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The New Generation of Antibody Therapeutics: Current Status and Future Prospects

Antibody sales are predicted to reach $50 billion this year. This Insight Pharma Report focuses on recent developments in the therapeutic antibody field and new technologies built on the foundations of previously successful and unsuccessful strategies.

Following a review of the business environment and market forces, this report examines:

  • The state of the art, and the needs and direction, of antibody technology today
  • Antibody conjugates and other payloads: construction, clinical development, and corporate activity
  • Multispecific and multifunctional antibodies: construction, clinical development, and corporate activity
  • Development of biosimilars and biobetters: commercial and regulatory issues
  • Advances in product development technologies and overcoming biomanufacturing challenges
  • IP challenges, deal structures, mergers and acquisitions
  • Marketed and clinical pipeline products, current status and future forecast
  • Strategies, technologies, and pipelines of selected new-generation antibody companies
  • Future potential impact of systems biology and nanotechnology
  • Strategic issues, economic outlook, and opportunities for future products
  • Insights from thought leaders interviewed for this report

The commercial clinical pipeline for antibodies is growing at a rate of 50 - 55 new mAbs per year. Today, about 314 mAb products are in clinical trials worldwide. ‘The New Generation of Antibody Therapeutics: Current Status and Future Prospects’ reviews antibodies in clinical development, profiles selected companies that may contribute to the next generation of cutting-edge antibody technology, and discusses notable collaborations within the antibody industry.

A number of immunotoxins currently in clinical trials are antibody-based reagents. As discussed in this Insight Pharma Report, a number of targets, drugs, and linkers are being evaluated. The last few years have seen striking improvements in the development of antibody-drug conjugate technology; it is clear that in the next few years a wave of such products will gain approval. Firms that profess expertise in the synthesis of immunoconjugates are discussed in this report.

Bispecific antibodies present unique possibilities for disease treatment. There is substantial interest in bispecific antibodies as a means to overcome some of the shortcomings of conventional recombinant antibodies that have slowed their successful performance and prevented FDA approval. Today, numerous bispecific antibodies are in clinical trials and may provide a new generation of antibody technologies. This Insight Pharma Report profiles selected bispecific antibody companies and cutting-edge concepts in bispecific antibody development.

‘The New Generation of Antibody Therapeutics: Current Status and Future Prospects’ discusses recent developments in bioprocessing relevant to the needs of the antibody sector. Also discussed are biosimilar antibody drugs, which are the subject of much interest with many patent expirations taking place. While the FDA has yet to approve a biosimilar, many large companies have been moving forward aggressively on such products. We review challenges and opportunities, commercial development and the marketplace, as well as regulatory issues concerning biosimilars.

Predictions for the future of cutting-edge antibody technologies are that robust growth will continue despite the many roadblocks and uncertainties in the overall picture of drug development. While the market will continue to be dominated by whole antibody molecules, it is anticipated that bispecific antibodies and antibody-drug conjugates will be a growing component of the overall market.

About the Author

K. John Morrow, Jr., PhD, is a writer and consultant for the biotechnology industry. He obtained his PhD in genetics from the University of Washington in Seattle, and completed his training with post-doctoral studies in Italy at the Universita di Pavia and in Philadelphia at the Fox Chase Cancer Institute. He has held faculty positions at the University of Kansas and at Texas Tech University Health Sciences Center. His writings include over 200 peer-reviewed journal papers, non - peer-reviewed coverage of the biotechnology industry, books, and marketing reports. A number of companies, including Meridian Bioscience, Affitech, Henderson-Morley Biotechnology, Brandwidth Communications, and Emergent Technologies have taken advantage of his consultancy services, provided through Newport Biotechnology Consultants. He resides in Newport, KY.

