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

OverviewIntroduction

History

Types

Mechanism of actionUse of biological response modifiersAdverse effects

Biosimilars

Summary

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

• 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

History

• William B Coley- Father of Biological Response Modifiers (BRM)

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

TypesMonoclonal antibodies

Costimulation inhibitors

Angiogenic inhibitors

IFN: IFN α

IL: IL 2, IL 6, IL 11

Tyrosine kinase inhibitors (TKIs)

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)

Differentiating agents tretinoin, bexarotene

Thalidomide

Proteosome inhibitors

β-glucans

Classification

Prefix Suffix

- mab (Monoclonal antibody)

- cept (Soluble receptor)

- inib (kinase inhibitor)

Mechanism of action

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

3) Miscellaneous

Promotion of cell differentiationEx- Colony Stimulating Factors

Interference with neoplastic changesEx- Retinoids

Prevention of metastasisEx- Angiogenic inhibitor

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

Nomenclature- suffix

Human Humanized

Murine Chimeric

umab zumab momab ximab

Humanized

17

Human Ab with complimentary determining region(CDR) or hypervariable region from non human source

– Daclizumab– Trastuzumab

Chimeric

18

Antigen binding parts (variable region) of mouseAb with effector parts (constant region) of human

– Infliximab– Abciximab – Rituximab

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

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)

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

On the basis of development

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

Mechanism of action of Monoclonal Antibodies

Generation of monoclonal antibodies

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

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

A/E of Rituximab

RashAnaphylactoid reaction

Hypotension,GI disturbances,feverSerious fungal,bacterial & viral infections

Reactivation of Hepatitis B virusFatal mucocutaneous reaction

Anemia & neutropenia

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

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

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

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

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

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

Costimulation inhibitorsAbatacept & belatacept

• CTLA4-Ig fusion protein

• Binds CD 80/86

• Resistant cases of rheumatoid arthritis & organ transplantation

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

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

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

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

Side effects

•Fever, chills, myalgia, headache, depression, nausea, anorexia, weight loss (flu-like syndrome)

•Myelosuppression –Rare, reversible within 1–3 days of discontinuation

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

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

Early side effects • Infusion reaction• flu-like symptoms • gastrointestinal effects

Toxicity• Hypotension• Ascites• Anasarca• Pulmonary edema

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

Tyrosine kinase inhibitors (TKIs)

Block phosphorylation & activation of downstream signaling of EGFR & other kinases

ImatinibGefitinibErlotinibDasatinibNilotinib

Lapatinib

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

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

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

Colony stimulating factors (CSFs)• Growth factors that mediate proliferation,

maturation, regulation & activation of hematopoietic cells.

G-CSF: GranulocyteGM-CSF : Granulocyte & Macrophage lineageEPO : ErythrocytesTPO : Platelets

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

Erythropoietin

Patients with chronic renal failure

HIV patients treated with zidovudin

Cancer patients treated with chemotherapy

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)

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

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)

• Adverse effects

Lenalidomide & Pomalidomide approved for use in patients

with primary & refractory Myeloma

Sedation & constipation-Most common

Peripheral sensory neuropathy- most serious

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

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

•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

Biosimilars

World Health Organization

“A biotherapeutic product which is similar in terms of quality, safety

& efficacy to an already licensed reference biotherapeutic product.”

Summary

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)

• 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)