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Dr. M G Azam Asstt. Professor Dept. of Pharmacy, NSU

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1 Dr. M G Azam Asstt. Professor Dept. of Pharmacy, NSU
Advanced Pharmacology-I (PHR5001) Lecture 12: Anti-ulcer Agents (H2 receptor antagonists) Ulcer is a break in skin or mucous membrane with loss of surface tissue, disintegration and necrosis of epithelial tissue Dr. M G Azam Asstt. Professor Dept. of Pharmacy, NSU

2 Introduction Definition: Anti-ulcer (Antisecretory) agents are the drugs which decreases the secretion of gastric acid in the stomach. Histamine - Powerful stimulant of Hydrochloric acid secretion from parietal (oxyntic)cells of gastric mucosa. Histamine (In larger dose )- increase secretion of pepsin. These actions are mediated by H2-receptor. The secretion of acid by these parietal cells are regulated by various mediators or receptors. Histamine H2 receptors G receptors-release gastrin & release gastric acid Acetylcholine (Ach) M3 receptor Histamine receptor on parietal cells: Autonomic system: food stimulates gastrin release, gastrin stimulates ECL cells, stimulates histamine release, histamine stimulates parietal cells secretion of HCl

3 What is Peptic Ulcer ? A peptic ulcer disease or PUD is an ulcer (defined as mucosal erosions ≥ 0.5 cm) of an area of the gastrointestinal tract exposed to the acid and pepsin secretion Gastritis is the precursor to PUD and it is clinically difficult to differentiate the two Stomach (called gastric ulcer): Relieved by food but pain may persist even after eating. Infrequent or absent remissions (>55 yrs) Duodenum (called duodenal ulcer): burning upper abdomen pain relieved by food but reappears 1-3 hrs after meals. Worse pain when stomach empty Esophagus (called Esophageal ulcer) Infection with Helicobacter pylori (a spiral-shaped gram-negative bacillus) is the leading cause of PUD (& associated with ulcers not induced by NSAIDs. H pylori colonize deep layers of mucosal gel that coats gastric mucosa and disrupts its protective properties. Causes of ulcers: Hypersecretion of acid and pepsin and GI infection of gm-ve bacteria H. Pylori. Stress, alcohol, ulcerogenic drugs (e.g. NSAIDs), male genders, age, & diet

4 Why Ulceration Occurs? High [H+] in the gastric lumen
Require defense mechanisms to protect oesophagus and stomach Mucus secretion: slows ion diffusion Prostaglandins: I2 and E2 (alcohol, aspirin ) Bicabonate ions High Blood Flow (nitric oxide) Imbalance primarily between Aggressive factors & Defensive factors: Defensive factors, e.g. mucus, HCO3, PG What may contribute imbalance ? Helicobacter pylori NSAIDs, Steroids (Glucocorticoids), Cytotoxic agents, Ethanol, Tobacco Severe physiologic stress (Burns, CNS trauma, Surgery, Severe medical illness Aggressive factors, e,g, acid, pepsin, bile etc.

5 Gastroesophageal Reflux Disease (GERD)
Common and GI motility disorder Acidity of Gastric contents – most common factor Acid contents reflux back into esophagus Intense burning, sometimes belching Can lead to esophagitis, and esophageal ulcers Barrett’s esophagus (A complication of severe chronic GERD involving changes in the cells of the tissue that line the bottom of the esophagus. These esophageal cells become irritated when the contents of the stomach back up (refluxes) and there is a small but definite increased risk of adenocarcinoma of the esophagus.) Commonly associated with obesity Improves with lifestyle management 5

6 Physiology of Acid Secretion
Gastric acid secretion is a complex, continuous process controlled by multiple central (neural) and peripheral (endocrine and paracrine) factors. Each factor attributes to a common physiological event-the secretion of H+ by parietal cell, which are located in the body and fundus of the stomach Neuronal(Ach), paracrine(histamine) and endocrine(gastric) factors all play important roles in the regulation of acid secretion. Their respective specific receptors (M3,H2,CCK2 receptor) have been automatically and/or pharmacologically localized to the baso lateral membrane of the parietal cell. Two major signaling pathways are present within the parietal cell.  I) the CAMP-dependent pathway and the ii) Ca2+dependent pathway. Schematic diagram the physiologic control of hydrogen ion secretion by the gastric parietal cell. ECL (enterochromaffin-like) cell; G(CCK-B), gastrin-cholecystokinin-B receptor; H, histamin; M1, M3, muscarinic receptors; ST2, somatostatin-2 receptor; ATPase, H+/K+ ATPase proton pump.

