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1. Rational design of universal immunotherapy for TfR1-tropic arenaviruses

Author

Thomas W. Geisbert, Vered Padler-Karavani, Sylvain Baize, Hadas Cohen-Dvashi, Ron Amon, Krystle N. Agans, Aliza Borenstein-Katz, Ron Diskin, Robert W. Cross, Mathieu Mateo, Weizmann Institute of Science [Rehovot, Israël], Tel Aviv University (TAU), The University of Texas Medical Branch (UTMB), Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), BSL-4 experiments using MACV were supported by the Pasteur-Weizmann joint research program collaborative research grant S-CR18069-02 to M.M. and R.D. BSL-4 operations of the Galveston National Laboratory and Department of Microbiology and Immunology are supported by NIAID/NIH Grant No. UC7AI094660 to T.W.G. The lab of R.D. is supported by research grants from the Enoch Foundation, from the Abramson Family Center for Young Scientists, from Ms. Rudolfine Steindling, and from the I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation (grants no. 1775/12 and 682/16)., Tel Aviv University [Tel Aviv], Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), and Bodescot, Myriam

Subjects
0301 basic medicine, New World Arenavirus, Viral protein, medicine.medical_treatment, Science, viruses, General Physics and Astronomy, Transferrin receptor, Biologics, Biology, Antibodies, Viral, medicine.disease_cause, Article, General Biochemistry, Genetics and Molecular Biology, Viral Proteins, 03 medical and health sciences, 0302 clinical medicine, Virology, Receptors, Transferrin, medicine, Arenaviridae Infections, Humans, lcsh:Science, X-ray crystallography, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Multidisciplinary, Transmission (medicine), Rational design, virus diseases, Arenavirus, General Chemistry, Immunotherapy, Antibodies, Neutralizing, Arenaviruses, 3. Good health, Hemorrhagic Fevers, 030104 developmental biology, Drug Design, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Biological warfare, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Receptors, Virus, lcsh:Q, 030217 neurology & neurosurgery
Abstract

Certain arenaviruses that circulate in rodent populations can cause life-threatening hemorrhagic fevers when they infect humans. Due to their efficient transmission, arenaviruses pose a severe risk for outbreaks and might be exploited as biological weapons. Effective countermeasures against these viruses are highly desired. Ideally, a single remedy would be effective against many or even all the pathogenic viruses in this family. However, despite the fact that all pathogenic arenaviruses from South America utilize transferrin receptor 1 (TfR1) as a cellular receptor, their viral glycoproteins are highly diversified, impeding efforts to isolate cross-neutralizing antibodies. Here we address this problem using a rational design approach to target TfR1-tropic arenaviruses with high potency and breadth. The pan-reactive molecule is highly effective against all arenaviruses that were tested, offering a universal therapeutic approach. Our design scheme avoids the shortcomings of previous immunoadhesins and can be used to combat other zoonotic pathogens., New World arenaviruses utilize the cellular transferrin receptor 1 (TfR1) to enter host cells. Here, the authors develop a TfR1-mimetic immunoadhesin, Arenacept, that targets viral spike complexes and exerts effective pan-reactive neutralization against pathogenic mammarenaviruses.

Published
2020
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2. The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration

