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Immunoprophylaxis and Therapy Commons

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Topical Anti-Tnf-Α Antibody Enhances Wound Healing In Diabetic Mice, Genevieve Broderick, Heather M. Strom, Ronald A. Ignotz 2014 University of Massachusetts Medical School

Topical Anti-Tnf-Α Antibody Enhances Wound Healing In Diabetic Mice, Genevieve Broderick, Heather M. Strom, Ronald A. Ignotz

UMass Center for Clinical and Translational Science Research Retreat

Chronic wounds such as venous leg ulcers and diabetic foot ulcers represent a significant health problem for which current treatment options are limited and not highly effective. These wounds have major impacts on the quality of life for affected individuals, frequently lead to amputation, and cost many thousands of dollars per year to treat. Assessment of wound fluid from such wounds indicates greatly elevated and persistently high levels of inflammatory cytokines, in particular Tumor Necrosis Factor-alpha (TNF-α). As such, these wounds are not in a physiologic state conducive to healing. Our study in diabetic mice (db/db) suggests that topical ...


Targeted Mutagenesis Of A Therapeutic Human Monoclonal Igg1 Antibody Prevents Gelation At High Concentrations, Paul Casaz, Elisabeth N. Boucher, Rachel Wollacott, Sadettin S. Ozturk, William D. Thomas Jr., Yan Wang 2014 University of Massachusetts Medical School

Targeted Mutagenesis Of A Therapeutic Human Monoclonal Igg1 Antibody Prevents Gelation At High Concentrations, Paul Casaz, Elisabeth N. Boucher, Rachel Wollacott, Sadettin S. Ozturk, William D. Thomas Jr., Yan Wang

UMass Center for Clinical and Translational Science Research Retreat

A common challenge encountered during development of high concentration monoclonal antibody formulations is preventing self-association. Depending on the antibody and its formulation, self-association can be seen as aggregation, precipitation, opalescence or phase separation. Here we report on an unusual manifestation of self-association, formation of a semi-solid gel or “gelation”. Therapeutic monoclonal antibody C4 was isolated from human B cells based on its strong potency in neutralizing bacterial toxin in animal models. The purified antibody possessed the unusual property of forming a firm, opaque white gel when it was formulated at concentrations >40 mg/mL and the temperature was <6oC. Gel formation was reversible and was affected by salt concentration or pH, suggesting a charge interaction between IgG monomers. However, formulation optimization could not completely prevent gelation at high concentrations so a protein engineering approach was sought to resolve the problem. A comparison of the heavy and light chain amino acid sequences to consensus germline sequences revealed 16 amino acid sequence differences in the framework regions that could be involved with gelation. Restoring the C4 framework sequence to consensus germline residues by targeted mutagenesis resulted in no gel formation at 50 mg/ml at temperatures as low as 0oC. Additional genetic analysis was used to identify the key residue(s) involved in the gelation. A single substitution in the native antibody, replacing heavy chain glutamate 23 with lysine, was found sufficient to prevent gelation, while a double mutation, replacing heavy chain serine 85 and threonine 87 with arginine, increased the temperature at which gel formation initiated. These results indicate that the temperature dependence of gelation may be related to conformational changes near the charged residues or the regions interact with. Our work provided a molecular strategy that can be applied to improve the solubility of other therapeutic antibodies.


Therapeutic Monoclonal Antibodies To Prevent Tuberculosis Infection, Andrew Crowley, Chloe Emery, Gregory W. Martens, Megan K. Proulx, Jon D. Goguen, Christopher M. Sassetti, Colby A. Souders 2014 University of Massachusetts Medical School

Therapeutic Monoclonal Antibodies To Prevent Tuberculosis Infection, Andrew Crowley, Chloe Emery, Gregory W. Martens, Megan K. Proulx, Jon D. Goguen, Christopher M. Sassetti, Colby A. Souders

UMass Center for Clinical and Translational Science Research Retreat

Mycobacteria tuberculosis (Mtb) is a major cause of human morbidity and mortality. Transmission occurs through inhalation of aerosolized Mtb and the initial infection is believed to occur primarily in the alveolar macrophage, although Mtb can infect other cells residing in the lung including dendritic cells, pneumocytes and M cells. Several molecules derived from Mtb are involved in the attachment of the organism to host receptors (opsonic and non-opsonic), which have been reasonably well elucidated. However, a complete understanding of how Mtb attaches to the host and the relative importance of each mechanism on the outcome of infection remains elusive. We ...


