Preclinical Development of Monoclonal Antibodies and Related Biologicals: Emerging technologies and new therapeutic candidates

Date: March 22, 2010
Pages: 392
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Publisher: Business Insights
Report type: Strategic Report
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Preclinical Development of Monoclonal Antibodies and Related Biologicals: Emerging technologies and new therapeutic candidates
Monoclonal antibodies form the fastest growing segment of the pharmaceutical industry, with total annual sales expected to top $50 billion in the next four years. 23 full-size monoclonal antibodies and three monoclonal antibody fragments have been launched so far, several having quickly reached ‘blockbuster status’ (annual sales of over $1 billion). Between 1995 and 2007, the number of monoclonal antibody-based drug candidates entering clinical trials more than tripled, and this expansion is continuing.

This report explains what monoclonal antibodies are, and why large pharmaceutical companies are investing so heavily both in developing such drugs internally and acquiring monoclonal antibody candidates from others. More than 80 popular and emerging technologies are named, explained and illustrated with original full-color diagrams.

The newest wave of drug candidates based on these technologies can be seen in more than 200 case studies, which identify every commercial company known to have carried out preclinical studies of therapeutic monoclonal antibodies in the last year. Finally, prospects and challenges for the future of this field are discussed, with opinions from scientific pioneers and industry leaders.

Key features of this report

  • Illustrated ‘beginners guide’ to monoclonal antibodies: What they are, how they are made and why they hold such great promise for the treatment of disease.
  • More than 80 descriptions of proprietary technologies currently in use around the world to select, produce and re-engineer monoclonal antibodies.
  • More than 30 original, full-color diagrams illustrating the science and technology of monoclonal antibodies, both as they appear in nature and in the myriad new forms now being assessed in preclinical trials.


  • Scope of this report

  • Understand the basic qualities of monoclonal antibodies and how these qualities translate into unique medical and commercial features for drug candidates.
  • Appreciate the challenges and risks of monoclonal antibodies, as well as their promise.
  • Assess promising new technologies for investment or in-licensing.
  • Identify which companies are involved in this field, and what they are doing.
  • Predict the kinds of drug that will enter clinical trials in the next 1-4 years and may reach the market in the next 5-10 years.


  • Key Market Issues

  • New monoclonal antibodies can be used to target new disease processes that are not currently addressed by any other therapies, thereby accessing market areas with high unmet demand.
  • The inherent specificity and predictability of monoclonal antibodies have been shown to shorten drug development times and increase rates of success in preclinical and clinical trials, relative to non-biological ‘small molecule’ drugs.
  • High barriers to entry currently prevent many new companies from entering this field. The techniques now used to create, select and modify monoclonal antibodies for human therapeutic use are protected by intellectual property, which the originators defend vigorously. However, several early patents on fundamental techniques will expire very soon.


  • Key findings from this report

  • Early challenges relating to immunogenicity, tissue penetration, administration and production of monoclonal antibodies are being addressed by myriad new technologies.
  • The competitive benefits of identifying and addressing new therapeutic targets continue to provide incentives for new target selection and monoclonal antibody identification programs.
  • Established techniques for ‘humanization’ of non-human monoclonal antibodies remain popular, despite the rise of newer ‘fully human’ monoclonal antibody technologies. This may be due to the robust nature of the earlier technologies and/or the imminent expiries of key patents.
  • Genetic engineering methods and novel ‘host cell’ production systems are being used to optimize and modify functions of monoclonal antibodies. Proprietary platforms using these methods have been widely licensed to many of the major players in the biopharmaceutical industry.


  • Key questions answered

  • What are monoclonal antibodies, and what can they do?
  • Why are so many companies developing them as therapeutic agents?
  • Which companies are currently working to validate and develop the latest generation of drug candidates based on monoclonal antibodies?
  • What technological and regulatory challenges face these companies in developing such candidates and bringing drugs to market?

  • Preclinical Development of Monoclonal Antibodies & Related Biologicals
    Executive summary 16
    An introduction to monoclonal antibodies 16
    Identifying non-human monoclonal antibodies 17
    Optimizing full-length antibodies 17
    Fully human monoclonal antibodies 18
    Antibody conjugates 19
    Novel binding molecules derived from antibodies 20

    CHAPTER 1 AN INTRODUCTION TO MONOCLONAL ANTIBODIES

    Summary 22
    Introduction 23
    Antibodies in nature 23
    Advantages of monoclonal antibodies as drugs 29
    Target range 29
    Predictability 30
    Pharmacokinetics 30
    Technology protection 30
    Challenges and opportunities for the next generation of monoclonal antibodies 31
    Target selection 31
    Species specificity 33
    Pharmacokinetics 34
    Manufacture 34
    Monoclonal antibody drugs already at market 35
    Orthoclone OKT3 35
    Remicade 36
    Rituxan 36
    Zenapax 37
    Synagis 37
    Humira 37
    Vectibix 38
    Simponi 38
    Lucentis 38
    Cimzia 39
    Tysabri 39
    Preclinical development of therapeutic drugs 40
    Proof of concept 40
    Safety profile 40
    Conclusions 42

