Antibody Therapeutics: Product Development, Market Trends, and Strategic Issues, Revised Edition

Table of Contents

Chapter 1: Executive Summary

• Key Points 2004-2006

Chapter 2: Introduction, Scope, and Objectives

• Early Status and Current Products
• Driving Forces
• Customers
• Competition
• Scope and Objective

Chapter 3: Hybridoma Technology and Antibody Gene Manipulation

• Introduction
• Historical Roots
  • A Long Record of Advance
  • Founders of Immunology
• Classical Antibody Development
  • Polyclonal Antibodies: Still Standing
  • Polyclonal Antibodies Detect a Multiplicity of Epitopes
• Hybridoma Technology
  • Origins
  • Monoclonal Antibody Production
  • Uses of MAbs
  • Disadvantages of MAb Technology
• Genetic Immunization
• Molecular Biology Applied To Antibody Characterization
  • Production of Antibody Libraries
  • Display Technologies
  • Rationally Designed Antibodies
  • Varieties of Engineered Antibodies
  • Bispecific Antibodies
  • Designing Antibodies with Human-like Qualities
    • Chimeric Antibodies
    • Humanized Antibodies
    • Human Antibodies: Transgenic Mouse System
• References

Chapter 4: Status of Therapeutic Antibody Products

• Introduction
  • Difficulty in Cancer Treatment
  • Antibody Engineering: Light at the End of the Tunnel?
• Therapeutic Anticancer Antibodies
  • Panorex® (edrecolomab)
  • Rituxan® (rituximab)
  • Herceptin® (traztuzumab)
  • Mylotarg® (gentuzumab)
  • Campath® (alemtuzumab)
  • Zevalin™ (ibritumomab)
  • Erbitux™ (cetuximab)
  • Avastin™ (bevicizumab)
• Immunoconjugated Anticancer Recombinant Antibodies
  • Challenges in Developing Immunoconjugated Recombinant Antibodies
  • Exploiting Apoptosis-related Strategies
  • Use of Antibody Fragments in Immunoconjugate Technology
  • Optimizing the Effector Function of Recombinant Antibodies
  • Signal Regulation Strategy for Improved Recombinant Antibodies
  • Bifunctional Linkers and Low Molecular Weight Toxins in Recombinant
  • Antibody Design
  • Alternative Approaches to Immunoconjugates
• Cardiovascular Disorders
• Infectious Diseases
• Inflammatory Diseases
  • Raptiva™ (efalizumab)
  • Remicade® (infliximab)
  • Humira™ (adalimumab)
  • Xolair™ (omalizumab)
• Transplantation
  • Orthoclone OKT3® (muromomab-CD3)
  • Simulect® (basiliximab)
  • Zenapax® (daclizumab)
• References

Chapter 5: Clinical Studies

• Approved Antibody Therapeutics
• Therapeutic Antibodies in Development
• Failed Antibody Therapeutics
• Catastrophic Clinical Trial
  • Failed, Cancelled, and Disapproved Clinical Studies
• Status of A Few Selected Ongoing Clinical Studies
  • Phase I Studies
  • Phase II Studies
  • Phase III Studies
  • Products Approved in 2002- 2004

Chapter 6: Large Scale Manufacturing

• Overview
• Companies Involved
• Risks of Innovation in Biomanufacturing
• Bioprocessing Technologies
• Production Systems
  • Escherichia Coli
    • Q-cell Technology
    • TAT System
  • Mammalian Cell Culture
    • Cell Lines
    • Bioreactor Technology
    • Cell Culture Media
  • Yeast
  • Insect Cells
  • Transgenic Plants: Plantabodies
  • Transgenic Animals
  • Robotic Peptide Synthesis
• Antibody Glycosylation Issues
• New Purification Tools
• Monitoring Technologies
• Is There a Shortage in Manufacturing Capability?
  • Factors Affecting Biomolecule Production
• Insulin: A Case History of Recombinant Protein Production
• The Future
• References

