IMMUNOMODULATORS

OVERVIEW
• Introduction
• Types Of Immunity
• Immunosuppressant
• Immunostimulants
• Newer drugs
• Summary
 INTRODUCTION

• The word immunity is derived from the Latin word

immunes which means “exempt from”.

• Immunity is usually defined as a state of relative

resistance to an infection.

• Substances capable of stimulating immune mechanism

are called as antigens.
IMMUNE SYSTEM OVERVIEW
 IMMUNOMODULATORS

Immune
Immunosupression immunostimulation
Tolerance

a state of unresponsiveness of the immune

system to substances or tissue that have
the capacity to elicit an immune response.
MECHANISM-OVERVIEW OF
IMMUNOSUPRESSANTS
1. Inhibition of gene expression
2. Selective attack on clonally expanding
lymphocytes
3. Inhibition of intracellular signalling
4. Neutralisation of Cytokines & receptors
required for T-cell stimulation
5. Selective depression of T-cells (or
others)
6. Inhibition of co-stimulation by APC
7. Inhibition of Lymphocyte-target cell
interactions
8. Supression of innate immune cells &
complement activation (not shown here)
 CLASSIFICATION-
IMMUNOSUPRESSANTS

Immunosupressants

Calcineurin Antiproliferative/ Biologicals

Glucocorticoids
Inhibitors Antimetabolites (Antibodies)
 SITES OF ACTION OF SELECTED
IMMUNOSUPPRESSIVE AGENTS ON T-
CELL ACTIVATION
DRUG SITE OF ACTION
• Glucocorticoids Glucocorticoid response elements in
DNA (regulate gene transcription)
• Muromonab-CD3 T-cell receptor complex (blocks
antigen recognition)
• Cyclosporine Calcineurin (inhibits phosphatase
activity)
• Tacrolimus Calcineurin (inhibits phosphatase
activity)
• Azathioprine Deoxyribonucleic acid (false
nucleotide incorporation)
• Mycophenolate Mofetil Inosine monophosphate
dehydrogenase (inhibits activity)
• Daclizumab, Basiliximab IL-2 receptor (block IL-2-mediated
T-cell activation)
• Sirolimus Protein kinase involved in cell-cycle
progression (mTOR) (inhibits
activity)
GLUCOCORTICOIDS

• Induce redistribution of lymphocytes – decrease in

peripheral blood lymphocyte counts

• Down regulation of IL-1, IL-2, IL-3, IL-6

• Inhibition of T cell proliferation

• Increase number of RBCs, platelets & neutrophils in

circulation

• Enhance rate of destruction of lymphoid cells

USES
• Transplant rejection
• GVH – BM transplantation
• Autoimmune diseases – RA, SLE, Hematological
conditions
• Psoriasis
• Inflammatory Bowel Disease, Eye conditions
TOXICITY
• Growth retardation
• Avascular Necrosis of Bone
• Risk of Infection
• Poor wound healing
• Cataract
• Hyperglycemia
• Hypertension
CALCINEURIN INHIBITORS

Tacrolimus Cyclosporine

 Perhaps the most effective immunosuppressive drugs

in routine use
 They target intracellular signalling pathways induced
as
a consequence of T cell–receptor activation
MOA-CALCINEURIN INHIBITORS

Sirolimus

Cyclosprine
Tacrolimus
CYCLOSPORINE
Cyclosporine, a cyclic polypeptide of 11 amino acids, is
produced by the fungus Beauveria nivea
 PK-
• 20-50% bioavailability
• CYP3A4
 USE –
• Clinical indications for cyclosporine are kidney, liver,
heart,
and other organ transplantation
• Rheumatoid arthritis and psoriasis.
TOXICITY
 Nephrotoxicity,
 GI complaints,
 Hypertension,
 Tremor,
 Hirsutism,
 Hyperlipidemia,
 Gum hyperplasia
 DI - Sirolimus aggravates cyclosporine-induced renal
dysfunction
TACROLIMUS
 Tacrolimus (FK506) is a macrolide antibiotic
produced by Streptomyces tsukubaensis
 PK-
• Variable
• Trough level correlates better with clinical
events (100-200 ng/mL )
• The t 1/2 of tacrolimus is 12 hours
• CYP3A4
 USE –
• prophylaxis of solid-organ allograft
rejection
• GVHD
 TOXICITY

