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Antibodies for Infectious Diseases

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Antibodies for Infectious Diseases

Edited by

James E. Crowe, Jr.Vanderbilt University Medical CenterNashville, Tennessee

Diana BoraschiNational Research CouncilNapoli, Italy

AND

Rino RappuoliNovartis VaccinesSiena, Italy

Washington, DC

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Copyright © 2015 American Society for Microbiology. All rights reserved. No part of this publication may be reproduced or transmitted in whole or in part or reused in any form or by any means, electronic or mechanical, including photocopying and recording, or by any information storage and retrieval system, without permission in writing from the publisher.

Disclaimer: To the best of the publisher’s knowledge, this publication provides information concerning the subject matter covered that is accurate as of the date of publication. The publisher is not providing legal, medical, or other professional services. Any reference herein to any specific commercial products, procedures, or services by trade name, trademark, manufacturer, or otherwise does not constitute or imply endorsement, recommendation, or favored status by the American Society for Microbiology (ASM). The views and opinions of the author(s) expressed in this publication do not necessarily state or reflect those of ASM, and they shall not be used to advertise or endorse any product.

Library of Congress Cataloging-in-Publication Data

Antibodies for infectious diseases / edited by James E. Crowe, Jr., Vanderbilt University Medical Center, Nashville, Tennessee, Diana Boraschi, National Research Council, Napoli, Italy, and Rino Rappuoli, Novartis Vaccines, Siena, Italy.pages cmIncludes bibliographical references and index.ISBN 978-1-55581-735-0 (alk. paper)1. Immunoglobulins. 2. Communicable diseases--Immunological aspects. I. Crowe, James E., Jr., editor. II. Boraschi, D. (Diana), editor. III. Rappuoli, Rino, editor. QR186.7.A534 2015616.07’98--dc232015009356eISBN: 978-1-55581-741-1doi:10.1128/978155581741110 9 8 7 6 5 4 3 2 1

All Rights ReservedPrinted in the United States of America

Address editorial correspondence to ASM Press, 1752 N St., N.W.,Washington, DC 20036-2904, USASend orders to ASM Press, P.O. Box 605, Herndon, VA 20172, USAPhone: 800-546-2416; 703-661-1593Fax: 703-661-1501E-mail: books@asmusa.orgOnline: http://estore.asm.org

Cover image: Cancer cell with high details (source: 123RF)

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Contents

Contributors ixPreface xvii

IntroductIon

1 History and Practice: Antibodies in Infectious Diseases 3 Adam Hey

General Features oF ImmunoGlobulIns

2 Functions of Antibodies 25 Donald N. Forthal

3 Antibody Structure 49 Robyn L. Stanfield and Ian A. Wilson

4 The Role of Complement in Antibody Therapy for Infectious Diseases 63 Peter P. Wibroe, Shen Y. Helvig, and S. Moein Moghimi

5 Immunoglobulin E and Allergy: Antibodies in Immune Inflammation and Treatment 75

Sophia N. Karagiannis, Panagiotis Karagiannis, Debra H. Josephs, Louise Saul, Amy E. Gilbert, Nadine Upton, and Hannah J. Gould

antIbody dIscovery approaches

6 Phage and Yeast Display 105 Jared Sheehan and Wayne A. Marasco

7 Efficient Methods To Isolate Human Monoclonal Antibodies from Memory B Cells and Plasma Cells 129

Davide Corti and Antonio Lanzavecchia

8 Use of Human Hybridoma Technology To Isolate Human Monoclonal Antibodies 141 Scott A. Smith and James E. Crowe, Jr.

9 Humanized Mice for Studying Human Immune Responses and Generating Human Monoclonal Antibodies 157

Ramesh Akkina

10 Antibodies: Computer-Aided Prediction of Structure and Design of Function 173 Alexander M. Sevy and Jens Meiler

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vi contents

pathoGen-specIFIc antIbodIes

11 Antibodies Targeting the Envelope of HIV-1 193 Luzia M. Mayr and Susan Zolla-Pazner

12 Committing the Oldest Sins in the Newest Kind of Ways—Antibodies Targeting the Influenza Virus Type A Hemagglutinin Globular Head 209

Jens C. Krause and James E. Crowe, Jr.

13 Prevention of Respiratory Syncytial Virus Infection: From Vaccine to Antibody 221

Kelly Huang and Herren Wu

14 Human Metapneumovirus 237 Jennifer E. Schuster and John V. Williams

15 Dengue Antibody-Dependent Enhancement: Knowns and Unknowns 249

Scott B. Halstead

16 Immunotherapeutic Approaches To Prevent Cytomegalovirus-Mediated Disease 273

Edith Acquaye-Seedah, Zachary P. Frye, and Jennifer A. Maynard

17 Rotavirus 289 Manuel A. Franco and Harry B. Greenberg

18 Bacterial Toxins—Staphylococcal Enterotoxin B 303 Bettina C. Fries and Avanish K. Varshney

technIcal advances

19 Antibody Engineering 321 Kin-Ming Lo, Olivier Leger, and Björn Hock

20 High-Throughput DNA Sequencing Analysis of Antibody Repertoires 345

Scott D. Boyd and Shilpa A. Joshi

21 Antibody Informatics: IMGT, the International ImMunoGeneTics Information System 363

Marie-Paule Lefranc

22 Probing Antibody-Antigen Interactions 381 Guocheng Yang, Stefanie N. Velgos, Shanta P. Boddapati,

and Michael R. Sierks

23 Radiolabeled Antibodies for Therapy of Infectious Diseases 399 Ekaterina Dadachova and Arturo Casadevall

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alternate systems For expressIon

24 Plant-Derived Monoclonal Antibodies for Prevention and Treatment of Infectious Disease 413

Andrew Hiatt, Kevin J. Whaley, and Larry Zeitlin

25 Vector-Mediated In Vivo Antibody Expression 427 Bruce C. Schnepp and Philip R. Johnson

Index 441

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Contributors

Edith Acquaye-SeedahDepartment of BiochemistryUniversity of Texas at AustinAustin, TX 78712

Ramesh AkkinaDepartment of Microbiology, Immunology, and PathologyColorado State University1619 Campus DeliveryFort Collins, CO 80523

Shanta P. BoddapatiDepartment of Biomedical EngineeringOregon Health and Science University3181 SW Sam Jackson Park RoadPortland, OR 97239

Scott D. BoydDepartment of PathologyStanford UniversityStanford, CA 94305

Arturo CasadevallDepartments of Microbiology and Immunology, and MedicineAlbert Einstein College of Medicine of Yeshiva University1695A Eastchester RoadBronx, NY 10461

Davide CortiHumabs BioMed SAvia Mirasole 1Bellinzona, 6500Switzerland

James E. Crowe, Jr.School of MedicineVanderbilt UniversityNashville, TN 37232

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x contRIBUtoRs

Ekaterina (Kate) DadachovaDepartments of Radiology, Microbiology and ImmunologyAlbert Einstein College of Medicine of Yeshiva University1695A Eastchester RoadBronx, NY 10461

Donald N. ForthalDepartment of Infectious Diseases3044 Hewitt HallUniversity of California, IrvineIrvine, CA 92617

Manuel A. FrancoFacultad de Ciencias y MedicinaPontificia Universidad JaverianaOficina 306, Edificio 50Carrera 7 # 40-62BogotáColombia

Bettina C. FriesDepartment of Medicine/Infectious Diseases and Department of Microbiology and ImmunologyAlbert Einstein College of MedicineBronx, NY 10461

Zachary P. FryeDepartment of Chemical EngineeringUniversity of Texas at AustinAustin, TX 78712

Amy E. GilbertCutaneous Medicine and Immunotherapy UnitSt. John’s Institute of DermatologyDivision of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy’s and St. Thomas’s Hospitals and King’s College London School of MedicineGuy’s HospitalLondon SE1 9RTUnited Kingdom

Hannah J. GouldRandall Division of Cell and Molecular BiophysicsDivision of Asthma, Allergy and Lung BiologyMRC and Asthma UK Centre for Allergic Mechanisms of AsthmaKing’s College LondonNew Hunt’s HouseGuy’s CampusLondon SE1 1ULUnited Kingdom

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contRIBUtoRs xi

Harry B. GreenbergDepartments of Medicine and Microbiology and ImmunologyStanford University School of Medicine and the VAPAHCSPalo Alto, CA 94305

Scott B. HalsteadDepartment of Preventive Medicine and BiometricsUniformed Services University of the Health SciencesBethesda, MD 20814

Shen Y. HelvigDepartment of PharmacyCenter for Pharmaceutical Nanotechnology and NanotoxicologyFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagen, DK-2100Denmark

Adam HeyPreclinical Safety, BiologicsNovartis AGBaselSwitzerland

Andrew HiattMapp Biopharmaceutical, Inc.6160 Lusk Blvd. #C105San Diego, CA 92121

Björn HockDepartment of Protein Engineering and Antibody TechnologiesMerck Serono, Merck KgaAFrankfurter Str. 250D-64293 DarmstadtGermany

Kelly HuangDepartment of Infectious DiseaseMedImmune, LLCOne MedImmune WayGaithersburg, MD 20878

Philip R. JohnsonThe Children’s Hospital of PhiladelphiaAbramson Research CenterPhiladelphia, PA 19104

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Debra H. JosephsCutaneous Medicine and Immunotherapy UnitSt. John’s Institute of DermatologyDivision of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy’s and St. Thomas’s HospitalsKing’s College London School of MedicineGuy’s HospitalLondon SE1 9RTUnited Kingdom