Isolation Of Human Antigen-Specific Antibodies From Memory B-Cells Nearly Two Years Post Vaccination, Stuart Nelson, Andrew Crowley, William D. Thomas Jr., Colby A. Souders 2014 University of Massachusetts Medical School

Isolation Of Human Antigen-Specific Antibodies From Memory B-Cells Nearly Two Years Post Vaccination, Stuart Nelson, Andrew Crowley, William D. Thomas Jr., Colby A. Souders

UMass Center for Clinical and Translational Science Research Retreat

Isolation and production of therapeutic human monoclonal antibodies (mAbs) traditionally utilizes a handful of techniques including antibody engineering, phage display, hybridoma generation from transgenic mice or EBV immortalization of B-cells. Over the past decade a new approach has emerged that attempts to extract antigen-specific memory B-cells from the peripheral blood of individuals vaccinated or infected with the target. Initial attempts focused on culturing B-cells and inducing differentiation to plasmablasts for analysis of antibody-antigen specificity, but results were largely mixed due to difficult culture conditions and/or rarity of target cells. With advancing technology in cell sorting, single antigen-specific memory B-cells ...


Structure-Based Design Of Broadly Neutralizing Hcv Antibody And Vaccine, Brian G. Pierce, Elisabeth N. Boucher, Heidi L. Smith, William D. Thomas Jr., Zhiping Weng, Yang Wang 2014 University of Massachusetts Medical School

Structure-Based Design Of Broadly Neutralizing Hcv Antibody And Vaccine, Brian G. Pierce, Elisabeth N. Boucher, Heidi L. Smith, William D. Thomas Jr., Zhiping Weng, Yang Wang

UMass Center for Clinical and Translational Science Research Retreat

Hepatitis C virus (HCV) chronically infects nearly 200 million people worldwide. Antibodies have the potential to prevent establishment of chronic HCV infection in individuals exposed to the virus. Several broadly neutralizing monoclonal antibodies capable of binding HCV surface glycoproteins have been identified, including HCV1 identified by MassBiologics at UMMS, which targets a highly conserved linear epitope. We utilized the recently solved structure of the HCV1-bound epitope to identify regions of the antibody that could be modified to potentially improve binding to a mutation (N415K) which facilitates escape from neutralization. Based on systematic in silico mutagenesis of HCV1 residues in the ...


Detection Of Cd8+ T Cell Responses In Individuals With Long-Term Type 1 Diabetes And Generation Of Human Cd8+ T Cell Lines Specific To Islet-Associated Autoantigens, Jenny Aurielle B. Babon, David M. Harlan, Sally C. Kent 2014 University of Massachusetts Medical School

Detection Of Cd8+ T Cell Responses In Individuals With Long-Term Type 1 Diabetes And Generation Of Human Cd8+ T Cell Lines Specific To Islet-Associated Autoantigens, Jenny Aurielle B. Babon, David M. Harlan, Sally C. Kent

UMass Center for Clinical and Translational Science Research Retreat

Type 1 diabetes (T1D) is an autoimmune disease characterized by the activation of lymphocytes against insulin-producing β-cells in the pancreas. In humans, CD8+ T cells are predominantly found in sites of insulitis and are considered to be one of the main drivers of β-cell destruction, thus indicating the need to analyze the frequency and function of these autoreactive CD8+ T cells. Peripheral blood mononuclear cells (PBMC) from individuals with long-term T1D were stained ex vivo for T cell surface markers and HLA-A2 pentamers containing known islet-associated epitopes to determine if there are autoreactive CD8+ T cells circulating in the periphery ...


Anti-Ppkcθ (T538) Delivery Via Cell Penetrating Peptide Mimics As A Novel Treatment Of Aplastic Anemia, Emrah Ilker Ozay, Gabriela Gonzalez-Perez, Joe Torres, Gregory N. Tew, Lisa M. Minter 2014 University of Massachusetts Medical School

Anti-Ppkcθ (T538) Delivery Via Cell Penetrating Peptide Mimics As A Novel Treatment Of Aplastic Anemia, Emrah Ilker Ozay, Gabriela Gonzalez-Perez, Joe Torres, Gregory N. Tew, Lisa M. Minter

UMass Center for Clinical and Translational Science Research Retreat

The objective of this study is to deliver anti-pPKCθ (T538) into T cells (hPBMCs) by using cell penetrating peptide mimics (CPPMs) to neutralize PKCθ activity both in vitro and in vivo, with the eventual goal of treating aplastic anemia (AA). AA is an immune-mediated bone marrow failure disease caused by T helper type 1 (Th1) autoimmune responses, which destroy blood cell progenitors. It was previously reported that protein kinase C theta (PKCθ), expressed specifically in T cells, plays an important role in T cell signaling by mediating Th1 differentiation. Mice treated with Rottlerin, a pharmacological inhibitor of PKCθ, are rescued ...


