF antagonism 3H-Bradykinin chemotaxis The Tachykinin Family Neurokinin 05/11/2011 Dr Aaditya 12
  13. 13. Immuno-modulatory Activity AutoimmuneProliferation of Cells Organ Transplant Response PFC (plaque forming CTLA-4 Knockout Inhibition of colony) Mouse allogenic transplant rejection Chemoluminescence Hypersensitivity in Influence on SLE-like in macrophages animals disorder in MRL/lpr mice Mitogen Induced Lymphocyte Acute GVHD in rats 05/11/2011 Dr Aaditya 13 Proliferation
  14. 14. MARKERS USED IN IMMUNOPHARMACOLOGY05/11/2011 Dr Aaditya 14
  15. 15. Traditional markers• Total leukocyte count• Differential count• Neutrophil/Lymphocyte Ratio• T-cell CD4+/CD8+ Ratio• T-cell CD4+CD45RO+ expression• Plasma glutamine• Plasma urea• Salivary IgA05/11/2011 Dr Aaditya 15
  16. 16. Newer markers of immune response• Plasma Cytokine levels – In fever, shock  TNF, INF-γ, IL-1,2,6,10• The soluble receptors of IL-2 (sIL-2R) and tumor necrosis factor (sTNF-R55 and sTNF-R75) – In suspected childhood maleria• Serum levels of β2-microglobulin, neopterin – In HIV 1& 2 patients• TNF, INF-γ, receptors of IL-2 (sIL-2R) etc – Used to determine chemotherapy regimen in cancer05/11/2011 Dr Aaditya 16
  17. 17. AGENTS MODIFYING THE IMMUNE RESPONSE05/11/2011 Dr Aaditya 17
  18. 18. GLUCOCORTICOIDS• First hormonal agents recognized as having lympholytic properties• Reduces the size and lymphoid content of the lymph nodes and spleen• Contact hypersensitivity mediated by DTH T cells, for example, is usually abrogated by glucocorticoid therapy• Glucocorticoids are first-line immunosuppressive therapy for both solid organ and hematopoietic stem cell transplant recipients, with variable results• Also used in variety of conditions like SLE, asthma 05/11/2011 Dr Aaditya 18
  19. 19. IMMUNOPHILIN LIGANDS• Cyclosporine – Peptide antibiotic  early stage in the antigen receptor- induced differentiation of T cells and blocks their activation – Binds to cyclophilin (a class of intracellular proteins called immunophilins) – Inhibits the cytoplasmic phosphatase, calcineurin, which is necessary for the activation of a T-cell-specific transcription factor – This transcription factor, NF-AT, is involved in the synthesis of interleukins (eg, IL-2) by activated T cells – Cyclosporine inhibits the gene transcription of IL-2, IL-3, IFN-g 05/11/2011 Dr Aaditya 19
  20. 20. IMMUNOPHILIN LIGANDS• Tacrolimus – It is not chemically related to cyclosporine, but their mechanisms of action are similar – Tacrolimus binds to the immunophilin FK-binding protein (FKBP)  inhibits calcineurin – Tacrolimus is 10-100 times more potent than cyclosporine in inhibiting immune responses• Both tacrolimus and cyclosporine are extensively used along with glucocorticoids for the suppression of immune response in cases of solid organ transplantation 05/11/2011 Dr Aaditya 20
  21. 21. PROLIFERATION SIGNAL INHIBITOR• Sirolimus (Rapamycin): – Binds to FK-506 binding protein 12 – It blocks molecular target of Rapamycin (mTOR)  leads to inhibition of interleukin driven T-cell proliferation A derivative of sirolimus, everolimus, is a – Itproliferation-signal inhibitor proliferation and is a potent inhibitor of B-cell that may be of immunoglobulin production benefit in decreasing rejection in cardiac – Also inhibits the mononuclear cell proliferative response transplantation to colony-stimulating factors chronic cardiac It is being investigated for – Sirolimus-eluting coronary stents have been shown to allograft vasculopathy reduce re-stenosis – Uses: combination therapy in solid organ transplant, management of Uveo-retinitis, 05/11/2011 Dr Aaditya 21