 Nephrotoxicity,
 Neurotoxicity (e.g., tremor, headache, motor
disturbances, seizures),
 GI complaints,
 hypertension,
 hyperkalemia,
 Hyperglycemia and diabetes
SIROLIMUS
 Sirolimus is a macrocyclic lactone produced by Streptomyces
hygroscopicus

 PK-
• Systemic availability is 15%
• A loading dose of three times the
maintenance dose will provide
nearly steady-state
• CYP3A4
 USE –
• Prophylaxis of organ transplant rejection usually in
combination
• At risk of calcineurin inhibitor–
MOA
associated nephrotoxicity
 TOXICITY

• Increase in serum cholesterol, Triglycerides

• Anemia
• Thrombocytopenia
• Hypokalemia
• Fever
• GI effects
• Risk of infection, tumors
 EVEROLIMUS
• Similar to sirolimus in mechanism, clinical efficacy, doses
& drug interactions

• Better absorbed orally

• Shorter half life (approx 40 hours)

• Shorter time taken to reach steady state

• Similar uses & toxicity

CYTOTOXIC AGENTS TO REDUCE
LYMPHOCYTE PROLIFERATION-

ANTIMETABOLITES:
• AZATHIOPRINE
• METHOTEXATE
• MYCOPHENOLATE MOFETIL
• LEFLUNOMIDE
ALYLATING AGENTS:
• CYCOPHOSPHAMIDE
AZATHIOPRINE
• Purine antimetabolite
• Selectively affects differentiation & function of T- cells
• Inhibits cytolytic T-lymphocytes, CMI is primarily
depressed

Uses
• Prevention of renal & other graft rejections
• Rheumatoid arthritis(lower doses)
 TOXICITY - AZATHIOPRINE

• Bone marrow suppression- leukopenia,

thrombocytopenia, anemia
• Increased susceptibility to infection
• Hepatotoxicity
• Alopecia
• GI toxicity

• Drug interaction: Allopurinol

 MYCOPHENOLATE MOFETIL
 It is an ester of mycophenolic acid (MPA).

 MOA –
 MMF is a prodrug that is rapidly
hydrolyzed to the active drug, MPA
 MPA - a selective, noncompetitive,
reversible inhibitor of inosine
monophosphate dehydrogenase (IMPDH),
 IMPDH is an enzyme @ de novo pathway
of guanine nucleotide synthesis
 B and T lymphocytes are highly
dependent on this pathway for cell
proliferation (others- salvage pathway)
USES - MYCOPHENOLATE
MOFETIL
• Prophylaxis of renal transplant rejection
• Mycophenolate mofetil+glucocorticoid+sirolimus –
non-nephrotoxic combination utilized in patients
developing renal toxicity with
cyclosporin/tacrolimus
• Toxicity
• GI, Hematological

– Diarrhea, Leucopenia
• Risk of Infection(CMV infections)
CYCLOPHOSPHOMIDE

• More marked effect on B cells & humoral immunity

• Used in BM transplantation in which short course
with high dose is given
• In other organ transplantations it is employed only as
a reserve drug
• In RA, it is rarely used
• Low doses are occasionally employed for
maintenance therapy in pemphigus, SLE & idiopathic
thrombocytopenic purpura
 METHOTREXATE

• Folate antagonist, potent immunosupressant

• Markedly depresses cytokine production &
cellular immunity & has anti-inflammatory
property
• Used as 1st line drug in many autoimmune diseases
like rapidly progressing RA, severe psoriasis,
pemphigus, myasthenia gravis, uveitis, chronic active
hepatitis
• Low dose as maintenance therapy is relatively well
tolerated
FINGOLIMOD(FTY720)
• Sphingosine 1 Phosphate Receptor agonist

