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, Ellen S.UV3, 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 Anti-VEGF Induced Reduction in Microvessel Density Does Not Correlate with Anti-Tumor Repsonse in Lung Cancer Xenografts(2013-01-22) Jacob, Antonia J.; Sullivan, Laura A.; Toombs, Jason E.; Minna, John D.; Brekken, Rolf A.Vascular endothelial growth factor-A (VEGF) is a primary stimulant of angiogenesis in pathological conditions including tumor progression. Strategies to block VEGF activity prevent or slow tumor growth in preclinical settings; however, clinical studies with bevacizumab, a monoclonal antibody (mAb) specific for VEGF have resulted in only modest benefit to a subset of patients with lung cancer. Previous studies in our laboratory defined the therapeutic efficacy of bevacizumab and an alternative anti-VEGF mAb (r84) in 12 non-small cell lung cancer (NSCLC) xenografts. Three NSCLC xenografts (Calu-6, A549 and Calu-3) showed intrinsic resistance to bevacizumab therapy. In the present study we evaluated whether microvessel density (MVD) could be used to 1) demonstrate if the anti-VEGF mAbs were effective at reducing VEGF-driven angiogenesis and 2) if MVD changes induced by bevacizumab or r84 correlated with overall therapeutic efficacy as determined by tumor size after chronic therapy. 3-5 tumors from animals bearing NSCLC xenografts treated with a control mAb (XTLl, bevacizumab or r84 were evaluated by immunohistochemistry for endothelial cells as a measure of microvessel density. Two independent endothelial cell markers were used, endomucin and CD31. In 11 of the 12 xenografts treatment with bevaclzumab or r84 significantly reduced MVD compared to XTL treatment, suggesting that bevacizumab and r84 do reduce VEGF-driven angiogenesis. However, the reduction in MVD induced by anti-VEGF therapy did not correlate with overall tumor response to therapy. These results strongly implicate resistance to anti-VEGF therapy is not mediated by activation af alternative angiogenic programs to compensate for VEGF blockade. Further the results suggest that tumor cell adaptation to therapy-induced hypoxia underlies poor therapeutic response to anti-VEGF strategies. Microarray of gene expression analysis of control treated tumors revealed several genes associated with metabolism, proliferation, and metastasis were significantly increased in tumors that displayed intrinsic resistant to bevacizumab. We conclude that response of tumor cells to therapy-induced hypoxia is a critical feature that drives the overall efficacy of anti-VEGF strategies.Item The biological therapy of breast cancer: Molecular targets and monoclonal antibodies HER2 and herceptin(2003-05-08) Haley, Barbara B.Item Chimeric ANTI-CD19 Monoclonal Antibodies for the Treatment of Precursor B Cell Acute Lymphoblastic Leukemia(2009-09-04) Tsai, Lydia Kar-Yuk; Vitetta, Ellen S.Thousands 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 Human monoclonal antibodies in clinical medicine(1991-12-12) Capra, J. DonaldItem Immune checkpoint inhibitor related endocrinopathies(2018-10-26) Ali, SadiaItem Immunotherapy: a new era in cancer treatment(2015-07-10) Nijhawan, DeepakItem Live Donor Renal Transplantation in India: Outcome and Comparison of Different Induction Therapies with a Focus on Gender Bias in Live Donor Renal Transplantation(2018-03-23) Khan, Maryam Idrees; Nwariaku, Fiemu; Rajora , Nilum; Tanriover , BekirBACKGROUND: As of 2014, an estimated 9% of the global population aged 18+ years was affected by diabetes. The World Health Organization (WHO) also estimated around 2.5% of deaths were attributed to diabetes in 2012 and more than 80% of those deaths occurred in low-middle income countries. It is apparent that diabetes and its complications are becoming a global issue as an increasing common, preventable, non-communicable disease. Along with cardiovascular disease, blindness, and neuropathy, end stage renal disease (ESRD) is one of the serious complications that can develop as a result of diabetes. Diabetes is the leading cause of ESRD in both developed countries like the United States and developing countries like India. India is a particularly interesting country to observe given their vast population base, rapid growing economy, genetic predisposition to diabetes and increased insulin resistance. It is estimated that 100,000 patients develop ESRD each year in India with diabetes as the main underlying cause (44% of all ESRD cases). Once a patient develops ESR, renal replacement therapy (RRT) is required to sustain life. RRT consists of three options: 1) hemodialysis (HD), 2) peritoneal dialysis (PD), or 3) renal transplant (RT). Of the three options, renal transplant is considered the best in terms of quality of life and cost effectiveness, but only about 5% of Indian patients with ESRD end up receiving RT. Most RT in India come from living donors rather than cadaveric donors like in the