Developing A Whole Plant Artemisia Annua Antimalarial Therapeutic: Pact, Pamela Weathers, Nicole Jordan, Praphapan Lasin, Melissa Towler, Douglas T. Golenbock, Mostafa Elfawal, Nicholas Reich, George Acquaah-Mensah, Stephen Rich 2014 University of Massachusetts Medical School

Developing A Whole Plant Artemisia Annua Antimalarial Therapeutic: Pact, Pamela Weathers, Nicole Jordan, Praphapan Lasin, Melissa Towler, Douglas T. Golenbock, Mostafa Elfawal, Nicholas Reich, George Acquaah-Mensah, Stephen Rich

UMass Center for Clinical and Translational Science Research Retreat

The GRAS plant Artemisia annua L. produces the sesquiterpene lactone, artemisinin. The current therapy for malaria is artemisinin + an older drug: artemisinin combination therapy (ACT). In Plasmodium chabaudi-infected mice, dried leaves of A. annua are more potent than equal amounts of pure artemisinin and may also prevent artemisinin drug resistance from emerging. This whole plant therapy is pACT: plant-based artemisinin combination therapy. Pharmacokinetics in healthy and infected mice given either pure artemisinin or pACT is different and showed that > 40 fold more artemisinin enters the blood when plant material is present; plant matrix enhanced bioavailability into serum. Dried leaves as ...


Use Of Cholera Toxin B As A Vaccine Adjuvant Activates Antigen Presenting Cells And Stimulates Production Of Pro-Inflammatory Cytokines, Heather C. Romlein 2014 Seton Hall University

Use Of Cholera Toxin B As A Vaccine Adjuvant Activates Antigen Presenting Cells And Stimulates Production Of Pro-Inflammatory Cytokines, Heather C. Romlein

Seton Hall University Dissertations and Theses (ETDs)

Francisella tularensis is an intracellular pathogen that has been classified as a category “A” bioterrorism agent by the Centers For Disease Control. To date, there is no approved vaccine to provide protection against this pathogen. Previous in vivo studies with mice have shown that a mucosally targeted vaccine preparation of inactivated F. tularensis (iFt) adjuvanted with Cholera toxin “B” (CTB), successfully granted full protection against a less virulent strain (FT LVS) of the bacterium and provided partial protection against a more virulent strain (SchuS4). However, the mechanisms of this protection are not fully understood. In this present study, an in ...


Natural And Exogenous Genome Editing In Wiskott-Aldrich Syndrome Patient Cells, Tamara J. Laskowski 2014 Texas Medical Center Library

Natural And Exogenous Genome Editing In Wiskott-Aldrich Syndrome Patient Cells, Tamara J. Laskowski

UT GSBS Dissertations and Theses (Open Access)

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease characterized by thrombocytopenia, recurrent infections and increased autoimmunity. This disease is caused by mutations in the WAS gene (WAS) which encodes for the WAS protein (WASp), exclusively expressed in hematopoietic cells and required for proper platelet production and lymphoid cell function. Approximately 11% of patients with WAS exhibit a phenomenon called Somatic Revertant Mosaicism which is characterized by the presence of lymphocytes which naturally revert back to normal phenotype by restoring WASp expression. To date, the mechanisms of this naturally-occurring gene therapy remains poorly understood, and the full extent of the ...


Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer 2014 University of Connecticut

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

University Scholar Projects

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed ...


Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer 2014 University of Connecticut

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

Honors Scholar Theses

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed ...


