Biological agents are substances derived from living organisms that are used clinically for disease prevention, diagnosis, and treatment. This document discusses several types of biological agents including monoclonal antibodies, interleukins, interferons, and protein kinase inhibitors. It provides examples of specific drugs, describes their mechanisms of action and clinical applications. While biological agents demonstrate promising results in cancer treatment, their development and production is complex and costs are currently high compared to conventional chemotherapy.

1. Najmdin Hasan
Jwan M. Ahmed
Hamid S. Alghurabi
Sahar Karimzadehnamini
Mohammad H. Alyami

2. Introduction
• A substance produced from a living organisms
or it is derivatives.
• Biological agents/drugs include antibodies,
interleukins, and vaccines.
It is used clinically for:
 Prevention
 Diagnosis
 Treatment of diseases (cancer diseases)
 Control or decrease side effects from other
cancer therapies such as chemotherapy , like
Neupogen (increase WBCs )
Erythropoietin (helps make RBCs)
Interleukin-II ( helps make Platelets)

3. Biological therapy
• New method for cancer treatment.
• Biological therapy helps immune system to
fight cancer.
• chemotherapy attack cancer cells directly.
• biological response modifiers therapy
BRMs(boost, direct, and strengthen the
weakened immune).

4. Edward Jenner (1749-1823) William Coley (1862-1936)
Paul Ehrlich (1854-1915)
Less than 30 years ago, FDA recognised
the use of interferon in the treatment of
hairy-cell leukaemia.
In(1992)IL-2 , and in (1994) IL-12 they
were approved by FDA to treat kidney
cancer and metastatic cancer, respectively.
Inject human with fluid taken from
cow with cowpox, vaccinia.
New York surgeon. Started using
biological therapy for cancer treatment.
German Nobel Prize winner in 1908.

5. General information
• There two types of body defence system.
1. Physical barrier (the skin, mucous
membranes, the lining of the respiratory
tract)
2. Immune system ; works by finding the
foreign organisms or cells and kill,
destroy or deactivate them by specific
process.

6. Immune System Cells
• Lymphocytes (WBCs) major immune cells:
T-cells, B-cells, and NK cells.
T-cells directly attack infected, foreign, or cancerous
cells.
 B-cells secrete antibodies, the proteins that
recognize and attach to foreign substances known as
antigens.
Natural Killer cells produce powerful chemical
substances that bind to and kill any foreign invader.

7. Types of Biological drugs
• Monoclonal antibody
• Interleukins
• Interferon
• Protein kinase inhibitors
• Hematopoietic Growth factors
– GM-CSF eg. Sargaromostim (Leukine® by Immunex)
– G-CSF eg. Filgrastim (Neupogen® by Amgen)
• Retinoid (vitaminA)
• Fusion proteins
http://www.vettherapeutics.com/

8. • Immunoglobulin, hormones,
enzymes and growth factors.
• Cytokine antagonists (anti
inflammatory)
• Vaccines
– traditional vaccines
– cancer vaccines
• To prevent cancer eg.HPV vaccine
• To help treat cancer eg. Sipuleucel-T
(Provenge®)
http://www.smi-online.co.uk/pharmaceuticals/uk/cancer-vaccines?utm_source=P-
042&utm_medium=BenthamScience&utm_campaign=WebBanner
Types of Biological drugs

9. Monoclonal antibody
Single type of antibody, eg.
Avastin®
• Unconjugated antibodies
• Conjugated antibody
• Radioimmunotherapy
– Carrier for β-emitting isotope
http://www.lonza.com/custom-manufacturing/chemical-manufacturing/antibody-drug-conjugates-adcs.aspx
http://www.nucmedconsultants.com/tutorials/rit-nhl/zevalin2.htm

10. Protein kinase inhibitors
Cancer growth blockers, eg.
Pazopanib®
Types are:
• Tyrosine kinase inhibitors
• Proteasome inhibitors
• mTOR inhibitors
• PI3K inhibitors
• Histone deacetylase inhibitors
• Hedgehog pathway blokers
http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/htmlcourse/page3