Table of Contents

Chapter - 1

  • Introduction, Scope, and Objectives
  • 1.1. Introduction
    • A Long History of Biotherapeutics
    • The Rise of Antibodies
    • The FDA Approval Process
    • Is the FDA Moving Too Slowly?
    • Cost Factors in Antibody Therapeutics
  • 1.2. Current Products
    • Avastin (bevacizumab)
    • Cimzia (certolizumab pegol)
    • SIMPONI (golimumab)
    • ILARIS (canakinumab)
    • STELARA (ustekinumab)
    • ARZERRA (ofatumumab)
    • Prolia (denosumab)
    • Actemra (tocilizumab)
    • Benlysta (belimumab)
    • YERVOY (ipilimumab)
    • ADCETRIS (brentuximab)
  • 1.3. Business Environment and Market Forces
    • World Economic Outlook
    • Economic Outlook for Antibody Technologies
    • Drug Development Costs
  • 1.4. Opportunities for Future Products Antibodies in Development
    • Phase III Antibody Studies
    • Elotuzumab
    • Naptumomab estafenatox
    • AMG 386
    • Itolizumab
    • Factor VIII-Fc and Factor XI-Fc
    • CINQUIL (reslizumab)
    • Obinutuzumab
    • Bosatria (mepolizumab)
    • Necitumumab
    • Ramucirumab
    • Epratuzumab
    • Tabalumab
    • Solanezumab
    • Farletuzumab
    • Secukinumab
    • Vedolizumab
    • Bapineuzumab
    • Inotuzumab (CMC-544)
    • Sarilumab
    • Zanolimumab (HuMax-CD4)
    • Girentuximab
    • Otelixizumab
    • Other Antibodies in Earlier Stages of Development
    • IL-1 - Blocking Therapies
    • Adimab Antibodies: MM-151
    • Daratumumab
    • Alzheimer's Disease: Therapeutic Antibodies
    • A Delivery Strategy That Overcomes the Blood-Brain Barrier
    • A New Trial Will Follow Progression from the Preclinical State to Expression of the Full-Blown Disease
    • New Antibody Selection Technologies
    • Novartis and AnaptysBio
    • Ylanthia (MorphoSys)
    • Small Engineered Bispecific Antibodies
    • Improving Efficacy and Druggability of mAbs
    • A New Yeast Display Technology
  • 1.5. Summary, Objectives, and Outlook

Chapter - 2

  • Antibody Conjugates and Other Payloads
  • 2.1. Past and Present
  • 2.2. General Methodology of Construction
  • 2.3. Notable Antibody-Toxin Conjugates
    • AGS-16M8F
    • AGS-5ME
    • Glembatumumab Vedotin-Auristatin E
    • Ontak/DT
    • Trastuzumab-Emtansine
    • Lorvotuzumab-Mertansine (IMGN901)
    • Cintredekin Besudotox
    • MR1-1 - PE
    • MEDI547-mcMMAF
    • CAT-8015 - PE
    • BL22-PE
    • LMB-2 - PE
    • SS1P-PE
    • Inotuzumab-Ozogamicin
    • PSMA ADC/PSMA ADC-Auristatin E
    • SAR-3419
    • Brentuximab-Vedotin
    • 2SGN-75 - Auristatin F
    • HuM195/rGel-rGelonin
    • RFT-5 - dgA
    • Moxetumomab Pasudotox (CAT-8015 - PE38)
    • CDX-011
  • 2.4. Clinical Trials HuM-195/rGel: A Unique Immunoconjugate
  • 2.5. Commercial Development
    • Aldevron (Formerly GENOVAC)
    • GenScript
    • Maine Biotechnology Services
    • Ambrx
    • Seattle Genetics
    • Genentech
    • Philogen
  • 2.6. Summary and Future Directions for Antibody-Drug Conjugates

Chapter - 3

  • Multispecific and Multifunctional Antibodies
  • 3.1. Challenges and Opportunities
  • 3.2. The Rundown on Bispecific Antibody Companies Ablynx
    • Affimed
    • Fresenius
    • MacroGenics
    • Merrimack
    • Micromet
    • Pfizer
    • Sanofi
    • Trion
    • Zyngenia
  • 3.3. Methods of Construction
  • 3.4. Recombinant Polyclonal Antibodies
  • 3.5. Anti-Angiogenic Antibodies: Boom or Bust
  • 3.6. Challenges and Opportunities in Immunocytokines
    • Provenance
  • 3.7. Cutting-Edge Concepts in Bispecific Antibody Development
    • DuoBody Technology
    • Chemically Programmed Antibodies: CovX
  • 3.8. Summary and Conclusions