United States. Induction therapy with interleukin-2 receptor alpha chain (IL2-RA) is recommended as a first line agent in LRT however comparative outcomes of induction therapy remains controversial in Indian LRT population. OBJECTIVE: To evaluate patient survival and allograft function in LRT with a specific focus on the Indian population between 2010 and 2014 and to access the impact of different induction therapies on the outcomes of Indian LRT patients. METHODS: A single center (Medanta Medicity, Gurgaon, India) dataset was retrospectively studies for patients receiving LRT from 2010 to 2014 (N=901) to compare effectiveness of IL2-RA to other induction options (no-induction and rabbit anti-thymocyte globulin [r-ATG]). IL2-RA and no induction were chosen for immunologically low risk patients. R-ATG was primarily given to the recipient with PRA>20% and HLA mismatch >5 antigen out of 6. Patient paper charts were analyzed for dates not included in the Medanta database which included follow-up dates with corresponding creatinine levels (at 3 months, 6 months, 1 year, and last follow up), date and type of rejection if applicable, graft loss and death. Patients included in the data set had their last follow up at Medanta within the last 6 months from the time data was collected. The patient data was used to calculate rejection rate, graft failure, and hazard ratio (HR) for overall graft failure. The main outcomes were the risk of acute rejection at one-year and overall allograft failure (graft failure or death) post-transplantation through the end of follow-up. RESULTS: Similar Kaplan Meier curves for overall graft survivals were observed among induction categories. Rejection rate was higher in no-induction and IL2-RA groups (~25%) compared to r-ATG induction. On univariate Cox analysis, compared to no-induction therapy, overall allograft failure was similar among induction categories. Most of the rejections were borderline or Banff Type I acute cellular rejections. CONCLUSION: Compared to no-induction therapy, IL2-RA induction was not associated with better outcomes in Indian LRT recipients. R-ATG appears to be an acceptable and possibly preferred induction alternative for IL2-RA in high rejection risk Indian patients.Item Monoclonal antibodies in clinical medicine: present and future perspectives(1981-05-21) Capra, J. DonaldItem "My cancer treatment is a pain in the neck": immune checkpoint inhibitor therapy: a rheumatologist's perspective(2018-06-22) Bermas, Bonnie L.Item New Approaches to the Development of Peptoid Vaccines(2015-04-07) Desmond, Angela; Pfeiffer, Julie K.; Vitetta, Ellen S.; Levine, Beth; Niederkorn, Jerry Y.; Ward, E. SallyThe ideal prophylactic vaccine against a toxin or pathogen should elicit the production of broadly protective antibodies against conserved epitopes. However, the epitopes that elicit these antibodies are often not immunodominant and even when they are, characterizing and synthesizing them can be difficult, particularly if they are conformational. The long-term goal of this work was to develop prophylactic vaccines that elicit such antibodies without epitope characterization. To develop such a vaccine platform, it was hypothesized that screening large one-bead-one-compound libraries of synthetic compounds with monoclonal antibodies that have already been shown to be broadly protective against a toxin or pathogen would allow the identification of mimetic B cell epitopes. For this platform, peptoids were chosen to construct one-bead-one-compound libraries. Peptoids are N-oligosubstituted glycines that resemble peptides but bear their side groups on backbone nitrogens instead of carbons. This renders them protease resistant and enormously diverse, since they are not restricted to the twenty standard amino acids. Furthermore, previous work had demonstrated that a monoclonal antibody could be used to screen libraries of peptoids. Moreover, while peptoids themselves were not immunogenic, the attachment of peptoids to carrier proteins using a linker elicited antibodies against the peptoid/linker. Such T-cell dependent antigens elicited high-affinity, class-switched antibodies. The goal of this dissertation research was to continue optimizing the magnetic and color-based assays by which peptoid vaccine candidates could be identified and to screen libraries with neutralizing monoclonal antibodies against West Nile virus and murine norovirus type 1. In addition, the immunogenicity of peptoids was further examined by designing a peptoid-carrier, using it to immunize rabbits, and demonstrating that anti-peptoid antibodies could be affinity-purified from the resulting antisera. This antibody was then used in further optimization of the magnetic screening assay to ensure that future screens will efficiently and specifically identify the best vaccine candidates.Item [News](1980-10-31) Williams, AnnItem 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 