7 Histamine uses the CAMP pathway whereas gastrin and Ach uses Ca2+ dependent pathway. Both pathway activates the H+/K+ ATPase. Ach release from postganglionic vagal fibres can stimulate directly gastric acid secretion though M3 (a specific muscarnic cholinergic receptor subtype). Ach. also indirectly affects the parietal cells though the stimulation of histamine release from the entrochromaffin-like cells in the fundus and the stimulation of gastric release from G cells in the gastric antrum. Histamine is released from ECL cells through the multifactorial pathway and is critical regulator of acid production through the H2 sub type of receptor. The release of gastric is regulated through the multifactorial pathway and it stimulates acid secretion predominantly in an indirect manner by causing the release of histamine from ECL cells; a direct effect of gastric or parietal cell is also seen but is less important. Prostaglandins E2 and I2 inhibit acid, stimulates mucous and bicarbonate secretion and dilate blood vessel. The mucous and the bicarbonate from an unstirred gel like layer protecting the mucosa from the gastric juice. Alcohol and bile can disrupt this layer. Locally produced prostaglandins stimulate the secretion of both mucous and bicarbonate

8 Mechanism The parietal cell contains receptors for gastrin, histamine (H2), and acetylcholine (muscarinic, M3). When acetylcholine or gastrin bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+/K+ ATPase (the proton pump) on the canalicular surface In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells have receptors for gastrin and acetylcholine and are the major source for histamine release. Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP). cAMP activates protein kinases that stimulate acid secretion by the H+/K+ ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation.

9 Comparison H1 receptor antagonist H2 receptor antagonist
Imidazole or other 5 membered heterocyclic ring (Imidazole is not necessary) Connecting chain of ring and terminal nitrogen is of 4 atoms Polar π e containing systems, amphoteric, unionized at pH 7.4 Hydrophobic (due to polar grp). Low partition coefficient High dipole moment Two aryl, heteroaryl rings in place of imidazole (bulky groups) Connecting chain of aryl and terminal nitrogen is of 2 to 3 atoms Ionic flexible chain at end. Ionized at pH 7.4 Hydrophobic (due to aryl rings). High partition coefficient value Low dipole moment

10 Treatment of ulcer H2 receptor antagonists are the most popular drug for the treatment of peptic ulcer. H2 receptor antagonists Must bind but not activate H2 receptor site They bring about sympathomimetic relief and promote ulcer healing. Gastric acid secretion involve H2 receptor which is competitively blocked by H2 blockers. In 1972, Black and co-workers first described selective H2 receptor blokade for acid secretion. With successful introduction of cimetidine, in 1977 other analogs like ranitidine, famotidine & roxatidine has been synthesized. Addition of a functional group to bind with another binding region and prevent the conformational change Addition of aromatic ring: unsuccessful Addition of non-polar, hydrophobic substituents, none antagonists, but

11 Historical development

12 (Famotidine) groups on ring showed better activity.
Ranitidine Replace imidazole ring with furan ring: 10x more active than Cimetidine Famotidine 30x more active than cimetidine Imidazole ring replaced by various Nitrogen containing heterocyclic ring to optimize the activity. Furan (Ranitidine) & thiazole (Nizatidine) showed good activity. Substitution in side chain with different basic as well as neutral groups were carried out like nitroamine ketene (Ranitidine) & sulfonylamidine (Famotidine) for better activity. Substitution of dimethyl amino methyl (Ranitidine & Nizatidine) and amidine (Famotidine) groups on ring showed better activity.