• Reduce recirculation of lymphocytes from lymphatic

system to blood & peripheral tissues

•Protects graft from T-cell-mediated attack

Uses
• Combination immunosuppression therapy in
prevention of acute graft rejection
Toxicity:

• Lymphopenia,Bradycardia,Macular edema
ANTIBODIES

ANTITHYMOCYT
E GLOBULIN

MONOCLONAL • MUROMONAB-CD3
• ANTI-IL-2 RECEPTOR ANTIBODY
ANTIBODIES (DACLIZUMAB, BASILIXIMAB)
• CAMPATH-1H (ALEMTUZUMAB)

• INFLIXIMAB
Anti-TNF Agents • ETANERCEPT
• ADALIMUMAB
ANTI-THYMOCYTE
GLOBULIN
• Polyclonal antibody purified from horse or rabbits
immunized with human thymic lymphocytes

• Binds to T lymphocytes & depletes them

• Potent immunosupressant

Uses
• Induction of immunosuppression – transplantation
• To suppress acute allograft rejection episodes

Toxicity
• Hypersensitivity
• Risk of infection, Malignancy
ANTI-CD3 MONOCLONAL
ANTIBODY
 Murine monoclonal antibody against the CD3 glycoprotein
expressed near to the T cell receptor on helper T cell

 Binds to CD3, a component of T-cell receptor complex

involved in
 antigen recognition
 cell signaling & proliferation
MUROMONAB-CD3
Antibody treatment

Rapid internalization of T-cell receptor

Rapid T-cell depletion from blood

Prevents subsequent antigen

recognition
 Use
• Treatment of acute organ transplant
rejection

Toxicity
• “Cytokine release syndrome”
• Aseptic meningitis, life threatening
pulmonary edema(rare)
 ANTI-IL-2 RECEPTOR
ANTIBODIES
• DACLIZUMAB & BASILIXIMAB

• Bind to IL-2 receptor with high affinity on surface of

activated T cells  Block IL-2 mediated T-cell activation

Uses
• Prophylaxis of Acute organ rejection & maintenance of graft

Toxicity
• Anaphylaxis, Opportunistic Infections
 CAMPATH-1H
(ALEMTUZUMAB)
• Monoclonal antibody binds CD52 – expressed on
lymphocytes, monocytes, macrophages
• Extensive lympholysis – Prolonged T & B cell
depletion

Uses
• CLL, Bone marrow transplantation, Renal
transplantation
Toxicity
• Opportunistic infections
ANTI-TNF AGENTS

• TNF – Cytokine at site of inflammation

• Infliximab
• Etanercept
• Adalimumab
 INFLIXIMAB

• Chimeric monoclonal antibody against TNFα

Uses
• Rheumatoid arthritis
• Chron’s disease – fistulae
• Psoriasis
• Psoriatic arthritis
• Ankylosing spondylosis

Toxicity
• Infusion reaction – fever, urticaria, hypotension, dyspnoea
• Opportunistic infections – TB, RTI, UTI
 ETANERCEPT

• Fusion protein
• Ligand binding portion of Human TNF-α receptor fused
to Fc portion of human IgG1
• Neutralizes both TNFα & TNFß
• Prevents activation of macrophages & T-cells

Uses
• Rheumatoid arthritis
• Also approved for severe/refractory ankylosing
spondylitis, plaque psoriasis
 LFA-1 Inhibitor - Efalizumab

• Recombinant humanized monoclonal Ab targeting CD11a

subunit of lymphocyte function associated antigen 1
• Blocks T-cell adhesion, activation, trafficking

Uses
• Organ transplantation
• Psoriasis

• Withdrawn from market in 2009 due to fatal brain

infections(bacterial sepsis, invasive fungal disease)
NEWER DRUGS
MOA USES TOXICITY

CETROLIZUMAB PEG-ANTI-TNF RA,CROHNS DISEASE, STUFFY

ANTIBODY PSORIATIC ARTHRITIS NOSE,DIAR
RHOEA
GOLIMUMAB TNF ALPHA RHEUMATOID INFECTION
INHIBITOR ARTHRITS ,CHEST
PAIN
ANAKINRA IL-1 RHEUMATOID FLU
ANTAGONIST ARTHRITIS SYMPTOM
S
RILONACEPT IL-1 GOUT FLU
ANTAGONIST SYPTOMS