The Effect Of Fluvastatin On Mast Cell Function: Genotype Dependence, Elizabeth M. Kolawole 2014 Virginia Commonwealth University

The Effect Of Fluvastatin On Mast Cell Function: Genotype Dependence, Elizabeth M. Kolawole

Theses and Dissertations

Fluvastatin, the HMG-CoA reductase inhibitor known for its role in the treatment of hypercholesterolemia and cardiovascular disease, has more recently been shown to play a role in the immune response. Given the critical role that mast cells play in allergy and inflammatory diseases such as asthma, which effects one third of America’s population, we assessed the effect of fluvastatin on mast cell and basophils function. We demonstrate that fluvastatin downregulated IgE-mediated cytokine production. Additionally, in vivo studies showed that fluvastatin suppressed IgE-mediated anaphylaxis. Interestingly, the effects of fluvastatin showed dependence on genetic background, as C57BL/6 mast cells were ...


Construction Of A Live-Attenuated Hiv-1 Vaccine Through Genetic Code Expansion, Nanxi Wang, Yue Li, Wei Niu, Ming Sun, Ronald Cerny, Qingsheng Li, Jiantao Guo 2014 University of Nebraska - Lincoln

Construction Of A Live-Attenuated Hiv-1 Vaccine Through Genetic Code Expansion, Nanxi Wang, Yue Li, Wei Niu, Ming Sun, Ronald Cerny, Qingsheng Li, Jiantao Guo

Qingsheng Li Publications

A safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) is urgently needed to combat the worldwide AIDS pandemic, but still remains elusive. The fact that uncontrolled replication of an attenuated vaccine can lead to regaining of its virulence creates safety concerns precluding many vaccines from clinical application. We introduce a novel approach to control HIV-1 replication, which entails the manipulation of essential HIV-1 protein biosynthesis through unnatural amino acid (UAA*)-mediated suppression of genome-encoded blank codon. We successfully demonstrate that HIV-1 replication can be precisely turned on and off in vitro.

Includes supporting information.


Serum Cytokine Profiles Associated With Specific Adjuvants Used In A Dna Prime-Protein Boost Vaccination Strategy, Rachel Buglione-Corbett, Kimberly Lea Pouliot, Robyn Lynn Marty-Roix, Kim West, Shixia Wang, Egil Lien, Shan Lu 2013 University of Massachusetts Medical School

Serum Cytokine Profiles Associated With Specific Adjuvants Used In A Dna Prime-Protein Boost Vaccination Strategy, Rachel Buglione-Corbett, Kimberly Lea Pouliot, Robyn Lynn Marty-Roix, Kim West, Shixia Wang, Egil Lien, Shan Lu

Open Access Articles

In recent years, heterologous prime-boost vaccines have been demonstrated to be an effective strategy for generating protective immunity, consisting of both humoral and cell-mediated immune responses against a variety of pathogens including HIV-1. Previous reports of preclinical and clinical studies have shown the enhanced immunogenicity of viral vector or DNA vaccination followed by heterologous protein boost, compared to using either prime or boost components alone. With such approaches, the selection of an adjuvant for inclusion in the protein boost component is expected to impact the immunogenicity and safety of a vaccine. In this study, we examined in a mouse model ...


Modulating Influenza And Heparin Binding Viruses’ Pathogenesis With Extrinsic Receptor Decoy Liposomes: A Dissertation, Gabriel L. Hendricks 2013 University of Massachusetts Medical School

Modulating Influenza And Heparin Binding Viruses’ Pathogenesis With Extrinsic Receptor Decoy Liposomes: A Dissertation, Gabriel L. Hendricks

GSBS Dissertations and Theses

Influenza is a severe disease in humans and animals, causing upwards of 40,000 deaths every year in America alone. Influenza A virus (IAV) also causes periodic pandemics every 10 to 50 years, killing millions of people. Despite this, very few effective therapies are available. All strains of IAV are prone to developing resistance to antibodies due to the high mutation rate in the viral genome. Because of this mutation rate, a yearly vaccine must be generated before every flu season, and efficacy varies year to year. IAV has also mutated to escape several of the clinically-approved small molecule inhibitors ...


Identification Of A Human Monoclonal Antibody To Replace Equine Diphtheria Anti-Toxin For The Treatment Of Diphtheria, Leila M. Sevigny, Brian J. Booth, Kirk J. Rowley, Brett A. Leav, Peter S. Cheslock, Kerry A. Garrity, Susan Sloan, Gregory J. Babcock, William D. Thomas, Mark Klempner, Yang Wang 2013 University of Massachusetts Medical School

Identification Of A Human Monoclonal Antibody To Replace Equine Diphtheria Anti-Toxin For The Treatment Of Diphtheria, Leila M. Sevigny, Brian J. Booth, Kirk J. Rowley, Brett A. Leav, Peter S. Cheslock, Kerry A. Garrity, Susan Sloan, Gregory J. Babcock, William D. Thomas, Mark Klempner, Yang Wang