  22. 22. ADR• Glucocorticoids: – Iatrogenic Cushings Syndrome, Adrenal Suppression, Peptic Ulcers, Bacterial And Mycotic Infections, Myopathy• Immunophilin Ligands: – Cyclosporine: Nephrotoxicity, Hypertension, Hyperglycemia, Liver Dysfunction, Hyperkalemia, Altered Mental Status, Seizures, And Hirsutism – Tacrolimus: nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkalemia, and gastrointestinal complaints• Sirolimus and Everolimus: Profound Myelosuppression (Especially Thrombocytopenia), Hepatotoxicity, Diarrhoea, Hypertriglyceridemia, And Headache 05/11/2011 Dr Aaditya 22
  23. 23. MYCOPHENOLATE MOFETIL• It inhibits T- and B-lymphocyte responses, including mitogen and mixed lymphocyte responses, probably by inhibition of de novo synthesis of purines• Used to treat steroid-refractory graft-versus-host disease in hematopoietic stem cell transplant patients• Toxicities: Gastrointestinal Disturbances (nausea and vomiting, diarrhea, abdominal pain) Headache, Hypertension and Reversible Myelosuppression (Primarily Neutropenia) 05/11/2011 Dr Aaditya 23
  24. 24. THALIDOMIDE• It has significant immunomodulatory actions and is currently studied for over 40 different illnesses• Currently used in the treatment of multiple myeloma at initial diagnosis and for relapsed- refractory disease• Response rates from 20 to 70%• The most important toxicity is teratogenesis.• Other adverse effects of thalidomide include peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, and increased risk of deep vein thrombosis 05/11/2011 Dr Aaditya 24
  25. 25. IMiDs• Immunomodulatory derivatives of thalidomide• Lenalidomide is an IMiD that in animal and in vitro studies has been shown to be similar to thalidomide in action, but with less toxicity, especially Selective cytokine inhibitory drugs (SelCIDs), are teratogenicity phosphodiesterase type 4 inhibitors with potent anti-• TNF-α activity but no T-cell co-stimulatory activity Showed its effectiveness in the treatment of the myelodysplastic syndrome with the chromosome 5q31 deletion• CC-4047 (Actimid) is another IMiD that is being investigated for the treatment of myelodysplastic syndrome, myeloma, and prostate cancer. 05/11/2011 Dr Aaditya 25
  26. 26. Immunostimulants• Immunostimulants are substances that modulate the immune system by stimulating the function of one or more of the system’s components• Classified as – Biological response modifyers • BCG • Levamisole • Thalidomide – Recombinant proteins • Interferons – Immunization – Others • Thymosin • Immunocynin 05/11/2011 Dr Aaditya 26
  27. 27. Recent advances in Immunostimulants• Auto immune diseases: – Traditionally only immunodepressents were used – Low dose naltrexone (LDN) has been used in the treatment of multiple sclerosis – Inosine Pranobex/Isoprinosine (Imunovir) may be helpful in rheumatic diseases (lupus/SLE, rheumatoid arthritis), multiple sclerosis and alopecia areata• IGIV used in the treatment of many disorders• β-Glucans (beta-glucans), echinacea are tried in cancer, radiation, shock, prevention of infection, wound healing, etc. 05/11/2011 Dr Aaditya 27
  28. 28. ANTIBODIES IN CLINICAL USE05/11/2011 Dr Aaditya 28
  29. 29. POLYCLONAL ANTIBODIES• Antilymphocyte antibodies (ALG)• Antithymocyte antibodies(ATG)• Immune globulin Intravenous (IGIV)• Hyperimmune immunoglobulins05/11/2011 Dr Aaditya 29
  30. 30. ATG AND ALG• Obtained by immunization of large animals such as horses with human lymphoid cells• They lead to destruction of T cells and impairment of cell mediated immunity• ATG for treatment of acute renal transplant rejection ( 1.5 mg/kg per day for 7 -14 days) and for preparation of bone marrow transplantation• ALG for preparation of bone marrow transplantation05/11/2011 Dr Aaditya 30
  31. 31. IGIV• Nonspecific polyclonal human immunoglobulin• Prepared from pools of healthy donors• Leads to reduction in helper T cells, increase in suppressor T cells, and decrease in spontaneous Ig production• Found to be useful in variety of immune syndromes ranging like ITP and SLE05/11/2011 Dr Aaditya 31
