Therapeutic Antibodies

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James E. Crowe - One of the best experts on this subject based on the ideXlab platform.

  • Structures of Ebola virus GP and sGP in complex with Therapeutic Antibodies
    Nature Microbiology, 2016
    Co-Authors: Jesper Pallesen, Charles D. Murin, Natalia De Val, Christopher A. Cottrell, Kathryn M. Hastie, Hannah L. Turner, Marnie L. Fusco, Andrew I. Flyak, Larry Zeitlin, James E. Crowe
    Abstract:

    The Ebola virus (EBOV) GP gene encodes two glycoproteins. The major product is a soluble, dimeric glycoprotein (sGP) that is secreted abundantly. Despite the abundance of sGP during infection, little is known regarding its structure or functional role. A minor product, resulting from transcriptional editing, is the transmembrane-anchored, trimeric viral surface glycoprotein (GP). GP mediates attachment to and entry into host cells, and is the intended target of antibody Therapeutics. Because large portions of sequence are shared between GP and sGP, it has been hypothesized that sGP may potentially subvert the immune response or may contribute to pathogenicity. In this study, we present cryo-electron microscopy structures of GP and sGP in complex with GP-specific and GP/sGP cross-reactive Antibodies undergoing human clinical trials. The structure of the sGP dimer presented here, in complex with both an sGP-specific antibody and a GP/sGP cross-reactive antibody, permits us to unambiguously assign the oligomeric arrangement of sGP and compare its structure and epitope presentation to those of GP. We also provide biophysical evaluation of naturally occurring GP/sGP mutations that fall within the footprints identified by our high-resolution structures. Taken together, our data provide a detailed and more complete picture of the accessible Ebolavirus glycoprotein landscape and a structural basis to evaluate patient and vaccine antibody responses towards differently structured products of the GP gene. The cryoEM structures of Ebola virus GP and sGP in complex with GP-specific and GP/sGP cross-reactive Antibodies provides insight into the oligomeric arrangement of sGP and a comparison of its structure and epitope presentation with GP.

  • structures of ebola virus gp and sgp in complex with Therapeutic Antibodies
    Nature microbiology, 2016
    Co-Authors: Jesper Pallesen, Charles D. Murin, Natalia De Val, Christopher A. Cottrell, Kathryn M. Hastie, Hannah L. Turner, Marnie L. Fusco, Andrew I. Flyak, Larry Zeitlin, James E. Crowe
    Abstract:

    The Ebola virus (EBOV) GP gene encodes two glycoproteins. The major product is a soluble, dimeric glycoprotein (sGP) that is secreted abundantly. Despite the abundance of sGP during infection, little is known regarding its structure or functional role. A minor product, resulting from transcriptional editing, is the transmembrane-anchored, trimeric viral surface glycoprotein (GP). GP mediates attachment to and entry into host cells, and is the intended target of antibody Therapeutics. Because large portions of sequence are shared between GP and sGP, it has been hypothesized that sGP may potentially subvert the immune response or may contribute to pathogenicity. In this study, we present cryo-electron microscopy structures of GP and sGP in complex with GP-specific and GP/sGP cross-reactive Antibodies undergoing human clinical trials. The structure of the sGP dimer presented here, in complex with both an sGP-specific antibody and a GP/sGP cross-reactive antibody, permits us to unambiguously assign the oligomeric arrangement of sGP and compare its structure and epitope presentation to those of GP. We also provide biophysical evaluation of naturally occurring GP/sGP mutations that fall within the footprints identified by our high-resolution structures. Taken together, our data provide a detailed and more complete picture of the accessible Ebolavirus glycoprotein landscape and a structural basis to evaluate patient and vaccine antibody responses towards differently structured products of the GP gene.

Jeffrey Easthamanderson - One of the best experts on this subject based on the ideXlab platform.

  • Therapeutic Antibodies reveal notch control of transdifferentiation in the adult lung
    Nature, 2015
    Co-Authors: Daniel Lafkas, Cecilia Chiu, Gladys De Leon Boenig, Christian Siltanen, Meijuan Zhou, Scott Stawicki, Amy L. Shelton, Yongmei Chen, Mike Reichelt, Jeffrey Easthamanderson
    Abstract:

    Prevailing dogma holds that cell-cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed. Mucociliary clearance in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor. In contrast to such situations in which cell fate decisions are made in rapidly dividing populations, cells of the homeostatic adult airway epithelium are long-lived, and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a Therapeutic foundation. Our discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation.

Jesper Pallesen - One of the best experts on this subject based on the ideXlab platform.