Author

Thomas Senage, Anu Paul, Thierry Le Tourneau, Imen Fellah-Hebia, Marta Vadori, Salam Bashir, Manuel Galiñanes, Tomaso Bottio, Gino Gerosa, Arturo Evangelista, Luigi P. Badano, Alberto Nassi, Cristina Costa, Galli Cesare, Rizwan A. Manji, Caroline Cueff de Monchy, Nicolas Piriou, Romain Capoulade, Jean-Michel Serfaty, Guillaume Guimbretière, Etienne Dantan, Alejandro Ruiz-Majoral, Guénola Coste du Fou, Shani Leviatan Ben-Arye, Liana Govani, Sharon Yehuda, Shirley Bachar Abramovitch, Ron Amon, Eliran Moshe Reuven, Yafit Atiya-Nasagi, Hai Yu, Laura Iop, Kelly Casós, Sebastián G. Kuguel, Arnau Blasco-Lucas, Eduard Permanyer, Fabrizio Sbraga, Roger Llatjós, Gabriel Moreno-Gonzalez, Melchor Sánchez-Martínez, Michael E. Breimer, Jan Holgersson, Susann Teneberg, Marta Pascual-Gilabert, Alfons Nonell-Canals, Yasuhiro Takeuchi, Xi Chen, Rafael Mañez, Jean-Christian Roussel, Jean-Paul Soulillou, Emanuele Cozzi, Vered Padler-Karavani, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR des Sciences Pharmaceutiques et Biologiques (Nantes Université - UFR Pharmacie), Tel Aviv University (TAU), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Università degli Studi di Padova = University of Padua (Unipd), Universitat Autònoma de Barcelona (UAB), Vall d'Hebron University Hospital [Barcelona], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Llobregat Hospital [Barcelona], Fondazione Avantea [Cremona, Italy], St. Boniface Hospital Albrechtsen Research Centre [Winnipeg], Israel Institute for Biological Research (IIBR), University of California [Davis] (UC Davis), University of California (UC), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Quironsalud Teknon Heart Institute [Barcelona, Spain] (QTHI), Mind the Byte [Barcelona, Spain], Molomics [Barcelona, Spain], Sahlgrenska Academy at University of Gothenburg [Göteborg], Institut Universitari de Ciència i Tecnologia [Barcelona, Spain] ((Inkemia Group) IUCT), DevsHealth [Barcelona, Spain] (DH), University College of London [London] (UCL), Bellvitge University Hospital [Barcelona, Spain], Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Dantan, Etienne, Senage, T, Paul, A, Le Tourneau, T, Fellah-Hebia, I, Vadori, M, Bashir, S, Galinanes, M, Bottio, T, Gerosa, G, Evangelista, A, Badano, L, Nassi, A, Costa, C, Cesare, G, Manji, R, Cueff de Monchy, C, Piriou, N, Capoulade, R, Serfaty, J, Guimbretiere, G, Dantan, E, Ruiz-Majoral, A, Coste du Fou, G, Leviatan Ben-Arye, S, Govani, L, Yehuda, S, Bachar Abramovitch, S, Amon, R, Reuven, E, Atiya-Nasagi, Y, Yu, H, Iop, L, Casos, K, Kuguel, S, Blasco-Lucas, A, Permanyer, E, Sbraga, F, Llatjos, R, Moreno-Gonzalez, G, Sanchez-Martinez, M, Breimer, M, Holgersson, J, Teneberg, S, Pascual-Gilabert, M, Nonell-Canals, A, Takeuchi, Y, Chen, X, Manez, R, Roussel, J, Soulillou, J, Cozzi, E, Padler-Karavani, V, Institut Català de la Salut, [Senage T] Institut du Thorax, Institut National de la Santé et de la Recherche Médicale UMR1087, University Hospital, Nantes, France. Institut National de la Santé et de la Recherche Médicale UMR 1246-SPHERE, Nantes University, Tours University, Nantes, France. [Paul A] Department of Cell Research and Immunology, Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. [Le Tourneau T, Fellah-Hebia I] Institut du Thorax, Institut National de la Santé et de la Recherche Médicale UMR1087, University Hospital, Nantes, France. [Vadori M] Consortium for Research in Organ Transplantation, Ospedale Giustinianeo, Padova, Italy. [Bashir S] Department of Cell Research and Immunology, Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel. [Galiñanes M] Servei de Cirurgia Cardíaca, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Evangelista A] Servei de Cardiologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Casós K] Servei de Cirurgia Cardíaca, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Infectious Diseases and Transplantation Division, Institut d’Investigació Biomèdica de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain. Grup de Recerca en Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Blasco-Lucas A] Servei de Cirurgia Cardíaca, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Cardiac Surgery Department, Bellvitge University Hospital, L’Hospitalet de Llobregat, Barcelona, Spain. [Permanyer E] Servei de Cirurgia Cardíaca, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Department of Cardiac Surgery, Quironsalud Teknon Heart Institute, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
[SDV]Life Sciences [q-bio], Immunology, enfermedades cardiovasculares::enfermedades cardíacas [ENFERMEDADES], Cardiovascular, Medical and Health Sciences, General Biochemistry, Genetics and Molecular Biology, Mice, Polysaccharides, Animals, Humans, Prospective Studies, Polysaccharide, Bioprosthesi, Bioprosthesis, 5.3 Medical devices, Animal, Calcinosis, Galactose, Otros calificadores::Otros calificadores::/cirugía [Otros calificadores], MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, General Medicine, Aortic Valve Stenosis, Aortic Valve Stenosi, Other subheadings::Other subheadings::/surgery [Other subheadings], Vàlvula aòrtica - Cirurgia, [SDV] Life Sciences [q-bio], Cardiovascular Diseases::Heart Diseases [DISEASES], Prospective Studie, Heart Disease, Aortic Valve, Immunoglobulin G, Antibody Formation, Calcinosi, Development of treatments and therapeutic interventions, Immunoglobulines, Human
Abstract

