Monoclonal Antibodies As Therapeutic Agents In Oncology And

Monoclonal antibodies as therapeutic agents in oncology and antibody gene therapy,[object Object],Misbahul_ferdous@yahoo.com,[object Object]

PRESENATATION BY,[object Object],DR MISBAHUL FERDOUS,[object Object], MBBS - 2007 ,[object Object], FMD (USTC) 2009,[object Object], PGT (CARDIOLOGY) 2008 NICVD,[object Object],NATINAL INSTITUTE OF CARDIOVASCULAR ,[object Object], DISEASES AND HOSPITAL. DHAKA .BANGLADESH ,[object Object], MD,CARDIOLOGY (COURSE) SHANDONG UNIVERSITY,[object Object], School of medicine,[object Object], CHINA,[object Object]

Key words,[object Object],Monoclonal antibody,[object Object],Oncology,[object Object],Antibody gene therapy,[object Object]

What is a monoclonal antibody,[object Object],A monoclonal antibody is a laboratory-produced molecule that's carefully engineered to attach to specific defects in your cancer cells. ,[object Object],Monoclonal antibodies are proteins produced in the laboratory from a single clone of a B cell, the type of cells of the immune system that make antibodies,[object Object]

How do monoclonal antibody drugs work?,[object Object],1.Make the cancer cell more visible to the immune system:,[object Object], The immune system attacks foreign invaders in your body, but it doesn't always recognize cancer cells as enemies. A monoclonal antibody can be directed to attach to certain parts of a cancer cell. In this way, the antibody marks the cancer cell and makes it easier for the immune system to find. ,[object Object],2. Block growth signals,[object Object]

3.Deliver radiation to cancer cells: By combining a radioactive particle with a monoclonal antibody, doctors can deliver radiation directly to the cancer cells.,[object Object]

Side effects of monoclonal antibody,[object Object],In general, the more common side effects caused by monoclonal antibody drugs include: ,[object Object],Allergic reactions, such as hives or itching ,[object Object],Flu-like symptoms, including chills, fatigue, fever, and muscle aches and pains ,[object Object],Nausea ,[object Object],Diarrhea ,[object Object],Skin rashes ,[object Object]

Rare, but more serious side effects of monoclonal antibody therapy may include: ,[object Object],Infusion reactions. Severe allergy-like reactions can occur and in very few cases lead to death. ,[object Object],Dangerously low blood cell counts. Low levels of red blood cells, white blood cells and platelets may lead to serious complications. ,[object Object],Skin problems,[object Object],Bleeding. Some of the monoclonal antibody drugs are designed to stop cancer from forming new blood vessels. There have been reports that these medications can cause bleeding. ,[object Object]

Gene therapy,[object Object],GENE THERAPY is a field of medicine in which genes are introduced into the body to cure diseases.,[object Object],It invovelves :,[object Object],Detection of gene ,[object Object],2) Determination & its role ,[object Object],3) Isolation & cloning ,[object Object],4) Introducing the gene by proper way.,[object Object], it is of two types :,[object Object],(a) germline gene therapy [done in germcells],[object Object],(b) somatic gene therapy [done in somatic cells],[object Object]

humanized monoclonal antibody,[object Object],A type of antibody made in the laboratory by combining a human antibody with a small part of a mouse or rat monoclonal antibody. The mouse or rat part of the antibody binds to the target antigen, and the human part makes it less likely to be destroyed by the body's immune system. ,[object Object]

chimeric antibody,[object Object],V domains,[object Object],Mouse,[object Object],Chimeric,[object Object],Human,[object Object],C domains,[object Object],[object Object]

infliximab (Remicade®, anti-TNF), for treatment of arthritis,[object Object]

Deregulated growth and lifespan

Resistance to control via apoptotic signals

Change in surface phenotype and markers

Structural and biochemical changes

Presence of tumour-specific antigens,[object Object]

Men710,040,[object Object],Women662,870,[object Object],2005 Estimated US Cancer Cases,[object Object],32% Breast,[object Object], 12% Lung / bronchus,[object Object],11% Colon / rectum,[object Object], 6% Uterine corpus ,[object Object], 4% Non-Hodgkin’s,[object Object], 4% Melanoma of skin,[object Object], 3% Ovary ,[object Object], 3% Thyroid,[object Object], 2% Urinary bladder,[object Object], 2% Pancreas,[object Object], 21% All Other Sites,[object Object],Prostate 33%,[object Object],Lung / bronchus 13%,[object Object],Colon / rectum 10%,[object Object],Urinary / bladder 7%,[object Object],Melanoma of skin 5%,[object Object],Non-Hodgkin’s 4%,[object Object],Kidney 3%,[object Object],Leukemia 3% ,[object Object],Oral Cavity 3%,[object Object],Pancreas 2%,[object Object],All Other Sites 17%,[object Object],*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.,[object Object],Source: American Cancer Society, 2005.,[object Object]

Spontaneous,[object Object],UV and ionizing radiation,[object Object],Chemical carcinogens,[object Object],Tumour induction,[object Object],Genetic abnormalities (XP),[object Object],Virus-induced (HepC, EBV, HPV),[object Object],Immunosuppression,[object Object],Causative agents,[object Object]

History of monoclonal antibody,[object Object],The discovery of monoclonal antibodies (mAbs) in 1975 by Kohler and Milstein ushered in cancer treatment to a modern era of targeted therapy . Therapeutic antibodies have become a major strategy in cancer therapy due to their ability to specifically bind to primary and metastatic cancer cells with high affinity,[object Object]

