Breast Cancer Therapy Using Antibody-Endostatin Fusion Proteins PDF Download
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Languages : en
Pages : 77
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The anti-angiogenic protein endostatin demonstrated considerable anti-tumor activity in animal models. However, limited anti-tumor activity has been observed in human Phase I/II trials. Trastuzumab has activity in HER2+ breast cancer used alone or in combination with chemotherapy. Prior studies using an anti-HER2 antibodymurine endostatin fusion demonstrated enhanced anti-tumor activity compared to anti-HER2 antibody or endostatin given alone or in combination. We generated two anti-HER2 human endostatin fusion proteins by fusing human wild type or a mutant form of human endostatin (huEndo- P125A) to the 3' end of a humanized anti-HER2 lgG3 antibody. HuEndo-P125A antibody fusion protein (alphaHER2-huEndo-P125A) inhibited VEGF and bFGF induced endothelial cell proliferation, and capillary formation in vitro, to a greater degree than wild type endostatin fusion protein (alphaHER2-huEndo), endostatin alone, or anti-HER2 antibody (alphaHER2 lgG3). Treatment of SKBR-3 breast cancer xenografts with anti-HER2 lgG3-huEndo-P125A fusion resulted in complete regression, and improved survival, compared to either alphaHER2 lgG3, human endostatin, or anti-HER2 lgG3-huEndo treated mice. alphaHER2-huEndo fusion proteins specifically targeted tumors expressing HER2 in mice simultaneously implanted with murine mammary tumor cell line EMT6 and EMT6 engineered to express HER2 antigen (EMT6-HER2). alphaHER2 huEndo-P125A fusion antibody showed enhanced anti-angiogenic and anti-tumor activity and inhibited EMT6- HER2 growth more effectively than huEndo (p = 0.003), or alphaHER2-huEndo (p = 0.004). Targeting anti-angiogenic proteins using antibody fusion proteins could improve clinical activity of anti-HER2 antibody and endostatin alike, and provides a versatile approach that could be applied to other tumor targets with alternative antibody specificities or using other antiangiogenic domains.
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Category :
Languages : en
Pages : 77
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Book Description
The anti-angiogenic protein endostatin demonstrated considerable anti-tumor activity in animal models. However, limited anti-tumor activity has been observed in human Phase I/II trials. Trastuzumab has activity in HER2+ breast cancer used alone or in combination with chemotherapy. Prior studies using an anti-HER2 antibodymurine endostatin fusion demonstrated enhanced anti-tumor activity compared to anti-HER2 antibody or endostatin given alone or in combination. We generated two anti-HER2 human endostatin fusion proteins by fusing human wild type or a mutant form of human endostatin (huEndo- P125A) to the 3' end of a humanized anti-HER2 lgG3 antibody. HuEndo-P125A antibody fusion protein (alphaHER2-huEndo-P125A) inhibited VEGF and bFGF induced endothelial cell proliferation, and capillary formation in vitro, to a greater degree than wild type endostatin fusion protein (alphaHER2-huEndo), endostatin alone, or anti-HER2 antibody (alphaHER2 lgG3). Treatment of SKBR-3 breast cancer xenografts with anti-HER2 lgG3-huEndo-P125A fusion resulted in complete regression, and improved survival, compared to either alphaHER2 lgG3, human endostatin, or anti-HER2 lgG3-huEndo treated mice. alphaHER2-huEndo fusion proteins specifically targeted tumors expressing HER2 in mice simultaneously implanted with murine mammary tumor cell line EMT6 and EMT6 engineered to express HER2 antigen (EMT6-HER2). alphaHER2 huEndo-P125A fusion antibody showed enhanced anti-angiogenic and anti-tumor activity and inhibited EMT6- HER2 growth more effectively than huEndo (p = 0.003), or alphaHER2-huEndo (p = 0.004). Targeting anti-angiogenic proteins using antibody fusion proteins could improve clinical activity of anti-HER2 antibody and endostatin alike, and provides a versatile approach that could be applied to other tumor targets with alternative antibody specificities or using other antiangiogenic domains.
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Languages : en
Pages : 0
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In the present grant we propose 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. We will use antibodies specific for HER2/neu, a molecule present on the surface of many breast cancers; its increased expression is associated with poor prognosis. To this antibody we will join the cytokines IL-2, IL-i 2, and GM-CSF. Expression of these cytokines by cancer cells has been shown to render them immunogenic. The anti-HER2/neu will be used to localize the cytokine at the tumor where it is expected to elicit an immune response. The resulting immune response would be expected to be specific not only for the targeting antigen, but also for other tumor associated antigens resulting in the destruction of both the tumor cells which express the targeting antigen as well as those that do not. Simultaneous targeting of more than one cytokine to the tumor would be expected to lead to synergism in immune activation and an even more potent immune response.
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Languages : en
Pages : 0
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Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. We constructed a recombinant adenovirus that expresses endostatin, which resulted in a significant delay of tumor progression of JC breast and Lewis lung carcinoma, and more importantly, in complete prevention of lung metastases formation in Lewis lung carcinoma. The inability to control pre-established tumors may be due to insufficient circulating endostatin levels or to inadequate local endostatin concentrations, both of which have been shown to be important for the anti-tumor effect of endostatin. Thus, we constructed a recombinant adenovirus expressing a murine Ig-endostatin fusion protein resulting in significantly higher circulating endostatin levels with improved anti-tumor activity. Furthermore, a tumor-targeted version of endostatin was made using homing peptides to activated endothelial cells (RGD, NGR) to increase directly endostatin concentrations in the tumor. Finally, conditionally replicating adenovirus (CRAD) targeted to the activated endothelium was very efficacious in selectively destroying 3-D capillary networks. In conclusion the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy in cancer. Changes in vector design resulting in higher transgene expression levels, tumor-targeted delivery of endostatin, or endothelial selective replication of adenovirus may prove to be an effective anti-cancer therapy.