Shilpa A. JoshiDepartment of PathologyStanford UniversityStanford, CA 94305

Sophia N. KaragiannisCutaneous Medicine and Immunotherapy UnitSt. John’s Institute of DermatologyDivision of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy’s and St. Thomas’s HospitalsKing’s College London School of MedicineGuy’s HospitalLondon SE1 9RTUnited Kingdom

Panagiotis KaragiannisCutaneous Medicine and Immunotherapy UnitSt. John’s Institute of DermatologyDivision of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy’s and St. Thomas’s HospitalsKing’s College London School of MedicineGuy’s HospitalLondon SE1 9RTUnited Kingdom

Jens C. KrauseChildren’s HospitalUniversity of Freiburg Medical Center79106 FreibergGermany

Antonio LanzavecchiaInstitute for Research in Biomedicinevia Vincenzo Vela 6Bellinzona, 6500Switzerland

xii contRIBUtoRs

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Marie-Paule LefrancLaboratoire d’ImmunoGénétique Moléculaire LIGMIMGT®, the international ImMunoGeneTics information system®Institut de Génétique Humaine IGHUniversité Montpellier 2UPR CNRS 1142Montpellier, 34396 cedex 5, 40202France

Olivier LegerDepartment of Protein Engineering and Antibody TechnologiesMerck Serono S.A.--Geneva9, chemin des Mines1202 GenevaSwitzerland

Kin-Ming LoDepartment of Protein Engineering and Antibody TechnologiesEMD Serono Research Institute45A Middlesex TurnpikeBillerica, MA 01821

Wayne A. MarascoDepartment of Cancer Immunology and AIDSDana-Farber Cancer InstituteHarvard Medical SchoolBoston, MA 02215

Jennifer A. MaynardDepartment of Chemical EngineeringUniversity of Texas at AustinAustin, TX 78712

Luzia M. MayrINSERM U1109Université de Strasbourg3 Rue Koeberlé67000 StrasbourgFrance

Jens MeilerDepartment of Chemistry and Center for Structural BiologyVanderbilt UniversityNashville, TN 37212

contRIBUtoRs xiii

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S. Moein MoghimiDepartment of PharmacyCenter for Pharmaceutical Nanotechnology and NanotoxicologyFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagen, DK-2100Denmark

Susan Zolla-PaznerNew York University School of Medicine550 First AvenueNew York, NY 10016

Louise SaulCutaneous Medicine and Immunotherapy UnitSt. John’s Institute of DermatologyDivision of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy’s and St. Thomas’s HospitalsKing’s College London School of MedicineGuy’s HospitalLondon SE1 9RTUnited Kingdom

Bruce C. SchneppThe Children’s Hospital of PhiladelphiaAbramson Research CenterPhiladelphia, PA 19104

Jennifer E. SchusterDepartment of PediatricsChildren’s Mercy HospitalKansas City, MO 64108-4619

Alexander M. SevyDepartment of Chemistry and Center for Structural BiologyVanderbilt UniversityNashville, TN 37212

Jared SheehanDepartment of Cancer Immunology and AIDSDana-Farber Cancer InstituteHarvard Medical SchoolBoston, MA 02215

Michael R. SierksDepartment of Chemical EngineeringArizona State UniversityTempe, AZ 85287-6006

xiv contRIBUtoRs

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Scott A. SmithThe Vanderbilt Vaccine Center and the Department of MedicineVanderbilt University Medical CenterNashville, TN 37232

Robyn L. StanfieldDepartment of Molecular BiologyThe Scripps Research Institute10550 North Torrey Pines RoadLa Jolla, CA 92037

Nadine UptonRandall Division of Cell and Molecular BiophysicsDivision of Asthma, Allergy and Lung BiologyMRC and Asthma UK Centre for Allergic Mechanisms of AsthmaKing’s College LondonNew Hunt’s HouseGuy’s CampusLondon SE1 1ULUnited Kingdom

Avanish K. VarshneyDepartment of Medicine/Infectious Diseases and Department of Microbiology and ImmunologyAlbert Einstein College of MedicineBronx, NY 10461

Stefanie N. VelgosMayo Clinic Arizona5777 East Mayo BoulevardPhoenix, AZ 85054

Kevin J. WhaleyMapp Biopharmaceutical, Inc.6160 Lusk Blvd. #C105San Diego, CA 92121

Peter P. WibroeCentre for Pharmaceutical Nanotechnology and NanotoxicologyDepartment of PharmacyFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagen, DK-2100Denmark

John V. WilliamsDepartment of PediatricsSchool of MedicineVanderbilt UniversityNashville, TN 37232-2581

contRIBUtoRs xv

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Ian A. WilsonDepartment of Molecular Biology and Skaggs Institute for Chemical BiologyThe Scripps Research Institute10550 North Torrey Pines RoadLa Jolla, CA 92037

Herren WuDepartment of Antibody Discovery and Protein EngineeringMedImmune, LLCOne MedImmune WayGaithersburg, MD 20879

Guocheng YangDepartment of Chemical EngineeringArizona State UniversityTempe, AZ 85287-6006

Larry ZeitlinMapp Biopharmaceutical, Inc.6160 Lusk Blvd. #C105San Diego, CA 92121

xvi contRIBUtoRs

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Preface

Antibodies form the principal foundation for modern intervention against in-fectious diseases. Emil Adolf von Behring was awarded the first Nobel Prize in Physiology or Medicine in 1901 “for his work on serum therapy, especially its appli-cation against diphtheria, by which he has opened a new road in the domain of med-ical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths.” Antibodies now provide the focus for understanding mechanisms of immunity to most infectious diseases, and they play a central role in passive immunotherapy and active vaccination as mechanisms or correlates of immunity. For most of the 20th century, immunotherapy was based on passive transfer of polyclonal hyperimmune animal serum, immune human serum, or even hyperimmune human serum. Georges J.F. Köhler and César Milstein re-ported the generation of monoclonal antibodies in 1979, for which they shared the 1984 Nobel Prize in Physiology or Medicine “for . . .the discovery of the princi-ple for production of monoclonal antibodies.” Since that time, entire fields related to antibodies for infectious diseases, including antibody gene cloning, engineer-ing, and expression; antibody libraries; and high-throughput antibody gene rep-ertoire sequence analysis have extended our capabilities to explore the diversity of antibody specificity and function with unprecedented depth and breadth.

This book provides a broad survey of many of the most important aspects of the field of antibodies for infectious diseases. The book begins with a general introduction, followed by chapters 2 through 5 on general features pertaining to structure, function, isotype, and the role of complement in antibody function. Chapters 6 through 10 review contemporary approaches for antibody discovery using phage and yeast display, plasma cell and memory B cell cloning, human hybridomas, humanized mice, and computational methods. Chapters 11 through 18 review in depth the biology of antibodies specific for particular pathogens, including viruses and bacterial toxins, to illustrate the role of antibodies in anti- microbial immunity with specific targets. These chapters reveal that attempts to raise effective antibody responses to each of these pathogens faces unique and pathogen-specific challenges. Chapters 19 to 23 cover major technical advances pertaining to antibody engineering, repertoire sequencing and analysis, and new methods for study or therapeutic use of antibodies, including radiotherapy. Fi-nally, chapters 24 and 25 cover new methods for expression of monoclonal anti-bodies, in plants or by transfer of antibody genes for in vivo expression in treated subjects.

Recent literature is exploding with new antibody-related techniques and re-ports of antimicrobial antibodies with unprecedented potency, breadth of activ-

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xviii PReface

ity, and therapeutic potential. We hope that this timely compilation of state-of-the-art reviews of major aspects of this field will be of interest to both antibody cognoscenti and those new to this exciting field. We thank the authors for their dedication in producing definitive reviews of the topics at hand.

James E. Crowe, Jr.Diana BoraschiRino Rappuoli

Index

AAV (adeno-associated virus), 428–436Abiotic surfaces, inhibition of bacterial attachment

to, 28Activation-induced cytidine deaminase (AID), 331,

332Active systemic anaphylaxis (ASA), 79–80Adalimumab, 11, 89, 330, 333–334ADC (antibody drug complex/conjugate), 9, 15,

334–335ADCC (antibody-dependent cellular cytotoxicity),

32–34, 65, 69–70, 322–326Adcetris (brentuximab vedotin), 15, 334, 335ADCP (antibody-dependent cellular phagocytosis),

322–323, 325ADCVI (antibody-dependent cell-mediated virus

inhibition), 33–34ADE. See Antibody-dependent enhancementAdeno-associated virus (AAV), 428–436Adhesins, 16, 27Adhesion of bacteria, interference with, 27–28AD-HIES (autosomal dominant hyper-IgE

syndrome), 81Affinity matrix, artificial, 151–152Affinity maturation, 174, 175, 330–334

broad neutralization versus, 184by mammalian display, 332–333in silico, 184–185by somatic hypermutation, 332by somatic mutations and computational design,

333in vitro, 331–333

without display, 333–334in vivo, 331

AFM (atomic force microscopy), 382, 386–389,391–395

Agglutination, 26Agglutinins, yeast, 115Aggregation, 26Agrobacterium tumefaciens, 414–415AID (activation-induced cytidine deaminase), 331,

332Alemtuzumab, 323, 324Algorithm, antibody docking, 180Allergen sensitization, 76Allergens

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IgE activation of immune response in presenceof, 76

interactions with IgE and Fcε triggeringhypersensitivity responses, 79

neutralizing antibody response induced by activeallergen immunotherapy, 89–90

Allergic inflammation, 75–95allergen-specific IgG antibody triggering

hypersensitivity responses, 79–80antibodies in treatment of allergies, 82–92cancer, 92–94clinical perspective, 75–76future roles of antibodies in therapy, 94–95IgE activation of immune response, 76IgE antibodies in infectious diseases, 80–82IgE effector cells, 77–79APCs, 78B cells, 78mast cells, 77–78monocytes and eosinophils, 78–79

