Immunopharmacology (MONOCLONAL ANTIBODIES) REVISION NOTES

Immunopharmacology
TONY SCARIA 2010 KMC

Tyrosine kinase receptor

Normal tyrosine kinase receptors
• PDGFR
• Insulin
• VEGFR
• EGFR

Abnormal tyrosine kinase

Imatinib binds ATP binding site of BCR-ABL
tyrosine kinase

Imatinib binds to ATP binding site of tyrosisne
kinase receptors
Imatinib inhibit tyrosine kinases (C KIT ,PDGFR ,BCR – ABL)
Inhibited
tyrosine kinase
C-kit PDGFR BCR-ABL
Used in GIST MDS Ph+ CML ‘
Ph+ ALL

S/E of imatinib
• Diarrhea
• Myelosuppression
• Fluid retention
• Hepatotoxicity
• Pleural effusion & arthralgia
• Hypopigmentation

Her1 / EGFR AMPLIFIED
IN
HER2/NEU
AMPLIFICATION IN
• Ca colon
• Head & neck
carcinoma
• Carcinoma lung
• Ca breast
• ca stomach
• Ca ovary

HER2/HER3 dimerization  strongest
mitogenic stimulation

• trastuzumabExtracellular
HER2/HER3
blocked by
• LapatinibIntracellular
HER2/HER3
blocked by

HER-1/EGFR (Erb B1) HER2/neu (Erb B2) Both HER1 & 2
• Erlotinib & Geftinib  nonsmall
cell ca
• Panitumomab & cetuximab
colon carcinoma
• Trastuzumab (breast ca) • Lapatinib (breast ca)

Geftinib erlotinib
• Inhibit tyrosine kinase activated by EGF
• Food increases absorption of erlotinib
by 100 %
• Used in
• Non small cell carcinoma of lung
• Pancreatic carcinoma
• s/e
• Rash
• Diarrhea

A/E of geftinib & erlotinib
• Acneform rash
• Conjunctivitis
• Hepatitis
• Diarrhea

EGFR inhibitors causes acneform rash

Cetuximab & panitumumab
• Cetuximab
• Used in ca colon
• Also in head & neck ca
• Panitumumab
• Used in metastatic ca colon

Cetuximab
Cetuximab EGFR • Colon cancer
• SCC of head & neck
Binds extracellular
domain of EGFR & blocks
binding of EGF & TGF
Panitumomab EGFR • Colon cancer Same as cetuxumab
Nimotuzumab EGFR • SCC
• Head & neck cancer
• Oncocytoma
• Malignant astrocytoma
Same

Cetuximab
• EGFR positive metastatic colorectal
carcinoma

A/E of cetuximab
• Acne like eruption
• Nail infection

Trastuzumab

A/E of trastuzumab
• Cardiomyopathy

Pertuzumab inhibit HER2 dimerization

Pertuzumab inhibit dimerization of
pertuzumab

Lapatinib
• Lapatinib is an orally active
chemotherapeutic agent used for
treatment of solid cancers. It is considered
to be a dual inhibitor of tyrosine kinase
enzyme domains. It blocks HER2 and
EGFR.
• Main advantage of the drug is its oral
administration. The drug has recently been
approved by FDA in combination with
capecitabine for transtuzumab resistant
patients of breast cancer over expressing
HER2/neu receptors
(Mnemonics: Lapatinib is used in breast lump (breast
cancer).We all have two breast so act on both the receptor)

Anti VEGF

•bevacizumabExtracellular
blocked by
•Sunitinib
•Sorafenib
Intracellular
tyrosine kinase is
blocked by

Ranibizumab
Anti VEGF used in diabetic retionopathy

Bevacizumab
• Bevacizumab is a monoclonal
antibody against VEGF and is
used as an anti-angiogenic drug.
• Metastatic colorectal carcinoma
• Used for DIABETIC RETINOPATHY
• It is mainly used for colorectal
carcinoma and is used off-label by
intravitreal injection to slow
progression of neovascular macular
degeneration.

• Bevacizumab
• Used in
• Colorectal carcinoma
• Ca lung
• Ca breast
• RCC
• A/E
• Decreased NO production
• Increased BP
• Thromboembolism
• MI
• Cardiotoxic
• Not used with other anticardiac drugs

Tyrosine kinase inhibitors of VEGF
Sunitinb Sorafenib
RCC blocks VEGF
GIST  block cKIT
RCC
Hepatocellular carcinoma
A/E • Yellowish discolouration of skin
• Rash
• Hypertension
• Mucosal inflammation
• Hand foot syndrome
• Alopecia
• Reversible posterior
leukoencephalopathy

Pegapatinib
• Also used in Age related
macular degeneration
• Pegaptanib is a pegylated
oligonucleotide that binds
extracellular VEGF (rather
than the VEGF receptor)
and is also given by
intravitreous injection to
slow macular degeneration

Ranibizumab
• Recombinant humanised IgG1 kappa isotope
• Used in age related macular degeneration

Cytokines act via JAK STAT Pathway

Tofacetinib
• Blocks jak stat pathway of cytokine mediated response
• Used in RA
• A/E
• Infection

Lymphocyte gene expression
inhibitor
Lymphocyte signalling inhibitor Lymphocyte proliferation
inhibitors
Glucocorticoid • Calcineurin inhibitor
 Cyclosporine
 Tacrolimus
• mTORpathway inhibitor
 Sirolimus
 Everolimus
• Antimetabolites
 Azathioprine
 MMF

