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Immunoprophylaxis and Therapy Commons

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The Hunt For Protective Correlates Of Immunity To Plasmodium Falciparum Malaria, Ann M. Moormann, V. Ann Stewart 2014 University of Massachusetts Medical School

The Hunt For Protective Correlates Of Immunity To Plasmodium Falciparum Malaria, Ann M. Moormann, V. Ann Stewart

Open Access Articles

Determining an immunologic correlate of protection against Plasmodium falciparum malaria has been the holy grail of natural infection studies, and sought after as an endpoint for malaria vaccine trials. An in vitro assay that provides an accurate and precise assessment of protective immunity to malaria would make smaller, short-duration studies feasible, rather than the currently powered study designs that use morbidity or mortality as outcomes. Such a biomarker would be especially desirable in situations where malaria control measures that result in decreases in clinical endpoints and putatively waning protective immunity have been implemented. In an article published in BMC Medicine ...


An Unstable Th Epitope Of P. Falciparum Fosters Central Memory T Cells And Anti-Cs Antibody Responses, Carlos A. Parra-Lopez, David Bernal -Estevez, Luis Eduardo Eduardo Vargas, Carolina Pulido -Calixto, Luz Mary Salazar, J. Mauricio Calvo-Calle, Lawrence J. Stern 2014 University of Massachusetts Medical School

An Unstable Th Epitope Of P. Falciparum Fosters Central Memory T Cells And Anti-Cs Antibody Responses, Carlos A. Parra-Lopez, David Bernal -Estevez, Luis Eduardo Eduardo Vargas, Carolina Pulido -Calixto, Luz Mary Salazar, J. Mauricio Calvo-Calle, Lawrence J. Stern

University of Massachusetts Medical School Faculty Publications

Malaria is transmitted by Plasmodium-infected anopheles mosquitoes. Widespread resistance of mosquitoes to insecticides and resistance of parasites to drugs highlight the urgent need for malaria vaccines. The most advanced malaria vaccines target sporozoites, the infective form of the parasite. A major target of the antibody response to sporozoites are the repeat epitopes of the circumsporozoite (CS) protein, which span almost one half of the protein. Antibodies to these repeats can neutralize sporozoite infectivity. Generation of protective antibody responses to the CS protein (anti-CS Ab) requires help by CD4 T cells. A CD4 T cell epitope from the CS protein designated ...


Protective Immunity And Safety Of A Genetically Modified Influenza Virus Vaccine, Rafael Polidoro Alves Barbosa, Ana Paula Carneiro Salgado, Cristiana Couto Garcia, Bruno Galvao Filho, Ana Paula de Faria Paula de Faria Goncalves, Braulio Henrique Freire Lima, Gabriel Augusto Oliveira Lopes, Milene Alvarenga Rachid, Andiara Cristina Cardoso Peixoto, Danilo Bretas de Oliveira, Marco Antonio Ataide, Carla Aparecida Zirke, Tatiane Marques Cotrim, Erica Azevedo Costa, Gabriel Magno de Freitas Almeida, Remo Castro Russo, Ricardo T. Gazzinelli, Alexandre de Magalhaes Vieira Machado 2014 University of Massachusetts Medical School

Protective Immunity And Safety Of A Genetically Modified Influenza Virus Vaccine, Rafael Polidoro Alves Barbosa, Ana Paula Carneiro Salgado, Cristiana Couto Garcia, Bruno Galvao Filho, Ana Paula De Faria Paula De Faria Goncalves, Braulio Henrique Freire Lima, Gabriel Augusto Oliveira Lopes, Milene Alvarenga Rachid, Andiara Cristina Cardoso Peixoto, Danilo Bretas De Oliveira, Marco Antonio Ataide, Carla Aparecida Zirke, Tatiane Marques Cotrim, Erica Azevedo Costa, Gabriel Magno De Freitas Almeida, Remo Castro Russo, Ricardo T. Gazzinelli, Alexandre De Magalhaes Vieira Machado

University of Massachusetts Medical School Faculty Publications

Recombinant influenza viruses are promising viral platforms to be used as antigen delivery vectors. To this aim, one of the most promising approaches consists of generating recombinant viruses harboring partially truncated neuraminidase (NA) segments. To date, all studies have pointed to safety and usefulness of this viral platform. However, some aspects of the inflammatory and immune responses triggered by those recombinant viruses and their safety to immunocompromised hosts remained to be elucidated. In the present study, we generated a recombinant influenza virus harboring a truncated NA segment (vNA-Delta) and evaluated the innate and inflammatory responses and the safety of this ...


Circulating Levels Of Soluble Micb In Infants With Symptomatic Primary Dengue Virus Infections, Daniel H. Libraty, Lei Zhang, AnaMae Obcena, Job D. Brion, Rosario Z. Capeding 2014 University of Massachusetts Medical School

Circulating Levels Of Soluble Micb In Infants With Symptomatic Primary Dengue Virus Infections, Daniel H. Libraty, Lei Zhang, Anamae Obcena, Job D. Brion, Rosario Z. Capeding

University of Massachusetts Medical School Faculty Publications

Dengue is the most prevalent arthropod-borne viral illness in humans. A MHC class I polypeptide-related sequence B (MICB) single nucleotide polymorphism (SNP) was previously associated with symptomatic dengue compared to non-dengue causes of acute febrile illnesses in infants. We measured circulating levels of soluble (s)MICB in the sera of infants with symptomatic primary dengue virus infections. We found that serum levels of sMICB increased between pre-infection and acute illness among infants with symptomatic primary dengue virus infections. The likelihood of being hospitalized with an acute primary DENV infection during infancy also tended to be higher with increasing acute illness ...


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 ...


