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1. Recent Advances in Immunopharmacology
Dr Aaditya

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
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3. THE NORMAL IMMUNE RESPONSE
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4. Immunity
Ability to resist almost all types of organisms or
toxins that tends to damage the tissues or
organ.
Immunity
Innate Acquired
Active Passive
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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 TCR
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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 &
proliferation
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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 toxicity
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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 DMARDS
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11. RECENT EVALUATION TECHNIQUES
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12. Anti Inflammatory
Models
Receptor binding
activity
Cytokines
Assays of Migration
and aggregation
Flow cytometry
Substance P
Polymorphonuclear
leukocyte TNF antagonism
3H-Bradykinin chemotaxis
The Tachykinin
Family
Neurokinin
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13. Immuno-modulatory
Activity
Autoimmune
Proliferation 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
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Proliferation

14. MARKERS USED IN
IMMUNOPHARMACOLOGY
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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 IgA
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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
cancer
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17. AGENTS MODIFYING THE IMMUNE
RESPONSE
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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
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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
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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
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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,
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22. ADR
• Glucocorticoids:
– Iatrogenic Cushing's 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
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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)
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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
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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.
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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
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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.
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28. ANTIBODIES IN CLINICAL USE
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29. POLYCLONAL ANTIBODIES
• Antilymphocyte antibodies (ALG)
• Antithymocyte antibodies(ATG)
• Immune globulin Intravenous (IGIV)
• Hyperimmune immunoglobulins
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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
transplantation
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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 SLE
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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 virus
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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 radiations
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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 product
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35. FIRST
MONOCLONAL
ANTIBODY
•Was produced by
Köhler and Milstein
in 1975
•Technique was
somatic cell
hybridization
•Nobel prize in
1984 for Physiology
and Medicine
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36. 05/11/2011 Dr Aaditya 36

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)
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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,
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39. HUMAN
MONOCLONAL
ANTIBODIES
Transgenic mice
Eg. Ipilimumab
Phage display
libraries
Eg. Adalimumab
Limitation – Lack of
species cross
reactive antibodies
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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 treatment
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41. ANTIBODIES AGAINST TUMOURS
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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. 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. 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-Hodgkin's 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
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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. 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-Hodgkin's 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. 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-
Hodgkin's 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. MABs USED AS IMMUNO-SUPPRESSANTS
AND ANTI-INFLAMMATORY AGENTS
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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. 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 Crohn's disease, ulcerative colitis,
rheumatoid arthritis, ankylosing spondylitis, and
psoriatic arthritis
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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 PML
05/11/2011 Dr Aaditya 51

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 basiliximab
05/11/2011 Dr Aaditya 52

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 in
05/11/2011 Dr Aaditya 53
susceptible cells in the airways

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. 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 Urtoxazumab
03/03/2007 Ocrelizumab Monoclonal antibodies Visilizumab 55

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 system's 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. 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 concentrations
Adverse events
• IFNα – immune mediated disorders, Alopecia
• IFNβ – local necrosis of the skin
• G-CSF – neutrophillic dermatitis
05/11/2011 Dr Aaditya 57

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. 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. 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. 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. GM-CSF
Therapeutic use Results with rhuGM-CSF
Fungal infections Decreases incidence, as an adjuvant with antifungal and
chemotherapy
HIV infection and its Increases CD4 counts, decreases viral load
complications
Vaccine adjuvant Enhances antibody response to Hep C Vaccine.
Increases seroconversion in flu vaccines
Antitumor therapy Prolongs disease free survival and overall survival
Immunotherapy for Decreases risk of relapse
AML
Mucositis, stomatitis & Reduces incidence and severity
diarrhea
Wound healing Decreases time to wound healing. Reduces mean ulcer
05/11/2011 surface area Dr Aaditya 62

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. 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. Technicalities And Formalities
Patents
• 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
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66. Technicalities And Formalities
Laws 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. Technicalities And Formalities
Laws 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
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68. 05/11/2011 Dr Aaditya 68

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
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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 antibodies
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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
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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
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