Biological response modifiers

BIOLOGICALS CLASSIFICATION AND DETAILS

1. Biological Response Modifiers In Biological Response Modifiers In
TherapeuticsTherapeutics
Guided by
Dr V M Motghare
Professor & head
Department of Pharmacology
G.M.C.H. Nagpur
Dr Ankita Jire
JR

2. Overview
Introduction
History
Types
Mechanism of action
Use of biological response modifiers
Adverse effects
Biosimilars
Summary

3. 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

4. •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

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

7. Some milestones…….
1982 First biotech product (synthetic human insulin)discovered

1986 First monoclonal antibody (mAb) treatment approved
1997Approval of first mAb-targeted chemotherapy
2002New mAb therapy for rheumatoid arthritis
2003
•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 carcinoma
2006First vaccine for the prevention of cervical cancer

8. Types
Monoclonal antibodies
Costimulation inhibitors
Angiogenic inhibitors
IFN: IFN­α
IL: IL­2, IL­6, IL­11
Tyrosine kinase inhibitors (TKIs)

9. TNF­α
Colony stimulating factors (CSFs)
- Erythropoietin (EPO)
­ Granulocyte­colony stimulating factor (G­CSF): filgrastim
­ Granulocyte­monocyte­colony stimulating factor (GM­
CSF): sargramostim
­ Thrombopoietin (TPO): recombinant human megakaryocyte
growth & development factor (rhuMGDF),recombinant
human thrombopoietin (rhuTPO)

10. Differentiating agents­tretinoin, bexarotene
Thalidomide
Proteosome inhibitors
β-glucans

11. Classification
Prefix Suffix
- mab (Monoclonal antibody)
- cept (Soluble receptor)
- inib (kinase inhibitor)

12. Mechanism of action

13. 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

14. 3) Miscellaneous
Promotion of cell differentiation
Ex- Colony Stimulating Factors
Interference with neoplastic changes
Ex- Retinoids
Prevention of metastasis
Ex- Angiogenic inhibitor

15. 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 antibody­based therapy
Chimerization/humanization
prolongs T
1/2
reduce antigenicity

16. Nomenclature- suffix
Human Humanized Murine Chimeric
umab zumab momab ximab

17. Humanized
17
Human Ab with complimentary determining
region(CDR) or hypervariable region from non human
source
–Daclizumab
–Trastuzumab

18. Chimeric
18
Antigen binding parts (variable region) of mouse
Ab with effector parts (constant region) of human

–Infliximab
–Abciximab
–Rituximab

19. Murine
19
Derived from mice
Patients treated with murine mAbs develop a human
antimouse antibody (HAMA) response
Rapid clearance of the mAb
Poor tumour penetration
Hypersensitivity reactions

90
Y-Ibritumomab

131
I -Tositumomab

21. 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)

22. Classification
On basis of mechanism
1)Interleukin receptors
IL-1 – Anakinra
2)Action on CD cell
CD3 – Muromonab
3)TNF α – Infliximab
4)VEGF – Bevacizumab
5)EGFR – Cetuximab
6)LFA
1
- Efalizumab
7)HER2/NEU –
Transtuzumab
8)Platelet receptors –
Abciximab
9)F-glycoprotein on
surface of RSV –
Palivizumab
10)IgE – Omalizumab
11)α1-integrin –
Natalizumab

23. On the basis of development

24. Types of monoclonal antibody
•Naked/Unarmed/Unmodified
•Conjugated/Armed
1)With toxin
Ex.Denileukin diftitox
2) Cytotoxic conjugates
Ex.Gemtuzumab
3) Radioimmune conjugates
Ex.
131
Iodine tositumomab
4) Bispecific Ab
Ex.Catumaxomab

25. Mechanism of action of Monoclonal
Antibodies

26. Generation of monoclonal antibodies

27. 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

28. 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

29. A/E of Rituximab
Rash
Anaphylactoid reaction
Hypotension,GI disturbances,fever
Serious fungal,bacterial & viral infections
Reactivation of Hepatitis B virus
Fatal mucocutaneous reaction
Anemia & neutropenia

30. 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 disease
Ulcerative colitis
psoriasis

31. 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

32. Monoclonal
Antibody
Target Indication
Abciximab Gp IIb/IIIa Antiplatelet
Adalimumab 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