Outcomes research; Risk factors Investigación de resultados; Factores de riesgo Recerca dels resultats; Factors de risc Bioprosthetic heart valves (BHVs) are commonly used to replace severely diseased heart valves but their susceptibility to structural valve degeneration (SVD) limits their use in young patients. We hypothesized that antibodies against immunogenic glycans present on BHVs, particularly antibodies against the xenoantigens galactose-α1,3-galactose (αGal) and N-glycolylneuraminic acid (Neu5Gc), could mediate their deterioration through calcification. We established a large longitudinal prospective international cohort of patients (n = 1668, 34 ± 43 months of follow-up (0.1–182); 4,998 blood samples) to investigate the hemodynamics and immune responses associated with BHVs up to 15 years after aortic valve replacement. Early signs of SVD appeared in

Published
2021
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3. Elicited and pre-existing anti-Neu5Gc antibodies differentially affect human endothelial cells transcriptome

Author

Xi Chen, Thomas Senage, Vered Padler-Karavani, Ludmilla Le Berre, Kristina M. Harris, Rafael Mañez, Stephen E. Gitelman, Ron Amon, Milan V. Teraiya, Hoa L. Mai, Cesare Galli, Cristina Costa, Manuel Galiñanes, Jean Christian Roussel, Thi Van Ha Nguyen, Sophie Brouard, Hélène Perreault, Béatrice Charreau, Thierry Le Tourneau, Jean-Paul Soulillou, Shani Leviatan Ben-Arye, Sarah Bruneau, Emanuele Cozzi, Richard Danger, Hai Yu, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Immunoregulation And Immunointervention in Transplantation and Autoimmunity (Team 4 - U1064 Inserm - CRTI), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Department of Cell Research and Immunology, Tel Aviv University [Tel Aviv], Service de Chirurgie Cardio-Thoracique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Chemistry [Winnipeg, Manitoba, Canada], University of Manitoba [Winnipeg], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), University of California [Davis] (UC Davis), University of California, Avantea Laboratory of Reproductive Technologies [Cremona, Italy], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Intensive Care Medicine Department [Barcelona, Spain], Hospital Universitario de Bellvitge, Department of Cardiac Surgery & Reparative Therapy of the Heart [Barcelona, Spain], Vall d'Hebron University Hospital [Barcelona]-Vall d’Hebron Research Institute (VHIR), Massachusetts General Hospital [Boston], Division of Pediatric Endocrinology and Diabetes [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Transplantation Immunology Unit [Padua, Italy] (Department of Transfusion Medicine), University of Padua–Ospedale Giustinianeo [Padua, Italy], The European Union Seventh Framework Program (FP7/2007/2013) under the Grant agreement 603049 for Translink consortium eralitat de Catalunya (Spain) (to C.C.). Richard Danger was supported by a Marie Skłodowska‐Curie fellowship (IF‐EF) from the European U(http://www.translinkproject.com/) (to C.G., J‐C.R., R.M., X.C., C.C., M.G., E.C., V.P‐K, and J‐P.S.). This work was also supported by a grant from The Israeli Ministry of Science, Technology and Space No. 3‐14353 (to V.P‐K). This work was also supported by Ministerio de Economía y Competitividad‐ISCiii (PI15/00181), by FEDER funds, a way to build Europe, and by the PERIS program from Gennion’s Horizon 2020 research and innovation programme under the Grant Agreement No. 7062, European Project: 603049,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,TRANSLINK(2013), Tel Aviv University (TAU), Unité de recherche de l'institut du thorax (ITX-lab), University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Università degli Studi di Padova = University of Padua (Unipd), Le Bihan, Sylvie, and Defining the role of xeno-directed and autoimmune events in patients receiving animal-derived bioprosthetic heart valves - TRANSLINK - - EC:FP7:HEALTH2013-09-01 - 2017-08-31 - 603049 - VALID

Subjects
0301 basic medicine, Chemokine, Endothelium, Xenotransplantation, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Transplantation, Heterologous, 030230 surgery, Biology, Antibodies, Transcriptome, N-glycolylneuraminic acid (Neu5Gc), anti-Neu5Gc antibodies, endothelial cells, sialic acid, xenotransplantation, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Transplantation, Endothelial Cells, Chemotaxis, Molecular biology, In vitro, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Cytokine, Immunoglobulin G, biology.protein, Antibody
Abstract

