Fusion Protein Technologies for Biopharmaceuticals

Name: Fusion Protein Technologies for Biopharmaceuticals | Applications and Challenges
Brand: Wiley
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Applications and Challenges

Stefan R. Schmidt(Herausgeber*in)

Wiley (Verlag)

Erschienen am 31. Januar 2013

672 Seiten

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Beschreibung

The state of the art in biopharmaceutical FUSION PROTEINDESIGN
Fusion proteins belong to the most lucrative biotechdrugs--with Enbrel® being one of the best-sellingbiologics worldwide. Enbrel® represents a milestone of moderntherapies just as Humulin®, the first therapeutic recombinantprotein for human use, approved by the FDA in 1982 andOrthoclone® the first monoclonal antibody reaching the marketin 1986. These first generation molecules were soon followed by aplethora of recombinant copies of natural human proteins, and in1998, the first de novo designed fusion protein was launched.
Fusion Protein Technologies for Biopharmaceuticalsexamines the state of the art in developing fusion proteins forbiopharmaceuticals, shedding light on the immense potentialinherent in fusion protein design and functionality. A widepantheon of international scientists and researchers deliver acomprehensive and complete overview of therapeutic fusion proteins,combining the success stories of marketed drugs with the dynamicpreclinical and clinical research into novel drugs designed for asyet unmet medical needs.
The book covers the major types of fusionproteins--receptor-traps, immunotoxins, Fc-fusions andpeptibodies--while also detailing the approaches fordeveloping, delivering, and improving the stability of fusionproteins. The main body of the book contains three large sectionsthat address issues key to this specialty: strategies for extendingthe plasma half life, the design of toxic proteins, and utilizingfusion proteins for ultra specific targeting. The book concludeswith novel concepts in this field, including examples of highlyrelevant multifunctional antibodies.
Detailing the innovative science, commercial realities, andbrilliant potential of fusion protein therapeutics, FusionProtein Technologies for Biopharmaceuticals is a must forpharmaceutical scientists, biochemists, medicinal chemists,molecular biologists, pharmacologists, and genetic engineersinterested in determining the shape of innovation in the world ofbiopharmaceuticals.

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Inhalt

1 - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges [Seite 1]
1.1 - Contents [Seite 7]
1.2 - Preface [Seite 25]
1.3 - Contributors [Seite 27]
1.4 - PART I: INTRODUCTION [Seite 31]
1.4.1 - 1 Fusion Proteins: Applications and Challenges [Seite 33]
1.4.1.1 - 1.1 History [Seite 33]
1.4.1.2 - 1.2 Definitions and Categories [Seite 34]
1.4.1.3 - 1.3 Patenting [Seite 35]
1.4.1.4 - 1.4 Design and Engineering [Seite 36]
1.4.1.4.1 - 1.4.1 Orientation of Fusion Proteins [Seite 36]
1.4.1.4.2 - 1.4.2 Linker Engineering [Seite 37]
1.4.1.4.3 - 1.4.3 Oligomerization of Fusion Proteins [Seite 38]
1.4.1.4.4 - 1.4.4 Immunogenicity [Seite 39]
1.4.1.4.5 - 1.4.5 Mutagenesis for Molecule Optimization [Seite 39]
1.4.1.5 - 1.5 Manufacturing [Seite 40]
1.4.1.5.1 - 1.5.1 Upstream Process [Seite 40]
1.4.1.5.2 - 1.5.2 Downstream Process [Seite 42]
1.4.1.5.3 - 1.5.3 Formulation [Seite 43]
1.4.1.5.4 - 1.5.4 Process Economies [Seite 43]
1.4.1.5.5 - 1.5.5 Glycosylation [Seite 44]
1.4.1.6 - 1.6 Regulatory Challenges [Seite 45]
1.4.1.7 - 1.7 Competition and Market [Seite 46]
1.4.1.8 - 1.8 Conclusion and Future Perspective [Seite 47]
1.4.1.9 - References [Seite 48]
1.4.2 - 2 Analyzing and Forecasting the Fusion Protein Market and Pipeline [Seite 55]
1.4.2.1 - 2.1 Introduction [Seite 55]
1.4.2.2 - 2.2 Market Sales Dynamics of the FP Market [Seite 55]
1.4.2.2.1 - 2.2.1 Enbrel Founded the FP Market Following Its Launch in 1998 [Seite 56]
1.4.2.2.2 - 2.2.2 We Forecast the FP Market Will Grow to $10.1 Billion by 2016 [Seite 56]
1.4.2.2.3 - 2.2.3 Growth Drivers and Restrictors that Impact the FP Market [Seite 57]
1.4.2.3 - 2.3 Individual Drug Sales Analysis [Seite 57]
1.4.2.3.1 - 2.3.1 Enbrel [Seite 57]
1.4.2.3.2 - 2.3.2 Orencia [Seite 58]
1.4.2.3.3 - 2.3.3 Nplate [Seite 59]
1.4.2.3.4 - 2.3.4 Dulaglutide and Albiglutide [Seite 59]
1.4.2.3.5 - 2.3.5 VEGFtrap-Eye [Seite 61]
1.4.2.4 - 2.4 Pipeline Database Analysis [Seite 62]
1.4.2.4.1 - 2.4.1 Breakdown by Stage of Development: Half of the FP Pipeline is in Phase II [Seite 63]
1.4.2.4.2 - 2.4.2 Therapeutic Focus of FPs: Oncology and Autoimmune Dominate [Seite 63]
1.4.2.4.3 - 2.4.3 FPs Developers and Partners: Many Big Pharma/Big Biotech Companies Have at Least One FP in Phase II Development or Above [Seite 64]
1.4.2.4.4 - 2.4.4 FP Development: Less Attractive for Earlier-Stage Drug Developers, but More Attractive for Big Pharma Licensees [Seite 64]
1.4.2.4.5 - 2.4.5 FPs Deal Analysis: We Believe FPs are an Attractive Target for Multinational Drug Companies [Seite 65]
1.4.2.5 - Disclaimer [Seite 66]
1.4.2.6 - Acknowledgment [Seite 66]
1.4.2.7 - References [Seite 66]
1.4.3 - 3 Structural Aspects of Fusion Proteins Determining the Level of Commercial Success [Seite 69]
1.4.3.1 - 3.1 Classification of FPs [Seite 69]
1.4.3.1.1 - 3.1.1 Pharmacokinetic, Targeting, and Activity FP Components [Seite 69]
1.4.3.1.2 - 3.1.2 FPs Classified by the Function of Each Component [Seite 70]
1.4.3.1.3 - 3.1.3 Half-Life Extension Represents a Dominant Theme (1c-7c) [Seite 71]
1.4.3.1.3.1 - 3.1.3.1 Fc Fusion is the Half-Life Extension Standard [Seite 71]
1.4.3.1.3.2 - 3.1.3.2 Albumin Fusion is the Most Advanced non-FcFP Half-Life Approach [Seite 71]
1.4.3.1.3.3 - 3.1.3.3 Nonfusion Alternatives [Seite 72]
1.4.3.1.4 - 3.1.4 Decoy Receptors are the Largest FP Group and Well Validated (1c) [Seite 73]
1.4.3.1.5 - 3.1.5 Extended Half-Life Ligands (4c) [Seite 73]
1.4.3.1.6 - 3.1.6 FPs Offer a Wide Range of Cell Death Mechanisms (3a-7b) [Seite 74]
1.4.3.1.6.1 - 3.1.6.1 Targeted Toxins (3a and 3b) [Seite 74]
1.4.3.1.6.2 - 3.1.6.2 Targeted Ligands (4a and 4b) [Seite 75]
1.4.3.1.6.3 - 3.1.6.3 Antigen-Mediated Cell Death (5a and 5b) [Seite 76]