13 H2 receptor antagonists

14 Classification of Anti-ulcer Drugs
Gastric Antisecretory Drugs HCl secretion Antagonize Rs. on Parietal Cell--- H2,M3, G Inhibitor of H+-Pump II. Antacids--- Neutralizations of secreted acid and pepsin activity III. Agents kill HP : Eradication of Helicobacter pylori by triple therapy: Almost all duodenal and 2/3 gastric ulcer pt’s infected with HP Therapy is directed at enhancing host defense or eliminating aggressive factors; i.e., H. pylori. II. Antimuscarinic drugs eg. pirenzipine IV. Cytoprotection eg. Bismuths compounds. Omeprazole / Lansoprazole / 30 mg bd Clarithromycin mg bd Amoxycillin / Metronidazole gm / 500 mg bd Given for 14 days

15 Ranitidine Proglumide Ca++ Ca++
HCl & pepsin Misoprostol Ranitidine Probanthine Pirenzepine Gastrin PGE2 Histamine _ + Proglumide ACh _ Compete Gastrin-R _ H2 M3 Adenyl cyclase + Gastrin receptor PGE receptor + + Ca++ ATP cAMP Ca++ + + + Protein Kinase (Activated) Derivatives of Prostaglandin: Misoprostol (PGE1), Enprostil Mucus-HCO3- increase ; Cytoprotective effect Pharmacologic Effects: Prevention of ulcers iduced by NSAIDs K+ H+ + K Parietal cell Proton pump _ Lumen of stomach Omeprazole _ Gastric acid Antacid

16 Classification of Anti-ulcer Drugs
Reduction in Gastric acid secretion: H2 antihistamines: Cimetidine, Ranitidine, Famotidine, Nizatidine and Roxatidine Proton pump inhibitors: Omeprazole, Lansoprazole Pantoprazole, Rabeprazole and Esomeprazole Anticholinergics: Pirenzepine, Propantheline and Oxyphenonium Prostaglandin analogue: Misoprostol 2. Acid Neutralizing agents: (ANTACIDS) Systemic: Sodium Bicarbonate and Sod. Citrate Nonsystemic: Magnesium hydroxide, Mag. Treisilicate, Aluminium hydroxide gel, Magaldrate and calcium carbonate Ulcer protectives: Sucralfate, Colloidal Bismuth sudcitrate Anti-H. pylori Drugs: Amoxicillin, Clarithromycin, metronidazole, tinidazole and tetracycline

17 H2 Antagonists Adverse Effect: MOA:
Cimetidine, Ranitidine, Famotidine, Roxatidine, Nizatidine MOA: Reversible competitive inhibitors of H2 receptor Highly selective, no action on H1 or H3 receptors All phases of gastric acid secretion Very effective in inhibiting nocturnal acid secretion (as it depends largely on Histamine ) Modest impact on meal stimulated acid secretion (as it depends on gastrin, acetylcholine and histamine) Volume of pepsin content and IF are also reduced Volume reduced by 60 – 70% - anti ulcerogenic effect Promote the healing of gastric (50 to 75%) and duodenal ulcers (70 to 90%) Kinetics: Bioavailability upto 80 % Absorption is not interfered by presence of food Can cross placental barrier and reaches milk Poor CNS penetration 2/3rd of the drugs are excreted unchanged in bile and urine Adverse Effect: Gynecomastia, prolactin , CYP , headache

18 Proton Pump Inhibitors
Most effective drugs in antiulcer therapy Prodrugs requiring activation in acidic pH. Block enzymes responsible for secreting HCl - binds irreversibly to H+K+ATPase Prototype: Omeprazole Omeprazole Substituted Benzimidazole derivative Diffuses into G. canaliculi = accumulation pH < 5 (proton catalyzed )= tetracyclic sulfenamide + sulphenic acid Covalent binding with sulfhydryl cysteines of H⁺K⁺ ATPase Irreversible inactivation of the pump molecule Acid suppressants regardless of stimulating factors Also inhibits gastric mucosal carbonic anhydrase H+/K+ ATPase F-ATPase: in mitocondria and chloroplasts; make ATP with proton gradient V-ATPase: (vacuolar) hydrolyze ATP to generate electrochemical gradient “Proton-Pump”

