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HANDBOOK OF
MONOCLONAL ANTIBODIES
Applications inBiology and Medicine
Edited by
Soldano FerroneDepartment of Microbiology and Immunology
New York Medical CollegeValhalla, New York
Manfred P. DierichInstitute of Hygiene
University of InnsbruckInnsbruck, Austria
np
Sole distribution by:Gothard House PublicationsGothard House, Henley-on-Thames,Oxon RG91AJTel: 0491 573602
NOYES PUBLICATIONSPark Ridge, New Jersey, U.S.A.
Contents and Subject Index
Preface vContributors vii
1. MONOCLONAL ANTIBODY PRODUCTION: PRINCIPLES ANDPRACTICE 1
Stephen Fazekas de St. GrothHistorical 1
The Case Against Antisera 1Production of Monoclonal Antibodies 2
Principles 2Practice, 1975 3Practice, 1983 5
Use and Misuse of Monoclonal Antibodies 7The Consequences of Heterogeneity 7
Cross Reactivity 7Affinity 7Isotypy 7
Criteria for the Effective Use of Monoclonals 8Purification of Antigens 8Antigenic Analysis 8Diagnostics 9Therapeutics 9
References 10
2. LYMPHOCYTE SUBPOPULATIONS IN RODENTS: FUNCTIONALSUBPOPULATIONS IN RODENTS 11
Mark R. Greenwood and R. Michael ParkhouseIntroduction 11Heterogeneity of T Cells 12
xi
xii Contents and Subject Index
Functional Heterogeneity of T Cells 12T Cell Markers 13
Thy-1 13Markers on Mouse T Cells 14Markers on Rat T Cells 16
Heterogeneity of B Cells 16Functional Heterogeneity in B Cells 17
Bi and B2 Cells 17The CBA/N Defect 17
.. ***" C3H/HeJ Mice 19Pre-Progenitor B Cells 19Virgin and Memory B Cells 20Immunoglobin on B Cells 20The Fc Receptor (FcR) 22la Antigens 22The Complement Receptor 23
Antisera and Monoclonal Antibodies which Recognize BCells 23
Lyb-2 23Lyb-3 24Lyb-5 24Lyb-7 24P e l 24MBLA 24Qa-1 and Qa-2 2419B5 2414.8 24DNL 19A 25RA.3-2C2 25
Concluding Remarks 25References 27
3. LYMPHOCYTE SUBPOPULATION SEPARATION BY MONOCLONALANTIBODIES 36
Rudiger W. BraunIntroduction 36Direct and Indirect Cytotoxicity 37Rosetting Procedures " 39Panning and Procedures 40Fluorescence Activated Cell Sorting 41Separation by Microspheres 42Affinity Chromatography 43Conclusions 43References 44
4. IMMUNOFLUORESCENCE ANALYSIS OF LEUCOCYTE/LYMPHO-CYTE MEMBRANE ANTIGENS WITH MONOCLONAL ANTIBODIES . .48
Wolfgang Ax and Sabine SchottlerIntroduction 48
Contents and Subject Index xiii
Materials 48Monoclonal Antibodies 49Conjugate 49Agar Slide 49Dilution Medium/Washing Solution 49
Procedure 49Lymphocyte/Leucocyte Isolation from Blood—RoomTemperature 49
Monocyte Isolation from Lymphocyte-Containing Layer ofDensity Gradient—37°C 49
Lymphocyte Fluorescence Labeling (0 - 4°C) 50Microscopic Evaluation 50
Principles 50Filter Sets for Epi-Fluorescence 51Preparation of Samples - Reading. . . . 51Microphotography 51Television 53
Discussion 53References 54
5. PHENOTYPING OF HUMAN NK CELLS WITH MONOCLONALANTIBODIES 56
Dietrich Kraft, Helmut Rumpold and OlegEreminIntroduction 56Characterization of NK Cells by MoAB Raised Against Cells of
the T, B and Myelomonocytic Cell Series 57Characterization of NK Cells by Anti-LGL MoAB 58
HNK-1 (Anti-Leu7) 58NK-8 593G8 59VEP13 59B73.1 62NKP-15 (Anti-Leulla) 64GO22 (Anti-Leullb) 64Comparison of the Anti-NK/PMNL FcryR MoAB B73.1, 3G8,
Anti-Leulla, Anti-Leullb and VEP13 64MoAB with Various Specificities 65
H25 and H366 65Anti-N901 65HNC-1A3 66