1.4.3.1.7 - 3.1.7 Antibody Fragment Fusions (6b and 7b) [Seite 76]
1.4.3.1.7.1 - 3.1.7.1 Bispecific Abs: Ab-Binding Domain Fused to Ab-Binding Domain (6b) [Seite 76]
1.4.3.1.7.2 - 3.1.7.2 Miniaturized Abs: Ab-Binding Domain Fused to Fc Effector (7b) [Seite 77]
1.4.3.1.7.3 - 3.1.7.3 Other Ab Fragment Structures [Seite 77]
1.4.3.1.8 - 3.1.8 Ab- and non-Ab-Targeting Decisions [Seite 77]
1.4.3.1.9 - 3.1.9 Targeted Enzymes (2a) [Seite 78]
1.4.3.2 - 3.2 Factors for Commercial Success [Seite 79]
1.4.3.2.1 - 3.2.1 Administration [Seite 79]
1.4.3.2.2 - 3.2.2 Efficacy Profile [Seite 80]
1.4.3.2.3 - 3.2.3 Safety Profile [Seite 81]
1.4.3.2.4 - 3.2.4 Cost Factors [Seite 82]
1.4.3.2.4.1 - 3.2.4.1 Manufacturing and Cost of Goods Sold [Seite 82]
1.4.3.2.4.2 - 3.2.4.2 Intellectual Property: Freedom to Operate and Protection from Copies [Seite 83]
1.4.3.3 - References [Seite 84]
1.4.4 - 4 Fusion Protein Linkers: Effects on Production, Bioactivity, and Pharmacokinetics [Seite 87]
1.4.4.1 - 4.1 Introduction [Seite 87]
1.4.4.2 - 4.2 Overview of General Properties of Linkers Derived From Naturally Occurring Multidomain Proteins [Seite 88]
1.4.4.2.1 - 4.2.1 Length of Linker Sequence [Seite 88]
1.4.4.2.2 - 4.2.2 Preference of Amino Acid Residues in Linker Sequence [Seite 88]
1.4.4.2.3 - 4.2.3 Hydrophobicity of Linkers [Seite 89]
1.4.4.2.4 - 4.2.4 Secondary Structures of Linkers [Seite 89]
1.4.4.3 - 4.3 Empirical Linkers in Recombinant Fusion Proteins [Seite 89]
1.4.4.3.1 - 4.3.1 Flexible Linkers [Seite 89]
1.4.4.3.1.1 - 4.3.1.1 Flexible Glycine and Serine Linkers [Seite 89]
1.4.4.3.1.2 - 4.3.1.2 Other Flexible Linkers [Seite 90]
1.4.4.3.2 - 4.3.2 Rigid Linkers [Seite 91]
1.4.4.3.2.1 - 4.3.2.1 Alpha Helix-Forming Linker (EAAAK)n [Seite 91]
1.4.4.3.2.2 - 4.3.2.2 Rigid (XP)n Linkers [Seite 92]
1.4.4.3.3 - 4.3.3 In Vivo Cleavable Linkers [Seite 92]
1.4.4.3.3.1 - 4.3.3.1 In Vivo Cleavable Disulfide Linker [Seite 92]
1.4.4.3.3.2 - 4.3.3.2 In Vivo Cleavable Protease-Sensitive Linkers [Seite 94]
1.4.4.4 - 4.4 Functionality of Linkers in Fusion Proteins [Seite 96]
1.4.4.4.1 - 4.4.1 Linkers Can Improve Biological Activity of Fusion Proteins [Seite 96]
1.4.4.4.2 - 4.4.2 Linkers Can Increase Expression Yield of Fusion Proteins [Seite 97]
1.4.4.4.3 - 4.4.3 Linkers Can Affect the PK of Fusion Proteins [Seite 98]
1.4.4.5 - 4.5 Conclusions and Future Perspective [Seite 100]
1.4.4.6 - References [Seite 101]
1.4.5 - 5 Immunogenicity of Therapeutic Fusion Proteins: Contributory Factors and Clinical Experience [Seite 105]
1.4.5.1 - 5.1 Introduction [Seite 105]
1.4.5.2 - 5.2 Basis of Therapeutic Protein Immunogenicity [Seite 105]
1.4.5.2.1 - 5.2.1 Relevance to Fusion Proteins [Seite 107]
1.4.5.3 - 5.3 Tools for Immunogenicity Screening [Seite 107]
1.4.5.3.1 - 5.3.1 In Silico Analysis Tools [Seite 107]
1.4.5.3.2 - 5.3.2 In Vitro Analysis Tools [Seite 109]
1.4.5.4 - 5.4 Approaches for Risk Assessment and Minimization [Seite 111]
1.4.5.4.1 - 5.4.1 Importance to Product Development [Seite 111]
1.4.5.4.2 - 5.4.2 De-immunization by Epitope Modification [Seite 112]
1.4.5.4.3 - 5.4.3 Tolerance Induction [Seite 112]
1.4.5.4.4 - 5.4.4 Regulatory T-Cell Epitopes in IgG Framework Regions: Tregitopes [Seite 113]
1.4.5.5 - 5.5 Case Study and Clinical Experience [Seite 113]
1.4.5.5.1 - 5.5.1 Observed Versus Predicted Immunogenicity of 21 Antibodies in Clinical Use [Seite 113]
1.4.5.5.2 - 5.5.2 Correlation of Clinical Immunogenicity of Fusion Proteins with In Silico Risk Estimates [Seite 113]
1.4.5.6 - 5.6 Preclinical and Clinical Immunogenicity Assessment Strategy [Seite 115]
1.4.5.6.1 - 5.6.1 Strategy and Recommendation [Seite 115]
1.4.5.7 - 5.7 Conclusions [Seite 117]
1.4.5.8 - Acknowledgment [Seite 117]
1.4.5.9 - References [Seite 117]
1.5 - PART II THE TRIPLE T PARADIGM: TIME, TOXIN, TARGETING [Seite 121]
1.5.1 - IIA TIME: FUSION PROTEIN STRATEGIES FOR HALF-LIFE EXTENSION [Seite 123]
1.5.1.1 - 6 Fusion Proteins for Half-Life Extension [Seite 123]
1.5.1.1.1 - 6.1 Introduction [Seite 123]
1.5.1.1.2 - 6.2 Half-Life Extension Through Size and Recycling [Seite 124]
1.5.1.1.2.1 - 6.2.1 Direct Genetic Fusions [Seite 124]
1.5.1.1.2.1.1 - 6.2.1.1 Albumin Fusions [Seite 124]
1.5.1.1.2.1.2 - 6.2.1.2 Fc Fusions [Seite 127]
1.5.1.1.2.1.3 - 6.2.1.3 Transferrin Fusions [Seite 129]
1.5.1.1.2.2 - 6.2.2 Half-Life Extension Through Attachment to Large Proteins [Seite 129]
1.5.1.1.3 - 6.3 Half-Life Extension Through Increase of Hydrodynamic Radius [Seite 130]
1.5.1.1.3.1 - 6.3.1 Repetitive Peptide Fusions [Seite 130]
1.5.1.1.3.2 - 6.3.2 Glycosylated Peptides [Seite 131]
1.5.1.1.4 - 6.4 Aggregate Forming Peptide Fusions [Seite 132]
1.5.1.1.5 - 6.5 Other Concepts [Seite 133]
1.5.1.1.6 - 6.6 Conclusions and Future Perspective [Seite 133]
1.5.1.1.7 - References [Seite 134]
1.5.1.2 - 7 Monomeric Fc-Fusion Proteins [Seite 137]
1.5.1.2.1 - 7.1 Introduction [Seite 137]
1.5.1.2.2 - 7.2 FcRn and Monomeric Fc-Fusion Proteins [Seite 138]
1.5.1.2.2.1 - 7.2.1 FcRn Expression and Function [Seite 138]
1.5.1.2.2.2 - 7.2.2 FcRn for the Delivery of Fc-Fusion Proteins [Seite 138]
1.5.1.2.3 - 7.3 Typical Applications [Seite 139]
1.5.1.2.3.1 - 7.3.1 Interferon Beta-Fc Monomer [Seite 140]
1.5.1.2.3.2 - 7.3.2 Interferon ?-Fc Monomer [Seite 140]
1.5.1.2.3.3 - 7.3.3 Factor VIII-Fc Monomer [Seite 141]
1.5.1.2.3.4 - 7.3.4 Factor IX-Fc Monomer [Seite 143]
1.5.1.2.4 - 7.4 Alternative Applications [Seite 144]
1.5.1.2.4.1 - 7.4.1 Follicle Stimulating Hormone-Fc-Fusion Proteins [Seite 145]
1.5.1.2.4.2 - 7.4.2 Cytokine-Fc-Fusion Proteins [Seite 145]
1.5.1.2.5 - 7.5 Expression and Purification of Monomeric Fc-Fusion Proteins [Seite 146]
1.5.1.2.6 - 7.6 Conclusions and Future Perspectives [Seite 148]
1.5.1.2.7 - References [Seite 148]
1.5.1.3 - 8 Peptide-Fc Fusion Therapeutics: Applications and Challenges [Seite 153]
1.5.1.3.1 - 8.1 Introduction [Seite 153]
1.5.1.3.2 - 8.2 Peptide Drugs [Seite 154]
1.5.1.3.2.1 - 8.2.1 The Limitations of Native Endogenous Peptides in Drug Development [Seite 154]
1.5.1.3.2.2 - 8.2.2 Chemical Modification of Peptides to Reduce Proteolytic Degradation [Seite 154]
