1. Biological Response Modifiers InBiological Response Modifiers In
TherapeuticsTherapeutics
Guided by
Dr V M Motghare
Professor & head
Department of Pharmacology
G.M.C.H. Nagpur
Dr Ankita Jire
JR
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
7. Some milestones…….
1982 First biotech product (synthetic human insulin)discovered
1986 First monoclonal antibody (mAb) treatment approved
1997 Approval of first mAb-targeted chemotherapy
2002 New 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
2006 First vaccine for the prevention of cervical cancer
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 T1/2
reduce antigenicity
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
20.
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)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
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
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
Recombinant
Natural
Pegylated forms
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
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.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 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
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
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.”
63. 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)
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)2nd
edition
• Pharmacology For MBBS (S K Shrivastava)
Editor's Notes
Observed that many cancer patients recovered after developing postoperative infections. He, thereby, concluded that fever upregulates the immunesystem in cancer patients, which then recognizes and destroys the invading tumor cells
Tnf alpha is oncostatic,causes macrophage activation,proinflammatory
CSFs are growth factors that mediate the proliferation, maturation, regulation, and activation of hematopoieticcells. [19] Generally, CSFs are named after the major cell lineages, which are affected by them; myeloid growthfactors include GMCSF, which affects both granulocyte and macrophage lineage and GCSF, which targets onlygranulocytes; EPO targets erythrocyte production; and TPO is associated with platelet generation
Endogenous erythropoietin is primarily produced in the kidney. In response to tissue hypoxia, more erythropoietin is produced through an increased rate of transcription of the erythropoietin gene. This results in correction of the anemia, provided that the bone marrow response is not impaired by red cell nutritional deficiency (especially iron deficiency), primary bone marrow disorders (see below), or bone marrow suppression from drugs or chronic diseases.
The loss of differentiation is one of the hallmarks of malignancy
RAS-Characterized by fever, peripheral edema, pulmonary opacities, hypoxemia, respiratory distress, hypotension, renal and hepatic dysfunction, rash, and serositis resulting in pleural and pericardial effusions. It is a cytokine release syndrome, sometimes called "cytokine storm," and all of the pathophysiologic consequences result from the release of inflammatory cytokines from malignant promyelocytes, probably independent of their differentiation to segmented neutrophils and hyperleukocytosis.