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?

Table of Content:

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 22

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 46

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 84

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 138

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 192

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 224

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