MOA of glucocorticoid

Calcineurin inhibitor
• Cyclosporine
• Tacrolimus

Cyclosporine Tacrolimus
Peptide Abx Macrolide Abx
Increased chance of nephrotoxicity
Less BM suppression
Hypertension hyperglycemia hepatotoxicity gum
hyperplasia neurotoxicity gum hyperplasia
Less hirsutism & gum hyperplasia

mTOR inhibitors

mTOR inhibitors
• 1. Sirolimus
• 2. Everolimus

mTOR inhibitors
• Sirolimus binds to FKBP inhibits mTOR 
prevents translation

S/E of sirolimus
• Thrombocytopenia
• Hepatotoxicity
• Hypertriglyceridemia  fibrate should be given along with sirolimus
• Headache

Everolimus
• Derivative of sirolimus
• Shorter t1/2 than sirolimus
• Indications
• Cardiac transplantation
• Drug eluting stent
• RCC

Antimetabolites used in
immunosuppression

Mycophenolate mefetil

MMF
• Inhibit purine synthesis in B & T lymphocytes /(only pathway to
produce guanine in B & T lymphocyte)
• A/E
• HTn

Immunomodulator
Aldesleukin IFN BCG
Recombinant IL2 Types α • Kaposis
sarcoma ,CML
• Hepatitis B & C
β Multiple sclerosis
γ c/c granulomatous
disease

A/E of IFN
• Flu like syndrome
• Neurotoxicity
• AI thyroiditis
• Alopecia
• Hepatotoxicity

Cytokine inhibitors
TNF α inhibitors IL1 inhibitor
• Etanercept
• Infliximab
• Adalimumab
• Anakinra
• Canakinumab
• Rilonacept

Monoclonal Ab

Nomenclature
-mumab Fully murine
-Ximab removed antigenic portion
-zumab Chimeric (humanised)
-umab Completely human

MOA of mab
• Attached to tail with Toxin or radiolabelled isotope
• Compliment mediated lysis
• Induction of apoptosis

Toxin attached to mab

Ozagamicin- gemtuzumab
• Ozagamicin (toxin )
attached to mab
• Used in AML
• Causes ds DNA breakage

Trastuzumab – emtansine
• Prevent microtubule
formation

Radiolabelled isotope attached to mab
Used in NHL
Ibritumomab Tositumomab
90Y attached to mab  beta radiation 131I attached to mab

Rx of NHL
• Over expression of CD20 in NHL
Rituximab CD20 NHL
Ibritumumab Directed against CD20
labelled with 90Y
NHL
Tositumumab Directed against CD20
labelled with 131I
NHL

alemtuzumab
• Against CD52 in CLL

Gemtuzumab is used in AML
• Anti CD33

OKT3  muromonab
• Murine monoclonal Ab directed
against CD3
• In organ transplantation if rejection
occurs

IL1 antagonist
Anakinra RA
Canakinumab Cryoprin associated periodic syndrome (CAPS)
Rilonacept Gout

IL1 antagonist
• Anakinra

• Rilonacept  IL1 trap

Canakinumab is mab against IL1
Canakinumab used in CAPS (cryoprin
associated periodic syndrome)

Efalizumab directed against LFA1  used in
psoriasis

OKT3 Against CD3 of t lymphocyte In organ transplantation
Ipulimumab Against CTLA4 Melanoma
Efalizumab Against LFA1 Psoriasis
Canakinumab Against IL1 CAPS
Rilonacept Against IL1 Gout
Anakinra Against IL1 RA

Drugs used in RA

Abatacept  binds to CD 80/86 & inhibits co
stimulatory signal

Eculizumab humanized against c5
used in PNH

Eculizumab used in PNH

Rituximab  anti CD20
B cell lymphoma

Infliximab
• IgGl chimeric monoclonal
antibody against TNF a
• Infliximab is an injectable
antibody that blocks the effects of
tumor necrosis factor alpha (TNF-
alpha).
• infliximab is used for treating
• the inflammation of Crohn's disease
and
• rheumatoid arthritis.
• Reiters syndrome

Other TNF α drugs
• Adalimumab
• Golimumab
• certolizumab
• Etanarcept

• Anti-TNF alpha drugs / infliximab
• contraindicated in patients
• who are pregnant,
• those with active infection.
• with heart failure.
• SLE
• Infliximab can produce SLE like illness and hence is avoideD. SLE produced by this drug often
involves lungs and pleurA. It is treated by corticosterioids

Adalimumab
• Human
• Anti TNF a

Certolizumab
• Humanised fab Anti TNF a linked 2 molecules of
PEG

Omalizumab  for bronchial asthma
• Against IgE

Monoclonal Ab in BA
Directed against
Omalizumab IgE
Mepolizumab IL1

Omalizumab against IgE

• Mepolizumab
• Directed against IL5

Natalizumab
• α4β1 antagonist
• Used in
• MS
• Crohns ds
• S/E
• PMLE

Basiliximab
• Prevents binding of IL2 to CD25

Dacilizumab also prevents binding of Il2 to
CD25

Dacilizumab
• IL2 receptor blocking mab
• Indicated for
• relapsing forms of MS
• Inadequate response to two or more drugs in Rx of MS

Ipuimumab blocks CTLA4 and activates
immune system used in melanoma

Belimumab in Rx of SLE

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