International audience; Humans cannot synthesizeN-glycolylneuraminic acid (Neu5Gc) but dietary Neu5Gc can be absorbed and deposited on endothelial cells (ECs) and diet-induced anti-Neu5Gc antibodies (Abs) develop early in human life. While the interaction of Neu5Gc and diet‐induced anti‐Neu5Gc Abs occurs in all normal individuals, endothelium activa-tion by elicited anti‐Neu5Gc Abs following a challenge with animal‐derived materials, such as following xenotransplantation, had been postulated. Ten primary human EC preparations were cultured with affinity‐purified anti‐Neu5Gc Abs from human sera obtained before or after exposure to Neu5Gc‐glycosylated rabbit IgGs (elicited Abs). RNAs of each EC preparation stimulated in various conditions by purified Abs were exhaustively sequenced. EC transcriptomic patterns induced by elicited anti-Neu5Gc Abs, compared with pre‐existing ones, were analyzed. qPCR, cytokines/chemokines release, and apoptosis were tested on some EC preparations. The data showed that anti‐Neu5Gc Abs induced 967 differentially expressed (DE) genes. Most DE genes are shared following EC activation by pre‐existing or anti‐human T‐cell globulin (ATG)‐elicited anti‐Neu5Gc Abs. Compared with pre‐existing anti‐Neu5Gc Abs, which are normal component of ECs environment, elicited anti‐Neu5Gc Abs down‐regulated 66 genes, including master genes of EC function. Furthermore, elicited anti-Neu5Gc Abs combined with complement‐containing serum down‐regulated most transcripts mobilized by serum alone. Both types of anti‐Neu5Gc Abs‐induced a dose‐ and com-plement‐dependent release of selected cytokines and chemokines. Altogether, these data show that, compared with pre‐existing anti‐Neu5Gc Abs, ATG‐elicited anti‐Neu5Gc Abs specifically modulate genes related to cytokine responses, MAPkinase cascades, chemotaxis, and integrins and do not skew the EC transcriptome toward a pro-inflammatory profile in vitro.

Published
2019
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4. Biomolecular Recognition of the Glycan Neoantigen CA19-9 by Distinct Antibodies

Author

Ron Amon, Shani Leviatan Ben-Arye, Hai Yu, Sarel J. Fleishman, Nova Tasnima, Maayan Eilon, Shira Warszawski, Aliza Borenstein-Katz, Vered Padler-Karavani, Ron Diskin, Hadas Cohen-Dvashi, and Xi Chen

Subjects
Models, Molecular, Protein Conformation, design, Antibody Affinity, Computational algorithm, Crystallography, X-Ray, Mice, 0302 clinical medicine, Models, Structural Biology, Monoclonal, Cancer, chemistry.chemical_classification, 0303 health sciences, Crystallography, biology, Antibodies, Monoclonal, CA19-9, Antigen binding, 3. Good health, Antibody, Carbohydrate antigen, Algorithms, Biochemistry & Molecular Biology, Glycan, CA-19-9 Antigen, Computational biology, Microbiology, Antibodies, Article, Medicinal and Biomolecular Chemistry, 03 medical and health sciences, Glycolipid, Antigen, Animals, Humans, structure, Molecular Biology, 030304 developmental biology, Prevention, Molecular, Computational Biology, chemistry, Mutation, X-Ray, biology.protein, glycans, Biochemistry and Cell Biology, Glycoprotein, 030217 neurology & neurosurgery
Abstract

Glycans decorate the cell surface, secreted glycoproteins and glycolipids, and altered glycans are often found in cancers. Despite their high diagnostic and therapeutic potential, however, glycans are polar and flexible molecules that are quite challenging for the development and design of high-affinity binding antibodies. To understand the mechanisms by which glycan neoantigens are specifically recognized by antibodies, we analyze the biomolecular recognition of the tumor-associated carbohydrate antigen CA19-9 by two distinct antibodies using X-ray crystallography. Despite the potential plasticity of glycans and the very different antigen-binding surfaces presented by the antibodies, both structures reveal an essentially identical extended CA19-9 conformer, suggesting that this conformer's stability selects the antibodies. Starting from the bound structure of one of the antibodies, we use the AbLIFT computational algorithm to design a variant with seven core mutations in the variable domain's light-heavy chain interface that exhibits tenfold improved affinity for CA19-9. The results reveal strategies used by antibodies to specifically recognize glycan antigens and show how automated antibody-optimization methods may be used to enhance the clinical potential of existing antibodies.