  32. 32. HYPERIMMUNE Ig• IGIV prepared from pools of selected human and animal donors• High titers of antibodies against a particular agent of interest• Used for the prevention or treatment of various infections such as rabies, tetanus, CMV infections, hepatitis B virus05/11/2011 Dr Aaditya 32
  33. 33. OTHER PUTATIVE APPLICATIONS• Blocking the action of cell surface receptors• Receptor binding and antagonism• Induction of apoptosis, ADCC and CDC• Inhibition of viral fusion and replication• Induction of cell death by radiations05/11/2011 Dr Aaditya 33
  34. 34. MONOCLONAL ANTIBODIES (mAb)• Antibodies produced from single clone of B cells• More selective and specific• Less toxic• Can be produced on a large scale without compromising the uniformity of the product05/11/2011 Dr Aaditya 34
  35. 35. FIRSTMONOCLONALANTIBODY•Was produced byKöhler and Milsteinin 1975•Technique wassomatic cellhybridization•Nobel prize in1984 for Physiologyand Medicine05/11/2011 Dr Aaditya 35
  36. 36. 05/11/2011 Dr Aaditya 36
  37. 37. LIMITATIONS• Human immune response – HAMA• Gradually reducing efficacy• Renal damage• Weak interactions between mouse antibody and human FcγRs (reduced effector function)• Mouse antibodies do not bind to human FcRn receptors ( reduced half life)05/11/2011 Dr Aaditya 37
  38. 38. SOLUTION• Chimeric antibodies (-ximabs) – Variable region of mouse antibody with constant region of human antibody Eg. Infliximab, Rituximab,Abciximab• Humanized antibodies (- zumabs)– CDRs from a mouse antibody attached to human antibody. Eg. Daclizumab,05/11/2011 Dr Aaditya 38
  39. 39. HUMANMONOCLONAL ANTIBODIESTransgenic mice Eg. IpilimumabPhage displaylibraries Eg. AdalimumabLimitation – Lack ofspecies crossreactive antibodies05/11/2011 Dr Aaditya 39
  40. 40. MUROMONAB-CD3• Murine monoclonal antibody  Directed against the CD3 molecule on the surface of human thymocytes and mature T cells• muromonab-CD3 blocks killing by cytotoxic human T cells and several other T-cell functions• It has proved more effective at reversing acute rejection than conventional steroid treatment05/11/2011 Dr Aaditya 40
  41. 41. ANTIBODIES AGAINST TUMOURS05/11/2011 Dr Aaditya 41
  42. 42. Antitumor MABs• Alemtuzumab is a humanized IgG1 with a kappa chain that binds to CD52 found on normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, and a small population of granulocytes. – Approved for the treatment of B-cell chronic lymphocytic leukemia – Patients receiving this antibody become lymphopenic and may also become neutropenic, anemic, and thrombocytopenic• Bevacizumab is a humanized IgG1 monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF from binding to its receptor – Antiangiogenic drug inhibit angiogenesis in tumors – First-line treatment of patients with metastatic colorectal cancer alone or in combination with 5-FU-based chemotherapy – Adverse events: hemorrhage,Aaditya 05/11/2011 Dr gastrointestinal perforations, 42
  43. 43. Antitumor MABs• Cetuximab is a human-mouse chimeric monoclonal antibody that targets epidermal growth factor receptor (EGFR) – Indicated for use in patients with metastatic colorectal cancer whose tumours over express EGFR• Gemtuzumab is a humanized IgG4 monoclonal antibody with a kappa light chain specific for CD33 (a sialoadhesion protein found on leukemic blast cells ) – Gemtuzumab is coupled to the cytotoxic agent, ozogamicin – Is approved for the treatment of patients 60 years and older in first relapse with CD33 acute myelogenous leukemia – Adverse events  severe myelosuppression, significant hepatotoxicity 05/11/2011 Dr Aaditya 43