IgE receptors, 76–77interactions between allergens, IgE, and Fcε

triggering hypersensitivity responses, 79

AllergoOncology, 94Allergy treatment, antibodies in, 82–92

antibodies targeting cytokines, chemokines, andtheir receptors, 88–89

clinical studies in 2012, 86–87future roles, 94–95IgG4, allergen specific, 90–92neutralizing antibody response induced by active

allergen immunotherapy, 89–90recombinant antibodies targeting IgE interactions

with Fcε receptors, 82–88specific immunotherapy (SIT), 90–92

Alternative pathway of complement activation, 66AMA (Antibody Modeling Assessment), 179–180Aminopterin, 148AMPV. See Avian pneumovirus/metapneumovirusAnalytic vaccinology, 136, 137Anaphylatoxins, 68–69Anaplasma phagocytophilum, 29Animal models

humanized mice, 158–160staphylococcal enterotoxin B, 307–309

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441

442 INDEX

Animal models (continued)vector-mediated in vivo antibody expression,

432–433

Anthim, 17Anthrax, 17, 114, 120, 420Antibacterials, 16–17Antibiotics

introduction of, 5pros and cons of antibody-based therapy relative

to, 14resistance to, 5, 13

Antibodyclasses, 10computer-aided prediction of structure and

design of function, 173–187effector functions, 10–11functions, 25–36generating, methods and platforms for, 10–12informatics, 363–377structure, 8–10, 49–59, 346–3473D, informatics and, 373–376

Antibody design, 183–187broad neutralization versus affinity maturation,

184overview, 183–184in silico affinity maturation, 184–185

Antibody dockingalgorithms, 180–181epitope mapping and, 180–183experimental data, 181–183modeling, 174, 175–176

Antibody drug complex/conjugate (ADC), 9, 15,334–335

Antibody engineering, 13–15, 321–337affinity maturation, 330–334antibody drug conjugates, 334–335antibody informatics and, 370bispecific antibodies, 335–337choice of Ig isotypes and subclasses, 322–324IgA, 322–323IgG1, 323IgG2, 323–324IgG3, 324IgG4, 324

Fc portion, 322–327glycosylation, Fc, 324–327humanization, 327–330next-generation antibodies, 334–337

Antibody gene rearrangements, 346–348Antibody gene transfer

for cancer, 435–436drawbacks of rAAV, 436for drug addiction, 435expression systems for, 429–432for HIV-positive individuals, 433proof-of-concept studies in animal models,

432–433

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for respiratory tract infections, 433–435Antibody modeling

canonical structure of CDRs, 176–178challenges in, 174, 175–176comparative, 176–180motivations for, 175predicting conformation of HCDR3, 177–178programs, platforms, and servers dedicated to,

179–180

Antibody Modeling Assessment (AMA), 179–180Antibody selection

AFM, 391–393FACS, 390–391SPR, 389–390

Antibody-based therapy. See also Immunotherapy;specific applications

allergic diseases, 82–92approved/pending therapies, 6–8, 65complement role in, 63–72cost of therapy/production, 12, 16examples, 16–18antibacterials, 16–17antifungals, 18antivirals, 17–18

future perspectives, 18–19history of, 3–19pros and cons, 14strategic considerations in developing, 12–16antibody engineering, 13–15antibody formats, 15–16avoiding escape mutants, 13“magic bullet” creation, 15

Antibody-dependent cell-mediated virus inhibition(ADCVI), 33–34

Antibody-dependent cellular cytotoxicity (ADCC),32–34, 65, 69–70, 322–326

Antibody-dependent cellular phagocytosis (ADCP),322–323, 325

Antibody-dependent enhancement (ADE),249–265

intrinsic ADE (iADE), 251, 254–258, 263–264Leishmania, 255, 258overview, 249–252

Antibody-dependent enhancement (ADE), denguevirus, 249–265

afferent phenomena, 252–261, 263–264enhancing antibodies, 252–258, 263–264genetic host factors contributing to DVPS

susceptibility, 252, 263role of dengue viruses in ADE, 258–261, 264

DENV-2enhanced growth in primary human monocytes,

258, 264genetic differences after infection with DENV-1,

259–261, 264genetic differences after infection with DENV-3,

260–261, 264

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strain differences in neutralization by DENV-1antibodies, 258–259, 264

efferent phenomena, 252, 253, 261, 264–265enhancing antibodies, 252–258attributes of iADE, 254–257, 263role of FcγRs, 257–258, 264role of infection sequence, 257, 263–264role of myloid cells, 257, 264sensitizing infection, 252–254, 263

Antifungals, 18Antigen

studies in humanized mice, 166target-agonist approach for antigen discovery in

vaccine design, 136–137

Antigen design

epitope grafting, 185–187neutralizing antibody elicited through, 185

Antigen presenting cells (APCs), 72, 76–78Antigen-antibody docking

algorithms, 180–181epitope mapping and, 180–183experimental data, 181–183modeling, 174, 175–176

Antigen-antibody interactions, probing, 381–395antibody selectionAFM, 391–393FACS, 390–391SPR, 389–390

atomic force microscopy (AFM), 382, 386–389,391–395

fluorescence-activated cell sorting (FACS), 382,384–386, 390–391, 394–395

overview, 381–382surface plasmon resonance (SPR), 382–384,

389–390, 394

Antilysosomal antibody, 184Antiretroviral therapy (ART), 433Antivirals, 17–18APCs (antigen presenting cells), 72, 76–78APV. See Avian pneumovirus/metapneumovirusAPV/AMPV. See Avian pneumovirus/

metapneumovirusAR-HIES (autosomal recessive hyper-IgE

syndrome), 81ART (antiretroviral therapy), 433ASA (active systemic anaphylaxis), 79–80Aspergillus fumigatus, 403Asthma

IgE and, 82–85omalizumab (Xolair), 83–85respiratory syncytial virus (RSV) and, 82

Atomic force microscopy (AFM), 382, 386–389,391–395

Atopic dermatitis, staphylococcal enterotoxin B,309–310

Attachment, interference with, 27–28Aurexis (tefibazumab), 16

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Aurograb, 16Autosomal dominant hyper-IgE syndrome

(AD-HIES), 81Autosomal recessive hyper-IgE syndrome

(AR-HIES), 81Avastin, 436Avian pneumovirus/metapneumovirus

(APV/AMPV), 238, 240Avidin-biotin bridging, 146

B cell receptor (BCR), 132, 357B cells

allergic inflammation and, 76, 78antibodies blocking CD23 functions, 83–84, 88antibody gene rearrangements, 346–348high-throughput DNA sequencing and, 346–348,

355–357human hybridoma technology, 141–152immortalized, 12, 130, 131–133, 143, 283mRNA for phage library, 106rotavirus and, 289–295, 298–299

Bacillus anthracis, 17antianthrax monoclonal antibodies discovered by

phage display, 114antianthrax monoclonal antibodies discovered by

yeast display, 120–121radioimmunotherapy (RIT), 404–405

Bacteria. See also specific bacteriaantibacterial monoclonal antibodiesdiscovered by phage display, 113–115discovered by yeast display, 119–121

antibody-based therapy examples, 16–17antibody-dependent cellular cytotoxicity

(ADCC), 33complement activation, 30–31, 64history passive antibody therapy, 4–5hyper-IgE syndrome (HIES), 82neutralization of infectivity, 26–27phagocytosis, 34–35plant-derived monoclonal antibody for bacterial

toxins, 420–421anthrax, 420Clostridium perfringens epsilon toxin, 420–421staphylococcal enterotoxin B, 421

radioimmunotherapy (RIT), 404–405sensitivity to infection, 82

Bacterial opsonophagocytosis killing assay, 132Bacteriophage. See Phage; Phage displayBAFF, 144Barcode, sequence, 354Bavituximab, 17Bcl-6, 130–131, 164Bcl-xL, 130–131, 164Benralizumab, 89Bevacizumab, 184, 330Bexxar (tositumumab), 15, 334, 399BIAcore SPR system, 383

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444 INDEX

Binding affinity, 180Binding constant, antibody, 382, 385–386, 389–390Binding interactions, antigen-antibody, 381. See also

Antigen-antibody interactions, probingBiological cloning methods, in human hybridoma

technology, 149–152Biological weapon, as staphylococcal enterotoxin B,

304Biopanning

AFM-based, 391–393magnetic bead-based, 392

Bispecific antibodies, 335–337Bite (bi-specific T cell engager), 9, 336Blinatumomab, 336BLT mice, 159, 160–164, 166–167BLyS, 144Bordetella pertussis, 34Borrelia, 27Botulism toxin, 113–114, 120Brentuximab vedotin (Adcetris), 15, 334, 335Brucella abortus, 33Brugia malayi, 33

Calicheamicin, 334Camelids, 54Cancer

allergic response against, 92–94AllergoOncology, 94antibody gene transfer for, 435–436“magic bullet” creation for, 15

Candida, 27Candida albicans, 18, 28, 31, 403–404Capillary morphogenesis protein 2, 420Carbohydrates, recognition of self, 55–57CaroRx, 417Catumaxomab, 336CCR5 receptor, 17, 53, 111, 161, 194, 198, 428, 433CCR9 (chemokines receptor 9), 294, 295CD2, 306CD4/CD4+ cells, 17, 53, 76, 112, 130

enterotoxins and, 303human immunodeficiency virus (HIV) and,

194–195, 199–200, 428, 433humanized mice and, 163

CD5+ cells, 163CD8/CD8+ cells, 70

dengue virus infection and, 262humanized mice and, 163–164in respiratory syncytial virus (RSV) disease, 224response to CMV, 276, 278staphylococcal enterotoxin B, 310