1.5.1.3.2.3 - 8.2.3 Constraining Peptides to be More Resistant to Protease Cleavage [Seite 155]
1.5.1.3.2.4 - 8.2.4 Peptide Therapeutics Play an Important Role in Drug Development [Seite 155]
1.5.1.3.2.5 - 8.2.5 Most Peptide Drugs Act as Receptor Agonists [Seite 155]
1.5.1.3.3 - 8.3 Technologies Used for Reducing In Vivo Clearance of Therapeutic Peptides [Seite 156]
1.5.1.3.3.1 - 8.3.1 PEGylation [Seite 156]
1.5.1.3.3.2 - 8.3.2 Human Serum Albumin Fusions [Seite 156]
1.5.1.3.3.3 - 8.3.3 Other Approaches [Seite 157]
1.5.1.3.4 - 8.4 Fc-Fusion Proteins in Drug Development [Seite 157]
1.5.1.3.4.1 - 8.4.1 The Structure of Fc-Fusion Proteins [Seite 157]
1.5.1.3.4.2 - 8.4.2 Fc-Fusion Therapeutics [Seite 157]
1.5.1.3.4.2.1 - 8.4.2.1 Enbrel® [Seite 158]
1.5.1.3.4.2.2 - 8.4.2.2 Amevive® [Seite 158]
1.5.1.3.4.2.3 - 8.4.2.3 Orencia® [Seite 159]
1.5.1.3.4.2.4 - 8.4.2.4 Arcalyst® (Also Known as IL-1 Trap or Rilonacept) [Seite 159]
1.5.1.3.4.2.5 - 8.4.2.5 Other Fc-Fusion Protein Therapeutics [Seite 161]
1.5.1.3.5 - 8.5 Peptide-Fc-Fusion Therapeutics [Seite 161]
1.5.1.3.5.1 - 8.5.1 Peptibody [Seite 161]
1.5.1.3.5.1.1 - 8.5.1.1 NPlate® (Romiplostim, AMG531) [Seite 161]
1.5.1.3.5.1.2 - 8.5.1.2 AMG 386 (2xCon4(C)) [Seite 161]
1.5.1.3.5.1.3 - 8.5.1.3 A-623 (AMG 623) [Seite 162]
1.5.1.3.5.1.4 - 8.5.1.4 Dulaglutide (LY2189265) [Seite 162]
1.5.1.3.5.2 - 8.5.2 MimetibodyTM Technology [Seite 163]
1.5.1.3.5.2.1 - 8.5.2.1 CNTO 528/CNTO 530 [Seite 163]
1.5.1.3.5.2.2 - 8.5.2.2 CNTO736 [Seite 163]
1.5.1.3.6 - 8.6 Considerations and Challenges for Engineering Peptide-Fc-Fusion Therapeutics [Seite 163]
1.5.1.3.6.1 - 8.6.1 Improving Activity [Seite 164]
1.5.1.3.6.2 - 8.6.2 Improving Stability [Seite 164]
1.5.1.3.6.3 - 8.6.3 Improving Pharmacokinetic Profile [Seite 165]
1.5.1.3.6.4 - 8.6.4 Improving Solubility and Reducing Aggregation [Seite 165]
1.5.1.3.6.5 - 8.6.5 Reducing Heterogeneity [Seite 165]
1.5.1.3.6.6 - 8.6.6 Isotype Selection [Seite 167]
1.5.1.3.6.7 - 8.6.7 Tailoring Fc-Effector Functions to Fit Individual Needs [Seite 167]
1.5.1.3.6.8 - 8.6.8 Reducing Immunogenicity [Seite 168]
1.5.1.3.7 - 8.7 Conclusions [Seite 168]
1.5.1.3.8 - Acknowledgment [Seite 168]
1.5.1.3.9 - References [Seite 168]
1.5.1.4 - 9 Receptor-Fc and Ligand Traps as High-Affinity Biological Blockers: Development and Clinical Applications [Seite 173]
1.5.1.4.1 - 9.1 Introduction [Seite 173]
1.5.1.4.2 - 9.2 Etanercept as a Prototypical Receptor-Fc-Based Cytokine Blocker [Seite 174]
1.5.1.4.3 - 9.3 Heteromeric Traps for Ligands Utilizing Multicomponent Receptor Systems with Shared Subunits [Seite 174]
1.5.1.4.3.1 - 9.3.1 Proof-of-Concept for High-Affinity Traps for Ligands Utilizing Multicomponent Receptor Systems [Seite 178]
1.5.1.4.3.2 - 9.3.2 Turning Heterodimeric Soluble Receptor-Based Ligand Traps into Therapeutics [Seite 180]
1.5.1.4.4 - 9.4 Development and Clinical Application of an Interleukin 1 Trap: Rilonacept [Seite 181]
1.5.1.4.5 - 9.5 Development and Clinical Application of a VEGF Trap [Seite 181]
1.5.1.4.6 - 9.6 "To Trap Or Not To Trap?" Advantages and Disadvantages of Receptor-Fc Fusions and Traps Versus Antibodies [Seite 182]
1.5.1.4.6.1 - 9.6.1 Multiple Ligand Binding [Seite 182]
1.5.1.4.6.2 - 9.6.2 Signaling of Receptor-Fc Fusions [Seite 184]
1.5.1.4.6.3 - 9.6.3 Immunogenicity [Seite 185]
1.5.1.4.7 - 9.7 Conclusion [Seite 185]
1.5.1.4.8 - Acknowledgment [Seite 185]
1.5.1.4.9 - References [Seite 185]
1.5.1.5 - 10 Recombinant Albumin Fusion Proteins [Seite 193]
1.5.1.5.1 - 10.1 Concept [Seite 193]
1.5.1.5.2 - 10.2 Technological Aspects [Seite 194]
1.5.1.5.3 - 10.3 Typical Applications and Indications [Seite 194]
1.5.1.5.3.1 - 10.3.1 Albumin Fusion Proteins in Late-Stage Development [Seite 197]
1.5.1.5.3.1.1 - 10.3.1.1 Interferon-? [Seite 197]
1.5.1.5.3.1.2 - 10.3.1.2 Glucagon-Like Peptide-1 [Seite 197]
1.5.1.5.3.1.3 - 10.3.1.3 Granulocyte Colony-Stimulating Factor [Seite 198]
1.5.1.5.3.2 - 10.3.2 Albumin Fusion Proteins in Early-Stage Development [Seite 198]
1.5.1.5.3.2.1 - 10.3.2.1 Interleukin-2 [Seite 198]
1.5.1.5.3.2.2 - 10.3.2.2 Insulin [Seite 198]
1.5.1.5.3.2.3 - 10.3.2.3 Growth Hormone [Seite 199]
1.5.1.5.3.2.4 - 10.3.2.4 Butyrylcholinesterase and Cocaine Hydrolase [Seite 199]
1.5.1.5.3.2.5 - 10.3.2.5 B-Type Natriuretic Peptide [Seite 199]
1.5.1.5.3.2.6 - 10.3.2.6 Erythropoietin [Seite 200]
1.5.1.5.3.2.7 - 10.3.2.7 Barbourin [Seite 200]
1.5.1.5.3.2.8 - 10.3.2.8 Hirudin [Seite 200]
1.5.1.5.3.2.9 - 10.3.2.9 Factor VII [Seite 200]
1.5.1.5.3.2.10 - 10.3.2.10 Factor IX [Seite 201]
1.5.1.5.3.2.11 - 10.3.2.11 Infestin-4 [Seite 201]
1.5.1.5.3.2.12 - 10.3.2.12 Thioredoxin [Seite 202]
1.5.1.5.3.2.13 - 10.3.2.13 Thymosin-?1 [Seite 202]
1.5.1.5.3.2.14 - 10.3.2.14 Antibody Fragments [Seite 202]
1.5.1.5.4 - 10.4 Successes and Failures in Preclinical and Clinical Research [Seite 202]
1.5.1.5.4.1 - 10.4.1 Interferon-? [Seite 202]
1.5.1.5.4.2 - 10.4.2 FVII and FIX [Seite 203]
1.5.1.5.5 - 10.5 Challenges [Seite 203]
1.5.1.5.6 - 10.6 Future Perspectives [Seite 204]
1.5.1.5.7 - 10.7 Conclusion [Seite 204]
1.5.1.5.8 - Acknowledgment [Seite 204]
1.5.1.5.9 - References [Seite 204]
1.5.1.6 - 11 Albumin-Binding Fusion Proteins in the Development of Novel Long-Acting Therapeutics [Seite 209]
1.5.1.6.1 - 11.1 Introduction [Seite 209]
1.5.1.6.2 - 11.2 Clinically Validated Half-Life Extension Technologies-An Overview [Seite 210]
1.5.1.6.2.1 - 11.2.1 PEGylation [Seite 210]
1.5.1.6.2.2 - 11.2.2 Serum Albumin Fusion [Seite 210]
1.5.1.6.2.3 - 11.2.3 Anti-Serum Albumin Domain Antibodies in the Development of Novel Half-Life Extension Technologies [Seite 211]
1.5.1.6.3 - 11.3 Interferon-a Fused to Human Serum Albumin or AlbudAb-A Direct Comparison of HSA and AlbudAb Fusion Technologies [Seite 212]
1.5.1.6.3.1 - 11.3.1 In Vitro Potency of HSA and AlbudAb Fusion Proteins [Seite 212]
1.5.1.6.3.2 - 11.3.2 Pharmacokinetics of HSA and AlbudAb Fusion Proteins [Seite 214]
1.5.1.6.3.3 - 11.3.3 In Vivo Efficacy of HSA and AlbudAb Fusion Proteins [Seite 215]
1.5.1.6.4 - 11.4 Nanobodies in the Development of Alternative Half-Life Extension Technologies Based on Single Immunoglobulin Variable Domains [Seite 216]
