Next-Generation Protein and Peptide Therapeutics
Business Insights
August 19, 2011 192 Pages - SKU: RET6506084
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Introduction
The utility of mAb therapeutics is balanced by many drawbacks: they are expensive to produce, have poor tissue penetration, can only be used to target cell-surface proteins or soluble proteins in circulation, and multi-layered intellectual property can deplete profits. This report examines the various alternatives protein and peptide constructs that have been proposed to provide solutions.
Features and benefits- Understand the limitations of monoclonal antibodies, how these relate to molecular structure, and which protein alternatives may offer solutions.
- Discover the most innovative delivery technologies that may broaden the applicability of protein therapeutics.
- Gain insight into the crucial issue of immunogenicity; understand the regulatory expectations for testing, and the potential options for minimizing.
- Compare the pros and cons of the next-generation protein therapeutics, and assess which are making progress through the clinic.
- Identify which companies are working at the cutting edge of protein therapeutic design, and generate ideas for investment and licensing opportunities.
Highlights
The recent sales performance of monoclonal antibody therapeutics, including three launched antibody fragments, has fuelled further innovation in antibody-derived therapeutics. Along with the development of those agents, progress has been made with novel binding proteins and peptides that avoid some of the drawbacks associated with antibodies.
Many collaborations involving large pharma companies are focused on the development of immunoconjugates featuring stable linker systems between an antibody or an antibody fragment and a highly potent drug for use in cancer therapy. These products target well-characterized tumor antigens.
Protein binders based on a scaffold other than that of an antibody have entered clinical trials, and one has recently been approved by the FDA. Agents based on human proteins offer many potential advantages over antibody-derived binders, including absent or lower immunogenicity.
Your key questions answered- What advantages could antibody fragments offer and how do the many proprietary technology platforms differ?
- What lessons have been learned in the development of immunoconjugates, and which companies are leading the way?
- What are the benefits of engineering non-antibody protein scaffolds, and which binding domains have been exploited to the best effect?
- What are the most promising strategies being applied to optimizing the properties of synthetic peptides, and which indications are being pursued?
- Which protein therapeutics are already being developed as part of a collaboration, and which could provide attractive licensing opportunities?
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- Executive Summary
- Introduction
- Delivery strategies
- Immunogenicity considerations
- Monoclonal antibody-derived fragments
- Immunoconjugates
- Engineered protein scaffolds
- Synthetic targetable peptides and proteins
- Market outlook
- About the author
- Disclaimer
- Introduction
- Summary
- Monoclonal antibodies as targetable protein therapeutics
- Molecular structure
- Evolution of fully human mAbs
- Manufacture of mAbs
- Engineering of the variable and Fc regions of antibodies
- Bispecific antibodies
- Therapeutic applications of monoclonal antibodies
- Drawbacks of mAbs as therapeutics
- General challenges
- Obstacles specific to cancer therapy
- Novel targeted protein therapeutics
- Delivery strategies
- Summary
- Introduction
- Improving parenteral delivery of biologics
- Current practice
- Formulations and devices
- Half-life extension technologies
- Depot systems
- Advances in nonparenteral delivery
- Nasal delivery
- Pulmonary delivery
- Other approaches
- Enhanced production systems
- Mammalian cells
- Non-mammalian cells
- Immunogenicity considerations
- Summary
- Induction of immunogenicity by protein therapeutics
- Mechanisms of immunogenicity
- Management of immunogenicity
- Clinical assessment of immunogenicity
- Regulatory expectations
- FDA Draft Guidance on immunogenicity testing
- Screening assays
- Confirmatory assays
- Neutralizing Assays
- Preclinical assessment of potential immunogenicity
- Importance
- T-cell epitope prediction and validation
- Monoclonal antibody-derived fragments
- Summary
- Introduction
- Prominent functional mAb fragments
- Classic monovalent fragments
- Single-domain antibodies
- Monomeric Fc fusions
- Multivalent fragments
- Advantages and disadvantages of fragments
- Interactions
- Production of fragments
- Progress of fragments through the clinic
- ReoPro
- Lucentis
- Cimzia
- Success rates
- mAb fragments in clinical trials
- scFv, Fab and di-Fab fragments
- Single-domain antibodies and monomeric Fc fusions
- Miscellaneous proprietary formats
- Proprietary mAb fragments in preclinical studies
- Biogen Idec (thermally stable scFv)
- AdAlta (shark antibodies)
- Genmab (UniBodies and DuoBodies)
- Affitech (diabodies)
- Avipep (Avibodies)
- Immunoconjugates
- Summary
- Introduction
- Targeted radioisotope delivery
- GlaxoSmithKline (BEXXAR; 131-I-tositumomab)
- Actinium Pharmaceuticals (HuM195-Bi-213/Ac-225)
- Bradmer Pharmaceuticals (Neuradiab)
- Pain Therapeutics (PTI-6D2-Re118)
- Peregrine Pharmaceuticals (Cotara)
- MAT Biopharma (Ferritarg)
- Philogen (F16-I-131/L19-I-131)
- Targeted toxin delivery
- The ideal characteristics of an antibody-drug conjugate
- ImmunoGen
- Seattle Genetics
- Immunomedics (SN-38)
- Bristol-Myers Squibb (MDX-1203)
- Novartis/Topotarget (Zemab)
- Pfizer/UCB-Celltech (CMC544)
- Celldex Therapeutics (CDX-011)
- MedImmune (CAT-8015)
- Viventia Biotech (VB4-845)
- Targeted cytokine delivery
- Antisoma (AS1409)
- Merck Serono
- Philogen
- Targeted delivery of other effector molecules
- Active Biotech (ANYARA)
- Celldex Therapeutics (CDX-1307)
- Engineered protein scaffolds
- Introduction
- Alternative binding proteins
- Origin of protein scaffolds
- Advantages over antibodies
- Targets and modes of action
- Delivery
- Immunogenicity
- Binders developed from human or ubiquitous domains
- The Kunitz domain
- Ankyrin domain
- Ubiquitin domain
- Fibronectin type III domain
- Lipocalin domain
- Fyn SH3 domain
- LDL receptor domain A
- Binders developed from bacterial domains
- Z domain of staphylococcal protein A
- Various stable subdomains
- Synthetic targetable peptides and proteins
- Summary
- Introduction
- Solid-phase and hybrid synthesis
- Overview
- Improvements in solid supports
- Strengths and weaknesses of peptides
- Optimization strategies
- Ligation
- Cyclization
- Heterodimerization
- Cytoconjugation
- Stabilization strategies
- Stapled peptides
- Other constrained peptides
- Disulfide-rich peptides
- Improvements in automatic peptide synthesizers
- Main classes of synthetic therapeutic peptides
- Somatostatins
- Vasopressins
- Calcitonins
- LHRH
- Glucagon and analogs
- Integrilin
- Fuzeon
- Symlin
- Peginesatide (Hematide)
- Novel peptides with intracellular targets
- Aileron’s stapled peptides
- Anchor Therapeutics’ pepducins
- Phylogica’s Phylomers
- KAI’s peptide PKC inhibitors
- Angiochem’s Angiopeps
- Compugen’s cell-penetrating peptides
- Market outlook
- Summary
- Drug success rates are falling
- Investing in biologics
- Sales performance of mAbs (2009-10)
- Improving on mAbs
- Sales of antibody fragments (2008-10)
- Capitalizing on shortcomings of mAbs
- Developing superior peptide drugs
- Appendix
- Scope
- Methodology
- Glossary/Abbreviations
- Bibliography/References
- Journal references
- Website references
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