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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: Roberto L. Ceriani
Publisher: Springer Science & Business Media
ISBN: 1461524431
Category : Medical
Languages : en
Pages : 227
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Today, advances in the area of immunology and breast cancer are made at an increasing rate, yielding an amount of information that can become unwieldy. The opportunity for scientists in this area of research to gather together to exchange results and working hypotheses represents, in my belief, a very attractive proposition. With this in mind, these workshops have been convened with two year intervals for the last ten years. In each of them, selected topics have been highlighted. The present workshop underscores the large advancements made in the molecular biology of both breast cancer associated antigens and their corresponding antibodies. Understanding the genetic information for the expression of these antigens has been recently advanced leading to preparation of molecularly engineered reagents for use in vaccination, serum assays, and immunizations for novel antibody production. In the anti-breast cancer antibody field the availability of molecular engineering approaches to humanize murine antibodies has induced intense interest in the creation of less immunogenic antibody forms that are now available for clinical testing. Clinical studies using anti-breast murine antibody continue to be carried out and are presented at this meeting establishing a base line for safety and efficaciousness in imaging and immunotherapy that it is hoped will be superseded by the humanized forms. Basic immunology and immunochemistry studies in breast cancer are also included in this workshop that demonstrate the fast pace at which this research is advancing in many laboratories worldwide.
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Languages : en
Pages : 17
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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.
Author: Michael S. Kinch
Publisher:
ISBN:
Category :
Languages : en
Pages : 51
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The DV antigen was identified in a screen of monoclonal antibodies that recognized tyrosine kinases and their substrates in breast cancer cells. DV was found to be differentially expressed in normal, non-malignant and malignant breast epithelial cells. In our funded proposal, we identified DV as the EphA2 receptor tyrosine kinase. We also found that EphA2 function is regulated by the E-cadherin tumor suppressor protein. Specifically, E-cadherin causes EphA2 to negatively regulate breast cancer cell growth and invasiveness. However, in the most aggressive breast cancers, E-cadherin function is frequently lost. Consequently, the EphA2 in metastatic cells is overexpressed and functionally altered and these changes cause EphA2 to promote metastatic cell growth. These defects in EphA2 could be overcome using monoclonal antibodies or fusion proteins and this facilitated selective inhibition of the growth and invasiveness of metastatic breast cancer cells. The information learned in our studies has identified a key regulator of breast cancer cell growth and invasiveness. Moreover, our studies indicate that EphA2 holds potential as a target for therapeutic intervention against metastatic breast cancer.
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Languages : en
Pages : 14
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The main objective of this proposal is to develop monoclonal antibodies as cell specific targeting vectors so that they are able to bind and carry DNA into cells. The molecularly engineered antibody targeted DNA to tumor cells, but the expression of the DNA was low. Different strategies have been examined to improve the expression. These strategies have included incorporation of a flu fusion peptide into the antibody/DNA complex, DNA condensation, and the role of viral origins of replication in the transport of naked DNA into the nucleus. The major barrier remained the cytoplasmic membrane. To achieve entry into the cytoplasm, the entire domain containing the flu fusion peptide, HA2, was engineered to contain a DNA binding domain, and expressed by the baculovirus/insect cell system. The fused HA2 protein, upon purification, was shown to have the signal peptide still attached. Thus, the HA2 did not have glycine as its N- terminal amino acid, which is essential for its fusogenic property. Thrombin and factor Xa recognition sites were incorporated into the N-terminus of HA2 to provide a way to get a N-terminus glycine in the HA2.
Author: American Association for Cancer Research
Publisher: CTI Meeting Technology
ISBN: 1005543747
Category : Health & Fitness
Languages : en
Pages : 3696
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Book Description
The AACR Annual Meeting is the focal point of the cancer research community, where scientists, clinicians, other health care professionals, survivors, patients, and advocates gather to share the latest advances in cancer science and medicine. From population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy; the AACR Annual Meeting highlights the work of the best minds in cancer research from institutions all over the world.
Author:
Publisher: Elsevier
ISBN: 0080490883
Category : Science
Languages : en
Pages : 475
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Book Description
Cell Surface Proteases provides a comprehensive overview of these important enzymes that catalyze the hydrolysis of a protein as it degrades to a simpler substance. In the 1990s, an explosion of new discoveries shed light on the role of cell surface proteases and extended it beyond degradation of extracellular matrix components to include its influence on growth factors, cell signaling, and other cellular events. This volume unites the scientific literature from across disciplines and teases out unified themes of interactions between cell surface proteases and interconnecting cell surface-related systems -- including integrins and other adhesion molecules. Scientists and students involved in developmental biology, cell biology and disease processes will find this an indispensable resource.* Provides an overview of the entire field of cell surface proteases in a single volume* Presents major issues and astonishing discoveries at the forefront of modern developmental biology and developmental medicine * A thematic volume in the longest-running forum for contemporary issues in developmental biology with over 30 years of coverage
