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Biological Response Modifiers Biological Response Modifiers In TherapeuticsIn Therapeutics
Guided byDr V M MotghareProfessor & head
Department of Pharmacology
G.M.C.H. Nagpur
Dr Ankita JireJR
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OverviewIntroduction
History
Types
Mechanism of actionUse of biological response modifiersAdverse effects
Biosimilars
Summary
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Introduction
Biological response modifiers are substances that modify immune responses. They can be both
endogenous (produced naturally within body) & exogenous (as pharmaceutical drugs) & they can
either enhance an immune response or suppress it
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• A biologic medical product is a vaccine, blood or blood component, allergenic,somatic cell, gene therapy, tissue recombinant therapeutic protein or living cell that is used as therapeutics to treat diseases
• Often 200 to 1,000 times size of small molecule drug & are far more complex structurally
• Highly sensitive, making them more difficult to characterize & produce
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History
• William B Coley- Father of Biological Response Modifiers (BRM)
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Some milestones…….1982 First biotech product (synthetic human
insulin)discovered 1986 First monoclonal antibody (mAb) treatment
approved1997 Approval of first mAb-targeted chemotherapy2002 New mAb therapy for rheumatoid arthritis2003
• Human genome mapped• First mAb for allergic asthma
2004• First mAb treatment for colorectal cancer• First mAb treatment for Multiple Sclerosis• First anti-angiogenic medicine for cancer • First mAb approved to treat EGFR-expressing
metastatic colorectal carcinoma2006 First vaccine for the prevention of cervical cancer
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TypesMonoclonal antibodies
Costimulation inhibitors
Angiogenic inhibitors
IFN: IFN α
IL: IL 2, IL 6, IL 11
Tyrosine kinase inhibitors (TKIs)
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TNF α
Colony stimulating factors (CSFs)
- Erythropoietin (EPO)
Granulocyte colony stimulating factor (G CSF): filgrastim
Granulocyte monocyte colony stimulating factor (GM CSF): sargramostim
Thrombopoietin (TPO): recombinant human megakaryocyte growth & development factor (rhuMGDF),recombinant human thrombopoietin (rhuTPO)
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Differentiating agents tretinoin, bexarotene
Thalidomide
Proteosome inhibitors
β-glucans
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Classification
Prefix Suffix
- mab (Monoclonal antibody)
- cept (Soluble receptor)
- inib (kinase inhibitor)
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Mechanism of action
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1) Direct action
Direct cytotoxic action on tumor cells Ex- Monoclonal antibodies
2) Indirect action
Restore, augment or modulate immune system to facilitate destruction of tumor cells
Ex- IFNs & ILs
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3) Miscellaneous
Promotion of cell differentiationEx- Colony Stimulating Factors
Interference with neoplastic changesEx- Retinoids
Prevention of metastasisEx- Angiogenic inhibitor
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Monoclonal Antibodies
The clones of similar antibodies that are directed against specific target antigens
Ex. Cancer cells express wide variety of antigens that are attractive targets for monoclonal antibody based therapy
Chimerization/humanization prolongs T1/2reduce antigenicity
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Nomenclature- suffix
Human Humanized
Murine Chimeric
umab zumab momab ximab
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Humanized
17
Human Ab with complimentary determining region(CDR) or hypervariable region from non human source
– Daclizumab– Trastuzumab
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Chimeric
18
Antigen binding parts (variable region) of mouseAb with effector parts (constant region) of human
– Infliximab– Abciximab – Rituximab
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Murine
19
Derived from mice Patients treated with murine mAbs develop a human
antimouse antibody (HAMA) responseRapid clearance of the mAbPoor tumour penetrationHypersensitivity reactions
90Y-Ibritumomab 131I -Tositumomab