Evidence for a Third Lymphocytic Lineage, as Ascertained byStudies with MoAB 66
Summary 66References 67
6. MONOCLONAL ANTIBODIES AND HUMAN MYELOMONOCYTICCELLS -. 71
Walter KnappIntroduction 71
xiv Contents and Subject Index
Cells of the Myelomonocytic Series 71Monoclonal Antibodies Reactive with Myelomonocy tic Cells 72
Granulocytic Antibodies 72Monocytic Antibodies 74Myelomonocytic Antibodies 76Receptors for Complement Components 76Monoclonal Antibodies to Fc-Receptors 77Nomenclature of Monoclonal Antibodies to Myelomonocytic
Cells 78Differentiation of Myelomonocytic Cells 79
Progenitor Cells 79Granulocytic Differentiation 79Monocytic Differentiation 80Macrophage Differentiation 81Dendritic Cells 82
Malignant Proliferations of Myelomonocytic Cells 82Acute Myeloid Leukemias (AML) 82Chronic Myelogenous Leukemia (CML) 84
References 84
7. MONOCLONAL ANTIBODIES AS PROBES TO DEFINE HUMANT CELL SURFACE STRUCTURES AND FUNCTIONS 91
Stefan C. Meuer, Stuart F. Schlossman and Ellis L. ReinherzIntroduction 91Monoclonal Antibodies to Human T Lymphocyte Surface
Antigens 92Differentiation and Function of Human T Lymphocytes 92The Biology of the Helper and Suppressor T Cell Subsets 95The Role of Surface Molecules for Human T Cell Recognition 97Clinical Applications 100References 103
8. MONOCLONAL ANTIBODIES AS TOOLS TO STUDY RECEPTOR-TRANSDUCER-EFFECTOR SYSTEMS 109
Manfred Schmitt, Richard G. Painter and Charles G. CochraneIntroduction 109Monoclonal Antibodies as Receptor Specific Analytic Probes I l lEffects of Monoclonal Antibodies on N-Formyl ChemotacticPeptide Mediated Stimulation of Human Neutrophils 116'
References 125
9. MONOCLONAL ANTIBODIES IN ENZYMOLOGY 131Franco Celada and Boris Rotman
Introduction 131Identification and Purification of Enzymes 132Anti-Enzyme MoAB to Detect Tumor-Related Specificities 133Functional MoAB to Study Association of Molecules on Cell
Organelles and Membranes 134
Contents and Subject Index xv
Multifunctional Enzyme Molecules 134Isozymes and Enzyme Complexes 135MoABs to Study Antibody-Mediated Effects on Protein
Conformation 137Definition of the Epitope 140Dissection of an Epitope 142New Methodology, Future Developments 143References 145
10. MONOCLONAL ANTIBODIES IN THE ANALYSIS OF STRUCTUREAND FUNCTION OF COMPLEMENT COMPONENTS 150
Reinhard BurgerIntroduction 150Production of Monoclonal Antibodies to Complement
Components: Methodological Aspects 151Immunization Protocol 151Antibody Assays 152
Monoclonal Antibodies to Complement Components of theClassical Pathway 152
Antibodies to Cl 152Ab 48.3 to Purified Clq 152Antibodies to Clq Bound to Immune Complexes and to
Neoantigenic Determinants of Clq 153Ab 146 Recognizing Membrane-Associated Clq with Fc
Receptor Function 154Antibodies to C4 and C2 154Antibodies to C3 155
Antibody WM1 to C3c 155Antibodies 3 , 4 and 9 to C3c, or C3g 155Antibodies to C3d 156Antibodies Against Functionally Relevant Sites of C3 . . . . 156
Antibodies to the Terminal Components C5, C6, C7, C8and C9 158
Monoclonal Antibodies to Components of the AlternativePathway 159
Antibodies to Factor B 159Antibodies to Factor D 160
Monoclonal Antibodies to the Serum Regulatory Proteins 160An Antibody to I (C3b INA) 160Antibodies to H '161
Naturally Occurring Monoclonal Antibodies to ComplementComponents: Nephritic Factor 161