CANAKINUMUM IL-1 IDIOPATHIC MUSCLE

AB ANTAGONIST ARTHRITIS PAIN,STUF
FY NOSE
TOCLIZUMAB IL-6 IDIOPATHIC FLU
ANTAGONIST ARTHRITIS SYMPTOM
S
NEWER DRUGS
IXEKIZUMAB,SE IL-17 ANTAGONIST RHEUMATOID FLU
CUKINUMAB,BR ARTHRITIS,PSO SYMPTOMS
OADLUMAB RIASIS
OMALIZUMAB ANTI-IGE ANTIBODY ALLERGIC
ASTHMA
BELIMUMAB B-LYMPHOCYTE GRAFT
STIMULATOR REJECTION
CYTOKINE INHIBITOR
BRENTUXIMAB ANTIBODY DRUG HODGKINS NEUTROPEN
VEDOTIN CONJUGATE-AGAINST LYMPHOMA IA,FATIGUE
CD30 ANTIGEN WTH
MMAE DRUG
ALEFACEPT LFA-3 INHIBITOR PLAQUE
PSORIASIS
TOLEROGENS
To induce T cell anergy or tolerance

Use cosuppressive pair to dampen thec immune

resonse

CTLA4 expressed on t cell surface interact with cd80

and cd86v to dampen an immune response

Potential tolerogens in renal transplant are anti cd80

and anti cd86 MAb
ABATACEPT
•1st generation CTLA4-Ig fusion protein, binds to
CD 80/86 on APC and inhibits T cell
costimulation
• Recently approved for cases of RA
• Undergoing trials in organ
transplantation

•BELATACEPT
•Newer CTLA4-Ig fusion protein
•Higher affinity for CD 80/86
•For kidney transplantation
HELMINTHIC THERAPY
Whipworm ova and hookworm used

Highly effective in relapsing-remitting multiple Sclerosis(RR-

MS), crohn’sdisease, allergies and asthma

Several proposed mechanisms are:

1. Re- polarisation of the th1 /th2 response: Down

regulate th1.
PD-1 INHIBITOR
DRUGS USES

NIVOLUMAB METASTATIC MELANOMA

PEMBROLIZUMAB METASTATIC MELANOMA

DABRAFENIB METASTATIC NON SMAL CELL

LUNG CANCER

VEMURAFENIB METASTATIC NON SMAL CELL

LUNG CANCER
 ANTI –D
IMMUNOGLOBULIN
• Human Ig G having high titre of antibodies against Rh
(D) antigen

• It binds the Rho Ag (-) antibody formation in Rh -ve

individuals

• It is used for prevention of postpartum /post – abortion

formation of antibodies in Rho-D negative, DU -ve women
who delivered or aborted an Rho-D +ve, DU +ve baby/ foetus
IMMUNOSTIMULANTS
• Levamisole
• Thalidomide
• BCG
• Recombinant Cytokines
– Interferons
– Interleukin-2
– Adlesleukin
– Colony Stimulating
Factors
TETRAMISOLE (LEVAMISOLE)
• Levamisole is orally active levo isomer of tetramisole,
restores depressed T-cell function

• Used as an adjunct in malignancies, aphthous ulcers &

recurrent herpes, also used as disease modifying
drug in Rheumatoid Arthritis

• Mainly acts by raising c-GMP levels through interaction

with thymopoietien receptor sites
• Leads to decrease in metabolic inactivation of c- GMP
accompanied with increased breakdown of c- AMP

• Increase in c-GMP level induces lymphocyte

proliferation & augmentation of chemotactic
responses

• This reflects into increased antibody production,

lymphokine production, increased phagocytosis
THALIDOMIDE
• Anxiolytic, antiemetic drug with antiinflammatory,
cytokine modulatory activity

• Enhanced T-cell production of cytokines – IL-2,

IFN-γ

• NK cell-mediated cytotoxicity against tumor cells

USE:
• Multiple myeloma, ENL
BACILLUS CALMATE
GUERIN(BCG)
VACCINE
• It is used as immunological enhancer to stimulate intact
immune system (i.e. a non-specific immunoenhancer.)
of the body.