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Examples • ab- + -ci- + -xi- + -mab: chimeric monoclonal
antibody used on the cardiovascular system
• tras- + -tu- + -zu- + -mab: humanized monoclonal antibody used against a tumor
• pali- + -vi- + -zu- + -mab: humanized mab used against a virus (RSV)
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Classification On basis of mechanism
1)Interleukin receptors
IL-1 – Anakinra
2)Action on CD cell CD3 – Muromonab
3)TNF α – Infliximab4)VEGF – Bevacizumab
5)EGFR – Cetuximab6)LFA1- Efalizumab
7)HER2/NEU – Transtuzumab
8)Platelet receptors – Abciximab
9)F-glycoprotein on surface of RSV –
Palivizumab
10)IgE – Omalizumab
11)α1-integrin – Natalizumab
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On the basis of development
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Types of monoclonal antibody
• Naked/Unarmed/Unmodified
• Conjugated/Armed
1)With toxinEx.Denileukin diftitox
2) Cytotoxic conjugatesEx.Gemtuzumab
3) Radioimmune conjugates
Ex.131Iodine tositumomab
4) Bispecific AbEx.Catumaxomab
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Mechanism of action of Monoclonal Antibodies
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Generation of monoclonal antibodies
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Rituximab Chimeric monoclonal antibody against CD20 B cell
antigen
MOA :
• Complement mediated lysis• Ab dependent cellular toxicity• Apoptisis of malignant cells & B cells
• Given as two i.v. infusions of 1000 mg separated by 2 weeks
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Uses of Rituximab
Rhematoid arthritis
Wegener’s granulomatosis
Microscopic polyangitis
Diffuse large B cell lymphoma
Other B cell Non-Hodgkin’s lymphomas(NHLs)
Chronic Lympocytic Leukemia (CLL)
Malignant lymphoma
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A/E of Rituximab
RashAnaphylactoid reaction
Hypotension,GI disturbances,feverSerious fungal,bacterial & viral infections
Reactivation of Hepatitis B virusFatal mucocutaneous reaction
Anemia & neutropenia
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Infliximab• Chimeric(25% mouse , 75% human) Monoclonal
antibody against TNF α
• I.V. infusion with “induction” at 0, 2 & 6 weeks & maintenance every 8 weeks thereafter
Uses
Rheumatoid arthritis Ankylosing spondilysis
Crohn’s diseaseUlcerative colitis
psoriasis
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A/E of Infliximab
Injection site reactions
Alopecia areata,hypertrichosis,erosive lichen planus
GI ulcers & large bowel perforation
Activation of HBV
Activation of latent TB
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MonoclonalAntibody
Target Indication
Abciximab Gp IIb/IIIa AntiplateletAdalimumab TNF α RA(rheumatoid arthritis)
Alefacept LFA-3 Plaque psoriasis
Alemtuzumab CD 52 B cell CLL,Multiple sclerosis
Basiliximab CD-25 Immunosuppressant
Brentuximab CD 30 Hodgkin lymphoma, Anaplastic large cell lympoma
Cetuximab EGFR Colorectal carcinoma
Certolizumab TNFα Crohn’s disease
Daclizumab CD-25 Immunosuppressant
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MonoclonalAntibody
Target Indication
Denosumab RANK ligand Osteoporosis
Epratuzumab CD 22 SLE
Etanercept TNF α RA (rheumatoid arthritis)
Gemtuzumab CD 33 AMLGolimumab TNFα RA, Psoriasis, Ankylosing
SpondylosisIbritumomab CD 20 B-cell NHL
Natalizumab Integrin-α4 Multiple sclerosis
Nimotuzumab EGFR Squamous cell carcinoma, Glioma
Tocilizumab IL 6 SLE , RA
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MonoclonalAntibody
Target Indication
Obinutuzumab CD-20 CLL
Ocrelizumab CD-20 Breast cancer
Ofatumumab CD 20 SLE
Omalizumab Ig E Bronchial asthma
Palivizumab Fusion protein
RSV
Panitumumab EGFR Colorectal carcinoma
Pertuzumab HER-2 Breast cancer
Trastuzumab her-2/neu Breast cancer, GI carcinoma
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Side effects• Headache, malaise, flu like syndrome
• Nausea, vomiting, loss of appetite
• Redness & irritation at injection site
• Immune response producing HAMA ("human anti-mouse antibodies")
• Immune complexes may cause damage to kidneys
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Costimulation inhibitorsAbatacept & belatacept
• CTLA4-Ig fusion protein
• Binds CD 80/86
• Resistant cases of rheumatoid arthritis & organ transplantation
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Angiogenesis Inhibitors• Angiogenesis consists of multiple coordinated, sequential &