CD19+ cells, 163CD20, 15CD21, 144CD22, 332CD23, 77–80, 83–84, 88CD28, 306

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CD30, 334CD33, 334CD34+ cells, 159–162CD40, 77, 132CD40L (CD40 ligand), 130, 132, 144, 164CD45+ cells, 160CD46, 71CD47, 167CD59, 71CD154CDC (complement-dependent cytotoxicity), 65,

68–71, 322–324CDCC (complement-dependent cell cytotoxicity),

65, 68, 70CDR. See Complementarity-determining regionCertolizumab pegol, 89, 334Cetuximab, 12, 184Chemical shift mapping, 181–183Chemokines, 77–78, 88–89Chemokines receptor 9 (CCR9), 294, 295Chimeric antibodies, 11, 16, 314Chronic lymphocytic leukemia (CLL), 70Classes of immunoglobulins, 10Classical pathway of complement activation,

65–66Clonality score, 356ClonePix, 152Clostridium botulinum

antibotulinum monoclonal antibodies discoveredby phage display, 113–114

antibotulinum monoclonal antibodies discoveredby yeast display, 120

Clostridium difficile, 17, 114–115Clostridium perfringens epsilon toxin, 420–421Clostridium tetani

antibacterial monoclonal antibodies discoveredby phage display, 115

passive antibody therapy, 4

CMV. See CytomegalovirusCoagulation, complement and, 63–64Cocaine, 435Cocktails of antibodies, 13, 17, 18–19Coincidence index, 356Colliers de Perles, 365, 366, 369–370Colorectal cancer, Erbitux (cetuximab) therapy for,

12Combinatorial library approaches, for humanization,

330Common cold viruses, IgE antibodies induced by,

82Complement

activation, 30, 64alternative pathway, 66antibody-mediated, 66–68classical pathway, 65–66lectin pathway, 66

antibody functions dependent on, 30–31

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antibody therapy and, 63–72antibody-mediated activation, 66–68IgA, 67–68IgG, 65–67IgM, 65–67

coagulation and, 63–64dengue vascular permeability syndrome (DVPS)

and, 261–262, 264homeostasis, role in, 63, 64–65inflammatory responses, 69manipulating Ab-mediated responses, 69–70increasing complement response, 69–70reducing negative effects of complement, 70

membrane attack complex (MAC), 68opsonization, 68–69overview of system, 63–65roles of, 63–65

Complementarity-determining region (CDR), 173affinity maturation, 184–185antibody docking, 180–181antibody gene rearrangements, 346–347CDR-IMGT lengths for antibody humanization

by grafting, 366cytotoxic drug delivery and, 15high-throughput DNA sequencing and, 346–347,

355–356humanization and CDR grafting, 327–330abbreviated CDRS containing SDRs (specificity-

determining residues), 328–329framework adaptation, 330framework shuffling, 329–330human string content optimization, 329main decision-making points, 328standard technology, 327–328superhumanization, 329veneering/resurfacing, 328

lengths and posttranslational modifications, 55modeling, 174, 176–181, 184recombination and, 175structure, 9–10, 50–55, 57–59canonical structure of, 176–178disulfides in, 54–55H3 structure, 51–53predicting conformation of HCDR3, 177–178

synthetic phage antibody libraries, 107–108

Complement-coated Ab transfer, 68Complement-dependent cell cytotoxicity (CDCC),

65, 68, 70Complement-dependent cytotoxicity (CDC), 65,

68–71, 322–324Computational design of antibodies, 183–187Computer-aided prediction of structure and design

of function, 173–187. See also Antibody design;Antibody modeling

Constant domains, 8–10, 174Contact-mode AFM, 387Convertases, 68

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Coronavirusesantiviral monoclonal antibodies discovered by

phage display, 112–113Middle East respiratory syndrome coronavirus

(MERS-CoV), 111, 112–113severe acute respiratory syndrome coronavirus

(SARS-CoV), 111, 112

Corynebacterium diphtheriae, passive antibody

therapy for, 4Cost of therapy, 12Coxiella burnetii, 33CpG, B cell immortalization using, 130, 131–133,

166Crossmab, 336Cryptococcus neoformans, 27, 28, 31, 35, 67, 323

labeled antibodies against, 15, 400–404monoclonal antibody therapy, 18

Cryptosporidium parva, 28CTLs (cytotoxic T lymphocytes), 224CXCR4 receptor, 17, 111, 161, 194, 198Cyanovirin, 419Cytogam, 280Cytokine inhibitors, for staphylococcal enterotoxin

B treatment, 311Cytokines. See also Chemokines; specific cytokines

to amplify B cells, 143–144antibodies targeting cytokines and their receptors,

88–89in antibody-dependent enhancement (ADE),

255–257, 264humanized mice and, 167immunocytokine (ICK), 335in immunodeficient mice strains, 158staphylococcal enterotoxin B and, 306–307,

311

Cytomegalovirus (CMV), 273–284

anti-CMV antibody structure, 55future challenges, 283–284immune response, 276–279latency, 276–278overview, 273–275structure and life cycle, 275–276studies in humanized mice, 166target-agonist approach for antigen discovery in

vaccine design, 136–137testing therapies for, 6therapeutic antibodies, 280–283monoclonal antibodies, 282–283polyclonal CMV-IVIG, 280–282table of antibody-based therapeutics, 281

Townes's strains, 279, 280treatment spectrum for high-risk demographic

groups, 274vaccine development, 279–280

Cytotect IVIG, 282, 283Cytotoxic drugs, antibody-delivered, 15Cytotoxic T lymphocytes (CTLs), 224

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Daclizumab, 330DC-SIGN, 326Dendritic cells, 76–78, 166, 256, 326Dengue hemorrhagic fever/dengue shock syndrome

(DHF/DSS), 251–253, 261–262, 264Dengue vascular permeability syndrome (DVPS),

251–253, 261, 263–265clinical features of, 251, 261genetic factors contributing to susceptibility, 252,

263sensitizing infection, 252–254, 263

Dengue virusafferent phenomena, 252–261, 263–264enhancing antibodies, 252–258, 263–264genetic host factors contributing to DVPS

susceptibility, 252, 263role of dengue viruses in ADE, 258–261, 264

antibody-dependent enhancement (ADE),249–265

antiviral monoclonal antibodiesdiscovered by phage display, 111discovered by yeast display, 118, 119

dengue hemorrhagic fever/dengue shocksyndrome (DHF/DSS), 251–253, 261–262,264

dengue vascular permeability syndrome (DVPS),251–253, 261, 263–265

DENV-2enhanced growth in primary human monocytes,

258, 264genetic differences after infection with DENV-1,

259–261, 264genetic differences after infection with DENV-3,

260–261, 264strain differences in neutralization by DENV-1

antibodies, 258–259, 264efferent phenomena, 252, 253, 261, 264–265enhancing antibodies, 252–258attributes of iADE, 254–257, 263role of FcγRs, 257–258, 264role of infection sequence, 257, 263–264role of myloid cells, 257, 264sensitizing infection, 252–254, 263

heterohybridomas, 149studies in humanized mice, 162

Dental caries monoclonal antibodies, 416–417Dependovirus, 429Design. See Antibody designDestabilization of organisms, 26DHF/DSS. See Dengue hemorrhagic fever/dengue

shock syndromeDielectrophoresis, 146–147Diphtheria, history of serum therapy for, 4Directed evolution, 184Dissociation constant, 386, 389–391Disulfide bonds, 8, 54–55DJ recombination, 50

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DNA sequencing. See High-throughput DNAsequencing

DOCK8, 81Drug addiction, antibody gene transfer, 435Duobody of Genmab, 324DVPS. See Dengue vascular permeability syndrome

EBI (European Bioinformatics Institute), 364Ebola, 5–6, 111, 113, 417–418EBV. See Epstein-Barr virusEffector functions of antibody, 10–11Effector silent antibodies, 325–326Efungumab, 18Ehrlichia risticii, 33ELAM, 306Electrofusion, in hybridoma production, 146–148Electron microscopy, antibody docking and, 181–183Electroporation, 146Enbrel (etanercept), 432Ensembl, 364Enterotoxins, staphylococcal, 303–304. See also

Staphylococcal enterotoxin BEntrez Gene, 364Entry, inhibition of, 28Enzyme-linked immunosorbent assay (ELISA), 382,

388Eosinophilia, in allergic conditions, 88–89Eosinophils, 78–79, 88–89Epitope

discontinuous, 186IMGT (International ImMunoGeneTics

information system), 374–376

Epitope drift, 330Epitope grafting, 185–187Epitope mapping

antibody docking and, 180–183HIV neutralizing antibodies, 429

Epsilon toxin, Clostridium perfringens, 420–421Epstein-Barr virus (EBV)

B cells immortalization using, 130, 131–133,143–145, 148, 283

high-throughput DNA sequencing applicationsfor study of, 356

studies in humanized mice, 161–164

Erbitux (cetuximab), 12ERK, 255Error correction strategies, for high-throughput

DNA sequencing, 353Escherichia coli, 17, 90, 327

adhesion, interference with, 27bacteriophages, 105enteropathogenic, 27uropathogenic, 27

Esterification, in atomic force microscopy (AFM),388

Etanercept, 89European Bioinformatics Institute (EBI), 364

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Evolutiondirected, 184viral, 110

FabFab-pIII phage display format, 109structure, 9, 50, 180yeast display and, 115–117

FACS (fluorescence-activated cell sorting), 115–117,382, 384–386, 390–391, 394–395