UMass Center for Clinical and Translational Science Research Retreat

Diphtheria anti-toxin (DAT) has been used to treat Corynebacterium diphtheriae infection for over one hundred years. While the global incidence of diphtheria has declined in the 20th century, the disease remains endemic in many parts of the world and significant outbreaks still occur. Diphtheria anti-toxin is an equine polyclonal antibody with considerable side effects that is in critically short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we cloned human monoclonal antibodies (HuMabs) directly from antibody secreting cells of human volunteers immunized with Td vaccine. We isolated a diverse panel of ...


Novel Imaging-Based Techniques Reveal A Role For Pd-1/Pd-L1 In Tumor Immune Surveillance In The Lung, Todd Bartkowiak 2013 Texas Medical Center Library

Novel Imaging-Based Techniques Reveal A Role For Pd-1/Pd-L1 In Tumor Immune Surveillance In The Lung, Todd Bartkowiak

UT GSBS Dissertations and Theses (Open Access)

The binding of immune inhibitory receptor Programmed Death 1 (PD-1) on T cells to its ligand PD-L1 has been implicated as a major contributor to tumor induced immune suppression. Clinical trials of PD-L1 blockade have proven effective in unleashing therapeutic anti-tumor immune responses in a subset of patients with advanced melanoma, yet current response rates are low for reasons that remain unclear. Hypothesizing that the PD-1/PD-L1 pathway regulates T cell surveillance within the tumor microenvironment, we employed intravital microscopy to investigate the in vivo impact of PD-L1 blocking antibody upon tumor-associated immune cell migration. However, current analytical methods of ...


Adjuvant-Specific Serum Cytokine Profiles In The Context Of A Dna Prime-Protein Boost Hiv-1 Vaccine: A Dissertation, Rachel Buglione-Corbett 2013 University of Massachusetts Medical School

Adjuvant-Specific Serum Cytokine Profiles In The Context Of A Dna Prime-Protein Boost Hiv-1 Vaccine: A Dissertation, Rachel Buglione-Corbett

GSBS Dissertations and Theses

In recent years, heterologous prime-boost vaccination constructs have emerged as a promising strategy to generate broad and protective immunity against a variety of pathogens. The utility of DNA vaccination in priming the immune system, in particular, has improved the immunogenicity of vaccines against difficult pathogens such as HIV-1. In addition, many vaccine formulations include an adjuvant to augment immune responses. However, the mechanisms and profiles of many adjuvants remain largely unknown, particularly in the context of such combination immunization approaches.

My thesis research studied the effects of several adjuvants, QS-21, aluminum hydroxide, MPL, and ISCOMATRIX™ adjuvant in the context of ...


Identification Of Human Monoclonal Antibodies Specific For Human Sod1 Recognizing Distinct Epitopes And Forms Of Sod1, Teresa J. Broering, Hongyan Wang, Naomi K. Boatright, Yang Wang, Katherine Baptista, Gilda Shayan, Kerry A. Garrity, Can Kayatekin, Daryl A. Bosco, C. Robert Matthews, Donna M. Ambrosino, Zuoshang Xu, Gregory J. Babcock 2013 University of Massachusetts Medical School

Identification Of Human Monoclonal Antibodies Specific For Human Sod1 Recognizing Distinct Epitopes And Forms Of Sod1, Teresa J. Broering, Hongyan Wang, Naomi K. Boatright, Yang Wang, Katherine Baptista, Gilda Shayan, Kerry A. Garrity, Can Kayatekin, Daryl A. Bosco, C. Robert Matthews, Donna M. Ambrosino, Zuoshang Xu, Gregory J. Babcock

University of Massachusetts Medical School Faculty Publications

Mutations in the gene encoding human SOD1 (hSOD1) can cause amyotrophic lateral sclerosis (ALS) yet the mechanism by which mutant SOD1 can induce ALS is not fully understood. There is currently no cure for ALS or treatment that significantly reduces symptoms or progression. To develop tools to understand the protein conformations present in mutant SOD1-induced ALS and as possible immunotherapy, we isolated and characterized eleven unique human monoclonal antibodies specific for hSOD1. Among these, five recognized distinct linear epitopes on hSOD1 that were not available in the properly-folded protein but were available on forms of protein with some degree of ...


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