interdependent steps regulated by finely balanced equilibrium between proangiogenic & antiangiogenic factors
• 5 strategies used as antiangiogenic therapy-
Inhibition of-Activated endothelial cells (EC) -EC intracellular signaling -Extracellular matrix remodeling -Adhesion molecules -Angiogenic mediators or their receptors
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Bevacizumab, cetuximab,panitumumab, trastuzumab
Erlotinib, sorafenib, sunitinib
Angiogenesis
inhibitor
Target Indication Toxicity
Bevacizumab
VEGF Metastatic colorectal
Cancer metastatic RCC
Non–small cell lung cancer
Advanced breast cancer
Hypertension , pulmonary
hemorrhage,GI perforation
Sunitinib VEGF -2 Metastatic Advanced RCC(Renal Cell
Ca)GIST
Bleeding, hypertension,
fatigue
Sorafenib VEGFR1VEGFR2VEGFR3
Hepatocellular carcinoma
Metastatic Renal cell carcinoma
Fatigue, nausea,anorexia,Bleeding,
hypertension
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Interferons• Act via specific cellular receptors linked with JAK STAT pathway to
stimulate formation of specific proteins which mediate their actions
• 3 major classes of human IFNs: alpha, beta & gamma
• 3 forms-
• Subcutaneous or intravenous• Recently oral use- recommended
RecombinantNatural Pegylated forms
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Clinical Uses of InterferonsINF-α
-chronic myelogenous leukemia-hairy cell leukemia-AIDS related Kaposis Sarcoma-Malignant melanoma-Hepatitis B & C-Renal Cell Ca
INF-β-Relapsing multiple sclerosis
INF-ɣ-Chronic granulomatous disease
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Side effects
•Fever, chills, myalgia, headache, depression, nausea, anorexia, weight loss (flu-like syndrome)
•Myelosuppression –Rare, reversible within 1–3 days of discontinuation
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Interleukins• Cytokines produced in body by lymphocytes are known as Interleukins
• IL 2 Increases cytolytic activity of antigen-specific cytotoxic T lymphocytes & natural
killer (NK) cells
Increases gene expression responsible for encoding lytic component of cytotoxic granules - perforin & granzymes
Lymphokine-activated killer (LAK) cells (Lymphocytes stimulated by IL-2) - effective in destroying tumors
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Uses of IL-2 (Aldesleukin)1) Metastatic RCC (Renal cell Cancer )2) Malignant melanoma
Other Interleukins
• IL-6 , IL-11
• Oprelvekin (Recombinant form of IL-11) Approved for treatment of malignancy- induced
thrombocytopenia
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Early side effects • Infusion reaction• flu-like symptoms • gastrointestinal effects
Toxicity• Hypotension• Ascites• Anasarca• Pulmonary edema
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IL 1 inhibitors • Anakinra• Recombinant form of IL-1 receptor antagonist• Dose – 100 mg s/c daily
• UsesRheumatoid arthritis Behcets disease
• A/E– Injection site reaction– Headache– ↑ risk of bacterial, viral infections
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Tyrosine kinase inhibitors (TKIs)
Block phosphorylation & activation of downstream signaling of EGFR & other kinases
ImatinibGefitinibErlotinibDasatinibNilotinib
Lapatinib
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Sr.No Tyrosine Kinase Inhibitor (TKI)
Therapeutic Uses
1. Imatinib First-line therapy in accelerated phase, chronic phase & blast crisis of chronic myeloid leukemia
2. Geftinib -Advanced NSCLC-Esophageal squamous cellCarcinomas-An initial treatment for pulmonaryAdenocarcinoma
3. Erlotinib Locally advanced or metastatic NSCLC4. Dasatinib Imatinib-resistant CML5. Nilotinib Imatinib-resistant CML6. Lapatinib -Front-line therapy in breast cancer
-An adjuvant therapy when patientshave progressed on Herceptin
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Tumor Necrosis Factor α Secreted by macrophages activated by endotoxins
Binds to receptor on cell membranes,initiates cellular activity & is cytotoxic
Cause direct destruction of tumor cell & its vasculature or stimulate NK cells
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Dose needed for clinical efficacy is extremely toxic
Phase I/II studies - IV infusion produces severe hypotension & hepatotoxicity
Isolated limb perfusion was tried in treatment of malignant melanoma & soft tissue sarcome sarcoma
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Colony stimulating factors (CSFs)• Growth factors that mediate proliferation,
maturation, regulation & activation of hematopoietic cells.