Factor VII, 64Fc

aglycosylated, 327antibody engineering, 14–15, 322–327fusion proteins, 9, 16glycosylation and effector functions, 324–327sialylation, 326–327structure, 9–10, 50, 174

Fcε, 76–77, 79, 82–88Fc-Fc receptor interactions, antibody functions

dependent on, 32–35FcγRs

allergic responses and, 79–80antibody engineering, 322–327role in antibody-dependent enhancement (ADE),

249, 250, 254–255, 257–258, 264

FcRn (neonatal Fc receptor), 10, 15, 326Feline infectious peritonitis virus, 250Filamentous phage, 105–106Fimbriae, 275' RACE, 350–351Flaviviruses, 251

antiviral monoclonal antibodies discovered byphage display, 111

antiviral monoclonal antibodies discovered byyeast display, 118, 119

Flow cytometryfluorescence-activated cell sorting (FACS),

115–117, 382, 384–386, 390–391, 394–395hybridoma cell sorting and, 151

Fluorescence-activated cell sorting (FACS), 115–117,382, 384–386, 390–391, 394–395

FMDV (foot-and-mouth disease virus), 26, 430–431,435

Food poisoning, staphylococcal enterotoxin B,309

Foot-and-mouth disease virus (FMDV), 26,430–431, 435

Foravirumab, 18Framework adaptation, 330Framework shuffling, 329–330Fucosylation, 324–325Functions of antibodies, 25–36

agglutination, 26aggregation, 26antibody-dependent cellular cytotoxicity

(ADCC), 32–34

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complement dependent, 30–31dependent on Fc-Fc receptor interactions, 32–35incentive for measuring, 25independent of effector cells/molecules, 26–29inflammation modulation, 35–36neutralization, 26–29overview of, 25–26phagocytosis, 34–35

Fungiantibody-based therapy examples, 18radioimmunotherapy (RIT) for fungal infections,

400–404yeast display, 115–121

Fusion, inhibition of, 28Fusion efficiency, 142Fusion methods for hybridoma production, 145–148

electrical cytofusion, 146–148PEG, 145–146viral, 145

Fusion partners for hybridoma production,148–149

Fusion proteins, 9, 16Fab-pIII phage display format, 109scFv-pIII phage display format, 108–109

Fv structure, 50

Galactose, yeast display and, 115Galectin-3, 77, 79Ganciclovir, 277Gel microdroplet encapsulation, 152Gell-Coombs immunopathology, 249Gemtuzumab, 324Gemtuzumab ozogamicin, 334Gene rearrangements, antibody, 346–348Genome Database, 364Giardia, 28Glycan shield, 56, 194GlycoFi, 325Glycosylation

Fc, 324–327of plant-derived monoclonal antibodies, 415–416

Glycotope, 325Golimumab, 89, 334Graft versus host disease (GVHD), 159Guided selection, 330Guy's 13, 416–417

HAART (highly active antiretroviral therapy),405–406

Haemophilus influenzae, 31history of serum therapy for, 4hyper-IgE syndrome, 81vaccine, 357

Half-life, immunoglobulin, 10Hamming distance, 354HCDR3, modeling, 177–180Heat shock proteins, 18, 27

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Heavy chainsantibody gene rearrangements and, 346–348domination of antibody-antigen interaction,

53–54paired heavy and light chain sequencing, 354in scFv-pIII phage display format, 108structure, 8–10, 50, 53–54, 174–175

Helper phage, 108–109Hemagglutinin

antibodies against, 28, 58, 111, 119, 132–135,210–216

antibodies targeting residues mediating receptorspecificity, 213–214

antibodies that mimic sialic acid, 214–215antibody response in humanized mice, 162characteristics of globular head versus stem HA

antibodies, 210cross-reactivity of globular head HA antibodies,

212–213future areas for study, 215–216

antigenic mapping, 211–212structure, 110–111, 209–211

Hematopoietic stem cellsHu-HSC mice, 159, 161–164, 166–167Hu-Liver-HSC mice, 160

Hemolytic uremic syndrome, 17Hepatitis B virus

combinations of antibodies against, 13studies in humanized mice, 162, 166

Hepatitis C virus, 17monoclonal antibodies against, 149studies in humanized mice, 166

Herceptin (trastuzumab), 325, 330, 335, 336, 436Herd immunity, respiratory syncytial virus (RSV)

and, 222Herpes simplex virus (HSV)

antibody-dependent cellular cytotoxicity(ADCC), 32–33

antiviral monoclonal antibodies discovered byphage display, 111

plant-derived monoclonal antibody, 418studies in humanized mice, 166

Heterohybridomas, 148–149HGNC (Human Genome Organization Nomenclature

Committee), 364Highly active antiretroviral therapy (HAART),

405–406High-throughput DNA sequencing, 345–357

antibody gene rearrangements, 346–348data analysis, 354–357alignment and parsing programs, 354–355applications in infectious disease research,

355–357primer trimming, 354quality scores, 354sequence barcode analysis, 354

future directions, 357

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instruments, 348–350overview, 345–346strategies for Ig repertoires, 350–3545' RACE, 350–351cell populations, 350error correction strategies, 353multiplexing and chimeric sequences, 352–353paired heavy and light chain sequencing, 354replicate library preparation, 353targeted PCR, 350–351template choice, 351–352

HighV-QUEST, 355Histoplasma capsulatum, 15, 403–404History of antibody-based therapy

monoclonal antibodies, 11–12passive antibody therapy, 4–5

HIV. See Human immunodeficiency virusHLA

CMV and, 278, 283humanized mice and, 164, 166, 167

HMPV. See Human metapneumovirus; Humanmetapneumovirus (HMPV)

Homeostasis, complement and, 63, 64–65Hooke's law, 388HRIG (human antirabies immunoglobulin), 419HSV. See Herpes simplex virusHTLV-1, 166Hu-HSC mice, 159, 161–164, 166–167Hu-Liver-HSC mice, 160Human antirabies immunoglobulin (HRIG), 419Human Genome Organization (HUGO), 364Human Genome Organization Nomenclature

Committee (HGNC), 364Human immunodeficiency virus (HIV)

antibody response to, 193–196conventional antibodies, 195neutralizing antibodies, exceptional broadly,

195–196pregnancy and, 196virus escape mechanisms, 194–195

antibody-dependent cellular cytotoxicity(ADCC), 33

anti-HIV antibody structure, 49, 53, 54, 57, 183,186

attachment, interference with, 27combinations of antibodies against, 13complement and, 30conformational masking, 194–195glycan shield, 56, 194HAART (highly active antiretroviral therapy),

405–406high-throughput DNA sequencing applications

for study of, 356IgG3 and, 324incidence and prevalence, 193monoclonal antibody against, 17, 130–131discovered by phage display, 112

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discovered by yeast display, 118–119mutation rate, 194neutralization of infectivity, 26–29, 58, 185–186neutralizing antibodiesexceptional broadly, 195–196importance of, 428–429as vaccine, 429

plant-derived monoclonal antibody, 418–419radioimmunotherapy (RIT), 405–407self-carbohydrate recognition by HIV antibodies,

56–57somatic hypermutation in immune systems

chronically exposed to, 348studies in humanized mice, 158–159, 161–164,

166target-agonist approach for antigen discovery in

vaccine design, 136vaccine development and immunogen design,

196–200, 427–429Abs targeting CD4 binding sites, 199–200Abs targeting membrane-proximal external

region (MPER), 200Abs targeting variable loops 1 and 2, 197–198Abs targeting variable loops 3, 198–199

Human metapneumovirus (HMPV), 132–133,237–244

age-related antibody development, 239antibody cross-protection, 238–239antibody response to infection, 239antibody specificity, 238antigenic proteins, 242–243F protein, 239, 241–244immunoglobulin classes after infection, 239induction of antibodies by immunization,

241–242monoclonal antibodies, 243–244phylogeny, 240seroprevalence of infection, 237–238

Human papillomavirus, 29Humanization

antibody engineering, 327–330antibody informatics and, 370CDR grafting, 327–330abbreviated CDRS containing SDRs (specificity-

determining residues), 328–329framework adaptation, 330framework shuffling, 329–330human string content optimization, 329main decision-making points, 328standard technology, 327–328superhumanization, 329veneering/resurfacing, 328

CDR-IMGT lengths for antibody humanizationby grafting, 366

combinatorial library approaches, 330guided selection, 330overview, 327

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Humanized mice, 157–168antigens studied in, 166future prospects, 167–168HLA restriction, 163–164, 164, 166, 167human cell reconstitution and antibody response,

162–163human immunodeficiency virus (HIV) studies,

158–159, 161–164, 166immunodeficient mouse strains, 158, 160monoclonal antibody generation in, 164–166mouse models, 158–160advantages and disadvantages, 166–167BLT mice, 159, 160–164, 166–167Hu-HSC mice, 159, 161–164, 166–167Hu-Liver-HSC mice, 160Hu-PBL mice, 158–159SCID-Hu mice, 159, 163

pathogens studied in, 166preparation, infection, and immunization,

160–162T-cell response in, 163–164

Humira (adalimumab), 11Hu-PBL mice, 158–159Hybridoma, 12

fusion methods, 145–148electrical cytofusion, 146–148PEG, 145–146viral, 145heterohybridomas, 148–149history, 141–142human hybridoma technology, 141–152advantages of, 141–142B cell source, 143–145biological cloning methods, 149–152disadvantages of, 142first human hybridomas, 142–143fusion methods, 145–148fusion partners, 148–149

trioma, 149

Hydrogen-deuterium exchange, 181–183Hyper-IgE syndrome (HIES), 82Hypersensitivity

allergic inflammation, 75–95serum therapy and, 4, 10–11

Hypoxanthine, 148

iADE (intrinsic antibody-dependent enhancement),251, 254–258, 263–264

Ibalizumab, 17Ibritumomab (Zevalin), 15, 334, 399Ichthyophthirius multifilis, 26ICK (immunocytokine), 335IFN. See InterferonIgA

agglutination and, 26antibody engineering, 322–323complement activation, 67–68

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IgA (continued)half-life, 10human metapneumovirus infection, 239–240plant-derived monoclonal antibody, 414, 416respiratory syncytial virus (RSV) monoclonal

antibody, 227rotavirus and, 291–299

IgBlast, 355IgD, rotavirus and, 291IgE, 75–95

allergic inflammation, 75–95antibodies in treatment of allergies, 82–92clinical perspective, 75–76IgE activation of immune response, 96IgE antibodies in infectious diseases, 80–82IgE effector cells, 77–79APCs, 78B cells, 78mast cells, 77–78monocytes and eosinophils, 78–79