1. H2 –histamine receptor antagonist eg. Ranitidine,Cimetidine,Famotidine, Nizatidine - Peptic ulcer (Gastric ulcer and duodenal ulcer) - Reflex oesophagitis 2. Proton Pump Inhibitor : Omeprazole Lansoprazole, Esomeprazole,Rabeprazole,Pantoprazole - Peptic ulcer - As one component Of therapy for H-pylori infection - Zollinger-Ellison syndrome 3. Antacid eg. Mg-trisillicate, Al-hydroxide alginates - Dyspepsia - Symptomatic relief of peptic ulcer - Esophageal reflex 4. Bismuth chelate -One component of therapy for H-pylori infection. Proton pump inhibitors are considered superior for acid suppression in most clinically significant acid-peptic diseases, including gastroesophageal reflux disease, peptic ulcers, and NSAID-induced ulcers. Proton pump inhibitors also are employed in combination with antibiotics to eradicate infection with H. pylori and thereby play a role in preventing recurrent peptic ulcers.

20 Screening methods:- Pyloric ligation induced gastric ulceration
2. Ethanol induced mucosal damage in rats 3. Stress ulcer through immobilization stress Lower & upper extremities fixed, wrapped in a wire gaze, kept at dark for 24 hr. 4. Indomethacin induced ulcers in rats After 10 min of admistering 20 mg/kg indomethacin, test drug is given orally. 6hr later , sacrifice in co2 , stomach is removed.

21 Pyloric ligation induced gastric ulceration
After 1h of treatment with test or std. (Ranitidine 50 mg/kg) , animals are anaesthetized with the help of anesthetic ether; the abdomen is opened by a small midline incision. Pyloric portion of the stomach is slightly lifted out and ligated. The stomach is replaced carefully and the abdominal wall is closed by interrupted sutures. Rats are sacrificed by an over dose of anaesthetic ether after four hours of pyloric ligation. Abdomen is opened and ligature is placed around esophagus. Stomach is removed and contents are drained to centrifuge tube. The volume of the gastric juice is measured and centrifuged at 2000 rpm for 10 min. From the supernatant, aliquots (1 ml of each) are taken for the determination of pH, total and free acidity. Each stomach is examined (by a 10Χ magnifier lens) for lesions in the fore stomach portion & indexed according to severity. Normal colored stomach (0) Red coloration (0.5) Spot ulcer (1) Hemorrhagic streak... (1.5) Deep Ulcers (2) Perforation (3) Mean ulcer score for each animal will be expressed as ulcer index. The causes of gastric ulcer pyloric ligation are believed to be due to stress induced increase in gastric hydrochloric acid secretion and/or stasis of acid and the volume of secretion is also an important factor in the formation of ulcer due to exposure of the unprotected lumen of the stomach to the accumulating acid. Pylorus ligation induced ulcers are due to auto digestion of the gastric mucosa and breakdown of the gastric mucosal barrier. These factors are associated with the development of upper gastrointestinal damage including lesions, ulcers. 0 - no ulcer, spot ulcer, 2 - deep ulcer, 3 - perforation % Inhibition of Ulceration =

22 Ethanol induced ulcer model
The ulcer is induced by administering ethanol to Albino rats (fasted for 36 h). One group represented the control group, which received ethanol Second & Third Groups received methanolic extract of A. Indicum 250 and 500 mg/kg and, Ranitidine, in the dose of 50 mg/kg were administered orally for Four group as reference standard drug. The gastric ulcers were induced in rats by administrating absolute ethanol (90%) (0.5 ml/100g) orally, after 45 min of methanolic extract and ranitidine treatment. They were kept in specially constructed cages to prevent coprophagia during and after the experiment. The animals were anaesthetized 1h latter with anaesthetic ether and stomach was incised along the greater curvature and ulceration will be scored A score for the ulcer is study similar to pyloric ligation induced ulcer model. Ethanol induced gastric lesion formation may be due to stasis in gastric blood flow which contributes to the development of the haemorrhage and necrotic aspects of tissue injury. Alcohol rapidly penetrates the gastric mucosa apparently causing cell and plasma membrane damage leading to increased intra cellular membrane permeability to sodium and water. The massive intracellular accumulation of calcium represents a major step in the pathogenesis of gastric mucosal injury. This leads to cell death and exfoliation in the surface epithelium.