G-CSF: GranulocyteGM-CSF : Granulocyte & Macrophage lineageEPO : ErythrocytesTPO : Platelets
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Recombinant human G-CSF (filgrastim) & GM-CSF (sargramostim)
IV bolus/continuous i.v. infusion or SC
Administered 24 –72 h after chemotherapy until high neutrophil count (1000/µL) has persisted for 3 consecutive days
Uses-Neutropenic fever secondary to cytotoxic chemotherapy -To reverse leukopenia as adjunctive therapy for HIV-associated infections
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Erythropoietin
Patients with chronic renal failure
HIV patients treated with zidovudin
Cancer patients treated with chemotherapy
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Adverse effects of CSF
G-CSF - Mild to moderate bone pain
GM-CSF – An acute reaction at first dose- fever, chills, hypotension & dyspnea
EPO - Increased thromboembolic & cardiovascular events (Hb >12 g/dL)
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Differentiating agentsTretinoin MOA- Retinoids bind with retinoic acid receptor α which
dimerizes with retinoid X receptor, which in turn displaces repressor of differentiation
Use-Acute promyelocytic leukemia
Clinical trials
A/E-Dry skin, cheilitis, bone tenderness, hyperlipidemia & retinoic acid syndrome
Reversal of oral, skin, cervical malignancies Prevention of head and neck, lung, skin tumor
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ThalidomideMOA : Suppresses TNF-α production
Reduce expression of proangiogenic factors such as VEGF & IL-6
Reduces phagocytosis by neutrophils
Induce NK cellsUse
First-line therapy in Multiple myeloma in combination with dexamethasone Myelodysplastic syndrome (MDS)
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• Adverse effects
Lenalidomide & Pomalidomide approved for use in patients
with primary & refractory Myeloma
Sedation & constipation-Most common
Peripheral sensory neuropathy- most serious
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Proteosome inhibitorsBortezomib
Proteasome inhibitor
Prevent break up & degradation of Protein IkB so NFkB is not released
Use- Multiple Myeloma & refractory mantle cell lymphoma
A/E-Peripheral neuropathy, diarrhoea, fatigue, Bone Marrow supression, thrombocytopenia
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β – Glucans: Naturally occurring BRMs β-Glucan occur naturally in some fungi & plants as
components of cell wall. Common sources -Medicinal mushrooms, bakers yeast & grains such as oats & barley
Ganoderma lucidium Trametes versicolor
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•Natural polysaccharide (complex sugar molecule) made up of chains of many glucose sugar units
•Promote cancer cell elimination by enhancing activity of macrophages, neutrophils, T cells, NK cells & B cells with appropriate antibodies
•β-Glucan is only found in nature & can not be synthesized in laboratory
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Biosimilars
World Health Organization
“A biotherapeutic product which is similar in terms of quality, safety
& efficacy to an already licensed reference biotherapeutic product.”
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Summary
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References • The pharmacological basis of therapeutics(Goodman
and Gillman)12th edition
• Basic And Clinical Pharmacology (Katzung) 13th edition
• Bisht M, Bist SS, Dhasmana DC. Biological response modifiers: current use and future prospects in cancer therapy.Indian Journal of Cancer 2010; 47( 4):443-9
• Medicine update 2016(KK Pareek ;Gurpreet Wander)
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• K.Sri Janaki et al /Int.J. ChemTech Res.2010,2(4)
• Alain Beck (2011) Biosimilar, biobetter and next generation therapeutic antibodies, mAbs, 3:2, 107-110, DOI: 10.4161/mabs.3.2.14785
• General pharmacology-Basic concepts(HL Sharma & KK Sharma)2nd edition
• Pharmacology For MBBS (S K Shrivastava)
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