Commercially Available Monoclonal Antibodies to ComplementComponents 162
Conclusion: Further Applications of Monoclonal Antibodiesto Complement 162
References 163
xvi Contents and Subject Index
11. MONOCLONAL ANTIBODIES AND COAGULATION 166Kenneth G. Mann, Jerry A. Katzmann, W. Barry Foster and
David N. PassIntroduction 166Methods of Monoclonal Antibody Preparation and Assay 172Quantitation of Monoclonal Antibody Binding 180Isolation of Coagulation Proteins and Preparation of Immuno-
depleted Plasma Using Monoclonal Antibodies 182#, Structural Analysis with Monoclonal Antibodies 185
von Willebrand Factor and Platelet Adhesion 189Anti-Platelet Monoclonal Antibodies 190Summary 191References 191
12. MONOCLONAL ANTIBODIES AND HUMAN CHLORIONICGONADOTROPIN: MAPPING OF EPITOPES AND RECEPTOR-INTERACTION SITES 195
Siegfried Schwarz, Peter Berger, Reinhard Kofler and Georg WickIntroduction 195Production and Characterization of Monoclonal Antibodies to
hCG and bLH 198Development of a Holo-hCG Specific Immuno Radio Metric
Assay (IRMA) 199Choice of MoAB 199IRMA-Protocol 199Validation of the 22-13*-IRMA 200
Mapping of hCG Epitopes 203Analysis of Results 205
Relationship of Receptor-Interaction Sites and ImmunologicalEpitopes of hCG 208
Measurement of Different Forms of hCG by Epitope-SelectiveIRMAs 210
Concluding Remarks and Perspectives 214References 216
Books 216Journals 216
13. MONOCLONAL ANTIBODIES AND VIRUSES: APPLICATION TOTHE EPSTEIN-BARR SYSTEM 221
Nikolaus Mueller-LantzschIntroduction 221Characterization of Late EBV Proteins by Monoclonal
Antibodies 222Procedure for Antibody Production 222Monoclonal Antibodies Against EBV Envelope Proteins 223Immunological Differences of EBV Strains Analyzed by
Monoclonal Antibodies 225
Contents and Subject Index xvii
EBV Specific Membrane Antigen (MA) Immunofluorescenceby Monoclonal Antibodies 226
Neutralization Potential of EBV Specific Monoclonal Anti-bodies 227
Monoclonal Antibody Specific for Capsid Antigen of EBV . . . 228Identification of Polypeptide Components of the EBV Early
Antigen Complex with Monoclonal Antibodies 229Monoclonal Antibodies to EBV-Induced Transformation-
Associated Cell Surface-Antigen •. 229Conclusions 230References 231
14. MONOCLONAL ANTIBODIES AND HERPES SIMPLEX VIRUSINFECTIONS 235
Joseph C. Glorioso and Myron LevineIntroduction 235Production of Anti-HSV Monoclonal Antibodies and Studies
of HSV Infection 237The Antigenic Structure of HSV Glycoproteins 238
Epitopes Defined by Synthetic Oligopeptides 238Analysis of Antigenic Sites Using Monoclonal Antibodies
and Antibody Selected Variants 239Monoclonal Antibody Selection of.Glycoprotein Deficient
Mutants and the Definition of Antigenic Domains 242Monoclonal Antibodies and Diagnosis of HSV Infections . . . . 244
Serotyping of HSV Isolates 245Detection of HSV Antigens in Herpetic Lesions 245Detection of HSV Antibodies in Body Fluids 246
Monoclonal Antibodies in Immune Protection 248Monoclonal Antibodies and the Molecular Biology of HSV
Infection 250Future Prospects and Directions 251References .251
15. MONOCLONAL ANTIBODIES AND BACTERIA 261Thomas F. Schulz and Manfred P. Dierich
Introduction 261Use of Monoclonal Antibodies in Investigating Aspects of Host-