  44. 44. Antitumor MABs• Rituximab: Chimeric murine-human monoclonal IgG1 (human Fc) that binds to the CD20 molecule on normal and malignant B lymphocytes – Approved for the therapy of patients with relapsed or refractory low-grade or follicular, B-cell non-Hodgkins lymphoma – drug appears to be synergistic with chemotherapy (eg, fludarabine, CHOP) for lymphoma• Trastuzumab is a recombinant DNA-derived, humanized monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor HER-2/neu – Blocks the natural ligand from binding and down-regulates the receptor – Metastatic breast cancer in patients whose tumors overexpress HER-2/neu 05/11/2011 Dr Aaditya 44
  45. 45. MABs Used to Deliver Isotopes to Tumours• Arcitumomab is a murine F(ab’)2 fragment from an anti- carcinoembryonic antigen (CEA) antibody labelled with technetium 99m (99mTc) that is used for imaging patients with metastatic colorectal carcinoma (immunoscintigraphy) to determine extent of disease• Capromab pendetide is a murine monoclonal antibody specific for prostate specific membrane antigen – coupled to isotopic indium (111In) – Used in immunoscintigraphy for patients with biopsy-confirmed prostate cancer 05/11/2011 Dr Aaditya 45
  46. 46. MABs Used to Deliver Isotopes to Tumours• Ibritumomab tiuxetan is an anti-CD20 murine monoclonal antibody labeled with isotopic yttrium (90Y) or 111In – Radiation provides the major antitumor activity – Approved for use in patients with relapsed or refractory low- grade, follicular, or B-cell non-Hodgkins lymphoma, including patients with rituximab-refractory follicular disease• Nofetumomab is a mouse monoclonal antibody coupled to 99mTc that is used for diagnostic purposes – It binds a 40 kD antigen found on many tumor cell types, but also on some normal cells – Accurate indicator of extent of disease in biopsy-confirmed small cell lung cancer except in those patients with brain or adrenal metastases 05/11/2011 Dr Aaditya 46
  47. 47. MABs Used to Deliver Isotopes to Tumours• Tositumomab is an anti-CD20 monoclonal antibody and is complexed with iodine 131 (131I) – Two-step therapy in patients with CD20-positive, follicular non- Hodgkins lymphoma whose disease is refractory to rituximab and standard chemotherapy – Toxicities: Severe Cytopenias such as thrombocytopenia and neutropenia• Satumomab is a murine monoclonal IgG1 antibody that binds to Tumour Associated Glycoprotein – 2 (TAG- 2) expressed on colorectal and ovarian adenocarcinomas – It is labelled with 111In Chloride – Used to diagnostically determine extent of cancer 05/11/2011 Dr Aaditya 47
  48. 48. MABs USED AS IMMUNO-SUPPRESSANTSAND ANTI-INFLAMMATORY AGENTS 05/11/2011 Dr Aaditya 48
  49. 49. ANTI-TNF-ALPHA MABS• Blocking TNF-a from binding to TNF receptors on inflammatory cell surfaces results in suppression of downstream inflammatory cytokines such as IL-1 and IL-6 and adhesion molecules involved in leukocyte activation and migration.• An increased risk of lymphoma is common to such agents• Adalimumab is a completely human IgG1 approved for use in rheumatoid arthritis – Adalimumab blocks the interaction of TNF-α with TNF receptors on cell surfaces; it does not bind TNF-β – Administration of adalimumab reduces levels of C- reactive protein, Erythrocyte Sedimentation Rate, Serum IL-6 and Matrix Metalloproteinases MMP-1 and MMP-3 05/11/2011 Dr Aaditya 49
  50. 50. ANTI-TNF-ALPHA MABS• Etanercept is a dimeric fusion protein composed of human IgG1 constant regions (CH2, CH3, and hinge, but not CH1) fused to the TNF receptor – It binds to both TNF-α and TNF-β and appears to have effects similar to that of infliximab – Etanercept is approved for adult RA, Polyarticular-course Juvenile RA, and Psoriatic Arthritis• Infliximab is a human-mouse chimeric IgG1 monoclonal antibody – Approved for use in Crohns disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis 05/11/2011 Dr Aaditya 50
