Antibody-Cytokine Fusion Proteins for the Therapy of Breast Cancer PDF Download
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Languages : en
Pages : 133
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Book Description
In this grant we proposed to explore the use of genetically engineered antibodies as therapeutic agents specifically attempting to augment and potentiate the host immune defense systems against breast cancer. The antibodies were to be specific for HER2/neu, a molecule present on the surface of many breast cancers; its increased expression is associated with poor prognosis. To these antibodies we proposed to join the cytokines IL-2, IL-12, and GM-CSF. Expression of these cytokines by cancer cells has been shown to render them immunogenic. The anti- HER2/neu antibody fusion proteins were intended to localize the cytokine at the tumor where it is expected to elicit an immune response. To accomplish our goals we proposed three specific aims. Specific Aim 1: To produce rL-2, IL-12, GM-CSF antibody fusion proteins specific for HER2/neu. Specific Aim 2: To evaluate the properties of the antibody fusion proteins in vitro. Specific Aim 3: To determine the properties of the antibody fusion proteins in vivo and their effectiveness in causing anti-tumor response. These there specific aims have been accomplished by the end of the third year of the present award.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 133
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Book Description
In this grant we proposed to explore the use of genetically engineered antibodies as therapeutic agents specifically attempting to augment and potentiate the host immune defense systems against breast cancer. The antibodies were to be specific for HER2/neu, a molecule present on the surface of many breast cancers; its increased expression is associated with poor prognosis. To these antibodies we proposed to join the cytokines IL-2, IL-12, and GM-CSF. Expression of these cytokines by cancer cells has been shown to render them immunogenic. The anti- HER2/neu antibody fusion proteins were intended to localize the cytokine at the tumor where it is expected to elicit an immune response. To accomplish our goals we proposed three specific aims. Specific Aim 1: To produce rL-2, IL-12, GM-CSF antibody fusion proteins specific for HER2/neu. Specific Aim 2: To evaluate the properties of the antibody fusion proteins in vitro. Specific Aim 3: To determine the properties of the antibody fusion proteins in vivo and their effectiveness in causing anti-tumor response. These there specific aims have been accomplished by the end of the third year of the present award.
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Languages : en
Pages : 0
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Over the past year our team has been actively investigating the immunotherapeutic potential of the antibody-cytokine fusion proteins. These molecules contain the antibody portion recognizing the tumor associated antigens, and is covalently linked to a potent immune stimulator. HuKS-1L2 fusion protein which is highly reactive with breast cancer cells became available to us for in vitro and in animal in vivo studies. We are still actively pursuing experiments to elucidate the mechanisms of targeting tumor cells for destruction and mechanisms of stimulation immune effector cells by this molecule, to ultimately translate these findings to clinical application. At this time similar fusion protein (hul4.l8-1L2) became available for clinical testing and we decided to refocus our efforts in this direction. At the UW-CCC we are currently performing an initial Phase I clinical trial involving an administration of this novel immunocytokine to the patients with GD-2 positive tumors, delivered as a single agent therapy. We are collecting serum specimens as well as cells from these patients. Studies are underway to assess the effects of this treatment, its safety and future applications. Findings from these studies will provide a baseline for clinical testing of other immunocytokines targeting human cancers.
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Category :
Languages : en
Pages : 0
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Author: Cornelia Halin
Publisher:
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Category :
Languages : en
Pages : 386
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Category :
Languages : en
Pages : 12
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To produce a more effective form of Herceptin and improve efficacy of human endostatin, we have constructed an anti-HER2 IgG3-human endostatin fusion protein by joining human endostatin to the 3 end of humanized anti-HER2 IgG3. The wild type and the mutant type (P125A) of human endostatin were constructed with FLAG tagging to distinguish from the endogenous human endostatin. The anti-HER2 IgG3-huEndo fusion proteins were constructed as wild type and mutant type (P125A) and were stably transfected into B myeloma cells. The secreted huEndo fusion proteins have a molecular weight of 220 kDa for the anti-HER2 IgG3-CH3-huEndo fusion protein and 160 kDa for the anti-HER2 IgG3-Hinge-huEndo fusion protein. The huEndo fusion proteins were faithfully secreted as the fully assembled H2L2 form.