1.5.1.6.5 - 11.5 Novel Half-Life Extension Technologies-Alternative Approaches to Single Immunoglobulin Variable Domains [Seite 217]
1.5.1.6.5.1 - 11.5.1 Serum Albumin Binding Peptides [Seite 217]
1.5.1.6.5.2 - 11.5.2 Serum Albumin Binding Small Molecules [Seite 217]
1.5.1.6.5.3 - 11.5.3 Hydrophilic Polymers [Seite 217]
1.5.1.6.6 - 11.6 Conclusions [Seite 218]
1.5.1.6.7 - References [Seite 219]
1.5.1.7 - 12 Transferrin Fusion Protein Therapies: Acetylcholine Receptor-Transferrin Fusion Protein as a Model [Seite 221]
1.5.1.7.1 - 12.1 Disease Overview [Seite 221]
1.5.1.7.2 - 12.2 Fusion Protein SHG2210 Design [Seite 222]
1.5.1.7.3 - 12.3 Characterization of SHG2210 [Seite 223]
1.5.1.7.3.1 - 12.3.1 SHG2210 Binding and Internalization Studies in Cells [Seite 223]
1.5.1.7.3.2 - 12.3.2 SHG2210 Anti-AchR Antibody Binding Studies [Seite 223]
1.5.1.7.3.3 - 12.3.3 SHG2210: Anti-AchR Antibody Complex Binding and Internalization Studies in Cells [Seite 224]
1.5.1.7.3.4 - 12.3.4 SHG2210 and SHG2210: Anti-AChR Antibody Complex Recycling Studies in Cells [Seite 225]
1.5.1.7.3.5 - 12.3.5 Antigenic Modulation Studies [Seite 225]
1.5.1.7.3.6 - 12.3.6 Summary of In Vitro Studies of SHG2210 [Seite 226]
1.5.1.7.4 - 12.4 Applications and Indications [Seite 226]
1.5.1.7.5 - 12.5 Future Perspectives [Seite 227]
1.5.1.7.6 - 12.6 Conclusion [Seite 228]
1.5.1.7.7 - References [Seite 228]
1.5.1.8 - 13 Half-Life Extension Through O-Glycosylation [Seite 231]
1.5.1.8.1 - 13.1 Introduction [Seite 231]
1.5.1.8.2 - 13.2 The Role of O-Linked Oligosaccharide Chains in Glycoprotein Function [Seite 232]
1.5.1.8.3 - 13.3 Designing Long-Acting Agonists of Glycoprotein Hormones [Seite 233]
1.5.1.8.3.1 - 13.3.1 Construction of Chimeric Genes and Expression Vectors [Seite 234]
1.5.1.8.3.2 - 13.3.2 Expression of Chimeric Genes [Seite 234]
1.5.1.8.3.3 - 13.3.3 Bioactivity of Designed Long-Acting Glycoproteins [Seite 235]
1.5.1.8.3.3.1 - 13.3.3.1 Follicle-Stimulating Hormone [Seite 235]
1.5.1.8.3.3.2 - 13.3.3.2 Thyrotropin(TSH) [Seite 235]
1.5.1.8.3.3.3 - 13.3.3.3 Erythropoietin (EPO) [Seite 235]
1.5.1.8.3.3.4 - 13.3.3.4 Human Growth Hormone (GH) [Seite 236]
1.5.1.8.4 - 13.4 Conclusions [Seite 237]
1.5.1.8.5 - References [Seite 237]
1.5.1.9 - 14 ELP-Fusion Technology for Biopharmaceuticals [Seite 241]
1.5.1.9.1 - 14.1 Introduction [Seite 241]
1.5.1.9.2 - 14.2 ELP-based Protein Purification [Seite 242]
1.5.1.9.3 - 14.3 ELPylated Proteins in Medicine and Nanobiotechnology [Seite 245]
1.5.1.9.4 - 14.4 Molecular Pharming: a New Application for ELPylation [Seite 247]
1.5.1.9.5 - 14.5 Challenges and Future Perspectives [Seite 251]
1.5.1.9.6 - 14.6 Conclusion [Seite 252]
1.5.1.9.7 - References [Seite 252]
1.5.1.10 - 15 Ligand-Receptor Fusion Dimers [Seite 257]
1.5.1.10.1 - 15.1 Introduction [Seite 257]
1.5.1.10.2 - 15.2 The GHLR-Fusions [Seite 258]
1.5.1.10.3 - 15.3 Expression and Purification [Seite 259]
1.5.1.10.4 - 15.4 Analysis of the LR-Fusions [Seite 259]
1.5.1.10.4.1 - 15.4.1 Characterization [Seite 259]
1.5.1.10.4.2 - 15.4.2 Biological Activity [Seite 260]
1.5.1.10.4.3 - 15.4.3 Pharmacokinetics [Seite 260]
1.5.1.10.4.4 - 15.4.4 Pharmacodynamics [Seite 262]
1.5.1.10.4.5 - 15.4.5 Immunogenicity [Seite 263]
1.5.1.10.4.6 - 15.4.6 Toxicology [Seite 264]
1.5.1.10.5 - 15.5 LR-Fusions: The Next Generation in Hormone Treatment [Seite 264]
1.5.1.10.6 - 15.6 Conclusion [Seite 264]
1.5.1.10.7 - References [Seite 264]
1.5.1.11 - 16 Development of Latent Cytokine Fusion Proteins [Seite 267]
1.5.1.11.1 - 16.1 Introduction [Seite 267]
1.5.1.11.2 - 16.2 Description of Concept [Seite 268]
1.5.1.11.3 - 16.3 Limitations of the Latent Cytokine Technology [Seite 270]
1.5.1.11.4 - 16.4 Generation of Latent Cytokines [Seite 272]
1.5.1.11.4.1 - 16.4.1 Molecular Design [Seite 272]
1.5.1.11.4.2 - 16.4.2 Expression of LAP-Fusion Proteins [Seite 273]
1.5.1.11.4.3 - 16.4.3 Purification of LAP-Fusion Proteins [Seite 273]
1.5.1.11.5 - 16.5 Applications and Potential Clinical Indications [Seite 274]
1.5.1.11.5.1 - 16.5.1 Multiple Sclerosis [Seite 274]
1.5.1.11.5.1.1 - 16.5.1.1 Interferon ? [Seite 274]
1.5.1.11.5.1.2 - 16.5.1.2 Interleukin 10 [Seite 275]
1.5.1.11.5.1.3 - 16.5.1.3 Erythropoietin [Seite 275]
1.5.1.11.5.1.4 - 16.5.1.4 Transforming Growth Factor-? [Seite 275]
1.5.1.11.5.2 - 16.5.2 Rheumatoid Arthritis [Seite 275]
1.5.1.11.5.2.1 - 16.5.2.1 Interferon ? [Seite 275]
1.5.1.11.5.2.2 - 16.5.2.2 Interleukine 10 [Seite 276]
1.5.1.11.5.2.3 - 16.5.2.3 Interleukine 4 [Seite 276]
1.5.1.11.6 - 16.6 Alternatives/Variants of Approach [Seite 276]
1.5.1.11.7 - 16.7 Challenges (Production and Development) [Seite 277]
1.5.1.11.8 - 16.8 Conclusions and Future Perspectives [Seite 278]
1.5.1.11.9 - Acknowledgments [Seite 279]
1.5.1.11.10 - References [Seite 279]
1.5.2 - IIB TOXIN: CYTOTOXIC FUSION PROTEINS [Seite 283]
1.5.2.1 - 17 Fusion Proteins with Toxic Activity [Seite 283]
1.5.2.1.1 - 17.1 Introduction [Seite 283]
1.5.2.1.2 - 17.2 Toxins [Seite 284]
1.5.2.1.2.1 - 17.2.1 Microbial Toxins [Seite 284]
1.5.2.1.2.2 - 17.2.2 Plant Toxins [Seite 287]
1.5.2.1.3 - 17.3 Immunocytokines [Seite 288]
1.5.2.1.3.1 - 17.3.1 Interleukin 2 Fusion Proteins [Seite 288]
1.5.2.1.3.2 - 17.3.2 GM-CSF Fusion Proteins, 258 17.3.3 Other Leukocyte Attracting [Seite 288]
1.5.2.1.3.3 - 17.3.3 Other Leukocyte Attracting Cytokines and Chemokines [Seite 288]
1.5.2.1.4 - 17.4 Human Enzymes [Seite 289]
1.5.2.1.4.1 - 17.4.1 Kinases [Seite 289]
1.5.2.1.4.2 - 17.4.2 RNAses [Seite 289]
1.5.2.1.4.3 - 17.4.3 Proteases [Seite 290]
1.5.2.1.4.4 - 17.4.4 Antibody-Directed Enzyme Prodrug Therapy [Seite 290]
1.5.2.1.5 - 17.5 Apoptosis Induction [Seite 291]
1.5.2.1.5.1 - 17.5.1 TNF Fusion Proteins [Seite 291]
1.5.2.1.5.2 - 17.5.2 FasL Fusion Proteins [Seite 292]
1.5.2.1.5.3 - 17.5.3 TRAIL Fusion Proteins [Seite 292]
1.5.2.1.5.4 - 17.5.4 Intrinsic Apoptosis Inducing Fusion Proteins [Seite 293]
1.5.2.1.6 - 17.6 Fc-Based Toxicity [Seite 293]
1.5.2.1.6.1 - 17.6.1 Antibody-Derived Cellular Cytotoxicity (ADCC) [Seite 293]
1.5.2.1.6.2 - 17.6.2 Antibody-Dependent Cell-Mediated Phagocytosis (ADCP) [Seite 294]
1.5.2.1.6.3 - 17.6.3 Complement-Dependent Cytotoxicity (CDC) [Seite 294]
1.5.2.1.6.4 - 17.6.4 Complement-Dependent Cell-Mediated Cytotoxicity (CDCC) [Seite 294]