33. Monoclonal
Antibody
Target Indication
Denosumab RANK ligand Osteoporosis
Epratuzumab CD 22 SLE
Etanercept TNF α RA (rheumatoid arthritis)
Gemtuzumab CD 33 AML
Golimumab TNFα RA, Psoriasis, Ankylosing
Spondylosis
Ibritumomab CD 20 B-cell NHL
Natalizumab Integrin-α4 Multiple sclerosis
Nimotuzumab EGFR Squamous cell carcinoma, Glioma
Tocilizumab IL 6 SLE , RA

34. Monoclonal
Antibody
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

35. 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

36. Costimulation inhibitors
Abatacept & belatacept
•CTLA4-Ig fusion protein
•Binds CD 80/86
•Resistant cases
of rheumatoid arthritis &
organ transplantation

37. 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

38. 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
SunitinibVEGF -2 Metastatic
Advanced RCC(Renal Cell Ca)
GIST
Bleeding,
hypertension,
fatigue
Sorafenib VEGFR1
VEGFR2
VEGFR3
Hepatocellular carcinoma
Metastatic Renal cell
carcinoma
Fatigue, nausea,
anorexia,
Bleeding,
hypertension

39. 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$7

A
Recombinant
Natural
Pegylated forms

40. Clinical Uses of Interferons
INF-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

41. Side effects
•Fever, chills, myalgia, headache, depression,
nausea, anorexia, weight loss (flu-like syndrome)
•Myelosuppression –Rare, reversible within 1–3
days of discontinuation

42. Interleukins
•Cytokines produced in body by lymphocytes are known as
Interleukins
•IL­2
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

43. 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

44. Early side effects
• Infusion reaction
• flu-like symptoms
• gastrointestinal effects
Toxicity
•Hypotension
•Ascites
•Anasarca
•Pulmonary edema

45. IL 1 inhibitors
•Anakinra
•Recombinant form of IL-1 receptor antagonist
•Dose – 100 mg s/c daily
•Uses
Rheumatoid arthritis
Behcets disease
•A/E
–Injection site reaction
–Headache
–
↑
risk of bacterial, viral infections

46. Tyrosine kinase inhibitors (TKIs)
Block phosphorylation & activation of downstream
signaling of EGFR & other kinases
Imatinib
Gefitinib
Erlotinib
Dasatinib
Nilotinib
Lapatinib

47. Sr.NoTyrosine 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 cell
Carcinomas
-An initial treatment for pulmonary
Adenocarcinoma
3.
Erlotinib Locally advanced or metastatic NSCLC
4.
Dasatinib Imatinib-resistant CML
5.
Nilotinib Imatinib-resistant CML
6.
Lapatinib -Front-line therapy in breast cancer
-An adjuvant therapy when patients
have progressed on Herceptin

48. 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

49. 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

50. Colony stimulating factors (CSFs)
•Growth factors that mediate proliferation, maturation,
regulation & activation of hematopoietic cells.
G-CSF: Granulocyte
GM-CSF : Granulocyte & Macrophage lineage
EPO : Erythrocytes
TPO : Platelets

51. 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

52. Erythropoietin
Patients with chronic renal failure
HIV patients treated with zidovudin
Cancer patients treated with chemotherapy

53. 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)

54. Differentiating agents
Tretinoin
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

55. Thalidomide
MOA :
Suppresses TNF-α production
 Reduce expression of proangiogenic factors such as VEGF
& IL-6
Reduces phagocytosis by neutrophils
 Induce NK cells
Use
First-line therapy in Multiple myeloma in combination
with dexamethasone
Myelodysplastic syndrome (MDS)

56. •Adverse effects
Lenalidomide & Pomalidomide approved for use in patients
with primary & refractory Myeloma
Sedation & constipation-
Most common
Peripheral sensory
neuropathy- most serious

57. Proteosome inhibitors
Bortezomib
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

58. 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

59. •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

60. Biosimilars
World Health Organization
“A biotherapeutic product
which is similar in terms of quality, safety &
efficacy to an already licensed reference
biotherapeutic product.”

62. Summary

63. References
•The pharmacological basis of therapeutics(Goodman
and Gillman)12
th
edition
•Basic And Clinical Pharmacology (Katzung) 13
th
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)

64. •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)2
nd
edition
•Pharmacology For MBBS (S K Shrivastava)