The approval of nine mAbs by the FDA for clinical tumor therapy signifies important progress in antibody study. They include,[object Object],rituximab (Rituxan®), ,[object Object],ibritumomab (Zevalin®),,[object Object],131I-tositumomab (Bexxar®), ,[object Object],gemtuzumabozogamicin(Mylotarg,[object Object],alemtuzumab (Campath®), ,[object Object],trastuzumab (Herceptin®) ,[object Object],bevacizumab (Avastin®), ,[object Object],cetuximab (Erbitux®),[object Object],panitumumab (Vectibix®).,[object Object]

These 9 mAbs can be dividedinto two groups according to their targets,[object Object],The first group is directed against antigens that are either specifically expressed by tumor cells, such as the HER-2/neu protein on breast cancer and other carcinomas, or are shared with normal cells, such as differential antigens (CD20, CD52,CD19, etc.). ,[object Object],The aim of using this type of antibodies is to induce tumor death by neutralizing the effect of a growth factor, ,[object Object],or by inducing apoptosis,,[object Object],or by activating effector mechanisms of the host.,[object Object]

The second group of therapeutic mAbs targets the stroma-tumor interactions.,[object Object], A leading example of this group is, an mAb that neutralizes vascular endothelial growth factor (VEGF),,[object Object],VGEF is a tumor-derived growth factor that increases neo-angiogenesis and thus supports tumor growth.,[object Object],mABs Neutralize the VEGF and finally blocks angiogenesis and leads to tumor starvation,[object Object]

Since 1997 there have been nine commercially available therapeutic mAbs approved by the FDA,[object Object], among which five are being used for treatment of hematologic malignancies ,[object Object],the other four for solid tumors ,[object Object]

Rituximab (Rituxan®),[object Object],the commercially most successful anti-cancer drug of all mABs,[object Object],Rituximab, which targets the CD20 surface receptor, that is strongly over expressed in most B-cell lymphomas, ,[object Object],This Rituximab is a chimeric, monoclonal IgG1 antibody that induces apoptosis, antibody-dependent cell cytotoxicity and complement-dependent cytotoxicity.,[object Object]

RITUXIMAB ATTACK THE- CD20,[object Object]

Rituximab has recently been approved to be administered as either a 4- or 8-dose weekly regimen in patients who have previously responded to rituximab, and in patients who have bulky tumors (>10 cm). ,[object Object],The overall response rate (ORR) was 50%, with 6% complete response (CR) and 44% partial response (PR) rates,[object Object]

Chop followed by rituximab,[object Object],the combination of six cycles of chemotherapy consisting of CHOP (cyclophosphamide, adriamycin, oncovin and prednisone) with concurrently administered rituximab in 40 patients with predominantly untreated follicular lymphoma greatly increased the response rate.,[object Object],55% CR,[object Object],40% PR,[object Object]

Side effect of the rituximab,[object Object],The main toxicities associated with rituximab included infusion-related chills, fever, nausea, vomiting and general fatigue. ,[object Object],Bone marrow suppression was not a significant side effect in patients treated with rituximab,[object Object]

The combination of anti-angiogenesis mAbs and chemotherapy resulting in synergistic anti-tumor efficacy,[object Object],Three distinct mechanisms may help to explain the chemosensitizing activity of anti-angiogenicmAbs:,[object Object],1.Normalizing tumor vasculature,[object Object],2. preventing rapid increase in tumor cell population ,[object Object],3. augmenting the antivascular effects of chemotherapy.,[object Object]

Antibody gene therapy as a new strategy for cancer treatment,[object Object],Although nine mAbs have been approved by the FDA,wider application of mAbs is limited due to the following reasons:,[object Object], (1) high dose and purity required for antibody,[object Object], protein treatment increase the production cost,[object Object],(2) the relatively large molecular weight of full-length antibody and high pressure within the tumor make it difficult for full-length antibody to penetrate into large-volume solid tumors, thus greatly reducing the therapeutic effect,[object Object]

Why mABs can not penetrate the solid tumours,[object Object],the large molecule full-length antibody has great difficulty entering solid tumors, due to :,[object Object],1.compacted stroma within the tumors ,[object Object],2. high intra-tumor pressure produced by lymphatic return barrier.,[object Object], Therefore, the anti-tumor efficacy of conventional antibody therapy is greatly reduced in treating large-volume solid tumors,[object Object]

Why adenovirus approved for gene therapy,[object Object],we chose adenovirus as the antibody gene transfer vector for the following reasons ,[object Object], (1) adenovirus has been used in more than 5000 clinical patients without significant adverse effects and toxicity, exhibiting the conclusive safety and efficacy as an in vivo vector ,[object Object],(2) adenoviral manufacture technologies are easy, convenient and simple,[object Object],(3) adenovirus is the only commercial product approved in the world for gene therapy,[object Object]

4. this adenovirus-mediated antibody expressing system could be a new approach for antibody therapy,[object Object],5. the complicated, expensive and time-consuming antibody protein preparation and purification procedures could be replaced by using adenovirus as an antibody expression tool for its technical simplicity and low cost,[object Object]

Strategy for improving antibody’s anti-tumor effect by exploiting mesenchymal stem cells,[object Object],mesenchymal stem cells (MSCs) can recognize the emitting signal from tumors and help to construct matrix or junction tissues for tumor growth, it would be an interesting attempt to use MSCs as a vehicle to deliver full-length antibody to tumors.,[object Object], In our study, the bone marrow derived primary mesenchymal stem cells (mBMSCs) were used as a vehicle to target tumor cells (our unpublished data),[object Object]

Monoclonal Antibodies As Therapeutic Agents In Oncology And

Monoclonal Antibodies As Therapeutic Agents In Oncology And

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