1.5.2.1.7 - 17.7 Peptide-Based Toxicity [Seite 294]
1.5.2.1.8 - 17.8 Conclusions and Future Perspectives [Seite 295]
1.5.2.1.9 - References [Seite 295]
1.5.2.2 - 18 Classic Immunotoxins with Plant or Microbial Toxins [Seite 301]
1.5.2.2.1 - 18.1 Introduction [Seite 301]
1.5.2.2.2 - 18.2 Toxins Used in Immunotoxin Preparation [Seite 302]
1.5.2.2.2.1 - 18.2.1 Diptheria Toxin [Seite 302]
1.5.2.2.2.2 - 18.2.2 Pseudomonas Exotoxin [Seite 302]
1.5.2.2.2.3 - 18.2.3 Ricin [Seite 304]
1.5.2.2.2.4 - 18.2.4 Gelonin and Saporin [Seite 304]
1.5.2.2.3 - 18.3 Immunotoxin Design and Synthesis [Seite 304]
1.5.2.2.4 - 18.4 Clinical Update of Immunotoxin Trials [Seite 308]
1.5.2.2.5 - 18.5 Challenges and Perspective of Classic Immunotoxins [Seite 314]
1.5.2.2.5.1 - 18.5.1 Adverse Events [Seite 314]
1.5.2.2.5.2 - 18.5.2 Immunogenicity [Seite 315]
1.5.2.2.6 - 18.6 Conclusions [Seite 316]
1.5.2.2.7 - References [Seite 316]
1.5.2.3 - 19 Targeted and Untargeted Fusion Proteins: Current Approaches to Cancer Immunotherapy [Seite 325]
1.5.2.3.1 - 19.1 Introduction [Seite 325]
1.5.2.3.2 - 19.2 Immunotherapeutic Strategy for Cancer: Fusion Proteins [Seite 326]
1.5.2.3.3 - 19.3 Immunotherapeutic Applications of Antibody-Targeted and Untargeted Fc Fusion Proteins [Seite 327]
1.5.2.3.3.1 - 19.3.1 Cytokine Fusion Proteins [Seite 328]
1.5.2.3.3.2 - 19.3.2 Chemokine Fusion Proteins [Seite 329]
1.5.2.3.3.3 - 19.3.3 Co-Stimulatory Fusion Proteins [Seite 329]
1.5.2.3.3.3.1 - 19.3.3.1 B7.1 Fusion Proteins [Seite 330]
1.5.2.3.3.3.2 - 19.3.3.2 CD137L Fusion Proteins [Seite 331]
1.5.2.3.3.3.3 - 19.3.3.3 GITRL Fusion Proteins [Seite 331]
1.5.2.3.3.3.4 - 19.3.3.4 OX40L Fusion Proteins [Seite 332]
1.5.2.3.3.4 - 19.3.4 Enzyme Fusion Proteins [Seite 333]
1.5.2.3.3.5 - 19.3.5 Vascular Targeting Fusion Proteins [Seite 334]
1.5.2.3.4 - 19.4 Combination Fusion Proteins Therapy [Seite 335]
1.5.2.3.4.1 - 19.4.1 Cytokine Fusion Protein Combinations [Seite 335]
1.5.2.3.4.2 - 19.4.2 Chemokine and Cytokine Synergy [Seite 336]
1.5.2.3.4.3 - 19.4.3 Co-Stimulatory Fusion Protein Combinations [Seite 336]
1.5.2.3.5 - 19.5 Mechanism of Action: Immunoregulatory T-Cell (Treg) Depletion and Fusion Protein Combination Therapy [Seite 336]
1.5.2.3.5.1 - 19.5.1 LEC Fusion Proteins in Combination with Treg Depletion [Seite 337]
1.5.2.3.5.2 - 19.5.2 CD137L and GITRL Fusion Proteins in Combination with Treg Depletion [Seite 338]
1.5.2.3.6 - 19.6 Future Directions [Seite 339]
1.5.2.3.7 - 19.7 Conclusion [Seite 339]
1.5.2.3.8 - Acknowledgments [Seite 340]
1.5.2.3.9 - References [Seite 340]
1.5.2.4 - 20 Development of Experimental Targeted Toxin Therapies for Malignant Glioma [Seite 345]
1.5.2.4.1 - 20.1 Introduction [Seite 345]
1.5.2.4.2 - 20.2 Targeted Toxins-General Considerations [Seite 346]
1.5.2.4.3 - 20.3 Delivery Mode and Pharmacokinetics of Targeted Toxins in the Brain [Seite 346]
1.5.2.4.4 - 20.4 Preclinical and Clinical Studies with Targeted Toxins [Seite 348]
1.5.2.4.4.1 - 20.4.1 IL4-PE (NBI-3001) [Seite 348]
1.5.2.4.4.2 - 20.4.2 TP-38 [Seite 349]
1.5.2.4.4.3 - 20.4.3 IL13-PE38 [Seite 350]
1.5.2.4.4.4 - 20.4.4 TransMID-107 (Tf-CRM107) [Seite 352]
1.5.2.4.5 - 20.5 Conclusions and Future Developments of Targeted Toxins [Seite 354]
1.5.2.4.6 - Disclosure [Seite 355]
1.5.2.4.7 - References [Seite 355]
1.5.2.5 - 21 Immunokinases [Seite 359]
1.5.2.5.1 - 21.1 Introduction [Seite 359]
1.5.2.5.2 - 21.2 Protein Kinases, Apoptosis, and Cancer [Seite 360]
1.5.2.5.2.1 - 21.2.1 General Properties of Protein Kinases [Seite 360]
1.5.2.5.2.2 - 21.2.2 Death-Associated Protein Kinases (DAPKs) [Seite 360]
1.5.2.5.2.3 - 21.2.3 The Role of DAPK1 and DAPK2 in Cancer [Seite 361]
1.5.2.5.3 - 21.3 Therapeutic Strategies to Restore Missing Kinase Expression [Seite 361]
1.5.2.5.3.1 - 21.3.1 Systemic Delivery of Demethylating Agents [Seite 361]
1.5.2.5.3.2 - 21.3.2 Nontargeted Reactivation of Specific Protein Kinases [Seite 362]
1.5.2.5.3.3 - 21.3.3 Targeted Reactivation of Specific Protein Kinases Using DAPK2-Based Immunokinases [Seite 362]
1.5.2.5.4 - 21.4 Analysis of Immunokinase Efficacy [Seite 363]
1.5.2.5.4.1 - 21.4.1 In Vitro Activity of Recombinant Immunokinase DAPK20-CD30L [Seite 363]
1.5.2.5.4.2 - 21.4.2 In Vivo Activity of Recombinant Immunokinase DAPK20-CD30L [Seite 363]
1.5.2.5.5 - 21.5 Outlook [Seite 364]
1.5.2.5.6 - References [Seite 364]
1.5.2.6 - 22 ImmunoRNase Fusions [Seite 367]
1.5.2.6.1 - 22.1 Introduction [Seite 367]
1.5.2.6.1.1 - 22.1.1 Immunotoxins [Seite 367]
1.5.2.6.1.2 - 22.1.2 Cytotoxic Activity of Ribonucleases [Seite 367]
1.5.2.6.1.3 - 22.1.3 Ribonuclease Targeting to Cancer Cells [Seite 368]
1.5.2.6.2 - 22.2 Development of ImmunoRNase Fusion Proteins as Biopharmaceuticals [Seite 369]
1.5.2.6.2.1 - 22.2.1 Immuno-Fusion Proteins of Eosinophil-Derived Endotoxin or Angiogenin [Seite 369]
1.5.2.6.2.2 - 22.2.2 Immuno-Fusion Proteins of Bovine Seminal Plasma RNase or Human Pancreatic RNase [Seite 371]
1.5.2.6.2.3 - 22.2.3 Immuno-Fusion Proteins of Onconase1 or Rana Pipiens Liver RNase [Seite 372]
1.5.2.6.2.4 - 22.2.4 Barnase Immuno-Fusion Proteins [Seite 373]
1.5.2.6.3 - 22.3 Aspects of ImmunoRNase Design and Production [Seite 374]
1.5.2.6.3.1 - 22.3.1 Molecular Size and Valency [Seite 374]
1.5.2.6.3.2 - 22.3.2 Interaction with Mammalian RNase Inhibitor [Seite 374]
1.5.2.6.3.3 - 22.3.3 Cleavable ImmunoRNases [Seite 375]
1.5.2.6.3.4 - 22.3.4 High-Level Production of ImmunoRNases [Seite 375]
1.5.2.6.4 - 22.4 Alternatives [Seite 376]
1.5.2.6.5 - 22.5 Conclusions and Future Perspectives [Seite 377]
1.5.2.6.6 - References [Seite 377]
1.5.2.7 - 23 Antibody-Directed Enzyme Prodrug Therapy (ADEPT) [Seite 385]
1.5.2.7.1 - 23.1 Introduction [Seite 385]
1.5.2.7.2 - 23.2 The Components [Seite 385]
1.5.2.7.2.1 - 23.2.1 The Target [Seite 385]
1.5.2.7.2.2 - 23.2.2 The Antibody [Seite 386]
1.5.2.7.2.3 - 23.2.3 The Enzyme [Seite 386]
1.5.2.7.2.4 - 23.2.4 Abzymes or Catalytic Antibodies [Seite 387]
1.5.2.7.2.5 - 23.2.5 Prodrugs [Seite 387]
1.5.2.7.3 - 23.3 ADEPT Systems with Carboxypeptidase G2 (CPG2) [Seite 387]
1.5.2.7.3.1 - 23.3.1 System 1: Antibody-Enzyme Conjugates [Seite 387]
1.5.2.7.3.1.1 - 23.3.1.1 Preclinical Studies [Seite 387]