    CHAPTER 2 IDENTIFYING NON-HUMAN MONOCLONAL ANTIBODIES

    Summary 46
    Introduction 47
    Technology platforms 47
    Hybridoma technology 48
    RabMAbs 48
    SLAM 48
    Human Response Platform 49
    DIAAD 49
    ImmuneY2 50
    iMAB 50
    Fusion Expression Technology 51
    ProMIS 51
    AbScreen 51
    AbProt 52
    BioArctic platform 52
    FunctionFIRST 52
    Case studies 52
    Abbott Labs 53
    AbGenomics 53
    Alethia 53
    Amorfix 53
    Arrowsmith Technologies 54
    AVEO 55
    BioSceptre 55
    Canadian Bio Med Systems 55
    Cangene 56
    CellAct 56
    CoGenesys 57
    Crucell 57
    CSL 58
    Daewoong 58
    DKFZ 58
    Epitomics 59
    Fusion Antibodies 59
    Ganymed Pharmaceuticals 60
    GeNeuro 60
    Genitope 60
    GSK 61
    Heat Biologics 61
    Immuno-Biological Labs 61
    ImmunoGen 62
    Immutep 62
    InflaRx 63
    Innate Pharma 63
    Inotek 63
    Intercell 64
    LigoCyte 64
    MedImmune 64
    Morphotek 65
    NeoGenix 65
    Northwest Biotherapeutics 66
    Novartis 66
    Novo Nordisk 67
    OncoMed 67
    Perseis Therapeutics 67
    Pfizer 68
    Pharma Research Toronto 69
    Prana Biotech 69
    Quest PharmaTech 69
    Recepta Biopharma 69
    Receptor-Logic 70
    Roche 70
    Shanghai CP Guojian 71
    Suzhou Stainwei Biotech 71
    Therapure 71
    ThromboGenics 71
    Thrombotargets 72
    Tolerx 72
    Trillium 73
    Vaccinex 73
    Wilex 73
    ZymoGenetics 74
    Conclusions 81

    CHAPTER 3 OPTIMIZING FULL-LENGTH ANTIBODIES

    Summary 84
    Introduction 85
    Technology platforms 86
    Chimeric antibodies 86
    CDR grafting 88
    SMART 90
    Superhumanisation 90
    Framework Patching 91
    Composite Human Antibody 91
    ATLAb 92
    Humaneering 92
    MLG 93
    DeImmunisation 93
    Humanation 93
    Human Engineering 94
    FcX 94
    The LEX System 94
    Potelligent 94
    Complegent 95
    BestMAb 97
    ImmunoBody 97
    EB66 97
    Synageva Expression Platform 98
    XmAb 98
    Sugar Engineered Antibodies 99
    Wox 99
    Case studies 101
    Abbott Labs 101
    Advanced Immune Therapeutics 102
    Alder Biopharm 102
    Alethia 103
    Alexion 103
    Antisoma 103
    Arana 104
    Attenuon 105
    AVEO 106
    BioArctic Neuroscience 106
    Biogen Idec 106
    Biolex 107
    BioXell 108
    China Synthetic Rubber Corp 108
    CSL 108
    CureTech 109
    Direvo 109
    DSX 109
    Eli Lilly 110
    Epitomics 110
    Faron Pharm 110
    Femta Pharm 110
    Forerunner Pharma Research 111
    Fusion Antibodies 111
    Galaxy Biotech 112
    Galileo Oncologics 112
    Genentech 113
    Glenmark 113
    GlycoForm 114
    Glycotope 114
    ImmunoCellular Therapeutics 114
    Immunomedics 115
    Innate Pharma 115
    InNexus Biotech 115
    Intellect Neurosciences 116
    Isu Abxis 116
    Janssen Alzheimer Immunotherapy 116
    KaloBios 117
    Keel Pharm 117
    LigoCyte 117
    Lpath 117
    Mabion 118
    MacroGenics 118
    MaimoniDex 119
    MAT Biopharma 119
    MedImmune 119
    Medtronic 120
    Micromet 120
    NKT Therapeutics 120
    Opsona 121
    Percipio 121
    Pharma Research Toronto 122
    ProtAb 122
    Scancell 123
    Selexys 123
    SinoMab Bioscience 124
    Synageva 124
    TaiMed 124
    Trillium 125
    United Biomedical 125
    Vascular Pharm 125
    VasGene 126
    Vegenics 126
    Vybion 126
    Xencor 127
    Conclusions 134