  51. 51. ALEFACEPT• It is an engineered protein consisting of the CD2- binding portion of leukocyte-function-associated antigen-3 (LFA-3) fused to a human IgG1 Fc region (hinge, CH1, and CH2), approved for the treatment of plaque psoriasis• It inhibits activation of T cells by binding to cell surface CD2, inhibiting the normal CD2/LFA-3 interaction EFALIZUMAB • Recombinant humanized anti-CD11a monoclonal antibody  Withdrawn due to PML05/11/2011 Dr Aaditya 51
  52. 52. BASILIXIMAB• It is a chimeric mouse-human IgG1 that binds to CD25, the IL-2 receptor alpha chain on activated lymphocytes• It functions as an IL-2 antagonist Immunosuppressant DACLIZUMAB• It is a humanized IgG1 that binds to the alpha subunit of the IL-2 receptor• Its indications are identical to that of basiliximab05/11/2011 Dr Aaditya 52
  53. 53. OMALIZUMAB • It is an anti-IgE recombinant humanized monoclonal antibody that is approved for the treatment of allergic asthma in adult and adolescent patients whose symptoms are refractory to inhaled corticosteroids • Abciximab is a Fab fragment of a murine-human monoclonal antibody that binds to the integrin GPIIb/IIIa receptor on activated platelets and inhibits fibrinogen, von Willebrand factor, and other adhesion molecules from binding to activated platelets, thus preventing their aggregation • Palivizumab is a monoclonal antibody that binds to the fusion protein of RSV, preventing infection in05/11/2011 Dr Aaditya 53 susceptible cells in the airways
  54. 54. FUTURE• Fully humanized monoclonal antibodies Epilimumab CTLA4 specific Denosumab RANK ligand specific Zanolimumab CD4 specific Golimumab TNF specific• PEGylation of fragments certolizumab pegol for Crohn’s disease• Abdegs – antibodies that increase IgG degradation
  55. 55. Humanized MAbs Atlizumab Pascolizumab Bapineuzumab Pecfusituzumab Erlizumab Pectuzumab Felvizumab Pertuzumab Fontolizumab Pexelizumab Inotuzumab ozogamicin Ralivizumab Labetuzumab Ranibizumab Lintuzumab Sibrotuzumab Matuzumab Siplizumab Mepolizumab Sontuzumab Motavizumab Talizumab Natalizumab Toralizumab Nimotuzumab Tucotuzumab celmoleukin Nolovizumab Umavizumab Numavizumab Urtoxazumab03/03/2007 Ocrelizumab Monoclonal antibodies Visilizumab 55
  56. 56. TGN1412- a disaster• CD28-SuperMAB• It is a humanised monoclonal antibody that not only binds to, but is a strong agonist for, the CD28 receptor of the immune systems T cells• B cell chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis• In its first human clinical trials, in March 2006, it caused catastrophic systemic organ failure in the subjects• Administered at a supposed sub-clinical dose of 0.1 mg per kg, some 500 times lower than the dose found safe in animals• Hospitalization of six volunteers on 13 March 2006.• One patient developed cancer of the GI tract 05/11/2011 Dr Aaditya 56
  57. 57. Interferons in therapy• Have a broad spectrum of antiviral activities as well as immunomodulating and antiproliferative properties• Not available orally, must be given IM, SC or IV• DNA recombinant technology - highly purified interferons• IFNs when bound to polyethylene glycol (PEG) have substantially longer half lives. Results in stable and sustained concentrationsAdverse events• IFNα – immune mediated disorders, Alopecia• IFNβ – local necrosis of the skin• G-CSF – neutrophillic dermatitis 05/11/2011 Dr Aaditya 57
  58. 58. Interferons in therapy• IFNα2b – Condyloma acuminatum - Chronic Hepatitis C - Chronic Hepatitis B, Chronic Hepatitis D? ( CML, melanoma, multiple myeloma, renal cell carcinoma)• IFNα2a - Chronic Hepatitis C - Chronic Hepatitis D - Multiple sclerosis• IFNαn3 - Condyloma acuminatum• Pegylated IFNα2b/a - Chronic Hepatitis C• IFN Alfacon - Chronic Hepatitis C• IFNγ – Chronic granulamtous diseases - Systemic sclerosis, osteopetrosis 05/11/2011 Dr Aaditya 58