1.5.2.7.3.1.2 - 23.3.1.2 Removal of Enzyme Activity from Blood [Seite 387]
1.5.2.7.3.1.3 - 23.3.1.3 First in Man ADEPT Study [Seite 388]
1.5.2.7.3.1.4 - 23.3.1.4 Results of the First in Man ADEPT Study [Seite 388]
1.5.2.7.3.1.5 - 23.3.1.5 Conclusions from the First in Man ADEPT Study [Seite 388]
1.5.2.7.3.2 - 23.3.2 The Second Clinical Study of ADEPT [Seite 388]
1.5.2.7.3.2.1 - 23.3.2.1 Conclusions from the Second Clinical Study of ADEPT [Seite 389]
1.5.2.7.3.3 - 23.3.3 The Third Clinical Study of ADEPT [Seite 389]
1.5.2.7.3.3.1 - 23.3.3.1 Conclusions from the Third Clinical Study of ADEPT [Seite 389]
1.5.2.7.4 - 23.4 Fusion Proteins [Seite 389]
1.5.2.7.4.1 - 23.4.1 The Fourth Clinical Study of ADEPT [Seite 390]
1.5.2.7.5 - 23.5 Immunogenicity [Seite 390]
1.5.2.7.6 - 23.6 Conclusions and Future Outlook [Seite 391]
1.5.2.7.7 - Acknowledgments [Seite 391]
1.5.2.7.8 - References [Seite 391]
1.5.2.8 - 24 Tumor-Targeted Superantigens [Seite 395]
1.5.2.8.1 - 24.1 Introduction: Tumor-Targeted Superantigens-AUnique Concept of Cancer Treatment [Seite 395]
1.5.2.8.2 - 24.2 Structure and Production of Tumor-Targeted Superantigens [Seite 396]
1.5.2.8.3 - 24.3 Tumor-Targeted Superantigens are Powerful Targeted Immune Activators and Useful for all Types of Malignancies [Seite 397]
1.5.2.8.4 - 24.4 Increasing the Therapeutic Window and Exposure by the Creation of a Novel TTS Fusion Protein with Minimal MHC Class II Affinity [Seite 400]
1.5.2.8.5 - 24.5 Clinical Experience with TTS Therapeutic Fusion Proteins [Seite 401]
1.5.2.8.5.1 - 24.5.1 Anatumomab Mafenatox [Seite 401]
1.5.2.8.5.2 - 24.5.2 Naptumomab Estafenatox [Seite 402]
1.5.2.8.6 - 24.6 Combining TTS with Cytostatic and Immunomodulating Anticancer Drugs [Seite 407]
1.5.2.8.7 - 24.7 Conclusions [Seite 409]
1.5.2.8.8 - References [Seite 409]
1.5.3 - IIC TARGETING: FUSION PROTEINS ADDRESSING SPECIFIC CELLS, ORGANS, AND TISSUES [Seite 413]
1.5.3.1 - 25 Fusion Proteins with a Targeting Function [Seite 413]
1.5.3.1.1 - 25.1 Introduction [Seite 413]
1.5.3.1.2 - 25.2 Targeting Organs [Seite 413]
1.5.3.1.2.1 - 25.2.1 Brain [Seite 413]
1.5.3.1.2.2 - 25.2.2 Liver [Seite 415]
1.5.3.1.2.3 - 25.2.3 Lung [Seite 416]
1.5.3.1.2.4 - 25.2.4 Bone [Seite 417]
1.5.3.1.2.5 - 25.2.5 Thrombus Targeting [Seite 417]
1.5.3.1.3 - 25.3 Intracellular Delivery [Seite 418]
1.5.3.1.3.1 - 25.3.1 Enzyme Replacement Therapy [Seite 418]
1.5.3.1.3.2 - 25.3.2 Cell Penetrating Peptides [Seite 419]
1.5.3.1.3.3 - 25.3.3 Antibody-Mediated Transduction [Seite 420]
1.5.3.1.3.4 - 25.3.4 Endosome Escape and Cytosol Translocation [Seite 420]
1.5.3.1.4 - 25.4 Oral Delivery [Seite 421]
1.5.3.1.5 - 25.5 Conclusions and Future Perspectives [Seite 422]
1.5.3.1.6 - References [Seite 423]
1.5.3.2 - 26 Cell-Penetrating Peptide Fusion Proteins [Seite 427]
1.5.3.2.1 - 26.1 Introduction [Seite 427]
1.5.3.2.2 - 26.2 Typical Applications and Indications [Seite 427]
1.5.3.2.3 - 26.3 Technological Aspects [Seite 429]
1.5.3.2.3.1 - 26.3.1 Creating CPP-Fusion Proteins [Seite 429]
1.5.3.2.3.2 - 26.3.2 Recombinant Fusion Protein Expression Systems [Seite 429]
1.5.3.2.3.3 - 26.3.3 Disulfide Bond [Seite 430]
1.5.3.2.3.4 - 26.3.4 Biotin-Avidin Fusion Model [Seite 431]
1.5.3.2.3.5 - 26.3.5 Expressed Protein Ligation [Seite 431]
1.5.3.2.3.6 - 26.3.6 Purification [Seite 431]
1.5.3.2.3.7 - 26.3.7 Purification Tag [Seite 431]
1.5.3.2.3.8 - 26.3.8 Affinity Chromatography [Seite 431]
1.5.3.2.3.9 - 26.3.9 Solid Phase Peptide Synthesis and High Performance Liquid Chromatography [Seite 432]
1.5.3.2.4 - 26.4 Successes and Failures in Preclinical and Clinical Research [Seite 432]
1.5.3.2.4.1 - 26.4.1 Preclinical Research [Seite 432]
1.5.3.2.4.2 - 26.4.2 CPPs Used in Clinical Trials [Seite 433]
1.5.3.2.5 - 26.5 Alternatives/Variants of This Approach [Seite 435]
1.5.3.2.6 - 26.6 Conclusions and Future Perspectives [Seite 435]
1.5.3.2.7 - Acknowledgments [Seite 436]
1.5.3.2.8 - References [Seite 436]
1.5.3.3 - 27 Cell-Specific Targeting of Fusion Proteins through Heparin Binding [Seite 443]
1.5.3.3.1 - 27.1 Why Target Heparan-Sulfate Proteoglycans with Fusion Proteins? [Seite 443]
1.5.3.3.2 - 27.2 Heparan Sulfate Structure and Biosynthesis Create Diversity and a Template for Targeting Specificity [Seite 445]
1.5.3.3.3 - 27.3 Tissue-Specific Expression of HSPGs and the Enzymes That Modify Them [Seite 446]
1.5.3.3.4 - 27.4 Heparin-Binding Proteins and Growth Factors [Seite 446]
1.5.3.3.5 - 27.5 Viruses Target Cells Through Heparin Binding [Seite 447]
1.5.3.3.6 - 27.6 Dissecting Heparin-Binding Protein Domains for Tissue-Specific Targeting [Seite 448]
1.5.3.3.7 - 27.7 Fusion Proteins Incorporating HBDs [Seite 448]
1.5.3.3.8 - 27.8 The Neuregulin 1 Growth Factor Has a Unique and Highly Specific HBD [Seite 449]
1.5.3.3.9 - 27.9 Using Neuregulin's HBD to Generate a Targeted Neuregulin Antagonist [Seite 449]
1.5.3.3.10 - 27.10 Tissue Targeting and Therapeutic Efficacy of a Heparin-Targeted NRG1 Antagonist Fusion Protein [Seite 450]
1.5.3.3.11 - 27.11 Conclusions and Future Perspectives [Seite 453]
1.5.3.3.12 - References [Seite 454]
1.5.3.4 - 28 Bone-Targeted Alkaline Phosphatase [Seite 459]
1.5.3.4.1 - 28.1 Detailed Description of the Concept [Seite 459]
1.5.3.4.2 - 28.2 Technical Aspects [Seite 460]
1.5.3.4.3 - 28.3 Applications and Indications [Seite 462]
1.5.3.4.4 - 28.4 Preclinical and Clinical Research [Seite 463]
1.5.3.4.5 - 28.5 Alternatives/Variants of This Approach [Seite 464]
1.5.3.4.6 - 28.6 Challenges in Production and Development [Seite 466]
1.5.3.4.7 - 28.7 Conclusions and Future Perspectives [Seite 466]
1.5.3.4.8 - Acknowledgments [Seite 467]
1.5.3.4.9 - References [Seite 467]
1.5.3.5 - 29 Targeting Interferon-a to the Liver: Apolipoprotein A-I as a Scaffold for Protein Delivery [Seite 471]
1.5.3.5.1 - 29.1 Detailed Description of the Concept [Seite 471]
1.5.3.5.1.1 - 29.1.1 Interferons [Seite 471]
1.5.3.5.1.2 - 29.1.2 Stabilization of IFN-? [Seite 472]
1.5.3.5.1.3 - 29.1.3 IFN-? Liver Targeting [Seite 473]
1.5.3.5.1.4 - 29.1.4 Apolipoprotein A-I as a Scaffold for Peptide and Protein Delivery [Seite 474]
1.5.3.5.1.5 - 29.1.5 Stabilization and Liver Targeting of IFN-? by Apolipoprotein A-I [Seite 475]