Parasite Relationship 262Introduction 262Infections Caused by Gram-Negative Organisms 262Infections Caused by Gram-Positive Organisms 265
Use of Monoclonal Antibodies to Investigate the SurfaceStructure of Bacteria 268
Attempts to Define Molecules Responsible for the Adhesionof Bacteria to Animal Cells 268
Attempts to Define Surface Structures Determining theAntigenic Phenotype of Bacteria 269
xviii Contents and Subject Index
Attempts to Investigate the Structure-Function Relationshipof Isolated Membrane Molecules 276
Monoclonal Antibodies to Bacterial Toxin 276Use of Monoclonal Antibodies in the Diagnosis of Infectious
Diseases 278Some Methods Employed in the Production of Monoclonal
Antibody to Bacteria ; 282Immunization Schedules 282Screening for Antibody Production of Hybridomas 283
f References 283
16. MONOCLONAL ANTIBODIES IN DIAGNOSTIC PATHOLOGY 293Salim E. Kabawat, Frederic I. Preffer and Atul K. Bhan
Introduction 293Staining Methods 294Characterization of Lymphocyte Subclasses 297
Analysis of Cell Mediated Reactions 301Characterization of Malignant Lymphomas 302
Monoclonal Antibodies in Tumor Diagnosis 304Differentiation Antigens 304
Hormones as Endocrine Markers 304Blood Group Antigens 305Major Histocompatibility Complex Antigens 305Antibodies to Intermediate Filaments 306Antibodies to Other Cellular Structural Proteins 310
Oncofetal and Oncoplacental Antigens 310Carcinoembryonic Antigen 310Alpha-Fetoprotein 313Human Chorionic Gonadotropin 313Other Oncoplacental Antigens 313
Tumor Associated Antigens 313Summary •. 317References 317
17. MONOCLONAL ANTIBODIES AND DETECTION OFMALIGNANCIES 329
Duane R. SchultzIntroduction 329Oncofetal Antigens 330
Alpha-Fetoprotein 330Carcinoembryonic Antigen 332Pancreatic Tumor-Associated Antigens 334
Colorectal Carcinoma-Specific Antigens 338Tumor Imaging with Monoclonal Antibodies 339Potential Problems Associated with Monoclonal Antibodies 340References 341
Contents and Subject Index xix
18. MONOCLONAL ANTIBODIES AND MELANOMAS 347Judith P. Johnson and Gert Riethmiiller
Introduction 347Melanoma Surface Antigens Defined by Monoclonal Anti-
bodies: The Evolution from Melanoma Specific toMelanoma Associated 348
la Like Antigens . 348p97 350Melanoma Associated Proteoglycan-Glycoprotein 351GD3 Ganglioside 351
••' Melanoma vs. Nevus and Melanocyte: Asking the RealQuestion 351
Looking for Tumor-Specific Markers with MonoclonalAntibodies: Asking the Right Question 353
References 354
19. MONOCLONAL ANTIBODIES AND CHARACTERIZATION OFHUMAN LYMPHOPROLIFERATIVE MALIGNANCIES 360
Daniel M. Knowles IIIntroduction 360T Lymphocyte Markers " 362OKT Monoclonal Antibodies 363Monoclonal Antibodies in the Phenotypic Characterization ofT Cell Malignancies 365
Monoclonal Antibody Leu 1/OKT1 367B Lymphocyte Markers 368Monoclonal Antibodies BA-1 and BA-2 369Monoclonal Antibodies Bl , B2, and B4 369OKB Monoclonal Antibodies 370Monoclonal Antibodies BL1, BL2, BL3 371Monoclonal Antibodies Pro-Iml and Pro-Im2 373Monoclonal Antibodies in the Phenotypic Characterization of
B Cell Malignancies 373Conclusion 376References 376
20. MONOCLONAL ANTIBODIES AND HUMAN HISTO-COMPATIBILITY ANTIGENS 382
Piergiorgio Natali, Aldo Bigotti, Carlo Russo, Kohsaku Sakaguchi,Muneo Igarashi and Soldano Ferrone
Monoclonal Antibodies to HLA Allospecificities Defined byConventional Alloantisera 385