  59. 59. Interleukin 2• Exerts its antitumor effects indirectly through augmentation of its immune function• High doses can produce tumor regression in cancers like metastatic melanomas and renal cell carcinoma• About 2 – 5 % patients may experience complete remissions that are durable• Side effects include: intravascular volume depletion, capillary leak syndrome, ARDS, hypotension, fever, hypersensitivity and impaired liver and renal functions.05/11/2011 Dr Aaditya 59
  60. 60. Interleukin - 11• Interleukin-11 (IL-11) is a cytokine that stimulates hematopoietic stem cells as well as megakaryocytes, resulting in increased platelet production.• It is produced commercially (Oprevelkin, Genetics Institute, Cambridge, MA, USA) by recombinant DNA in Escherichia coli.• The commercial product is a 177 amino acid polypeptide.• It is indicated for the prevention of severe thrombocytopenia and reduction of platelet transfusions in patients with non-myeloid malignancies 05/11/2011 Dr Aaditya 60
  61. 61. GM-CSF (Filgrastim)• GM-CSF was first identified based on its ability to stimulate the clonal proliferation of myeloid precursors in vitro.• The biologic effects of GM-CSF are mediated via binding to receptors expressed on the surface of target cells.• The GM-CSF receptor is expressed on granulocyte, erythrocyte, megakaryocyte, and macrophage progenitor cells as well as mature neutrophils, monocytes, macrophages, dendritic cells, plasma cells, certain T lymphocytes, vascular endothelial cells, uterine cells, and myeloid Aaditya 05/11/2011 Dr leukemia cells. 61
  62. 62. GM-CSFTherapeutic use Results with rhuGM-CSFFungal infections Decreases incidence, as an adjuvant with antifungal and chemotherapyHIV infection and its Increases CD4 counts, decreases viral loadcomplicationsVaccine adjuvant Enhances antibody response to Hep C Vaccine. Increases seroconversion in flu vaccinesAntitumor therapy Prolongs disease free survival and overall survivalImmunotherapy for Decreases risk of relapseAMLMucositis, stomatitis & Reduces incidence and severitydiarrheaWound healing Decreases time to wound healing. Reduces mean ulcer 05/11/2011 surface area Dr Aaditya 62
  63. 63. PegFilgrastim• The addition of a 20 kDa polyethylene glycol moiety to filgrastim  virtually eliminate renal clearance.• The major remaining mode of clearance of pegfilgrastim is the neutrophil itself through a ‘self-regulating’ mechanism .• Single dose of pegfilgrastim after chemotherapy led to a steady state serum concentration of this cytokine during the post chemo-therapy period, through the neutrophil nadir until subsequent neutrophil recovery .• Pegfilgrastim stimulates the expansion of early myeloid precursors and the more rapid maturation and differentiation of neutrophils.• As adequate neutrophil recovery occurs, these cells clear pegfilgrastim from the serum through G-CSF receptor–ligand binding over a rapid time course of 24–48 h. 05/11/2011 Dr Aaditya 63
  64. 64. PegFilgrastim• Clinical trials are needed to further define the role of pegfil- grastim with other chemotherapy regimens and in other disease settings, particularly to explore more dose-dense regimens of every 2 weeks or even weekly chemotherapy.• Although previous trials have administered pegfilgrastim 24 h after chemotherapy, there is interest in examining the dosing of pegfilgrastim on the same day as chemotherapy.• Furthermore, to take advantage of the self-regulating properties of pegfilgrastim, studies of this agent in the setting of prolonged neutropenia such as the post-transplant setting and acute myeloid leukemia, are of particular interest. 05/11/2011 Dr Aaditya 64