IgE receptors, 76–77interactions between allergens, IgE, and Fcε

trigger hypersensitivity responses, 79allergic response against cancer, 92–94allergy treatment, antibodies in, 82–92antibodies targeting cytokines, chemokines, and

their receptors, 88–89clinical studies in 2012, 86–87future roles of antibodies in therapy, 94–95IgG4 triggered protective immunity with

immunotherapy, 90–92neutralizing antibody response induced by active

allergen immunotherapy, 89–90recombinant antibodies targeting IgE interactions

with Fcε receptors, 82–88enterotoxin induction of, 310half-life, 10IgE antibodies in infectious diseases, 80–82bacterial infections, 81parasitic infections, 80–81viral infections, 82

IgE receptors, 76–77IgG

allergen-specific IgG antibody triggeringhypersensitivity responses, 79–80

antibody engineeringFc glycosylation and effector functions, 324–327IgG1, 323IgG2, 323–324IgG3, 324IgG4, 324

antibody response humanized mice, 162–163, 166antibody-dependent cellular cytotoxicity (ADCC)

and, 322–326complement activation, 65–67complement-dependent cytotoxicity (CDC) and,

322–324

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Fc sialylation, 326–327half-life, 10human metapneumovirus infection, 239–240IgG4, allergen specific, 90–92plant-derived monoclonal antibody, 414, 416respiratory syncytial virus (RSV) monoclonal

antibody, 227–228rotavirus, 290–295structure, 9–10, 173–175subtypes, 67

IgMantibody response humanized mice, 162–163, 166complement activation, 65–67half-life, 10rotavirus and, 291–293, 299

iHMMunealign, 355IL-1, 306IL-2, 158, 164, 306–307, 312, 314IL-4, 255IL-4, antibodies targeting, 88IL-5, antibodies targeting, 88–89IL-6, 134, 257, 307IL-9, antibodies targeting, 89IL-10, 90–92, 255–257, 263IL-12, 255, 307IL-13, antibodies targeting, 88IL-21, 130, 144Illumina high-throughput DNA sequencing

instruments, 349–350IMGT (International ImMunoGeneTics information

system), 348, 363–377antibody 3D structures, 373–376IMGT/2Dstructure-DB, 376IMGT/3Dstructure-DB card, 373IMGT/3Dstructure-DB chain details, 373IMGT/3Dstructure-DB contact analysis, 374IMGT/DomainSuperimpose, 376IMGT/mAb-DB, 376IMGT/StructureQuery, 376paratope and epitope, 374–376

antibody engineering, importance of, 370availability and citation, 377Colliers de Perles, 365, 366, 369–370humanization, importance of, 370IMGT/DomainGapAlign, 370–373IMGT/LIGM-DB, 376nomenclature, 364overview, 363–374paratope and epitope, 374–376standardized and integrated system, 366–367targeted and customized therapeutic antibodies,

376–377unique numbering, 364–366anchors for V and C domains, 365–366CDR-IMGT lengths for antibody humanization

by grafting, 366highly conserved amino acids, 366

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V- and C-domain 2D representations, 369V- and C-domain amino acid sequence analysis,

370–373V-domain nucleotide sequence analysis, 367–369IMGT/HighV-QUEST for deep sequencing,

367–369IMGT/V-QUEST, 367

IMGT-ONTOLOGY, 364, 366–367Immune complex formation, 4Immune system

allergic inflammation, 75–95modulation by antibodies, 35–36transplantation of human into mice, 158–162

Immunization, for human metapneumovirus(HMPV), 241–242

Immunoadhesins, 431–434Immunocytokine (ICK), 335Immunoglobulin. See also Antibody; specific

immunoglobulin classesantibody gene rearrangements, 346–348high-throughput DNA sequencing strategies for

Ig repertoires, 350–354

Immunotherapy

cytomegalovirus (CMV)monoclonal antibodies, 282–283polyclonal CMV-IVIG, 280–282vaccine, 279–280

human metapneumovirus (HMPV)induction of antibodies by immunization,

241–242monoclonal antibodies, 243–244

radioimmunotherapy (RIT), 399–408respiratory syncytial virus (RSV), 225–231intravenous immunoglobulin (IVIG), 225–226monoclonal antibody, 226–231

rotavirus, 296–298staphylococcal enterotoxin B, 311–315passive immunotherapy, 313–315vaccines, 312–313

Indels, unusual, 57Inducible nitric oxide synthase (iNOS), 256Infectivity, neutralization of, 26Inflammation. See also Allergic inflammation

complement, 69Fc sialylation and, 326–327modulation by antibodies, 35–36in respiratory syncytial virus (RSV) disease, 224

Infliximab, 89, 330, 334Influenza virus

antibody gene transfer, 433–434antibody-dependent cellular cytotoxicity

(ADCC), 33anti-influenza antibody structure, 49, 54, 57complement and, 30H1N1, 210–214, 434–435H2N2, 210H5N1, 215, 435

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hemagglutininantibodies against, 28, 58, 111, 119, 132–135, 162,

210–216structure, 110–111, 209–211

heterohybridomas, 149inhibition of fusion/entry, 28inhibition of liberation, 29intracellular inhibition, 29monoclonal antibodies against, 149discovered by phage display, 110–112discovered by yeast display, 118, 119screening monoclonal antibodies by neutralization,

132–133neutralization mechanism, 58

Informatics, antibody, 363–377analysis of V-domain nucleotide sequences,

367–369antibody 3D structures, 373–376antibody engineering, importance of, 370humanization, importance of, 370nomenclature, 364overview, 363–374standardized and integrated system, 366–367targeted and customized therapeutic antibodies,

376–377unique numbering, 364–366V- and C-domain 2D representations, 369V- and C-domain amino acid sequence analysis,

370–373

Innate immune system, complement functions in,

63iNOS (inducible nitric oxide synthase), 256Interferon (IFN)

antibody-dependent enhancement (ADE) and,250, 255–257, 263

staphylococcal enterotoxin B and, 306–307, 310,314–315

Interleukins. See also specific interleukinsallergic inflammation and, 76–78to amplify B cells, 144antibodies targeting, 88–89humanized mice and, 167hyper-IgE syndrome and, 81in immunodeficient mice strains, 158staphylococcal enterotoxin B and, 306–307, 312,

314

Intermittent contact-mode AFM, 388Internalization of antibodies, 29International ImMunoGeneTics information

system. See IMGTIntrabodies, 29Intravenous immunoglobulin (IVIG), 5

for cytomegalovirus, 280–282for respiratory syncytial virus (RSV), 225–226

Intrinsic antibody-dependent enhancement (iADE),251, 254–258, 263–264

Ion Torrent platform, 349

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JAK/STAT signaling, 256Japanese encephalitis virus, 254, 263–264Jawless vertebrates, 53–54Junctional diversity, 175, 184

Kadcyla (ado-trastuzumab emtansine), 15Kaposi's sarcoma-associated herpesvirus, 166Knobs-into-holes technology, 336

Lebrikizumab, 88Lectin pathway of complement activation, 66Legionella pneumophilia, 31Leishmania, 30

intrinsic antibody-dependent enhancement(iADE), 255, 258

studies in humanized mice, 166

Lentiviruses, antibody-dependent cellular

cytotoxicity (ADCC) and, 33Light chains

antibody gene rearrangements and, 346–348paired heavy and light chain sequencing, 354in scFv-pIII phage display format, 108structure, 8, 50, 174–175

Limiting dilution cloning, 150Lineweaver-Burke plot, 385Listeria moncytogenes, 29LocusLink, 364Lovastatin, 314Lymphoblastoid cells, 144Lysozyme-antilysozyme binding, 389

“Magic bullet” creation, 15Magnetic assisted cell sorting (MACS), 115–116Magnetic bead-based biopanning, 392Major histocompatibility complex (MHC)

CMV and, 278humanized mice and, 162–163, 167staphylococcal enterotoxin B and, 304–308, 311,

313

Mammalian display, affinity maturation of antibody

by, 332–333Mannose-activating serine proteases (MASPs), 66Mannose-binding lectin (MBL), 66MARMs (monoclonal antibody resistant mutants),

243–244Mass spectromtery, staphylococcal enterotoxin B

and, 310Mast cells, 77–78Mating type, yeast, 115Maytansinoids, 335MCP-1 (monocyte chemoattractant protein 1),

307–308Mean fluorescence intensity (MFI), 385–386Measles virus

IgE antibodies induced by, 82inhibition of, 29

Membrane attack complex (MAC), 68

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Membrane-proximal external region (MPER), HIV,200

Memory B cellsefficient methods to isolate monoclonal

antibodies from, 129–137frequency in circulation, 142immortalization, 130, 131–133