  • Structures of Ebola virus GP and sGP in complex with Therapeutic Antibodies
    Nature Microbiology, 2016
    Co-Authors: Jesper Pallesen, Charles D. Murin, Natalia De Val, Christopher A. Cottrell, Kathryn M. Hastie, Hannah L. Turner, Marnie L. Fusco, Andrew I. Flyak, Larry Zeitlin, James E. Crowe
    Abstract:

    The Ebola virus (EBOV) GP gene encodes two glycoproteins. The major product is a soluble, dimeric glycoprotein (sGP) that is secreted abundantly. Despite the abundance of sGP during infection, little is known regarding its structure or functional role. A minor product, resulting from transcriptional editing, is the transmembrane-anchored, trimeric viral surface glycoprotein (GP). GP mediates attachment to and entry into host cells, and is the intended target of antibody Therapeutics. Because large portions of sequence are shared between GP and sGP, it has been hypothesized that sGP may potentially subvert the immune response or may contribute to pathogenicity. In this study, we present cryo-electron microscopy structures of GP and sGP in complex with GP-specific and GP/sGP cross-reactive Antibodies undergoing human clinical trials. The structure of the sGP dimer presented here, in complex with both an sGP-specific antibody and a GP/sGP cross-reactive antibody, permits us to unambiguously assign the oligomeric arrangement of sGP and compare its structure and epitope presentation to those of GP. We also provide biophysical evaluation of naturally occurring GP/sGP mutations that fall within the footprints identified by our high-resolution structures. Taken together, our data provide a detailed and more complete picture of the accessible Ebolavirus glycoprotein landscape and a structural basis to evaluate patient and vaccine antibody responses towards differently structured products of the GP gene. The cryoEM structures of Ebola virus GP and sGP in complex with GP-specific and GP/sGP cross-reactive Antibodies provides insight into the oligomeric arrangement of sGP and a comparison of its structure and epitope presentation with GP.

  • structures of ebola virus gp and sgp in complex with Therapeutic Antibodies
    Nature microbiology, 2016
    Co-Authors: Jesper Pallesen, Charles D. Murin, Natalia De Val, Christopher A. Cottrell, Kathryn M. Hastie, Hannah L. Turner, Marnie L. Fusco, Andrew I. Flyak, Larry Zeitlin, James E. Crowe
    Abstract:

    The Ebola virus (EBOV) GP gene encodes two glycoproteins. The major product is a soluble, dimeric glycoprotein (sGP) that is secreted abundantly. Despite the abundance of sGP during infection, little is known regarding its structure or functional role. A minor product, resulting from transcriptional editing, is the transmembrane-anchored, trimeric viral surface glycoprotein (GP). GP mediates attachment to and entry into host cells, and is the intended target of antibody Therapeutics. Because large portions of sequence are shared between GP and sGP, it has been hypothesized that sGP may potentially subvert the immune response or may contribute to pathogenicity. In this study, we present cryo-electron microscopy structures of GP and sGP in complex with GP-specific and GP/sGP cross-reactive Antibodies undergoing human clinical trials. The structure of the sGP dimer presented here, in complex with both an sGP-specific antibody and a GP/sGP cross-reactive antibody, permits us to unambiguously assign the oligomeric arrangement of sGP and compare its structure and epitope presentation to those of GP. We also provide biophysical evaluation of naturally occurring GP/sGP mutations that fall within the footprints identified by our high-resolution structures. Taken together, our data provide a detailed and more complete picture of the accessible Ebolavirus glycoprotein landscape and a structural basis to evaluate patient and vaccine antibody responses towards differently structured products of the GP gene.

Daniel Lafkas - One of the best experts on this subject based on the ideXlab platform.

  • Therapeutic Antibodies reveal notch control of transdifferentiation in the adult lung
    Nature, 2015
    Co-Authors: Daniel Lafkas, Cecilia Chiu, Gladys De Leon Boenig, Christian Siltanen, Meijuan Zhou, Scott Stawicki, Amy L. Shelton, Yongmei Chen, Mike Reichelt, Jeffrey Easthamanderson
    Abstract:

    Prevailing dogma holds that cell-cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed. Mucociliary clearance in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor. In contrast to such situations in which cell fate decisions are made in rapidly dividing populations, cells of the homeostatic adult airway epithelium are long-lived, and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a Therapeutic foundation. Our discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation.

  • Therapeutic Antibodies reveal Notch control of transdifferentiation in the adult lung
    Nature, 2015
    Co-Authors: Daniel Lafkas, Cecilia Chiu, Gladys De Leon Boenig, Christian Siltanen, Meijuan Zhou, Scott Stawicki, Amy L. Shelton, Yongmei Chen, Mike Reichelt, Xiumin Wu
    Abstract:

