Browsing by Subject "Antibodies, Monoclonal"
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Item Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer: Characterizing a New Therapy and Investigating Potential Mechanisms of Resistance(2012-07-20) Sullivan, Laura Anne; Brekken, Rolf A.Angiogenesis is the development of blood vessels from a pre-existing vascular network. This process is essential during growth, development and wound healing and plays a critical role in the growth and progression of cancer. Initial tumor size is restricted by the diffusion capacity of oxygen and nutrients from surrounding blood vessels. Therefore, to progress beyond a volume of several millimeters, a tumor must stimulate angiogenesis to generate a vascular network that will supply the tumor with the necessary blood, oxygen and nutrients that will allow for continued growth, invasion and metastasis. Over forty years ago, Judah Folkman hypothesized that targeting tumor angiogenesis would be beneficial for cancer patients. One of the first targets for this new class of drugs was vascular endothelial growth factor (VEGF) a predominant mediator of physiological and pathological angiogenesis. Bevacizumab (Avastin®, Genentech/Roche), a humanized monoclonal antibody that recognizes human VEGF and blocks VEGF from binding to VEGF receptor (VEGFR) 1 and 2, was the first anti-angiogenic drug approved by the United States Food and Drug Administration for the treatment of cancer and remains the gold standard for this class of therapeutics. The Brekken laboratory, in collaborations with Peregrine Pharmaceuticals and Affitech A/S has generated a fully human monoclonal antibody, r84 that recognizes mouse and human VEGF and blocks VEGF binding only to VEGFR2. The data presented in the first half of this dissertation demonstrate the specificity of r84 for VEGF in vitro and in vivo, the efficacy of r84 to control tumor growth and the superior safety profile of r84 as compared to bevacizumab. Although anti-angiogenic therapy was highly anticipated to have great success in patients, overall results have been somewhat disappointing with modest improvements in patient progression free survival and few improvements to overall survival. In addition, with the expanding use of anti-angiogenic drugs such as bevacizumab and a host of receptor tyrosine kinase inhibitors in the clinic, it is becoming increasingly apparent that not all tumors respond or maintain sensitivity to treatment. Therefore, it is increasingly important to identify mechanisms of resistance to anti-angiogenic therapy so that new drug targets can be identified and/or patients can be appropriately screened for markers that can predict for resistance or sensitivity to anti-angiogenic therapy de novo. Non-small cell lung cancer (NSCLC), the most common form of lung cancer, claims the most new diagnoses and cancer-related deaths than any other cancer worldwide and the therapeutic options currently available for this disease, including bevacizumab have done little to change this statistic. The latter half of this thesis focuses on the in vivo screening of human NSCLC cell lines to identify mechanisms of resistance to the anti-angiogenic monoclonal antibodies bevacizumab and r84 in non-small cell lung cancer.Item The Anti-Tumor Activity of UV3, an Anti-CD54 Antibody, In SCID Mice Xenografted With a Variety of Human Tumor Cell Lines(2008-09-12) Brooks, Kimberly Joe; Vitetta, EllenUV3, a monoclonal antibody that specifically recognizes human CD54, also known as intercellular adhesion molecule-1 (ICAM-1) was previously developed for the treatment of multiple myeloma. Even at low doses UV3 was highly effective at prolonging the survival of SCID mice with advanced multiple myeloma. Since CD54 is expressed on many different cancer types, we have now investigated the anti-tumor activity of UV3 in several other CD54+ tumors. A panel of 28 human non-Hodgkin's lymphoma, breast, prostate, non-small cell lung, pancreatic, and melanoma tumor cell lines was examined for reactivity with UV3, and 24 were strongly positive. A representative CD54+ cell line from each cancer type was then grown in SCID mice, and UV3 was administered using different dose regimens. UV3 prolonged survival and/or slowed tumor growth in all of the investigated tumor models, although it was not curative. When UV3 or gemcitabine were administered to SCID mice xenografted with non-small cell lung or pancreatic tumor cell lines, UV3 was as effective as the chemotherapy alone. However, the best anti-tumor responses were observed when gemcitabine and UV3 were administered together. In order to better understand how UV3 mediates its anti-tumor activity, some mechanisms of action were also investigated. Previous studies in multiple myeloma cells indicated that UV3 did not directly inhibit tumor cell growth or cell adhesion and that the Fc portion of UV3 was required for activity in mice. Similarly, in this study, UV3 did not induce cell cycle arrest or apoptosis in any of the tumor cell lines evaluated, and UV3 did mediate Fc effector mechanisms. However, the involvement of both Fc-dependent and Fc-independent mechanisms is suggested by the results, although the specific Fc-independent mechanisms are unknown. UV3 has already been chimerized (cUV3), and both toxicology studies and clinical trials are in the planning stage to assess the safety and activity of cUV3 in patients with one or more of these tumors.Item Chimeric ANTI-CD19 Monoclonal Antibodies for the Treatment of Precursor B Cell Acute Lymphoblastic Leukemia(2009-09-04) Tsai, Lydia Kar-Yuk; Vitetta, EllenThousands of people are diagnosed with B cell malignancies every year, yet the only FDA-approved immunotherapies for them are based on anti-CD20 monoclonal antibodies (MAbs). However, CD20 is not expressed on precursor B cell acute lymphoblastic leukemia (pre-B ALL), and CD20 expression is often lost following anti-CD20 