23 Dr. M G Azam Asstt. Professor Dept. of Pharmacy, NSU
Advanced Pharmacology-I (PHR5001) Lecture 13: MONOCLONAL ANTIBODIES AS THERAPEUTIC AGENTS Introduction Types of monoclonal antibodies Production of mAbs Therapeutic applications: Discovery of their innate properties hinted at great therapeutic potential: High-specificity in binding Already present in the body Can activate and couple components of the immune system Modification to structure and refinement in production methods have made antibodies a viable modern drug Dr. M G Azam Asstt. Professor Dept. of Pharmacy, NSU

24 M/A: Blocking action of molecular targets:
Antibody is a class of immunological proteins (globular glycoproteins/ “Immunoglobulin” produced by plasma cells (B lymphocytes) in response to a specific antigen. Antibodies function as markers, binding to the antigen so that the antigen molecules can be recognized and destroyed by phagocytes. The part of the antigen that the antibody binds to is called the epitope. The epitope is thus a short amino acid sequence that the antibody is able to recognize. Antibodies are useful tools for the immune system to combat pathogens. Antibodies have 2 major functions: 1. Recognize and bind antigen 2. Induce immune responses after binding Antigen (antibody generator) –Antigen is any foreign agent that is recognized by the immune system and antibodies produced against to destroy it. mAbs have identical paratopes (region of the antibody that binds the epitope). Epitope – region of the antigen recognized by an antibody. M/A: Blocking action of molecular targets: Can work antagonistically by binding a receptor to prevent activation Can also bind the antigen and prevent activation

25 Polyclonal Abs * Used in Mixture of antibodies similar to sera
MONOCLONAL ANTIBODIES (Mab) An antibody produced by a single clone of cells. monoclonal antibody is a single pure type of antibody. MAbs are identical. They are directed toward same epitope. So more efficient and specific. * Used in Biomedical research Diagnosis of diseases Treatment of diseases such as infection, cancer, etc. Polyclonal Abs Monoclonal antibodies permit diagnostic tests that are specific, and function as probes. A monoclonal antibody is the result of a single B-cell - cancer-cell fusion, that is grown up into a clonal population (thus mono-clonal). have identical idiotype/specificity (it is lots of one antibody). Georg Kohler and Cesar Milstein fuse mouse lymphocytes with neoplastic mouse plasma cells to yield hybridomas that produce specific antibodies. Monoclonal antibodies were produced in mice using a technique described by Köhler and Milstein et al..They were awarded the Nobel Prize in 1984 (along with Jerne) for their work. PAb: Antibody molecules which differ in their epitope binding and complementarity region amino acid sequence, however share overall target specificity. Polyclonal antibodies are a mixture of antibodies with different antigen binding sites that may bind to different epitopes or antigens of the immunizing agent with varying affinities. They may be of different antibody classes. The serum obtained from an immunized animal is referred to as a polyclonal antiserum. Mixture of antibodies similar to sera Antibodies that are obtained from different B cell resources. They are a combination of immunoglobulin molecules secreted against a specific antigen, each identifying a different epitope.

26 Structure of antibody Consist of four polypeptide chains, somewhat resembling to a Y shape. i) 2 identical Light chains ( L chains) ii) 2 identical Heavy chains ( H chains) Disulphide bonds hold 4 polypeptide chains Ig domain: 110 amino acids; globular domain used in many proteins. Variable domains, Constant domains, Hinge. Fab: fragment antigen binding Fc: fragment crystallizable (effector functions) The variable region mediates binding Affinity for a given antigen is determined by the variable region The variable region confers absolute specificity for an antigen The constant region mediates immune response after binding Different classes of constant regions generate different isotypes Different isotypes of antibody have differing properties CDR: Complementarity-Determining Regions

27 Heavy Chain Diagram Distribution IgA α or IgD δ IgE ε IgG γ IgM μ
Immunoglobulin (Ig) Class Heavy Chain Diagram Distribution IgA α or External Secretions IgD δ B Cell surface receptor IgE ε Cells that secrete histamines IgG γ Main antibody in serum Most Stable IgM μ First antibody secreted in development