Published
2021
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5. Glycans in immune recognition and response

Author

Ron Amon, Eliran Moshe Reuven, Vered Padler-Karavani, and Shani Leviatan Ben-Arye

Subjects
Glycan, Glycosylation, medicine.medical_treatment, Biology, Biochemistry, Analytical Chemistry, Targeted therapy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, Antigen, Polysaccharides, Neoplasms, medicine, Humans, 030304 developmental biology, 0303 health sciences, Immunogenicity, Organic Chemistry, Immunity, General Medicine, Immunotherapy, 3. Good health, chemistry, Immunology, biology.protein, Antibody, 030215 immunology
Abstract

Glycans at the forefront of cells facilitate immune recognition processes. Cancer cells commonly present altered cell surface glycosylation, especially manifested in the expression of sialic acid at the termini of glycolipids and glycoproteins. Although tumor-associated carbohydrate antigens (TACAs) result in expression of altered-self, most such carbohydrates do not elicit strong humoral responses. Various strategies had been devised to elicit increased immunogenicity of such TACA aiming for potent immunotherapeutic antibodies or cancer vaccines. However some carbohydrates are immunogenic in humans and hold potential for novel glycotherapies. N-Glycolylneuraminic acid (Neu5Gc) is a foreign immunogenic sugar in humans originating from the diet (e.g., red meat) and subsequently expressed on the cell surface, especially accumulating on carcinoma. Consequently, the human immune system detects this non-self carbohydrate generating a broad anti-Neu5Gc antibody response. The co-existence of Neu5Gc/anti-Neu5Gc within humans spurs chronic inflammation mediated disease, including cancer. Concurrently, anti-Neu5Gc antibodies hold potential for novel targeted therapy. αGal is another foreign immunogenic carbohydrate antigen in humans and all humans have circulating anti-Gal antibodies. This review aims to describe the immunogenicity of Neu5Gc and its implications for human diseases, highlighting differences and similarities with αGal and its potential for novel targeted theranostics.

Published
2014
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6. A combined computational-experimental approach to define the structural origin of antibody recognition of sialyl-Tn, a tumor-associated carbohydrate antigen

Author

Shani Leviatan Ben-Arye, Sarel J. Fleishman, Christoffer Norn, Ron Amon, Vered Padler-Karavani, Spandana Makeneni, Anita K. Nivedha, Hai Yu, John Glushka, Oliver C. Grant, Robert J. Woods, Tal Marshanski, and Xi Chen

Subjects
0301 basic medicine, Models, Molecular, Carbohydrate, Glycan, Microarray, Carbohydrate chemistry, medicine.drug_class, Cells, lcsh:Medicine, Bioengineering, Computational biology, Molecular Dynamics Simulation, Monoclonal antibody, Antibodies, Article, 03 medical and health sciences, Mice, Antigen, Models, Antibody Specificity, Monoclonal, medicine, Animals, Humans, Antigens, Tumor-Associated, Carbohydrate, Computer Simulation, Antigens, lcsh:Science, Cells, Cultured, Cancer, Cultured, Multidisciplinary, biology, Chemistry, Prevention, lcsh:R, Tumor-Associated, Rational design, Molecular, Antibodies, Monoclonal, 3. Good health, 030104 developmental biology, HEK293 Cells, Docking (molecular), biology.protein, lcsh:Q, Immunization, Antibody, Biotechnology
Abstract

Anti-carbohydrate monoclonal antibodies (mAbs) hold great promise as cancer therapeutics and diagnostics. However, their specificity can be mixed, and detailed characterization is problematic, because antibody-glycan complexes are challenging to crystallize. Here, we developed a generalizable approach employing high-throughput techniques for characterizing the structure and specificity of such mAbs, and applied it to the mAb TKH2 developed against the tumor-associated carbohydrate antigen sialyl-Tn (STn). The mAb specificity was defined by apparent KD values determined by quantitative glycan microarray screening. Key residues in the antibody combining site were identified by site-directed mutagenesis, and the glycan-antigen contact surface was defined using saturation transfer difference NMR (STD-NMR). These features were then employed as metrics for selecting the optimal 3D-model of the antibody-glycan complex, out of thousands plausible options generated by automated docking and molecular dynamics simulation. STn-specificity was further validated by computationally screening of the selected antibody 3D-model against the human sialyl-Tn-glycome. This computational-experimental approach would allow rational design of potent antibodies targeting carbohydrates.

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