Chapter 7: Business Development and Partnering

• Collaboration and Partnering
• Mergers and Acquisitions

Chapter 8: Patents and Intellectual Property Issues

• Introduction
• Intellectual Property Issues
  • Antibody Function Modulation Technologies
  • Litigation between CAT and Abbott
• Antibody Humanization
• Human Antibody Technology
• Antibody Production
  • Boss Patent, New Cabilly and MedImmune lawsuit
  • Xoma Patents
• Litigations and Co-licensing
  • CAT vs. Morphosys
  • CAT vs. Crucell
  • Cross-licensing between CAT and Xoma
  • Cross-licensing between CAT and Dyax
  • Cross-licensing between Xoma and Morphosys
  • Cross-licensing between Xoma and Dyax
• Court Rulings about Importing Data
• More Litigations
  • Xoma vs. Biosite
  • Applied Molecular Evolution vs. Morphosys
  • Corixa and GlaxoSmithKline vs. IDEC
  • Genentech vs. Chiron
  • Genentech, Novartis, and Tanox Settle Disputes involving Xolair and TNX-901
• The Single-Chain Antibody Technology
• Recent IP Issuance and Related Activities
  • Dyax's Patent Revoked
  • MorphoSys Obtains Approval for HuCALR Patent
  • MorphoSys Obtains Additional U.S. Patents on Antibody Technologies
  • Peregrine Receives US and European Patent
  • Genentech and Protein Design Labs Settle Patent License Dispute
  • A US Patent Issued on Polyclonal Antibody Libraries
• Abstracts of the Selected Patents Mentioned in the Text
  • Patent Number: US 4,816,397
  • Patent Number: US 4,816,567
  • Patent Number: US 5,175,384
  • Patent Number: US 5,223,409
  • Patent Number: US 5,225,539
  • Patent Number: US 5,403,484
  • Patent Number: US 5,427,908
  • Patent Number: US 5,434,340*
  • Patent Number: US 5,530,101
  • Patent Number: US 5,565,332
  • Patent Number: US 5,571,698
  • Patent Number: US 5,580,717
  • Patent Number: US 5,585,089
  • Patent Number: US 5,569,825
  • Patent Number: US 5,591,669
  • Patent Number: US 5,693,761
  • Patent Number: US 5,693,762
  • Patent Number: US 5,723,323
  • Patent Number: US 5,763,192
  • Patent Number: US 5,814,476
  • Patent Number: US 5,817,483
  • Patent Number: US 5,824,514
  • Patent Number: US 5,837,500
  • Patent Number: US 5,849,500
  • Patent Number: US 5,859,205
  • Patent Number: US 5,885,793
  • Patent Number: US 5,939,598
  • Patent Number: US 5,969,108
  • Patent Number: US 5,976,862
  • Patent Number: US 6,054,561
  • Patent Number: US 6,150,584
  • Patent Number: US 6,162,963
  • Patent Number: US 6,180,370
  • Patent Number: US 6,204,023
  • Patent Number: US 6,248,516
  • Patent Number: US 6,335,163
  • Patent Number: EP 368684

Chapter 9: Market Status

• Revenues from the Early Products
  • Reopro®
  • Rituxan®
  • Herceptin®
  • Remicade®
  • Synagis®
• Revenues from the Recently Approved Products
  • Avastin™
  • Erbitux™
  • Xolair™
  • Raptiva™
• New Product Approvals
  • Lucentis™
  • Tysabri®