1.5.3.5.1.6 - 29.1.6 Unexpected Properties of the Fusion Protein of Interferon-? and Apolipoprotein A-I [Seite 476]
1.5.3.5.2 - 29.2 Technological Aspects [Seite 477]
1.5.3.5.3 - 29.3 Typical Applications and Indications [Seite 477]
1.5.3.5.4 - 29.4 Alternatives and Variants of This Approach [Seite 478]
1.5.3.5.5 - 29.5 Conclusions and Future Perspectives [Seite 478]
1.5.3.5.6 - References [Seite 478]
1.6 - PART III BEYOND THE TRIPLE T-PARADIGM [Seite 483]
1.6.1 - IIIA NOVEL CONCEPTS, NOVEL SCAFFOLDS [Seite 485]
1.6.1.1 - 30 Signal Converter Proteins [Seite 485]
1.6.1.1.1 - 30.1 Introduction [Seite 485]
1.6.1.1.2 - 30.2 Historical Roots of Signal Conversion: Artificial Veto Cell Engineering and Protein Painting [Seite 485]
1.6.1.1.2.1 - 30.2.1 Artificial Veto Cell Engineering [Seite 486]
1.6.1.1.2.2 - 30.2.2 Protein Painting [Seite 487]
1.6.1.1.3 - 30.3 Trans Signal Converter Proteins [Seite 488]
1.6.1.1.4 - 30.4 Expanding Trans Signal Conversion Options: Redirecting Signals [Seite 489]
1.6.1.1.5 - 30.5 From Trans to Cis Signal Conversion: Driving Auto-Signaling [Seite 490]
1.6.1.1.6 - 30.6 Mechanistic Dividends of Chimerization [Seite 491]
1.6.1.1.7 - 30.7 Targeting Multiple Diseases with Individual Signal Converters [Seite 492]
1.6.1.1.8 - 30.8 Structural Constraints in SCP Design [Seite 493]
1.6.1.1.9 - 30.9 Coding SCP Functional Repertoires [Seite 493]
1.6.1.1.10 - 30.10 Expanding the Catalog of Inhibitory SCP [Seite 494]
1.6.1.1.11 - 30.11 Immune Activating SCP [Seite 496]
1.6.1.1.12 - 30.12 Experimental Tools for Screening SCP Candidates [Seite 497]
1.6.1.1.13 - 30.13 SCP Frontiers: Mining the Surface Protein Interactome, Rewiring Cellular Networks [Seite 497]
1.6.1.1.14 - References [Seite 498]
1.6.1.2 - 31 Soluble T-Cell Antigen Receptors [Seite 505]
1.6.1.2.1 - 31.1 Soluble T-cell Antigen Receptor (STAR) Fusion Technology and Utilities [Seite 505]
1.6.1.2.1.1 - 31.1.1 Three Domains Single-Chain TCR (scTCR) Format and scTCR-Fusions [Seite 506]
1.6.1.2.1.2 - 31.1.2 Mutagenesis and Multimerization for Improved Target Recognition [Seite 507]
1.6.1.2.2 - 31.2 Expression and Purification of Recombinant Star Fusion Proteins [Seite 507]
1.6.1.2.3 - 31.3 Clinical and Research Product Applications [Seite 508]
1.6.1.2.3.1 - 31.3.1 Cancer Therapeutics [Seite 508]
1.6.1.2.3.2 - 31.3.2 Viral Therapeutics [Seite 509]
1.6.1.2.3.3 - 31.3.3 Diagnostic and Research Applications [Seite 510]
1.6.1.2.4 - 31.4 Preclinical Testing Using Star Fusion Proteins [Seite 511]
1.6.1.2.4.1 - 31.4.1 Preclinical Efficacy, Pharmacokinetic, and Toxicity Studies [Seite 511]
1.6.1.2.4.2 - 31.4.2 Antitumor Mechanism-of-Action Studies of ALT-801 [Seite 513]
1.6.1.2.4.3 - 31.4.3 Preclinical Efficacy Studies of Anticancer p53 Specific scTCRIgG1 Fusion Proteins [Seite 515]
1.6.1.2.4.4 - 31.4.4 Evaluation of Combination p53-Specific STAR Fusion Protein and Chemotherapy Regimens in Tumor Efficacy Models [Seite 516]
1.6.1.2.5 - 31.5 Clinical Development of ALT-801 [Seite 517]
1.6.1.2.5.1 - 31.5.1 Monotherapy Clinical Study with ALT-801 [Seite 517]
1.6.1.2.5.2 - 31.5.2 ALT-801/Chemotherapy Phase II Studies [Seite 517]
1.6.1.2.6 - 31.6 Alternatives/Variants of This Approach [Seite 518]
1.6.1.2.6.1 - 31.6.1 Development of Novel TCR-Targeted IL-15 Superagonist Fusions [Seite 518]
1.6.1.2.6.2 - 31.6.2 Cell-Based Therapies [Seite 519]
1.6.1.2.7 - 31.7 Challenges [Seite 519]
1.6.1.2.8 - 31.8 Conclusions and Future Perspectives [Seite 520]
1.6.1.2.9 - Acknowledgments [Seite 520]
1.6.1.2.10 - References [Seite 520]
1.6.1.3 - 32 High-Affinity Monoclonal T-Cell Receptor (mTCR) Fusions [Seite 525]
1.6.1.3.1 - 32.1 Introduction: The T Cell Receptor (TCR) as a Targeting Molecule [Seite 525]
1.6.1.3.2 - 32.2 Engineered High-Affinity Monoclonal TCRs (mTCR) [Seite 527]
1.6.1.3.3 - 32.3 mTCR-Based Fusion Proteins for Therapeutic Applications [Seite 530]
1.6.1.3.4 - 32.4 Immune-Mobilizing Monoclonal TCRs Against Cancer (ImmTAC) [Seite 530]
1.6.1.3.5 - 32.5 Conclusions and Future Perspectives [Seite 533]
1.6.1.3.6 - Acknowledgments [Seite 534]
1.6.1.3.7 - References [Seite 534]
1.6.1.4 - 33 Amediplase [Seite 537]
1.6.1.4.1 - 33.1 Introduction [Seite 537]
1.6.1.4.2 - 33.2 Source, Physico-Chemical Properties and Formulation [Seite 538]
1.6.1.4.2.1 - 33.2.1 Production Cell Line [Seite 538]
1.6.1.4.2.2 - 33.2.2 Drug Substance [Seite 538]
1.6.1.4.2.3 - 33.2.3 Drug Product [Seite 539]
1.6.1.4.3 - 33.3 Preclinical Studies [Seite 540]
1.6.1.4.3.1 - 33.3.1 In Vitro Biological Properties [Seite 540]
1.6.1.4.3.1.1 - 33.3.1.1 Plasminogen Activator Activity [Seite 540]
1.6.1.4.3.1.2 - 33.3.1.2 In Vitro Thrombolytic Activity [Seite 540]
1.6.1.4.3.1.3 - 33.3.1.3 Fibrin Specificity [Seite 540]
1.6.1.4.3.1.4 - 33.3.1.4 Inhibition by Plasma Protease Inhibitors [Seite 540]
1.6.1.4.3.1.5 - 33.3.1.5 Binding to Fibrin [Seite 540]
1.6.1.4.3.1.6 - 33.3.1.6 Clot Penetration [Seite 540]
1.6.1.4.3.2 - 33.3.2 Pharmacodynamics: In Vivo Studies [Seite 541]
1.6.1.4.3.2.1 - 33.3.2.1 Thrombolytic Activity in Rabbits [Seite 541]
1.6.1.4.3.2.2 - 33.3.2.2 Thrombolytic and Haemorrhagic Effects in Rabbits [Seite 541]
1.6.1.4.3.2.3 - 33.3.2.3 Fibrinolytic Activity of Amediplase in Rats [Seite 541]
1.6.1.4.3.2.4 - 33.3.2.4 In Vivo Thrombolytic Activity of Amediplase in Dogs [Seite 541]
1.6.1.4.3.3 - 33.3.3 Pharmacokinetics [Seite 541]
1.6.1.4.3.3.1 - 33.3.3.1 Pharmacokinetics of Amediplase in Monkeys [Seite 541]
1.6.1.4.3.3.2 - 33.3.3.2 Pharmacokinetics of Amediplase in Rats [Seite 541]
1.6.1.4.3.3.3 - 33.3.3.3 The In Vivo Fate of Amediplase in Rats [Seite 542]
1.6.1.4.3.4 - 33.3.4 Toxicology [Seite 542]
1.6.1.4.4 - 33.4 Human Studies [Seite 542]
1.6.1.4.4.1 - 33.4.1 1K2 Study: A Phase I Single Ascending Dose Study [Seite 542]
1.6.1.4.4.2 - 33.4.2 2K2 Study: A Phase II, Multicenter, Open-Label, Dose-Finding, Pilot Study [Seite 543]
1.6.1.4.4.3 - 33.4.3 3K2 Study: A Double-Blind, Randomized, Parallel Group Study to Compare the Efficacy and Safety of Two Doses of Amediplase [Seite 544]
1.6.1.4.5 - 33.5 Historical Comparison with Other Thrombolytics [Seite 547]
1.6.1.4.6 - 33.6 Conclusions and Future Perspectives [Seite 547]