Use of Monoclonal Antibodies in the Lymphocytotoxic Assayfor HLA Typing 388
New Information Derived from the Application of Anti HLAMonoclonal Antibodies 389
Conclusion 398References 398
xx Contents and Subject Index
21. MONOCLONAL ANTIBODIES IN THE THERAPY OF RENALTRANSPLANT REJECTION 404
Charles B. CarpenterT Cell Differentiation Antigens 405Selection of a Monoclonal Antibody for In Vivo Use 407Testing of Anti-Human Monoclonal Antibodies in Primates 409Reversal of Acute Renal AHograft Rejection in Man 410
OKT3 410Anti-T12 411
f CBL1 413Immunogenicity of Mouse Monoclonal Antibodies 414Treatment of Acute Graft-Versus-Host Disease (GVHD) 414Conclusions 415References 416
22. MONOCLONAL ANTIBODIES AS THERAPEUTIC TOOLS INMEDICINE 419
Jean-Francois Bach and Lucienne ChatenoudIntroduction 419Specific Problems of Monoclonal Antibody Production for
Clinical Use 420Experimental and Human Therapeutic Use of Monoclonal
Antibodies 421Nonspecific Immunosuppression (Antilymphocyte
Antibodies) 421Specific Immunosuppression in Autoimmune Diseases 423Immunotherapy of Leukemia and Cancer 424Serotherapy of Infectious and Parasitic Diseases 426Cure of Intoxication (Antidrug Antibodies) 427
Mechanisms of In Vivo Action of Monoclonal Antibodies 427Escape Mechanisms from the Therapeutic Effect of Monoclonal
Antibodies and Their Prevention 428Antigenic Modulation 428Xenosensitization 429Immunotoxins 431
Conclusions and Prospectives 432References 432
23. MONOCLONAL ANTIBODIES IN THE THERAPY OF MALIGNANTDISEASES 436
Robert O. Dill man and Ivor RoystonIntroduction 436
Introductory Comments 436Advantages of Monoclonal Antibodies over Antisera 436
Monoclonal Antibodies as Passive Therapy 437Passive Cytotoxic Therapy 437Heterologous Antisera Trials 438Monoclonal Antibody Therapy in Animal Models 440
Contents and Subject Index xxi
Monoclonal Antibodies as Passive Cytotoxic Therapy 441Review of Trials 441Binding to Target Cells 443Biological and Clinical Effects 443Toxicity and Side Effects 444Bioavailability and Pharmacokinetics 446Free Antigen 446Antigenic Modulation/Immunoselection 447Endogenous Anti-Mouse Antibody 447
Monoclonal Antibodies as Regulatory Therapy 447General Considerations 447Anti-Idiotype Monoclonal Antibodies 448Anti-Transferrin Receptor Therapy 450Conclusions Regarding Passive MoAB Therapy 450
Monoclonal Antibody Conjugates as Active Therapy 451Radioisotope Conjugates 451
General Considerations 451Isotope-Antisera Conjugate Experience 452Radioimmunodetection and Radioimmunotherapy with
Monoclonal Antibodies in Animal Models 453Radioimmunoscintigraphy in Humans with Monoclonal
Antibody Conjugates 453Other Considerations 455Conclusions 456
Chemotherapy Conjugates 456General Considerations 456Therapy in Animal Models 456Therapy in Man 457Conclusions 457
Immunotoxin Conjugates 457General Considerations 457Immunotoxins In Vitro 458Immunotoxins in Animal Models 458Conclusions Regarding Immunotoxins 459
Monoclonal Antibodies in Bone Marrow Transplantation 459General Considerations 459Allogeneic Marrow Transplantation 459
In Vivo Anti-GVHD 459In Vitro Anti-GVHD 460
Autologous Marrow Transplantation 460Concluding Remarks 461References 462
APPENDIX: LIST OF COMMERCIALLY AVAILABLE MONOCLONALANTIBODIES 473