    Inhibitory Antibodies to two specific human and mouse Notch ligands, Jagged1 and Jagged2, are generated and shown to have beneficial effects in a goblet cell metaplasia asthma model; systemic Jagged1 inhibition transdifferentiates secretory cells into ciliated cells in the mouse, demonstrating that Jagged1 from ciliated cells normally holds back secretory cells to adopt the ciliated fate. Notch signalling in cells of the mammalian airways dictates the differentiation of progenitors to secretory or ciliated cells, two major cell types of this tissue. Christian Siebel and colleagues have prepared inhibitory mouse and human Antibodies to two specific Notch ligands, JAG1 and JAG2. They make the surprising discovery that JAG1 inhibition following injection promotes the conversion of secretory cells to ciliated cells in the mouse, demonstrating that JAG1 from ciliated cells normally holds back differentiated secretory cells from adopting this ciliated fate. These Antibodies have beneficial effects in a mouse asthma model, converting mucus-producing cells into ciliated cells. Prevailing dogma holds that cell–cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed1. Mucociliary clearance2,3 in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor4,5,6,7,8. In contrast to such situations in which cell fate decisions are made in rapidly dividing populations9,10, cells of the homeostatic adult airway epithelium are long-lived11,12,13, and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation14. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a Therapeutic foundation15. Our discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation.

Sang Taek Jung - One of the best experts on this subject based on the ideXlab platform.

  • Engineering Therapeutic Antibodies targeting G-protein–coupled receptors
    Experimental & Molecular Medicine, 2016
    Co-Authors: Migyeong Jo, Sang Taek Jung
    Abstract:

    G-protein–coupled receptors (GPCRs) are one of the most attractive Therapeutic target classes because of their critical roles in intracellular signaling and their clinical relevance to a variety of diseases, including cancer, infection and inflammation. However, high conformational variability, the small exposed area of extracellular epitopes and difficulty in the preparation of GPCR antigens have delayed both the isolation of Therapeutic anti-GPCR Antibodies as well as studies on the structure, function and biochemical mechanisms of GPCRs. To overcome the challenges in generating highly specific anti-GPCR Antibodies with enhanced efficacy and safety, various forms of antigens have been successfully designed and employed for screening with newly emerged systems based on laboratory animal immunization and high-throughput-directed evolution.Antibody therapy: Targeting cell surface receptorsAntibody therapy that targets frequently occuring cellular receptors has become a possibility for the treatment of diverse diseases. Treatment with Therapeutic Antibodies has proven highly effective in several clinical settings. G-protein coupled receptors (GPCRs) are prime targets of such therapy, as there are over 800 different GPCRs, all crucial to cell signalling pathways. However, difficulty in isolating GPCRs from cells has prevented development of Antibodies that target them. Migyeong Jo and San Taek Jung from Kookmin University, Korea, have reviewed new approaches to isolating GPCRs and synthesizing GPCR mimics that induce antibody production. Such advances have led to approval of one Therapeutic antibody in Japan and to several clinical trials in the US and Europe. The authors predict that GPCR antibody therapy could be used to treat cancer, infection and inflammation in the near future.

  • Engineering Therapeutic Antibodies targeting G-protein–coupled receptors
    Experimental & Molecular Medicine, 2016
    Co-Authors: Migyeong Jo, Sang Taek Jung
    Abstract:

    G-protein–coupled receptors (GPCRs) are one of the most attractive Therapeutic target classes because of their critical roles in intracellular signaling and their clinical relevance to a variety of diseases, including cancer, infection and inflammation. However, high conformational variability, the small exposed area of extracellular epitopes and difficulty in the preparation of GPCR antigens have delayed both the isolation of Therapeutic anti-GPCR Antibodies as well as studies on the structure, function and biochemical mechanisms of GPCRs. To overcome the challenges in generating highly specific anti-GPCR Antibodies with enhanced efficacy and safety, various forms of antigens have been successfully designed and employed for screening with newly emerged systems based on laboratory animal immunization and high-throughput-directed evolution. Antibody therapy that targets frequently occuring cellular receptors has become a possibility for the treatment of diverse diseases. Treatment with Therapeutic Antibodies has proven highly effective in several clinical settings. G-protein coupled receptors (GPCRs) are prime targets of such therapy, as there are over 800 different GPCRs, all crucial to cell signalling pathways. However, difficulty in isolating GPCRs from cells has prevented development of Antibodies that target them. Migyeong Jo and San Taek Jung from Kookmin University, Korea, have reviewed new approaches to isolating GPCRs and synthesizing GPCR mimics that induce antibody production. Such advances have led to approval of one Therapeutic antibody in Japan and to several clinical trials in the US and Europe. The authors predict that GPCR antibody therapy could be used to treat cancer, infection and inflammation in the near future.

  • Tailoring immunoglobulin Fc for highly potent and serum-stable Therapeutic Antibodies
    Biotechnology and Bioprocess Engineering, 2013
    Co-Authors: Sang Taek Jung
    Abstract:

    Antibody Fc region, a recruiter and a frontline commander in the combat against cancer and infectious pathogens, mediates potent immune effector functions by engaging Fc receptors and serum complement proteins. Recent studies indicate that the Fc region is particularly amenable to modifications that enhance potency and serum stability through amino acid substitution and glycan modification. In order to modulate the interaction of the Fc domain with Fc-binding ligands (FcγRs, C1q, and FcRn), various engineering strategies have been employed; these studies are discussed in this review.