  65. 65. Technicalities And FormalitiesPatents• The exclusive right of an inventor to manufacture the product invented by him for a fixed period – Antibodies (murine, humanized or human) – All natural immune components used therapeutically which are manufactured by a specific process • Interferons (INF-β 1a patent by Biogen, brand name AVONEX) • Interleukins (Oprevelkin) • G-CSF (filgastrim patent by AMGEN, brand name NEUPOGEN)• www.Iprlawindia.com• www.freepatentsonline.com 05/11/2011 Dr Aaditya 65
  66. 66. Technicalities And FormalitiesLaws and guidelines• Guidelines of – Source of biological substances (origin of feeder cells) – Fusion partner (mylenoma, human lymphoblastoid-B cell line,etc) – Safety of production of biological substances (viral and bacterial infections) – All the cell lines should be periodically reviewed and compared with cryopreserved samples of cell lines – Quality control Production And Quality Control Of Monoclonal Antibodies Directive 75/318/EEC Dec06 05/11/2011 Dr Aaditya 66
  67. 67. Technicalities And FormalitiesLaws and guidelines• Laws regarding the research of new drugs due to patent problems• Laws regarding manufacture of drugs due to patent problems• US FDA has guidelines for the production, storage and use of biological compounds 05/11/2011 Dr Aaditya 67
  68. 68. 05/11/2011 Dr Aaditya 68
  69. 69. Mechanism Of Autoimmunity(1) Exposure of self-reactive T lymphocytes to antigens previously sequestered from the immune system (eg, lens protein, myelin basic protein).(2) Molecular mimicry by invading pathogens, in which immune responses are directed at antigenic determinants on pathogens that share identical or similar epitopes with normal host tissue. This phenomenon occurs in rheumatic fever following Streptococcus pyogenes infection, in which heart damage is thought to arise from an immune response directed against streptococcal antigens shared with heart muscle. The suggested viral etiology of autoimmune diseases has been ascribed to immune responses (both cell-mediated and humoral) directed against virus epitopes that mimic sequestered self antigens.(3) Inappropriate expression of class II MHC molecules on the membranes of cells that normally do not express class II MHC (eg, islet β cells). Increased expression of MHC II may increase presentation of self peptides to T helper cells, which in turn induce CTL, TDTH, and B-lymphocyte cells that react against self antigens 05/11/2011 Dr Aaditya 69
  70. 70. IMMUNOSUPPRESSIVE ANTIBODIES• Development of hybridoma technology by Milstein and Kohler in 1975• Hybridomas consist of antibody-forming cells fused to immortal plasmacytoma cells• Genetic engineering techniques involve production of chimeric and humanized versions of murine monoclonal antibodies05/11/2011 Dr Aaditya 70
  71. 71. CYTOTOXIC AGENTS• Azathioprine (Antimetabolite) produces immunosuppression by interfering with purine nucleic acid metabolism at steps that are required for the wave of lymphoid cell proliferation that follows antigenic stimulation• Cyclophosphamide (Alkylating Agent) destroys proliferating lymphoid cells• Leflunomide is an inhibitor of pyrimidine synthesis• Hydroxychloroquine suppress intracellular antigen processing and loading of peptides onto MHC class II molecules by increasing the pH of lysosomal and endosomal compartments, thereby decreasing T-cell activation 05/11/2011 Dr Aaditya 71
  72. 72. RECENT CYTOTOXIC AGENTS• Ixabepilone – An analog of epothilone B that blocks tubulin polymerization in a way similar to that of the taxanes – Is being tried for highly resistant malignant breast cancer and non squamous cell lung cancer 05/11/2011 Dr Aaditya 72

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