immunotherapy. CD19 is a pan B cell membrane antigen that is restricted to the B cell lineage and expressed on B cell lymphomas and pre-B ALLs. Previous studies have shown that a murine anti-human CD19 MAb, HD37, has efficacy in SCID mice with human B cell tumors. Furthermore, homodimers consisting of two conjugated IgG molecules of HD37 are more effective than monomers at inducing tumor cell death. Yet, their large size prevents effective tumor penetration, and normal Fc effector funtions are often not retained. Murine antibodies are also highly immunogenic. Therefore, the objective of this study was to construct, express, and test the in vitro and in vivo activities of chimeric divalent and tetravalent HD37 MAbs. Both chimeric HD37 MAbs and the murine HD37 MAb were equally effective at mediating antibody dependent cellular cytotoxicity (ADCC) with mouse effector cells. The anti-tumor activities of all three MAbs were identical in SCID mice xenografted with human B cell tumors. However, the chimeric tetravalent MAb has a higher binding affinity and a longer half-life of dissociation than either of the divalent MAbs. Moreover, the chimeric tetravalent MAb mediated ADCC and complement dependent cytotoxicty (CDC) more efficiently than the divalent MAbs when human effector cells and human complement were used. None of the MAbs were cytotoxic to target cells in the absence of effector cells or complement. These data suggest that 1) the HD37 MAbs effectively extend the mean survival time of SCID mice engrafted with human B cell tumors; 2) more than two of the tetravalent HD37 MAb's binding sites are active; and 3) because in vitro results show that the chimeric tetravalent MAb is more effective than the divalent MAbs at mediating ADCC and CDC with human effector cells and complement, the chimeric tetravalent HD37 MAb could be superior to the divalent MAbs in humans.Item NK Cell Function and Tumor Resistance in Mice Transgenic for Antibody to NK Inhibitory Receptors(2005-05-03) Gandhi, Namita Anikumar; Bennett, MichaelTumor surveillance has been proposed as a means whereby the immune system monitors and eliminates transformed cells before their growth. Transformed cells that survive the immune response are escape variants selected by nature as they have developed mutations in immune recognition components. To boost immune response to these tumors, several types of immunotherapies are being studied but so far have had minimal success when translated into patient studies. Among proposed immunotherapeutic approaches, monoclonal antibody treatments have shown the best efficacy in human clinical trials. NK cells, cytolytic effector cells of the innate immune system, are implicated in tumor surveillance. Inhibitory Ly49 receptors determine the specificity of murine NK cells by recognizing of MHC class I molecules expressed on the target cell. This allows the transmission of inhibitory signals through intracellular signals to block NK cytotoxicity. Many tumors express sufficient levels of self MHC class I and are able to escape lysis by NK cells. Our lab has been studying the inhibitory regulatory pathways in natural killer cells and has developed an approach for enhancing the ability of NK cells to kill tumor cells. We have focused on studying the inhibitory function of the murine Ly49 receptors and provided evidence that blocking of negative signals on two inhibitory receptors, Ly49C and I, with a monoclonal antibody (5E6), allow NK cells to kill syngeneic leukemia cells more efficiently providing an enhanced anti-tumor effect. To study further the effect of Ly49C/I receptor blockade and improve tumor rejection, we developed a transgenic model whereby the 5E6 Fab antibody fragments are constitutively secreted to allow the sustained blockade of the Ly49C/I receptor. These studies detail the generation of these Tg mice and their characterization in relation to NK and T cell receptor development, tolerance, autoimmunity and tumor surveillance. In addition, we demonstrated an effect of blocking inhibitory receptors on NK cells to delay tumor establishment in a nascent tumor model of murine chronic myelogenous leukemia.Item Understanding the Mechanism of Action of UV3, an Anti-CD54 Monoclonal Antibody, in the Therapy of Multiple Myeloma(2005-05-04) Coleman, Elaine J.; Vitetta, Ellen S.Multiple myeloma is a hematopoietic malignancy involving the uncontrolled proliferation of a single clone of plasma cells or plasma cell progenitors in the bone marrow. Previously, a monoclonal antibody called UV3, which recognizes human CD54/ICAM-1, was developed for the therapy of multiple myeloma. UV3 is highly effective at treating advanced multiple myeloma in SCID mice with human multiple myeloma xenografts. UV3 does not inhibit homotypic tumor cell adhesion or their adhesion to the bone marrow. UV3 does not induce apoptosis of tumor cells or block cell growth. Previous work evaluating F(ab)'2 fragments of UV3 demonstrated that they were effective in mediating anti-tumor activity, suggesting that other mechanisms also contributed to the anti-tumor activity of UV3. One possibility to explain how UV3 exerts its anti-tumor activity could be that UV3 inhibits the secretion of pro-angiogenic cytokines and molecules, resulting in an inhibition of angiogenesis. To this end, our goal was to evaluate the angiogenic signals from human multiple myeloma cells and determine whether UV3 would interfere with such signals. In addition, we further examined the role of the Fc portion of UV3 in mediating anti-tumor activity. We found that multiple myeloma cell lines secrete some pro-angiogenic cytokines and molecules, and although UV3 may induce a minor anti-angiogenic effect, the Fc portion of UV3 was critical for its anti-tumor activity. In addition, we found that UV3 prolonged the survival of SCID mice with Daudi lymphoma, which suggests UV3 may be effective in treating a variety of hematological malignancies.