• BCG & its methanol extracted residue (MER) contain

muramyl dipeptide as an active immunostimulant
ingredient

• T-lymphocytes are principle target cells for the action of

BCG vaccine.
• It causes stimulation of macrophage function, phagocytic
activity, lysosomal enzyme activity & chemotaxis
mechanisms

• It induces the production of lymphocyte-activity factor

resulting of phase I of immune response.

• Because of its activity against tumour antigen it is beneficial

in treatment of lung & breast cancer, acute lympholytic
& myelogeneous leukaemia.

• It is available as unlyophilized, live or killed lyophilized form.

 INTERFERONS

• Low molecular weight glycoprotein cytokines

produced by host cells in response to viral infections
• Immunomodulatory activity
• Bind to cell surface receptors – initiate intracellular
events
– Enzyme induction
– Inhibition of cell proliferation
– Affect viral replication
– Increased Phagocytosis
 INTERFERON ALFA-2B
• Hairy cell leukemia
• Malignant melanoma
• Kaposi sarcoma
• Chronic Hepatitis B

Adverse reactions
• Flu-like symptoms – fever, malaise, headache
• CVS- hypotension, Arrhythmia
• CNS- depression, altered behaviour
 INTERLEUKIN-2
(ALDESLEUKIN)
• Proliferation of cellular immunity – Lymphocytosis,
eosinophilia, release of multiple cytokines – TNF, IL-1, IFN-γ
• Promotes differentiation of T-cells

Uses
• Metastatic renal cell carcinoma
• Malignant Melanoma

Toxicity
• Flu- like symptoms- fever, headache, fatigue
• Hypotension, drowsiness, confusion, loss of appetite
OTHER CYTOKINES
OPRELVEKIN-(RIL11) MEGAKARYOCYTE THROMBOCYTOPENI
STIMULATOR A
SARGRAMOSTIM-CSF PROLIFERATION OF NEUTROPENIA
HAMATOPIETIC
CELLS
FILGRASTIM-CSF NEUTOPHILL NEUTROPENIA
PROGENITOR
STIMULATOR
PEGFILGRASTIM-CSF PROLIFERATION OF NEUTROPENIA
HAMATOPIETIC
CELLS
CELL BASED THERAPY(CANCER
VACCINES)

 Immune cells specific for the tumor will be activated, grown

and returned to the person with cancer where the immune
cells provoke an immune response against the cancer

 Eg: Sipuleucel-T(Provenge) for prostate cancer

A complete sipuleucel-T treatment repeats three courses, with two weeks
between successive courses
AUTOLOGOUS IMMUNE
ENHANCEMENT THERAPY

• Patient's own peripheral blood-derived NK cells,

Cytotoxic T Lymphocytes and other relevant
immune cells are expanded in vitro and then
reinfused

• Mostly for CANCER

• There are also studies proving their efficacy

against Hepatitis C Viral infection, Chronic
fatigue Syndrome and HHV6 infection.
 Conclusion
• Immunology is one of the most rapidly developing
areas of medical biotechnology research
• Immunomodulators are going to be central part of 21st
centuary medicine
• Immunomodulation is a normalising process which
correct weak immune systems & temper immune
systems that are overactive
• Immunomodulators are becoming a viable adjunct to
established modalities offering a novel approach for
the treatment of infectious disease in coming decades
 References

• Patil U.S, Jaydeokar A.V, Bandawane D.D,

immunomodulators : a pharmacological review,
international journal of pharmacy & pharmaceutical
sciences, vol 4, suppl 1, 2012

• Essentials of Medical Pharmacology: K.D. Tripathi,

7th edition

• Rang.H.P, Dale.M.M, Ritter.J.M, FlouerR.J, Pharmacology,

Philadelphia, Churchil livingstone-elsevier, 7th edition