1.6.1.4.7 - Acknowledgment [Seite 547]
1.6.1.4.8 - References [Seite 547]
1.6.1.5 - 34 Breaking New Therapeutic Grounds: Fusion Proteins of Darpins and Other Nonantibody Binding Proteins [Seite 549]
1.6.1.5.1 - 34.1 Introduction [Seite 549]
1.6.1.5.2 - 34.2 Novel Scaffolds-Alternatives to Antibodies [Seite 549]
1.6.1.5.2.1 - 34.2.1 Success and Limitations of Antibodies [Seite 549]
1.6.1.5.2.2 - 34.2.2 Natural Binding Proteins [Seite 550]
1.6.1.5.2.3 - 34.2.3 Tailoring Nonantibody Binding Protein [Seite 551]
1.6.1.5.2.4 - 34.2.4 DARPins-Designed Ankyrin Repeat Proteins [Seite 552]
1.6.1.5.3 - 34.3 New Therapeutic Concepts with Nonantibody Binding Proteins [Seite 553]
1.6.1.5.3.1 - 34.3.1 Natural Fusion Protein Examples [Seite 553]
1.6.1.5.3.2 - 34.3.2 Fusion Proteins with Nonantibody Binding Proteins [Seite 553]
1.6.1.5.3.2.1 - 34.3.2.1 Bivalent and Bispecific Molecules [Seite 553]
1.6.1.5.3.2.2 - 34.3.2.2 Multispecific Constructs [Seite 554]
1.6.1.5.3.2.3 - 34.3.2.3 Critical Advantage of Multispecific Nonantibody Binding Proteins [Seite 555]
1.6.1.5.3.2.4 - 34.3.2.4 Combining Scaffolds with Other Effector Proteins [Seite 555]
1.6.1.5.4 - 34.4 Scaffold-Fusion Proteins Beyond Antibody Possibilities [Seite 555]
1.6.1.5.5 - Acknowledgments [Seite 556]
1.6.1.5.6 - References [Seite 556]
1.6.2 - IIIB MULTIFUNCTIONAL ANTIBODIES [Seite 559]
1.6.2.1 - 35 Resurgence of Bispecific Antibodies [Seite 559]
1.6.2.1.1 - 35.1 A Brief History of Bispecific Antibodies [Seite 559]
1.6.2.1.2 - 35.2 Asymmetric IgG-Like Bispecific Antibodies [Seite 560]
1.6.2.1.3 - 35.3 Symmetric IgG-Like Bispecific Antibodies [Seite 561]
1.6.2.1.4 - 35.4 IgG-Like Bispecific Antibodies with Fused Antibody Fragments [Seite 563]
1.6.2.1.5 - 35.5 Bispecific Constructs Based on the Fcg Fragment [Seite 564]
1.6.2.1.6 - 35.6 Bispecific Constructs Based on Fab Fragments [Seite 565]
1.6.2.1.7 - 35.7 Bispecific Constructs Based on Diabodies or Single-Chain Antibodies [Seite 566]
1.6.2.1.8 - 35.8 Bifunctional Fusions of Antibodies or Fragments with Other Proteins [Seite 568]
1.6.2.1.9 - 35.9 Bispecific Antibodies for Various Functions: How to Select the Right Format? [Seite 569]
1.6.2.1.10 - References [Seite 571]
1.6.2.2 - 36 Novel Applications of Bispecific DART1 Proteins [Seite 575]
1.6.2.2.1 - 36.1 Introduction [Seite 575]
1.6.2.2.2 - 36.2 DART® Proteins [Seite 576]
1.6.2.2.3 - 36.3 Application of DART® to Cross-Link Inhibitory and Activating Receptors [Seite 576]
1.6.2.2.4 - 36.4 Application of Bispecific Antibodies in Oncology [Seite 577]
1.6.2.2.4.1 - 36.4.1 CD16-Based DART® Proteins [Seite 577]
1.6.2.2.4.2 - 36.4.2 CD3/TCR-Based DART® Proteins [Seite 577]
1.6.2.2.5 - 36.5 U-DART Concept for Screening DART® Candidate Targets and mAbs [Seite 579]
1.6.2.2.6 - 36.6 U-DART Concept for Applications in Autoimmune and Inflammatory Disease [Seite 579]
1.6.2.2.6.1 - 36.6.1 Inhibition of Basophil Degranulation [Seite 583]
1.6.2.2.7 - 36.7 Conclusions and Future Perspectives [Seite 584]
1.6.2.2.8 - References [Seite 584]
1.6.2.3 - 37 Strand Exchange Engineered Domain (Seed): A Novel Platform Designed to Generate Mono and Multispecific Protein Therapeutics [Seite 587]
1.6.2.3.1 - 37.1 Introduction [Seite 587]
1.6.2.3.2 - 37.2 Technical Aspects [Seite 588]
1.6.2.3.2.1 - 37.2.1 Workflow [Seite 588]
1.6.2.3.2.2 - 37.2.2 Therapeutic Formats [Seite 590]
1.6.2.3.2.3 - 37.2.3 Biophysical Properties [Seite 591]
1.6.2.3.2.4 - 37.2.4 Biological Properties [Seite 592]
1.6.2.3.3 - 37.3 Potential Therapeutic Applications [Seite 592]
1.6.2.3.4 - 37.4 Future Perspectives [Seite 596]
1.6.2.3.5 - 37.5 Conclusions [Seite 597]
1.6.2.3.6 - Acknowledgments [Seite 597]
1.6.2.3.7 - References [Seite 597]
1.6.2.4 - 38 CovX-Bodies [Seite 601]
1.6.2.4.1 - 38.1 The CovX-Body Concept [Seite 601]
1.6.2.4.2 - 38.2 Technological Aspects [Seite 601]
1.6.2.4.2.1 - 38.2.1 Scaffold Antibody [Seite 601]
1.6.2.4.2.2 - 38.2.2 Linker Design [Seite 605]
1.6.2.4.2.3 - 38.2.3 Choice of Payload [Seite 607]
1.6.2.4.2.4 - 38.2.4 Manufacture, Process, Characterization [Seite 608]
1.6.2.4.3 - 38.3 Applications of the CovX-Body Technology [Seite 608]
1.6.2.4.3.1 - 38.3.1 CVX-060, a Selective Angiopoietin-2 Targeting CovX-Body [Seite 608]
1.6.2.4.3.2 - 38.3.2 CVX-241, an Example of a Bispecific Antibody [Seite 610]
1.6.2.4.3.3 - 38.3.3 CVX-343, Fusion of a Small Protein with CVX-2000 [Seite 611]
1.6.2.4.4 - References [Seite 611]
1.6.2.5 - 39 Modular Antibody Engineering: Antigen Binding Immunoglobulin Fc CH3 Domains as Building Blocks for Bispecific Antibodies (mAb2) [Seite 613]
1.6.2.5.1 - 39.1 Introduction [Seite 613]
1.6.2.5.2 - 39.2 Immunoglobulin Fc as a Scaffold [Seite 613]
1.6.2.5.3 - 39.3 Design of Libraries Based on the Human IgG1 CH3 Domain [Seite 614]
1.6.2.5.4 - 39.4 TNF-?-Binding Fcab: Selection and Characterization of Fcab TNF353-2 [Seite 615]
1.6.2.5.5 - 39.5 Conclusions and Future Perspectives [Seite 618]
1.6.2.5.6 - Acknowledgments [Seite 618]
1.6.2.5.7 - References [Seite 619]
1.6.2.6 - 40 Designer Fusion Modules for Building Multifunctional, Multivalent Antibodies, and Immunoconjugates: The Dock-and-Lock Method [Seite 621]
1.6.2.6.1 - 40.1 Introduction [Seite 621]
1.6.2.6.2 - 40.2 DDD/AD Modules Based on PKA and AKAP [Seite 622]
1.6.2.6.3 - 40.3 Advantages and Disadvantages of the DNL Method [Seite 622]
1.6.2.6.3.1 - 40.3.1 Advantages of the DNL Method [Seite 622]
1.6.2.6.3.2 - 40.3.2 Disadvantages of the DNL Method [Seite 623]
1.6.2.6.4 - 40.4 Fab-Based Modules [Seite 623]
1.6.2.6.5 - 40.5 IgG-AD2-Modules [Seite 624]
1.6.2.6.6 - 40.6 Hexavalent Antibodies [Seite 625]
1.6.2.6.7 - 40.7 More Antibody-Based-Modules and Multivalent Antibodies [Seite 626]
1.6.2.6.8 - 40.8 Nonantibody-Based DNL Modules [Seite 627]
1.6.2.6.9 - 40.9 IFN-a2b-DDD2 Module and Immunocytokines [Seite 627]
1.6.2.6.10 - 40.10 Variations on the DNLTheme [Seite 628]
1.6.2.6.10.1 - 40.10.1 Alternative Linker Modules [Seite 628]
1.6.2.6.10.2 - 40.10.2 Alternative Covalent Stabilization [Seite 628]
1.6.2.6.11 - 40.11 Conclusions and Future Perspective [Seite 629]
1.6.2.6.12 - References [Seite 629]
1.7 - INDEX [Seite 633]

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