Chapter - 4

  • Biosimilars and Biobetters: Opportunities and Challenges
  • 4.1. Biosimilars: Challenges and Opportunities
    • An Uncertain Period
    • A Rundown on Biosimilars
    • Will Biosimilar Cost Savings Materialize?
  • 4.2. Commercial Development and Marketplace
  • 4.3. Role of the EMA and FDA in Approval and Regulation of Biosimilars
    • EU Initiative
    • Canadian Biologics Regulatory Guidelines
    • US Regulation and the Affordable Healthcare Act
  • 4.4. Biobetters: Unique Products or Improved Biosimilars?

Chapter - 5

  • Advances in Product Development Technologies
  • 5.1. Overview
  • 5.2. Biomanufacturing Challenges
  • 5.3. Overview of Bioprocessing Technology
    • Escherichia coli
    • Other Bacterial Hosts
    • Yeast
    • Saccharomyces cerevisiae
    • Pichia pastoris
    • Insect Cells
    • Dictyostelium discoideum
  • 5.4. Downstream Processing: Improvements in Product Purification
  • 5.5. New Emerging TechnologiesMore and Better Disposables
    • Dealing with Inclusion Bodies
    • Modifying Proteins to Improve Their Stability
    • New Wrinkles in Bioprocessing
    • Wanted: Very Rapid Micropurification Strategies
    • Non-Natural Amino Acids
    • Improvements in Product Purification from Plant Material
  • 5.6. Failed Technologies and Lessons Learned Failed Therapeutics
    • Inclusion Bodies
    • Host Cell Proteases, Endotoxins, and Pyrogens

Chapter - 6

  • IP Challenges, Deal Structures, Mergers & Acquisitions, and Future Opportunities
  • 6.1. IP Thicket for Biosimilars
  • 6.2. Collaboration and Partnering
    • Symphogen
    • Activartis Biotech
    • MorphoSys
    • ImmunGene
    • BioInvent
    • Eli Lilly
    • Apexigen and Gansu Duyiwei Biological Pharmaceutical
    • GlaxoSmithKline-Tolerx Collaboration
  • b>6.3. Mergers and Acquisitions
    • Bristol-Myers Squibb Completes Acquisition of Inhibitex
    • Biogen Idec to Pay Up to $562.5 Million for Stromedix
    • Sanofi Signs Rare Disease Pact with CRG
    • Illumina Rejects Roche Tender Offer

Chapter - 7

  • Marketed and Pipeline Products
  • 7.1. Marketed Products: Current Status and Future Forecast
  • 7.2. Clinical Development: Lessons Learned From Successes and Failures
  • 7.3. The Centocor Experience with Centoxin

Chapter - 8

  • Profiles of Selected New-Generation Antibody Companies
  • 8.1. Overview
    • MacroGenics
    • Micromet
    • Bicycle Therapeutics
  • 8.2. Business Strategy
  • 8.3. Technology and Product Pipeline Zyngenia
    • Philogen
    • T2 Biosystems
    • Molecular Partners
    • Tolerx
    • Crescendo Biologics
    • Haptogen
    • Trion, MacroGenics, and Micromet

Chapter - 9

  • Strategic Issues
  • 9.1. Outlook for the Future
    • Why Do Antibodies Fail?
    • Naked or Nattily Dressed: Which Is Best?
    • Escape from the Valley of Death
    • Next Five Years
    • Alternative Affinity Tools
    • Technologies, 10 Years Plus
    • Intracellular Immunity
    • Demands, Needs, Directions
    • New Target Search
    • Cost Containment
    • We Need to Quit Overpromising
    • Systems Biology Is Not the Holy Grail
    • There Are No Surprises
  • 9.2. Systems Biology and Design of Innovative Therapies Building More Antibodies
    • Future of the Proteome
    • Systems Biology Companies
  • 9.3. Immunotherapeutics and Vaccines
  • 9.4. Impact of Nanotechnology in Antibody Therapeutics Development
    • Magnetic Nanoparticles
    • Antibody-Conjugated Nanoparticles
    • Nanodelivery Systems for Antibodies
    • Nanotechnology and Regulatory Concerns