A Population Of Langerin-Positive Dendritic Cells In Murine Peyer's Patches Involved In Sampling Beta-Glucan Microparticles, Magdia De Jesus, Gary R. Ostroff, Stuart M. Levitz, Toni R. Bartling, Nicholas J. Mantis 2014 University of Massachusetts Medical School

A Population Of Langerin-Positive Dendritic Cells In Murine Peyer's Patches Involved In Sampling Beta-Glucan Microparticles, Magdia De Jesus, Gary R. Ostroff, Stuart M. Levitz, Toni R. Bartling, Nicholas J. Mantis

University of Massachusetts Medical School Faculty Publications

Glucan particles (GPs) are 2-4 mum hollow, porous shells composed of 1,3-beta-D-glucan that have been effectively used for oral targeted-delivery of a wide range of payloads, including small molecules, siRNA, DNA, and protein antigens. While it has been demonstrated that the transepithelial transport of GPs is mediated by Peyer's patch M cells, the fate of the GPs once within gut-associated lymphoid tissue (GALT) is not known. Here we report that fluorescently labeled GPs administered to mice by gavage accumulate in CD11c+ DCs situated in Peyer's patch sub-epithelial dome (SED) regions. GPs appeared in DCs within minutes after ...


Blockade Of The Programmed Death-1 (Pd1) Pathway Undermines Potent Genetic Protection From Type 1 Diabetes, Nora M. Kochupurakkal, Annie J. Kruger, Sudipta Tripathi, Bing Zhu, La Tonya Adams, Daniel B. Rainbow, Aldo A. Rossini, Dale L. Greiner, Mohamed H. Sayegh, Linda S. Wicker, Indira Guleria 2014 University of Massachusetts Medical School

Blockade Of The Programmed Death-1 (Pd1) Pathway Undermines Potent Genetic Protection From Type 1 Diabetes, Nora M. Kochupurakkal, Annie J. Kruger, Sudipta Tripathi, Bing Zhu, La Tonya Adams, Daniel B. Rainbow, Aldo A. Rossini, Dale L. Greiner, Mohamed H. Sayegh, Linda S. Wicker, Indira Guleria

University of Massachusetts Medical School Faculty Publications

AIMS/HYPOTHESIS: Inhibition of PD1-PDL1 signaling in NOD mice accelerates onset of type 1 diabetes implicating this pathway in suppressing the emergence of pancreatic beta cell reactive T-cells. However, the molecular mechanism by which PD1 signaling protects from type 1 diabetes is not clear. We hypothesized that differential susceptibility of Idd mouse strains to type 1 diabetes when challenged with anti PDL1 will identify genomic loci that collaborate with PD1 signaling in suppressing type 1 diabetes.

METHODS: Anti PDL1 was administered to NOD and various Idd mouse strains at 10 weeks of age and onset of disease was monitored by ...


Influenza Virus Drug Resistance: A Time-Sampled Population Genetics Perspective, Matthieu Foll, Yu Ping Poh, Nicholas Renzette, Anna Ferrer Admetlla, Claudia Bank, Hyunjin Shim, Anna Sapfo Malaspinas, Gregory Ewing, Ping Liu, Daniel Wegmann, Daniel R. Caffrey, Konstantin B. Zeldovich, Daniel N. A. Bolon, Jennifer Wang, Timothy F. Kowalik, Celia A. Schiffer, Robert W. Finberg, Jeffrey D. Jensen 2014 University of Massachusetts Medical School

Influenza Virus Drug Resistance: A Time-Sampled Population Genetics Perspective, Matthieu Foll, Yu Ping Poh, Nicholas Renzette, Anna Ferrer Admetlla, Claudia Bank, Hyunjin Shim, Anna Sapfo Malaspinas, Gregory Ewing, Ping Liu, Daniel Wegmann, Daniel R. Caffrey, Konstantin B. Zeldovich, Daniel N. A. Bolon, Jennifer Wang, Timothy F. Kowalik, Celia A. Schiffer, Robert W. Finberg, Jeffrey D. Jensen

University of Massachusetts Medical School Faculty Publications

The challenge of distinguishing genetic drift from selection remains a central focus of population genetics. Time-sampled data may provide a powerful tool for distinguishing these processes, and we here propose approximate Bayesian, maximum likelihood, and analytical methods for the inference of demography and selection from time course data. Utilizing these novel statistical and computational tools, we evaluate whole-genome datasets of an influenza A H1N1 strain in the presence and absence of oseltamivir (an inhibitor of neuraminidase) collected at thirteen time points. Results reveal a striking consistency amongst the three estimation procedures developed, showing strongly increased selection pressure in the presence ...


Computational Design Of The Affinity And Specificity Of A Therapeutic T Cell Receptor, Brian G. Pierce, Lance M. Hellman, Moushumi Hossain, Nishant K. Singh, Craig W. Vander Kooi, Zhiping Weng, Brian M. Baker 2014 University of Massachusetts Medical School

Computational Design Of The Affinity And Specificity Of A Therapeutic T Cell Receptor, Brian G. Pierce, Lance M. Hellman, Moushumi Hossain, Nishant K. Singh, Craig W. Vander Kooi, Zhiping Weng, Brian M. Baker

University of Massachusetts Medical School Faculty Publications

T cell receptors (TCRs) are key to antigen-specific immunity and are increasingly being explored as therapeutics, most visibly in cancer immunotherapy. As TCRs typically possess only low-to-moderate affinity for their peptide/MHC (pMHC) ligands, there is a recognized need to develop affinity-enhanced TCR variants. Previous in vitro engineering efforts have yielded remarkable improvements in TCR affinity, yet concerns exist about the maintenance of peptide specificity and the biological impacts of ultra-high affinity. As opposed to in vitro engineering, computational design can directly address these issues, in theory permitting the rational control of peptide specificity together with relatively controlled increments in ...


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