28 Production of Monoclonal Antibodies
A mouse is immunized with the specific antigen“X”. This will allow the mouse to produce antibodies. The spleen cells producing specific antibodies are removed. Fusion of spleen cells with tumor cells (myeloma cells) in a culture medium is done. The resulting cell is called a hybridoma. Hybridoma cells are continuously growing cell line. Each hybridoma will produce relatively large quantities of monoclonal antibody molecules. These hybridomas have antibody producing capability from lymphocytes & have ability to grow continuously (immortal) from malignant cells. Separate the hybridomas from unfused cells. Culture selected hybridoma cells for the production of monoclonal antibodies in large quantity. Remain indefinitely and maintained by in vitro; that is, in culture vessels or in vivo-in the body of an animal so that antibodies will be produced in body and can be recovered later from body fluid. First, a mouse is inoculated with the antigen to which the MA are to be produced. After this, the spleen is removed and fused with myeloma cells in order to produce the hybridomas that will be selected according to the antibody produced. Grow in culture in HAT (Hypoxanthine aminopterin thymidine) medium that work in presence of Hypoxanthine Guanine PhosphoRibosyl Transferase (HGPRT) and screened the hybridomas producing specific antibodies. Only one in several hundred cell hybrids will produce antibodies of the desired specificity. Because of immortality hybridoma cells may be frozen for future use.

29 Pioneered by Georges Kohler and Cesar Milstein in 1975
Pioneered by Georges Kohler and Cesar Milstein in Method of production of antibodies is called as somatic cell hybridization. Monoclonal Antibody is produced by cell lines or clones obtained from the immunized animals with the substance to be studied. Cell lines are produced by fusing B cells from the immunized animal with myeloma cells (cancer producing cells).

30 Purification of monoclonal antibody :
Affinity chromatography is used for purification of mAbs. This method separates molecules on their differing affinities for a ligand. Antigen can be bound to the support matrix (small, chemically reactive beads) in order to purify antigen-specific antibody from a polyclonal antiserum. Specific antibody is eluted by altering the pH, which disrupt antibody-antigen bonds.

31 Application of monoclonal antibody :
1. Research tools: Identification of cell surface marker Purification of proteins and enzymes Detection assays Genetic engineering Structure of cell membrane Sufix of Antibody Human: -umab Humanized: -zumab Murine: -momab Chimeric: -ximab 2. Clinical diagnosis: Some monoclonal antibodies have been introduced into human medicine to suppress the immune system. e.g Muromonab-CD3 (OKT3) and two humanized anti-CD3 monoclonals. Bind to the CD3 molecule on the surface of T cells. Used to prevent acute rejection of organ, e.g., kidney, transplants. (Transweb, 1996). Cancers Leukemia Viral disease Allergic reaction AIDS 3. Treatment of diseases:

32 Diagnostic tests Monoclonal antibodies are widely used as diagnostic and research reagents. Once monoclonal antibodies for a given substance have been produced, they can be used to detect the presence of this substance. The Western blot test detect the protein on a membrane. Monoclonal antibodies can also be used to purify a substance with techniques called affinity chromatography. Other monoclonal antibodies allow rapid diagnosis of hepatitis, influenza, herpes and streptococcal infections. Antibodies are used in several diagnostic tests to detect small amounts of drugs, toxins or hormones. Monoclonal Antibodies also used in ELISA (enzyme linked immunosorbant Assay) for detection of viruses. Standardized, unlimited amounts of reagents for diagnosis or therapy (human antibodies or “humanized” antibodies can be made).