    CHAPTER 4 FULLY HUMAN MONOCLONAL ANTIBODIES

    Summary 138
    Introduction 139
    Technology platforms 139
    Phage display 139
    MBAS 141
    CBAS 142
    HuCAL 142
    MAbstract 142
    ActivMAb 143
    Adimab platform 143
    XenoMouse 143
    UltiMAb 145
    VelocImmune 145
    Open Monoclonal Technology 146
    Xenerex 146
    SEBVI 147
    Cloning the Human Response 147
    Viventia platforms 147
    Natural Human Antibodies 148
    MabIgX 148
    Reverse Translational Medicine 148
    I-STAR 149
    CellSpot 149
    iBioLaunch 149
    Case studies 150
    Adimab 150
    Acorda Therapeutics 150
    Affitech 151
    Agensys 153
    Alopexx 153
    AstraZeneca 154
    BioFactura 155
    Biotherapix 156
    CellAct 156
    Celldex 156
    Centocor 157
    Crucell 158
    CSL 158
    Dyax 158
    Emergent BioSolutions 158
    Functional Genetics 159
    GenMab 159
    Crucell 160
    GSK 160
    Humabs 160
    Human Antibodomics 161
    Humanyx 161
    iBio 162
    ImClone 162
    IMED 163
    Immune System Therapeutics 163
    IQ Therapeutics 164
    Kenta Biotech 164
    Kyowa Hakko Kirin 165
    MabVax 165
    Mapp Biopharmaceutical 166
    Medarex 166
    MedImmune 167
    Merck & Co 168
    Micromet 169
    MorphoSys 169
    NatImmune 170
    Neurimmune 170
    NovImmune 170
    Novo Nordisk 171
    Omeros Corp 172
    Oncaidia 172
    OncoMed 172
    Oxford BioTherapeutics 173
    Panacea 173
    Patrys 174
    Peregrine 175
    PharmAbcine 176
    sanofi-aventis 176
    Theraclone 177
    Trellis Bioscience 178
    U3 Pharma 178
    Vaccinex 179
    Vegenics 179
    Xoma 180
    Conclusions 189

    CHAPTER 5 ANTIBODY CONJUGATES

    Summary 192
    Introduction 193
    Technology platforms 193
    Antibody Drug Conjugate 193
    Targeted Antibody Payload 195
    Probodies 195
    Antibody cloaking 197
    Targeted Photodynamic Therapy 197
    AlbudAb 198
    hyFc 198
    Ligand traps 198
    CovX-Body 200
    Dynamic Cross-Linking 200
    LEC technology 200
    Case studies 201
    Algeta 201
    Aphios 201
    ArmaGen Technologies 201
    Asan Medical Center 202
    Bayer Schering 202
    Beijing ABT 203
    Biogen Idec 203
    BioTransformations 203
    Boehringer Ingelheim 204
    Celldex 204
    Cytoguide 205
    CytomX 205
    Dompe 206
    EnGeneIC 206
    FDA 206
    Forerunner Pharma Research 207
    Galileo Oncologics 207
    Genentech 207
    Genexine 208
    ImmunoGen 208
    Immunomedics 209
    InNexus Biotech 210
    Medarex 210
    MedImmune 211
    Merrimack 211
    Morphotek 212
    Mycenax 212
    NCI 212
    Oncaidia 213
    OncoTherapy Science 213
    Panacea 214
    Peregrine 214
    Pfizer 214
    Pivotal BioSciences 215
    Seattle Genetics 215
    Symphogen 215
    Transgene Biotek 216
    Viventia 216
    Conclusions 222

    CHAPTER 6 NOVEL BINDING MOLECULES DERIVED FROM ANTIBODIES

    Summary 224
    Introduction 225
    Technology platforms 226
    Fab 226
    TetraMABs 227
    scFv 227
    Immuna 228
    [scFv]2 228
    BiTE 229
    Avibodies 230
    TandAb 233
    Flexibody 234
    V-NAR 234
    Nanobody 236
    Domain Antibodies 238
    Heteropolymer 242
    UniBody 243
    Domain Exchanged Antibodies 244
    SMIP 246
    SCORPION 247
    DVD-Ig 248
    Case studies 249
    Abbott Labs 249
    Ablynx 249
    AdAlta 250
    Affimed 250
    Avipep 251
    Beijing ABT 251
    Biogen Idec 252
    Calmune 252
    Elusys 253
    ESBATech 253
    Galileo Oncologics 253
    Glycotope 254
    GSK 254
    Inmunova 255
    MAT Biopharma 256
    Micromet 256
    Novartis 257
    PharmAbcine 257
    Trubion 257
    Suzhou Stainwei Biotech 258
    Taligen 259
    Vegenics 259
    Conclusions 264
    Appendix 266
    Primary research methodology 266
    Glossary 267
    Index 278