References

  • Appendix
  • List of Consultants
  • Company Index

FIGURES

  • Figure 1.1. A Slow Rate of Approval for Antibodies
  • Figure 1.2. Structure of the Akt Molecule
  • Figure 1.3. Anti-TNF Agents Infliximab, Adalimumab, and Certolizumab Pegol
  • Figure 1.4. STELARA Molecule
  • Figure 1.5. Zoledronic Acid
  • Figure 1.6. Global GDP Growth
  • Figure 1.7. R&D Expenditures Continue an Upward Trend, While Approval Rates Keep Dropping
  • Figure 1.8. CD38 Molecule
  • Figure 1.9. Structure of the Three-Helical Albumin-Binding Domain (ABD) from Streptococcal Protein G (PDB: 1GJT)
  • Figure 2.1. Chemical Structures of mAb-Drug Conjugates
  • Figure 2.2. An Antibody-Drug Conjugate
  • Figure 2.3. Denileukin Diftitox (Ontak)
  • Figure 2.4. Recombinant Immunotoxin BL22 and LMB-2
  • Figure 2.5. How the PSMA ADC Works
  • Figure 3.1. A Conventional Antibody and Its Derived Fragments
  • Figure 3.2. The Scaffold Antibody and the Bispecific CVX-241 Antibody
  • Figure 3.3. Structure and Size Comparison of Tetravalent Antibodies and Native Divalent Antibodies With Western Blot Analysis of the Purified Anti-CD20 mAbs Separated by SDS-PAGE
  • Figure 3.4. Symphogen's Sym004 mAb Mixture Enables Novel Mechanism of Action
  • Figure 3.5. Peregrine Clinical Trials in Progress
  • Figure 8.1. Display of Philogen Technology
  • Figure 8.2. Iron Oxide Nanoparticles (Orange) Coated With a Dextran Polymer and Bound to a Detector Antibody
  • Figure 8.3. A 4-Repeat DARPin Molecule
  • Figure 9.1. Outline of the Immune Surveillance Theory
  • Figure 9.2. Mechanism of Action of Whole IgG mAbs
  • Figure 9.3. Antibody Fab Fragments Complexed with Peptide Epitopes
  • Figure 9.4. Structure of the Armadillo Repeat Region of Beta-Catenin
  • Figure 9.5. A Biosensor Platform
  • Figure 9.6. Honeycombed Particles Filled with Cancer Drugs Act like Time-Release Capsules at Tumor Site

TABLES

  • Table 1.1. FDA-Approved Recombinant Antibodies
  • Table 1.2. Costs of the Most Expensive Drugs
  • Table 1.3. Various Estimates of Pharma Sales
  • Table 1.4. Phase III Antibody Trials
  • Table 1.5. IL-1 - Blocking Therapies Marketed or In Development for the Treatment of Autoimmune Disorders
  • Table 1.6. Many Antibodies Are Directed Against the Same Target
  • Table 2.1. Immunotoxins: Current Status of Clinical Trials
  • Table 3.1. Bispecific Antibodies in Clinical Trials
  • Table 4.1. EMA-Approved Biosimilars
  • Table 5.1. Non-Microbial Protein Production Platforms
  • Table 5.2. Important Approved Therapeutic Protein-Based Products From E. coli
  • Table 5.3. Various Polishing Options
  • Table 6.1. Notable Antibody Collaborations
  • Table 9.1. Properties of Affinity Molecules
  • Table 9.2. Systems Biology Companies
  • Table 9.3. Antibodies Against Infectious Disease Agents in Current Trials
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