33 Monoclonal antibody in cancer therapy:
By means of genetic engineering, so-called chimeric antibodies are prepared that contain both human and mouse sections. The mouse section is located in the variable region of the antibody that contains the antigen- binding site, while the human section is in the constant region. After the variable region binds to the cancer antigen, the human section activates complement and cytotoxic T cells to destroy the cancer cell. Antibodies are used in the radioimmunodetection and radioimmunotherapy of cancer, and some new methods can even target only the cell membranes of cancerous cells Naked mAbs: Without any drugs, radioactive materials or toxins. B. Conjugated mAbs: They are combined with chemotherapy drugs (Chemolabeled Ab) or radioactive material or toxins (Immunotoxin)

34 Antibody-directed enzyme prodrug therapy (ADEPT)
Antibody-directed enzyme prodrug therapy (ADEPT). Immunoliposomes are antibody-conjugated liposomes. Liposomes can carry drugs or therapeutic nucleotides and when conjugated with monoclonal antibodies, may be directed against malignant cells. Radioimmunotherapy (RIT) involves the use of radioactively conjugated murine antibodies against cellular antigens. Most research currently involved their application to lymphomas,

35 Make the cancer cell more visible to the immune system
When a monoclonal antibody attaches to a cancer cell, it can: Make the cancer cell more visible to the immune system Block growth signals Deliver radiation to cancer cells. Slip powerful drugs into cancer cells

36 mAbs as antitumor agents
Trastuzumab is effective only in cancers where HER2 is over-expressed. After binding to HER2, the Mab causes an increase in p27, a protein that halts cell proliferation. Another MAb, Pertuzumab, which inhibits dimerization of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012 Trastuzumab HER2 (Human Epidermal Growth Factor Receptor 2) also known as CD340 (cluster of differentiation340) /p185 is a protein that in humans is encoded by the ERBB2 gene. Amplification or over-expression of this gene has been shown to play an important role in the pathogenesis and progression of certain aggressive types of breast cancer

37 Antitumor therapy Antibody Target Treatment(s) Trastuzumab HER2
Approved in Trastuzumab HER2 Breast cancer & lymphomas 1998 Rituximab CD20 B cell lymphomas 1997 Tositumomab 2003 Alemtuzumab CD52 Chronic lymphocytic leukemia 2001 Bevacizumab Vascular endothelial growth factor Colorectal cancer 2004 Cetuximab Epidermal growth factor receptor Panitumumab EGF receptor Gemtuzumab CD33 Acute myelogenous leukemia 2000 Ibritumomab Non Hodgkin lymphoma 2002 Today, 20 therapeutic mAbs are on the market in the US. However, an estimated 500 antibody-based therapies are currently under development B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase (CD45R+, CD117+) and progressively increasing in concentration until maturity

38 Rituximab Pharmacology and M/A
Rituxan is the first MAb approved in 1997 by FDA. Chimeric MAb that binds to the antigen CD20 found on B-lymphocytes (normal B cell and most malignant B cells). CD20 is involved in cell cycle initiation, regulation and differentiation by activation of B-cells from the G0 to G1 phase. It also operates as a calcium channel. Used in low, intermediate and high grade lymphomas/Non-Hodgkin Lymphoma (NHL) (in combination with cyclophosphamide, doxorubicin, vincristine and prednisone). It can also be given with radioimmunotherapy given directly to the tumor site M/A: Rituximab causes CD20-positive cell death by antibody dependent cell-mediated cytotoxicity, direct effects via CD20 ligation, and complement-mediated lysis. B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells. Alemtuzumab: binds to CD52 antigenic sites and triggers complement–dependent cellular cytotoxicity or antibody-dependent cellular toxicity and direct cellular apoptosis via NK activity. Rise in Alemtuzumab concentrations corresponds to a simultaneous decline in circulating CD52-positive malignant lymphocytes. This exhibits target-mediated drug disposition. FDA approves for use in B-cell CLL patients treated with alkylating agents and failed fludarabine therapy.12-wks or 16 wks iv or sc administration of 30mg thrice weekly can be given. The anti-CD20 mAB Ofatumumab (Genmab) was approved by FDA in Oct 2009 for Chronic lymphocytic leukemia. Additional anti-CD20 antibody therapeutics under development (phase II or III clinical trials in 2008) include : AME-133v (by Applied Molecular Evolution), IMMU-106 (veltuzumab).