Chapter 10: Company Profiles

Table of Exhibits

• Exhibit 2.1 Selection of Phage Antibodies from an Antibody Library
• Exhibit 2.2 Mechanisms of Actions In Vivo of Therapeutic Antibodies
• Exhibit 2.3 List of Companies Involved in the Discovery and Development of Antibody Therapeutics
• Exhibit 2.4 List of Therapeutic Monoclonal Antibodies Approved for Additional Indications, September 2006
• Exhibit 2.5 Primary Technology Portfolio of a Selected Group of Antibody Companies
• Exhibit 3.1 Major Events in the History of Immunology Compiled from Various Sources
• Exhibit 3.2 Basic Structure of an IgG Molecule
• Exhibit 3.3 A Space-filling Model of an IgG Molecule
• Exhibit 3.4 The GENOVAC Technology for the Production of Polyclonal (Steps 1- 4) and Monoclonal Antibodies (Steps 1- 7)
• Exhibit 3.5 Choices when Constructing a Binding-site Library
• Exhibit 3.6 Scheme Showing the Principle of Selection and Improvement of Binding Sites
• Exhibit 3.7 Schematic Diagram of Ribosomal Display
• Exhibit 3.8 Comparison of Structural Features of Human Antibody, Camelid Antibody, and Nanobodies
• Exhibit 3.9 Schematic Diagram Showing Structural Features of Single Chain Antibody (scFv) and Fab Fragment
• Exhibit 3.10 Various Forms of Bispecific Antibodies
• Exhibit 3.11 Various Types of Antibodies
• Exhibit 3.12 Schematic Diagram of the Generation of Human Antibody Mouse
• Exhibit 4.1 Various Mechanisms of Antibody Actions
• Exhibit 4.2 Approved Monoclonal Antibodies for the Treatment of Various Cancers
• Exhibit 4.3 Schematic Diagram Showing the Mechanism of ADCC
• Exhibit 4.4 Schematic Diagram Showing the Structural Feature of Epidermal Growth Factor Receptor and the Binding to its Ligand (egf)
• Exhibit 4.5 EGFR Expression in Various Tumors
• Exhibit 4.6 Approved Antibody Therapeutic for the treatment of Cardiovascular Disorders
• Exhibit 4.7 Summary of Antibody Studies in the Prevention and Treatment of Infectious Diseases
• Exhibit 4.8 Approved Antibody for the Treatment of Infectious Disease
• Exhibit 4.9 Approved MAbs for the Treatment of Inflammatory Diseases
• Exhibit 4.10 Inflammation in the Rheumatoid Joint
• Exhibit 4.11 Mode of Action of Xolair™
• Exhibit 4.12 Market for Drugs to Treat Asthma in US $ Million
• Exhibit 4.13 Approved MAb for the Treatment of Transplantation
• Exhibit 5.1 List of Approved Therapeutic Monoclonal Antibodies for Major Markets, September 2006
• Exhibit 5.2 List of Therapeutic Monoclonal Antibodies Approved for Additional Indications, September 2006
• Exhibit 5.3 Therapeutic Categories of Approved MAbs
• Exhibit 5.4 Types of MAbs Approved Between 1986 and 2006
• Exhibit 5.5 Types of MAbs Currently in Development
• Exhibit 5.6 List of Monoclonal Antibody Therapeutics in Development (assembled by alphabetized company names)
• Exhibit 5.7 List of Monoclonal Antibody Therapeutics in Development (assembled by therapeutic indication in alphabetical order)
• Exhibit 5.8 Therapeutic Categories of Clinical Trials
• Exhibit 5.9 Therapeutic Antibodies at Various Development Stages
• Exhibit 5.10 List of Late-Stage Clinical Trial Failures
• Exhibit 6.1 Distribution of Cell Culture Reactor Capability by Reactor Volume, Projected for 2006
• Exhibit 6.2 Selected North American Contract Manufacturer, Primarily of Biotherapeutics
• Exhibit 6.3 Selected Contract Manufacturers Outside of North America
• Exhibit 6.4 Selected Manufacturers Offering Excess Capacity Contracts
• Exhibit 6.5 Native and Engineered Disulfide Bond formation Pathways in the E. coli Periplasm
• Exhibit 6.6 A comparison of Widely Used Cell Lines for the Manufacturing of Biotherapeutics
• Exhibit 6.7 Processing of Asn-linked Oligosaccharides to a Representative Biantennary Complex Glycoprotein Structure
• Exhibit 7.1 Selected Companies with Antibody Discovery Platforms Which Formed Alliances in the Discovery and Development of Antibody Therapeutics
• Exhibit 7.2 Selected Companies with Antibody Engineering and Expression Platforms Which Formed Alliances
• Exhibit 7.3 Valuation of Collaborations
• Exhibit 7.4 Selected M&As In 2005 And Early 2006
• Exhibit 7.5 Detailed List of Alliances Involving a Selected Number of Antibody Drug Discovery and Development Companies
• Exhibit 8.1 Issued Patents of Xencor
• Exhibit 8.2 Patent Applications of Xencor
• Exhibit 8.3 Additional Patent Applications Related to Enhanced Antibody Function
• Exhibit 8.4 Issued Patents of Kyowa Hakko and BioWa
• Exhibit 8.5 Patent Applications of Kyowa Hakko and BioWa
• Exhibit 8.6 Flow-chart Showing Various Technologies Important for MAb Discovery, Modulation and Production and the Primary IP Holders of the Technologies
• Exhibit 8.7 Key Antibody Phage Display patents of Cambridge Antibody Technology
• Exhibit 8.8 Single-chain Antibody IP Portfolio of Micromet/Enzon
• Exhibit 8.9 A Selected List of Relevant US Patents
• Exhibit 9.1 Yearly Fundraising by the Biotechnology Industry
• Exhibit 9.2 Status of Market Capitalization of a Selected Group of Antibody Companies
• Exhibit 9.3 Major Monoclonal Antibody Sales, 2003- 2005
• Exhibit 9.4 Yearly Revenues Earned and Forecasted for Antibody Therapeutics
• Exhibit 9.5 Annual Sale of Rituxan® in $ million, 2001 - 2005
• Exhibit 9.6 Annual Sale of Herceptin® in $ million, 2000 - 2003
• Exhibit 9.7 Revenues Generated by RemicadeR, 2000 - 2005
• Exhibit 9.8 Revenues Generated by SynagisR, 2000 - 2005
• Exhibit 9.9 Quarterly Sales of Synagis® from 2001 to 2005
• Exhibit 9.10 Comparative Sales of Humira™ and Avastin™, 2003 to 2005
• Exhibit 9.11 Current and Projected Sales of Avastin™