    LIST OF FIGURES

    Figure 1.1: The B-cell receptor 26
    Figure 1.2: Immunoglobulin G, subclass 1 27
    Figure 1.3: Immunoglobulin G, subclass 3 28
    Figure 1.4: Features of monoclonal antibody technology 32
    Figure 3.5: Chimeric antibody technology 87
    Figure 3.6: CDR grafting 89
    Figure 3.7: Complegent® technology 96
    Figure 5.8: An Antibody Drug Conjugate 194
    Figure 5.9: Probody™ technology 196
    Figure 5.10: An AlbudAb™ 198
    Figure 5.11: An EGF ligand trap 199
    Figure 6.12: Antigen binding fragment (Fab) 226
    Figure 6.13: A [Fab]2 fragment 227
    Figure 6.14: A single chain variable fragment (scFv) 228
    Figure 6.15: An [scFv]2 molecule 229
    Figure 6.16: A diabody 230
    Figure 6.17: A triabody 231
    Figure 6.18: A tetrabody 232
    Figure 6.19: A TandAb 233
    Figure 6.20: A Flexibody 234
    Figure 6.21: A shark antibody (IgNAR) 235
    Figure 6.22: A V-NAR fragment 236
    Figure 6.23: A camelid antibody 237
    Figure 6.24: A Nanobody® 238
    Figure 6.25: A Domain Antibody (dAb) 239
    Figure 6.26: A bivalent Dual-targeting dAb™ 240
    Figure 6.27: An IgG-like Dual-targeting dAb™ 240
    Figure 6.28: A mAb-dAb 241
    Figure 6.29: An antibody heteropolymer 243
    Figure 6.30: A UniBody® 244
    Figure 6.31: A Domain Exchanged Antibody 245
    Figure 6.32: A SMIPTM 246
    Figure 6.33: An scFv-based SCORPIONTM antibody 247
    Figure 6.34: A Dual-Variable Domain Immunoglobulin™ 248

    LIST OF TABLES

    Table 2.1: Preclinical mAbs with no known humanization or engineering 75
    Table 2.2: Preclinical mAbs with no known humanization or engineering (ctd 1) 76
    Table 2.3: Preclinical mAbs with no known humanization or engineering (ctd 2) 77
    Table 2.4: Preclinical mAbs with no known humanization or engineering (ctd 3) 78
    Table 2.5: Preclinical mAbs with no known humanization or engineering (ctd 4) 79
    Table 2.6: Preclinical mAbs with no known humanization or engineering (ctd 5) 80
    Table 3.7: Antibody engineering technologies 100
    Table 3.8: Antibody engineering technologies (ctd 1) 101
    Table 3.9: Preclinical mAbs with engineered amino acid sequences or glycosylation patterns 128
    Table 3.10: Preclinical mAbs with engineered amino acid sequences or glycosylation patterns (ctd 1) 129
    Table 3.11: Preclinical mAbs with engineered amino acid sequences or glycosylation patterns (ctd 2) 130
    Table 3.12: Preclinical mAbs with engineered amino acid sequences or glycosylation patterns (ctd 3) 131
    Table 3.13: Preclinical mAbs with engineered amino acid sequences or glycosylation patterns (ctd 4) 132
    Table 3.14: Preclinical mAbs with engineered amino acid sequences or glycosylation patterns (ctd 5) 133
    Table 4.15: Preclinical ‘fully human’ mAbs 181
    Table 4.16: Preclinical ‘fully human’ mAbs (ctd 1) 182
    Table 4.17: Preclinical ‘fully human’ mAbs (ctd 2) 183
    Table 4.18: Preclinical ‘fully human’ mAbs (ctd 3) 184
    Table 4.19: Preclinical ‘fully human’ mAbs (ctd 4) 185
    Table 4.20: Preclinical ‘fully human’ mAbs (ctd 5) 186
    Table 4.21: Preclinical ‘fully human’ mAbs (ctd 6) 187
    Table 4.22: Preclinical ‘fully human’ mAbs (ctd 7) 188
    Table 5.23: Preclinical antibody conjugates 217
    Table 5.24: Preclinical antibody conjugates (ctd 1) 218
    Table 5.25: Preclinical antibody conjugates (ctd 2) 219
    Table 5.26: Preclinical antibody conjugates (ctd 3) 220
    Table 5.27: Preclinical antibody conjugates (ctd 4) 221
    Table 6.28: Antibody-derived binding molecules in preclinical development 260
    Table 6.29: Antibody-derived binding molecules in preclinical development (ctd 2) 261
    Table 6.30: Antibody-derived binding molecules in preclinical development (ctd 3) 262
    Table 6.31: Antibody-derived binding molecules in preclinical development (ctd 4) 263

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