11. Interferons
• Interferon-α
– Rofeon-A® by Roch Lab,
Wellferon® by Glaxo Wellcome
Inc
• Interferon-β
– Betaseron® by Berlex
Laboratories.
• Interferon-ɤ
– Actimmune® by InterMune
Pharmaceuticals Inc.
http://srxawordonhealth.com/category/hepatitis-c/
http://blog.lef.org/2012/01/hormones-that-boost-immune-system.html

12. Bevacizumab
• Bevacizumab (avastin®) is a drug made by
company Genentech.
• It and was approved by the FDA for the
treatment of:
Metastatic Colorectal Cancer (2004)Non-Small Cell Lung Cancer (2006)Glioblastoma (2009)Metastatic Renal Cell Carcinoma (2009)Metastatic HER2-negative breast cancer (2008).
http://cvs.com/search/_/N-3nZ2i?searchTerm=protein+supplements&pt=drug&navNum=40http://www.avastin.com/hcp/crc/index.htmlhttp://www.avastin.com/hcp/lung/index.htmlhttp://www.avastin.com/hcp/gbm/index.htmlhttp://www.avastin.com/hcp/kidney/index.html

13. Production
• It is humanized recombinant monoclonal
antibody
http://cmr.asm.org/content/17/4/926/F1.expansion.html (amended)

14. Mechanism of action
http://www.angioworld.com/DominiqueGarrel.html (amended)

15. http://www.wjgnet.com/2218-4333/full/v2/i2/WJCO-2-125-g013.htm

16. Clinical Studies
http://www.avastin.com/hcp/crc/efficacy/overview/index.html
EstablishedefficacyofAvastinplusIFLinMCRC

17. Advantages
• Broad Spectrum
• Long half-life
• Relatively less side effects & Toxicity

18. Limitations
• Resistance
• Long treatment
• Adverse effects and Complications

19. Current State
• Still under clinical investigation
• Eye diseases
• Ovarian Cancer
• Pediatric Osteosarcoma

20. Pazopanib (Votreint)
•Drug Properties:
-A second-generation multitargeted tyrosin kinase
inhibitor (RTKs):
- Indazolylpyrimidine
*Vascular endothelial growth factor receptor (VEGFR)-1,-2 and -3
*Platelet-derived growth factor receptor (PDGFR)𝛂, β
*C-Kit tyrosine kinase
- Excellent antiangiogenic, antitumour activity
-Synergism with chemotherapeutic drugs
•

21. - Renal cell carcinoma (RCC)
- Immunotherapy until 2005, 6 new
treatment; 3 kinase inhibitors:
Sorafenib, Sunitinib and Pazopanib
*2009 by FDA
*June 2010 by EMA (European
Medicines Agency)
Adopted from: Jie, J.L., Douglas, S.J.,(2010) Modern Drug Synthesis

22. Advanced soft tissue sarcoma
*April 2012 by FDA
-Phase II or III for:
Breast, lung, cervical, liver, thyroid
prostate and colorectal cancer
http://www.charonboat.com/2009/02/charonboat_dot_com_sarcoma1.jpg

23. (Adopted from: Li, Y., et al., 2011)
-Synergistic efficacy with docetaxel in D-resistance bladder cancer cells.

24. Rational for targeting
VEGF and PDGF in RCC:
• Proliferation and survival cancer cells
• of cancer cellsLoss of function of the von
Hippel-Lindau tumour gene
• Accumulation of hypoxia-inducible
factor(HIF)
• Upregulation of VEGF and PDGF

25. Mechanism of Action
Sunitinib, Sorafenib and Pazopanib also target other RTKs that may
be important for their therapeutic effects