Meningitis, history of serum therapy for, 5Mepolizumab, 88Metapneumovirus. See also Human

metapneumovirus (HMPV)avian, 238, 240phylogeny, 240

MHC. See Major histocompatibility complexMice

heterohybridomas, 148–149humanized, 157, 168. See also Humanized miceimmunodeficient strains, 158, 160monoclonal antibody production in, 130staphylococcal enterotoxin Bmonoclonal antibodies for treatment of, 313–314mouse model, 307–308

Microscopyatomic force microscopy (AFM), 382, 386–389,

391–395electron microscopy, antibody docking and,

181–183

Middle East respiratory syndrome coronavirus

(MERS-CoV), 111, 112–113Modeling. See Antibody modelingMOE modeling server, 179Monoclonal antibody

anti-infectious, 65approved/pending therapies, 6–8, 65complement and, 67, 68–71cost of therapy, 12defined, 11history, 11–12, 141–142hybridoma and, 12immunotherapycytomegalovirus (CMV), 282–283human metapneumovirus (HMPV), 243–244respiratory syncytial virus (RSV), 226–231

neutralization of infectivity and, 26–27phage display, 106, 109–115antibacterial mAbs discovered, 113–115antiviral mAbs discovered, 110–113

plant-derived, 413–421production, 12efficient methods to isolate from memory B cells

and plasma cells, 129–137high-throughput cellular screens, 130–135human hybridoma technology, 141–152in mice, 130, 157–168in plants, 413–416single-cell reverse transcription (RT)-PCR, 130,

133, 135

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specificity of, 12, 13staphylococcal enterotoxin B, 313–315chicken, 314chimeric, 314human, 314–315murine, 313–314

yeast display, 118–121antiviral mAbs discovered, 118–119bacterial mAbs discovered, 119–121

Monoclonal antibody resistant mutants (MARMs),243–244

Monocyte chemoattractant protein 1 (MCP-1),307–308

Monocytes, 78–79Motavizumab/motavizumab-YTE, 228–229, 231MPER (membrane-proximal external region), HIV,

200Murray Valley encephalitis virus (MVEV), 250Mutagenesis, affinity maturation and, 331–333Mutations, escape in antibody therapy, 13Mycobacterium tuberculosis, 27Myeloma, hybridoma production and, 148–149Myoltarg (gemtuzumab ozogamicin), 15

NALP3 inflammasome complex, 72Nanobody, 231Nanoparticles, 71Natalizumab, 324National Center for Biotechnology Information

(NCBI), 364Neisseria gonorrhoeae, 31Neisseria meningitidis, 4, 31, 33, 35Neonatal Fc receptor (FcRn), 10, 15, 326Neuraminidase, antibodies against, 29, 58Neutralization, 26–29

antibody design, 184complement and, 65defined, 26inhibition of fusion/entry, 28interference with attachment, 27–28intracellular, 29mechanisms of, 57–58by monoclonal antibodies discovered by phage

display, 110“multiple hit” phenomenon, 27neutralizing antibody elicited throughantigen design, 185

epitope grafting, 185–187neutralizing antibody response induced by active

allergen immunotherapy, 89–90postattachment, 28–29preattachment, 26–27screening by, 132–133

Nicotiana, 415–421NK cells

antibody-dependent cellular cytotoxicity (ADCC)and, 322, 323, 325, 326

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in immunodeficient mice strains, 158NMR spectroscopy, 181–183NOG mice, 158–160Nonobese diabetic (NOD)-SCID mice, 158, 160, 161NS1, dengue virus, 260–262, 264–265NSG mice, 158–161Nude mice, 158Numax (motavizumab), 17

OKT3, 11–12, 283Omalizumab (Xolair), 83–88Opsonization, 68–69OraVax, 227Ouabain, 148

Pagibaximab, 16Palivizumab, 6, 17, 18, 65, 137, 227–231, 321, 434Panobacumab, 16Parainfluenza virus, 30Paramyxoviruses, 30, 222Parasites

antibody-dependent cellular cytotoxicity(ADCC), 33

complement and, 31IgEmechanisms of protection in parasitic infections,

80–81interference with attachment, 28phagocytosis, 35replication inhibition by IgA, 29

Passive antibody therapy. See also Monoclonalantibody

antibody gene transfer, 429–436for cytomegalovirus, 280–283future roles in allergic disease treatment, 94history of, 4–5for HIV, 428–429intravenous immunoglobulin (IVIG), 5, 225–226,

280–282for respiratory synctial virus, 225–226for rotavirus, 296–297side effects, 4, 10–11staphylococcal enterotoxin B, 313–315

Pathogenicity islands, 304PCR, 350–354Pearl chain formation, 147Penicillin, discovery of, 5Pentoxifylline, 311Peptide antagonists, for staphylococcal enterotoxin

B treatment, 311Permeabilization, 146Phage. See also Phage display

described, 105–106helper, 108–109recovery using AFM, 394

Phage display, 105–115, 129–130, 184antibody display formats, 108–109Fab-pIII display, 109

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Phage display (continued)scFv-pIII display, 108–109

discovery of antibodies for infectious diseases by,109–115

antibacterial antibodies, 113–115antiviral antibodies, 110–113

library selection procedure, 106–107overview, 105–106purpose of, 106sources of antibody genes for display libraries,

106–108immune phage antibody libraries, 106–107naïve phage antibody libraries, 106synthetic phage antibody libraries, 107–108

yeast display compared, 116–117

Phagemid vectors, 108Phagocytosis

antibody function and, 34–35antibody-dependent cellular phagocytosis

(ADCP), 322–323, 325

Pichia pastoris, 90PIGS server, 179PIII phage antibody display

Fab-pIII, 109scFv-pIII, 108–109

Pili, 27Plant-derived monoclonal antibody, 413–421

bacterial toxins, 420–421anthrax, 420Clostridium perfringens epsilon toxin, 420–421staphylococcal enterotoxin B, 421

infectious disease targets, 416–421dental caries, 416–417Ebola virus, 417–418herpes simplex virus, 418human immunodeficiency virus (HIV), 418–419rabies, 419respiratory synctial virus (RSV), 419in vivo studies, 417West Nile virus, 419–420

production, 413–416controlling Mab N glycosylation, 415–416rationale, 413–414transgenic technologies for, 414transient technologies for, 415

for purification of infectious disease antigens, 421

Plasma cells

efficient methods to isolate monoclonalantibodies from, 129–137

long-term culture, 133–134

Plasmodium, 28Plasmodium falciparum, 28, 31

ADCC, 33phagocytosis, 35studies in humanized mice, 166

Platforms, antibody modeling, 179–180Pneumococcal pneumonia, serum therapy for, 4

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Pneumococcal vaccine, 357Pneumovirinae (subfamily), 222Poisson distribution, 150Poliovirus

aggregation of, 26inhibition of vesicle escape, 28

Polyethylene glycol (PEG)-mediated cell fusion,142, 145–146

Polymerase chain reaction (PCR), 350–354Posttranslational modification, 50–53PREVENT study, 226PRO140, 17Programs, antibody modeling, 179–180Protein Data Bank, 49, 175–176, 178–180Pseudomonas aeruginosa, 16–17, 26

Quadroma technology, 336Quality scores, DNA sequencing, 354

Rabies, 17–18, 419RACE (rapid amplification of cDNA ends), 350–351Radioimmunoassay (RIA), 382Radioimmunotherapy (RIT), 399–408

bacterial infections, 404–405fungal infections, 400–404HIV, 405–407overview, 399–400

Radioisotopesantibody drug conjugates, 334labeled antibodies, 15, 399–408

Rapamycin, 311Rapid amplification of cDNA ends (RACE), 350–351Raxibacumab, 17, 114Recombinant adeno-associated virus (rAAV),

428–436Recombination, 50, 174, 184Resilizumab, 89RespiGam, 226Respiratory diseases. See also specific etiologic agents

antibody gene transfer for, 433–435staphylococcal enterotoxin B and, 310

Respiratory syncytial virus (RSV), 221–232antibody gene transfer, 433–434antiviral monoclonal antibodies discovered by

phage display, 111clinical features of infection/disease, 221–222combinations of antibodies against, 13epitope grafting, 186–187F protein, 222–223, 225, 227, 239, 242–244future opportunities for treatment and prevention,

231–232herd immunity, 222IgE antibodies induced by, 82immunoprophylaxis, 225–231intravenous immunoglobulin (IVIG), 225–226monoclonal antibody, 226–231

motavizumab/motavizumab-YTE, 228–229, 231

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overview, 221–224palivizumab for, 6, 17, 18, 65, 137, 227–231, 321pathogenesis, 223plant-derived monoclonal antibody, 419ribavirin for, 224screening monoclonal antibodies by neutralization,

132structure and life cycle, 222–223target-agonist approach for antigen discovery in

vaccine design, 137vaccine, 224–225

Resurfacing, 328Reverse vaccinology, 198RG mice, 158–160, 162, 164Rhinitis, staphylococcal enterotoxin B and, 310Rhinovirus

IgE antibodies induced by, 82interference with attachment, 27

RIA (radioimmunoassay), 382Ribavirin, 224RIT. See RadioimmunotherapyRituximab (Rituxan), 11, 70, 325RNA interference (RNAi), 231Roche/454 platform, 349Root mean square deviation (RMSD), 180–181Rosetta Design, 186Rosetta Antibody, 179Rosetta Dock algorithm, 180–181Ross River virus (RRV), 250, 257Rotarix vaccine, 297Rotavirus, 289–299

antibody response against, 290–296compartmentalization of rotaviris-B cells,

293–295Ig gene usage of rotavirus-B cells, 292–293mechanism of protection and specificity of

rotavirus-Ig, 295–296ontology of rotavirus-B cells and rotavirus-Ig,

290–292future challenges, 298–299overview, 289–290therapeutic/prophylactic applications of rotavirus

antibodies, 296–298

RSV. See Respiratory syncytial virus

Saccharomyces cerevisiae, 115Salmonella, 33Salmonella enterica serovar Typhimurium, 26, 166Scaffold, epitope grafting and, 186–187scFv. See Single-chain variable fragmentsscFv-pIII display, 108–109Schistosoma haematobium, 80Schistosoma mansoni, 33, 80SCID-Hu mice, 159, 163SEBILS (SEB-induced lethal shock), 307–308,