39 Therapeutic agents: Antibody Target Treatment(s) Other uses
Supportive Care OTK3 (muromonab-CD3) T-cell CD3 receptor Transplant Rejection Daclizumab IL2 Receptor Infliximab TNF α Rheumatoid arthritis Omalizumab Ig E Allergy related Asthma Natalizumab T cell VLA4 receptor Multiple sclerosis therapy Adalimumab Inflammatory diseases Basiliximab Today, 20 therapeutic mAbs are on the market in the US. However, an estimated 500 antibody-based therapies are currently under development The monoclonal anti-T cell antibody OKT3, used to treat severe acute rejection, has fallen into disfavor, as it commonly brings severe cytokine release syndrome and late post-transplant lymphoproliferative disorder Other uses Abciximab Glycoprotein IIb/IIIa Antiplatelet/Thrombosis Efalizumab CD11a Psoriasis Palivizumab An epitope of F protein of RSV Respiratory Syncytial Virus

40 Tissue transplantation
Muromonoab-CD3: Muromonoab-CD3 is used for the treatment of acute organ transplant rejection. It is effective in preventing graft rejection after kidney, heart or liver transplantation. Muromonoab-CD3 is effective in patients who after acute cardiac or liver allograft rejection do not respond to steroid therapy. CD3 (cluster of differentiation 3) T-cell co-receptor is a protein complex and is composed of four distinct chains. These chains associate with a molecule known as the T-cell receptor (TCR)

41 Infliximab (Remicade- J & J):
It is a chimeric monoclonal antibody produced by recombinant DNA technology and is directed against TNF-α. It is composed of human constant and mouse variable regions. Infliximab binds to the soluble and the membrane bound form of TNFα, resulting in the neutralization of its biological activity. Monoclonal antibodies have been shown to be clinically effective in suppressing inflammation in RA. some mAbs, such as anti-CD4, improve disease for a prolonged period in animal models of RA. Infliximab Administered intravenously. Designated for use in patients who did not respond to methotrexate Proven to slow the clinical and radiological progression of rheumatoid arthritis Rheumatoid Arthritis is a chronic, autoimmune disease characterized by Severe joint inflammation, Increased synovial fluid , and thickened synovial membrane. It occurs due to destruction of bone and cartilage in several joints & Elevated levels of pro-inflammatory cytokines TNF(Tumor necrosis factor)-α, IL-1, IL-6

42 Efalizumab Efalizumab is a humanized IgG1 antibody produced by recombinant DNA technology. It exhibits immunosuppressive function. It binds to CD11a, which is the α-subunit of leukocyte function antigen (LFA)-1. Efalizumab decreases the cell surface expression of CD11a, which is expressed on all leukocytes. Psoriasis is a disease of the immune system that involves T lymphocytes. It results from complex communications that cause activation of T lymphocytes and trafficking to the skin. Further reactivation causes inflammation and overproduction of skin, resulting in lesions and plaques

43 In infectious diseases
IN DIABETES MELLITUS In the treatment of diabetes, novel and improved therapeutic modalities for those individuals with impaired insulin secretory function would be helpful. Currently, long-acting basal insulins are given daily, or more often, and are associated with both hypoglycemia and weight gain. Therefore, a highly specific, ultra-long-acting activator of INSR, such as a monoclonal antibody, would represent a new paradigm in diabetes therapy. XMetA, an allosteric activator of INSR both in vitro and in vivo, has the potential to normalize glycemic control in a model of insulinopenic diabetes without causing hypoglycemia or promoting weight gain. Biotechnology field is committed to MAbs and continues to find new ways both to press onward with current processes and to some extent it reduces the economic pressures to develop radically new concepts and technologies that could make monoclonals even more widespread. In infectious diseases Of the more than 20 monoclonal antibodies generated to combat infectious diseases that are in clinical development in 2011, most are in phase 1 or 2 and are directed against either viruses or bacterial toxins.

44 Thank ou A chimeric antibody is an antibody made by combining genetic material from a nonhuman source, like a mouse, with genetic material from a human being. Chimeric antibodies are generally around two thirds human, reducing the risk of a reaction to foreign antibodies from a non-human animal when they are used in therapeutic treatments. A closely related concept is a humanized antibody, made in a similar way but containing closer to 90% human genetic material.

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