BIOLOGICAL AGENTS AS DRUGS

Najmdin Hasan

Jwan M. AhmedHamid S. Alghurabi

Sahar KarimzadehnaminiMohammad H. Alyami

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)

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).

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.

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.

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.

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 (vitamin A)

• Fusion proteins http://www.vettherapeutics.com/

• 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

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.aspxhttp://www.nucmedconsultants.com/tutorials/rit-nhl/zevalin2.htm

Protein kinase inhibitors

Cancer growth blockers, eg. Pazopanib®

Types are:• Tyrosine kinase inhibitors• Proteasome inhibitors• mTOR inhibitors• PI3K inhibitors• Histone deacetylase inhibitors• Hedgehog pathway blokershttp://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/htmlcourse/page3

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

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

Production• It is humanized recombinant monoclonal

antibody

http://cmr.asm.org/content/17/4/926/F1.expansion.html (amended)

Mechanism of action

http://www.angioworld.com/DominiqueGarrel.html (amended)

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

Clinical Studies

http://www.avastin.com/hcp/crc/efficacy/overview/index.html

Established efficacy of Avastin plus IFL in MCRC

Advantages

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

Limitations

• Resistance• Long treatment• Adverse effects and Complications

Current State

• Still under clinical investigation• Eye diseases• Ovarian Cancer• Pediatric Osteosarcoma

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) , β 𝛂*C-Kit tyrosine kinase

- Excellent antiangiogenic, antitumour activity-Synergism with chemotherapeutic drugs•

•

- 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

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

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

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

Mechanism of Action

Sunitinib, Sorafenib and Pazopanib also target other RTKs that may be important for their therapeutic effects

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

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.

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

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

Biologics VS Chemotherapy

• Chemistry.• Mode of action.• Metabolism.• Adverse effects• Route of administration.• Cost

Chemistry

BIOLOGICS

CONVENTIONAL AGENT

• Large molecule(MW >> 1 kDa)

• Genetic technique

• Heat sensitive

• Heterogeneous

• Small molecule (MW < 1 kDa)

• Synthetized chemicals

• Stable

• Homogeneous

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

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

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)

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

Route of administration

BIOLOGICS

CONVENTIONAL AGENT

• Ineffective orally (made of protein)

• Some are effective orally (chemical compound)

Cost

BIOLOGICS

CONVENTIONAL AGENT

• Very Expensive (Produced by advanced Biotechnology)

• Relatively not expensive (prepared by chemical synthesis)

• 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

• 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

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