311–312, 314Secretory IgA, plant-derived monoclonal, 414

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SEED (strand-exchange engineered domain), 336Self-carbohydrate recognition, 55–57Semliki Forest virus, 30Sendai virus

for fusion in hybridoma production, 145inhibition of, 29

Sensitizing infection, in dengue vascularpermeability syndrome (DVPS), 252–254, 263

Serum sickness, 4Serum therapy

history of, 4–5pros and cons of antibody-based therapy relative

to, 14for toxin-mediated diseases, 311

Servers, antibody modeling, 179–180Severe acute respiratory syndrome coronavirus

(SARS-CoV), 111, 112Severe combined immunodeficiency (SCID) mice,

158–161, 163, 406–407Sharks, 54Shiga toxin, 17Shigella flexneri, 33Sialic acid, antibodies that mimic, 214–215Sialylation, Fc, 326–327Silanization, in atomic force microscopy (AFM), 388Simian immunodeficiency virus (SIV), 428Sindbis virus, 26Single-cell reverse transcription (RT)-PCR, 130, 133,

135Single-chain variable fragments (scFv)

scFv-pIII phage display format, 108–109yeast display and, 115–117

SIT (specific immunotherapy), 90–92Site-directed mutagenesis, 181–183, 312–313SnugDock algorithm, 181SoDA2, 355Somatic hypermutation, 175, 184

antibody gene rearrangements, 348in vitro affinity maturation by, 332

Somatic recombination, 175Specific immunotherapy (SIT), 90–92SPR (surface plasmon resonance), 382–384,

389–390, 394Spring constant, 388Staphylococcal enterotoxin B, 303–315

animal models, 307–309mouse, 307–308nonhuman primate, 308–309piglet, 308rabbit, 308rat, 308

biological and pathological activities, major, 307as biological weapon, 304clinical manifestation and epidemiology, 309–310atopic dermatitis, 309–310food poisoning, 309respiratory diseases, 310

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Staphylococcal enterotoxin B (continued)toxic shock syndrome, 309ulcerative colitis, 310

description of agent, 304–306diagnosis, 310future challenges, 315immune cell interaction with, 306–307infection, 304–307overview, 304plant-derived monoclonal antibody, 421SEBILS (SEB-induced lethal shock), 307–308,

311–312, 314treatment, 310–315cytokine inhibitors, 311immunotherapy, 311–315peptide antagonists, 311Vβ domains, 311

Staphylococcus aureus. See also Staphylococcalenterotoxin B

antibacterial monoclonal antibodies discoveredby phage display, 115

complement evasion, 71enterotoxins, 303–315hyper-IgE syndrome, 81methicillin-resistant (MRSA), 5, 16, 65, 115single-chain variable fragments (ScFv) targeting, 16vancomycin-resistant, 5

STAT3, 81STAT5, 164Strand-exchange engineered domain (SEED), 336Streptavidin-biotin interaction, 388–389Streptococcus, history of serum therapy for, 4Streptococcus mutans, 16, 416–417Streptococcus pneumoniae, 33, 34–35, 67

history of serum therapy for, 4hyper-IgE syndrome, 81labeled antibodies against, 15monoclonal antibodies against, 149radioimmunotherapy (RIT), 404–405

Structure of antibodies, 8–10, 49–59antibody gene rearrangements and, 346–348basics of, 8–10, 50–51CDR H3, 51–53computer-aided prediction of structure and

design of function, 173–187disulfides in CDRs, 54–55glycan shield, 55–57heavy chain domains, 53–54mechanisms of antibody neutralization and, 57–58posttranslational modification, 50–53recombination and, 50relation of sequence, structure, and function, 173–175self-carbohydrate recognition, 55–57unusual indels, 57

Substance P, 309Superantigens, enterotoxins as, 303–305, 315Superhumanization, 329

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Surface biomembrane force probe, 389Surface plasmon resonance (SPR), 382–384,

389–390, 394Sym003, 231Synagis, 6, 12, 17, 18, 321, 419, 434. See also

PalivizumabSynthetic phage antibody libraries, 107–108

T cell receptor (TCR)CMV and, 278–279, 283diversity estimates, 357informatics and, 363–364, 370staphylococcal enterotoxin B and, 304–307, 313, 314

T cellsantibody-dependent enhancement (ADE) and,

255–256cytotoxic T lymphocytes (CTLs) in respiratory

syncytial virus (RSV) disease, 224response in humanized mice, 159, 163–164staphylococcal enterotoxin B and, 306–307

T helper (Th) cells, 76, 78, 224, 255–256, 310Talizumab (TNX-901), 83Tapping mode AFM, 388T-DM1, 335Tefibazumab, 16Terminal deoxynucleotidyltransferase (TdT), 363TERT, 149Tetanus toxoid, 162, 166Th17 cells, 81Thravixa, 17Thymidine, 148Tissue remodeling, 78–79TNF-α. See Tumor necrosis factor alphaToll-like receptors

complement and, 63monoclonal antibody production and, 132–133,

143, 166

Tositumumab, 15, 334, 399Total internal reflection (TIR), 382–383Toxic shock syndrome (TSS), 306, 309Toxic shock syndrome toxin 1 (TSST-1), 166, 303,

308, 309, 312, 313Toxins

antibacterial monoclonal antibodies discoveredby phage display, 113–115

passive antibody therapy, 4plant-derived monoclonal antibody for bacterial

toxins, 420–421staphylococcal enterotoxin B, 303–315

Toxoplasma gondii, 29Tralokinumab, 88Trastuzumab (Herceptin), 325, 330, 335, 336, 436Trichinella spiralis

ADCC, 33IgE and, 80–81interference with attachment, 28

Trioma, 149

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Trypanosoma brucei, 31TSS (toxic shock syndrome), 306, 309TSST-1 (toxic shock syndrome toxin 1), 166, 303,

308, 309, 312, 313Tumor necrosis factor alpha (TNF-α), 77

antibodies targeting, 89, 333–334staphylococcal enterotoxin B and, 306–307, 312,

313, 315

Ulcerative colitis, staphylococcal enterotoxin B and,310

Ultrasound, electroacoustic fusion and, 146

Vaccineagainst adhesins, 27cytomegalovirus (CMV), 279–280high-throughput DNA sequencing applications

for study, 356–357human immunodeficiency virus (HIV), 196–200,

427–429respiratory syncytial virus (RSV), 224–225reverse vaccinology, 198rotavirus, 297–298staphylococcal enterotoxin B, 312–313

Vaccine designanalytic vaccinology, 136, 137target-agonist approach for antigen discovery,

136–137

Valortim, 17Variable domains, 8–10, 174–175

antibody gene rearrangements and, 346–348rotavirus-B cells and, 292–293in scFv-pIII phage display format, 108

Vascular endothelial cell growth factor receptor-2(VEGFR2), 435

Vβ domains, for staphylococcal enterotoxin Btreatment, 311

VD recombination, 50Vector-mediated in vivo antibody expression, 427–436

antibody gene transferfor cancer, 435–436drawbacks of rAAV, 436for drug addiction, 435expression systems for, 429–432for HIV-positive individuals, 433proof-of-concept studies in animal models,

432–433for respiratory tract infections, 433–435

expression systems for antibody gene transfer,429–432

proof-of-concept studies in animal models, 432–433

Veneering, 328Vertebrate Genome Annotation (Vega) Browser, 364Vesicular stomatitis virus, for fusion in hybridoma

production, 145Vibrio cholerae, 26Viral attachment, interference with, 27–28

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Virus. See also specific virusesantibody-based therapy examples, 17–18antiviral monoclonal antibodies discovered by

phage display, 110–113antiviral monoclonal antibodies discovered by

yeast display, 118–119evolution, 110for fusion in hybridoma production, 145IgE antibodies induced by, 82neutralization, 26–29, 110phagocytosis, 34plant-derived monoclonal antibodyEbola virus, 417–418herpes simplex virus, 418human immunodeficiency virus (HIV), 418–419rabies, 419respiratory synctial virus (RSV), 419West Nile virus, 419–420

Viruslike particleshuman metapneumovirus immunization with,

239, 241, 243rotavirus and, 290–291, 293

V(D)J recombination, 50, 174, 184. See alsoAntibody gene rearrangements

V-QUEST, 355

WAM modeling server, 179Wellcome Trust Sanger Institute, 364West Nile virus, 28

antibody-dependent enhancement (ADE), 250antiviral monoclonal antibodies discovered by

phage display, 111, 113antiviral monoclonal antibodies discovered by

yeast display, 118, 119complement and, 30dengue virus cocirculation with, 254plant-derived monoclonal antibody, 419–420studies in humanized mice, 162, 163

WHO-International Nonproprietary Names(WHO-INN), 364

World Health Organization-International Union ofImmunological Societies (WHO-IUIS), 364

Xolair (omalizumab), 83–88X-ray crystallography, 179

Yeast, 115Yeast display, 115–121

discovery of antibodies for infectious diseases by,117–121

antibacterial antibodies, 119–121antiviral antibodies, 118–119

overview, 115–116phage display compared, 116–117

Zanamir, 58Zevalin (ibritumomab), 15, 334, 399

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