26. Preclinical Activity
• Orally administered, 800 mg per day
• In vitro inhibitory concentration (IC50) of 10, 30 and 47nm(VEGFR-1,-2,-
3 respectively)
• In vitro inhibited with an IC50 of 7 nm treatment of HUVEC, Selectively
inhibited VEGF-induced proliferation of HUVEC IC50=21 nm
• Greater than 1400-fold selective activity against tumour cells
• Greater than 48-fold against fibroblasts
• Anti tumour efficacy:Prostate, colon, lung, melanoma, head and neck
• Excellent in vivo inhibition in mice with Matrigel plug and corneal
micropocket assays
• Good oral exposure in both mice and dog and 49% oral bioavailabilty in
dogs

27. Clinical trial
• Phase I: Dose-escalation study, 56 patients
enrolled in VEG10003 (50mg 3 times a week t0
2000 mg daily)
• Phase II: Randomized discontinuation
design trial, 160 to 230 patients VEG102616
• Phase III: Randomized, placebo-controlled,
multicancer, international trial, 350 patients
( advanced RCC), 800 mg once daily or
placebo.

28. Clinical data (Safety and efficacy)
• Randomized, double-blind, placebo-controlled trial
• 435 patients who recieved either no prior or one prior
cytokine-besed systemic therapy
• All patients had clear cell histology(90%) or
predominantly clear-cell histology(10%) and similar
porportions had prior nephrectomy
• Randomized to recieve Placebo or Propanotib
• Primary end point: Progression free-survival(PFS)
• Median PFS Pazopanib 9.2 month
• placebo group 4.2 month

29. Side effects
• Different toxicity profile :
• decrease in the overall frequency of chronic
fatigue, cardiac disease
• Increasing the frequency of hepatic toxicity
and hypertension
• Cardiovascular side effects

30. Biologics VS Chemotherapy
• Chemistry.
• Mode of action.
• Metabolism.
• Adverse effects
• Route of administration.
• Cost

31. Chemistry
BIOLOGICS CONVENTIONAL
AGENT
• Large
molecule(MW >> 1 kDa)
• Genetic technique
• Heat sensitive
• Heterogeneous
• Small molecule
(MW < 1 kDa)
• Synthetized chemicals
• Stable
• Homogeneous

32. Mode of action
BIOLOGICS CONVENTIONAL
AGENT
• Helps the immune system
fight cancer.
• Non linear dose-response
• Biological effect
• Attacks the cancer cells
directly.
• Linear dose–response
• Pharmacological effect

33. Metabolism
BIOLOGICS CONVENTIONAL
AGENT
• Cytochrome P450
Independent
• Catabolized to
endogenous amino acids
• Most of them have a high
half-life
• Cytochrome P450
involvement.
• Metabolized to active
and inactive products
• Half-life vary, relatively
lower half-life

34. Adverse effect
Classification of adverse effects of biological agents.
TYPE α Reactions related to cytokine and cytokine released
syndrome.
TYPE β Reactions include both immediate and delayed
hypersensitivity reactions.
TYPE γ Reactions are related to immune imbalance syndrome.
TYPE δ Cross-reactions related to the expression of the same
antigen on different tissue.
TYPE ε Reactions are non-immunological side-effects (new and
original unexpected functions of biological agent)

35. Adverse effects induced by Traditional agents
Type A Pharmacological activity of the drug
Type B Immune-mediated and are thus not predictable
Type C AND D Short and long term toxicities
Type E withdrawal of the drug
Adverse effect

36. Route of administration
BIOLOGICS CONVENTIONAL
AGENT
• Ineffective orally (made
of protein)
• Some are effective orally
(chemical compound)

37. Cost
BIOLOGICS CONVENTIONAL
AGENT
• Very Expensive
(Produced by advanced
Biotechnology)
• Relatively not expensive
(prepared by chemical
synthesis)

38. • Biological agents have a potential with a
promising results (they are of high interest
now especially in Oncology)
• Provide better response with fewer side effects
(have an accurate targeting)
• Powerful Supplement with chemotherapy
Conclusion

39. • The cost is high (but it will be cheaper in the
future when these drugs are produced in
abundance)
• Currently, many of these drugs are produced
and tested in clinical trials (but the problem is
that they take years being tested in clinical
trials to gain their approval by the FDA for
different indications)
Conclusion

40. References
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