Author: Steven M. Chamow
Publisher: Wiley-Liss
ISBN: 9780471183587
Category : Science
Languages : en
Pages : 312
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Thoroughly detailed and illustrated, this book examines the construction, properties, applications, and problems associated with specific types of fusion molecules used in clinical and research medicine. The editors present an overview of the field, followed by nine chapters divided into two general sections based on the two primary parts of the antibody molecule: Fab fusion proteins and Fc fusion proteins. In addition, numerous renowned scientists in the field have contributed outlines demonstrating man-made molecules that will be required not only to overcome the limitations of monoclonal antibodies, but also to extend the principle of selective targeting. Divided into specific, accessible sections, Antibody Fusion Proteins includes: * Chapters describing Fc fusion proteins, as well as several classes of antigen-binding proteins * Complete details on the design and molecular construction of genetically engineered fusion molecules * Useful information on molecular purification, large-scale production, practical applications, and their therapeutic potential * The latest data on forming fusion proteins with toxins, cytokines, or enzymes that can activate a prodrug
Author: Christian Pascal Hess
Publisher:
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Category :
Languages : en
Pages :
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Author: Brian A. Baldo
Publisher: Springer
ISBN: 3319304720
Category : Medical
Languages : en
Pages : 623
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This long overdue title provides a comprehensive, up-to-date, state-of-the art review of approved biologic therapies, with coverage of mechanisms of action, Indications for therapy, immunogenicity and a detailed examination of adverse effects and safety of the many and diverse therapeutic agents presented in a total of 13 chapters. It is predicted that by 2016, biologics will make up half of the world's 20 top-selling drugs and by 2018, biologic medicine sales will account for almost half of the world's 100 biggest selling drugs. Recombinant proteins dominate the growing list of the more than 200 approved biotherapeutic agents with targeted antibodies, fusion proteins and receptors; cytokines; hormones; enzymes; proteins involved in blood-clotting, homeostasis and thrombosis; vaccines; botulinum neurotoxins; and, more recently, biosimilar preparations, comprising the majority of approved biologics. Written with clinicians, other health care professionals, and researchers in mind, Safety of Biologics Therapy examines, in a single volume, the full range of issues surrounding the safety of approved biologic therapies. A good understanding of the risks and safety issues of modern biologics therapy is increasingly being demanded of all those connected with their development, handling, prescribing, administration and subsequent patient management. In addition to being of great value to clinicians in all branches of medicine, and to nurses, pharmacists and researchers, this book will prove invaluable for students taking undergraduate and graduate courses in the above disciplines and in the biomedical sciences.
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Category :
Languages : en
Pages : 11
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In Antibody-Directed Enzyme-Prodrug Therapy (ADEPT), antibody - enzyme constructs localize to tumor tissue the toxification of non-toxic prodrugs. Recombinant fusion proteins may overcome limitations of chemical conjugates regarding stability and size. As a general model system, we have constructed fusion proteins of an antibody against the tumor antigen A33 with cytosine deaminase (CD), which converts 5-fluorocytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) . Using a T7 polymerase-based expression system, a plasmid vector was designed to allow cloning of the scFv either preceding or following the enzyme. The fusion proteins were produced in E. coli and purified and renatured from inclusion bodies. Antibody and enzyme activities were confirmed by separate functional assays. To test the complete ADEPT system in vitro, A33-positive cell cultures were incubated with the fusion protein, washed, and cultured for 48h in the presence of 5-PC. While fusion protein or up to I mM 5-PC alone had no effect on cell growth, their sequential combination quantitatively increased median 5-PC toxicity. Preincubation with anti-A33 blocked this effect. A control fusion protein with GFP instead of CD had no effect on 5-PC toxicity. While avidity of the constructs remains to be improved, these data prove the feasibility of scPv-based ADEPT in principle. Currently, this system is transferred using breast-cancer-specific antibodies Fl9 and 3Sl93.
Author: Jason Laurence Hornick
Publisher:
ISBN:
Category :
Languages : en
Pages : 342
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