Potentiating Antibody Therapy by Targeting Complement on Cancer Cells(2017-04-03) Carstens, Elizabeth Jane; Wiestner, Adrian; Dunbar, Cynthia; Choti, MichaelBACKGROUND: Monoclonal antibodies (mAb) are a key component of treatment regimens for hematologic malignancies, but mAb-induced antigen loss on tumor cells can lead to treatment failure. Loss of cell surface CD20 can occur in the treatment of lymphoid malignancies with anti-CD20 antibodies (mAbs) (eg rituximab, ofatumumab) through trogocytosis. This is a frustrated form of phagocytosis, where the target CD20 antigen is removed with a piece of target cell plasma membrane by the immune effector cell, thus creating "escape variants", which are no longer sensitive to the anti-CD20 therapy. In a clinical trial we initiated with anti-CD20 mAb ofatumumab in chronic lymphocytic leukemia (CLL), we observed that these escape variants carried covalently bound complement activation fragments, especially C3d. Indeed, C3d opsonized CLL cells persisted for weeks in circulation. (Beurskens et al., 2012). At final restaging after combined ofatumumab and chemotherapy treatment, many patients had CD20 negative, but C3d positive disease. This suggests that a single mAb is insufficient to deplete cancer cells due to antigen escape. OBJECTIVE: C3d may constitute a neoantigen that could be exploited to re-target cells that have escaped from anti-CD20 mAb therapy. METHODS: To target complement opsonized cells we generated a human IgG1 mouse chimera mAb specific to C3d that is not competed by full length C3 in serum. To test whether targeting C3d can eliminate escape variants after anti-CD20 therapy, we collected blood samples from CLL patients before (Day 1) and 24 hours after administration of ofatumumab (Day2). To demonstrate that anti-C3d targeting was able to effectively circumvent antigen loss in vitro, we tested the anti-C3d mAbs ability to perform complement dependent cytotoxicity (CDC), antibody dependent cytotoxicity (ADCC), apoptosis and phagocytosis on Day 2 CLL cells. To test CDC, Day 2 CLL and previously treated CD20+ cell lines were incubated with anti-C3d mAb and normal human serum and stained for cell death. Similarly, ADCC was tested by coincubating Day 2 cells with an NK cell line in the presence of mAb. To evaluate phagocytosis, CLL cells were incubated with macrophages for six hours in the presence of antibody and imaged using flow cytometry to evaluate degree of internalization. We also tested the efficacy of the anti-C3d mAb in vivo, using two mouse models. First, we transferred peripheral blood mononuclear cells obtained from CLL patients on Day 2 into NSG mice. Mice were treated with either isotype antibody, ofatumumab or anti-C3d mAb. Mice were sacrificed and tumor burden was quantified in peripheral blood and spleen. To evaluate impact on survival, we subcutaneously xenografted HBL2 cells, a CD20+ mantle cell lymphoma (MCL) line, into SCID mice. All mice received an injection of human C3 and either anti-CD20 mAb (rituximab or ofatumumab) alone, anti-CD20 and anti-C3d mAb or isotype control. Caliper measurements of the tumor longest dimension and survival were measured. RESULTS: Anti-C3d mAb did not bind CLL cells obtained pre-treatment but bound cells obtained on Day 2. Day 2 CLL was effectively killed through CDC, NK cell mediated ADCC, and phagocytosis but not apoptosis. Phagocytosis of Day 2 CLL cells in response to anti-C3d treatment was two-fold higher than that observed on Day 1 CLL treated with ofatumumab. Importantly, non B lymphocytes were neither bound nor killed by the anti-C3d mAb, consistent with the highly targeted and selective deposition of C3d on CD20+ cells by ofatumumab in vivo. Our anti-C3d mAb effectively reduced tumor burden in both peripheral blood and spleen of the mice relative to mice treated with isotype control in the CLL primary NSG model. Our anti-C3d antibody extended time to tumor development and also prolonged survival in the MCL model differentially from CD20 targeting alone. CONCLUSION: Collectively, our results identify C3d as a marker for leukemic cells that have escaped in vivo antibody treatment and provide proof of principle evidence for the clinical utility of C3d-targeting. In essence, we present an approach to utilize endogenous complement molecules as targets for immunotherapy. This approach relies on prior treatment with monoclonal antibodies that activate the complement cascade and thus covalently link complement component C3d to tumor cells. We conclude that anti-C3d mAbs can potentiate the anti-tumor activity of complement-fixing antibodies and eliminate antigen loss variants that survive after antibody therapy.Item [Southwestern News](1997-07-08) Steeves, Susan A.Item Treatment of rheumatic diseases with monoclonal antibodies(1991-06-20) Lipsky, Peter E.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.Item [UT Southwestern Medical Center News](2008-06-16) Siegfried, Amanda