SpringerLink Springer Biomedical and Life Sciences eBooks 2017 English+International

Incluye referencias bibliográficas e índice

Preface; The Complexity of ADCs and ITs; Contents; Chapter 1: Chemical Assembly of Antibody-Drug Conjugates; 1.1 Introduction; 1.2 Conjugation via Natural Amino Acid Residues; 1.2.1 Random Conjugation at Native Cysteine Residues; 1.2.2 Site-Specific Conjugation at Engineered Cysteine Residues; 1.2.3 Stabilization of Maleimide Linkage; 1.2.4 Hydrophilic Spacers; 1.2.5 Cysteine-Bridged Conjugation; 1.2.6 Site-Specific Conjugation at Engineered Selenocysteine Residues; 1.2.7 Random Conjugation at Native Lysine Residues; 1.2.7.1 Maytansinoid ADCs; 1.2.7.2 Calicheamicin ADCs.

1.3 Conjugation via Unnatural Amino Acids1.3.1 Site-Specific Conjugation at Engineered p-Acetyl-Phe Residues; 1.3.2 Site-Specific Conjugation at Engineered p-Azidomethyl-Phe Residues; 1.3.3 Site-Specific Conjugation at Engineered Formylglycine Residues; 1.4 Conclusions; References; Chapter 2: Preclinical Evaluation of ADCs Delivering Highly Potent Pyrrolobenzodiazepine (PBD) Dimers; 2.1 Background to the PBDs; 2.2 Antibody PBD Conjugates (APCs); 2.2.1 C2-Linked APCs; 2.2.2 N10-Linked APCs; 2.3 Emerging Clinical Data; 2.4 Properties and Advantages of APCs; 2.5 Conclusions; References.

4.2 Preclinical Activities of Inotuzumab Ozogamicin4.3 Preclinical and Clinical Experience with Gemtuzumab Ozogamicin; 4.4 Ephrin-A4 (EFNA4): A Novel Target for Calicheamicin Conjugates; 4.5 Antitumor Activity of the EFNA4-ADC Against CSCs in Triple Negative Breast Cancer (TNBC) and Ovarian Carcinomas (OVCA)PDX ... ; 4.6 Conclusions and Future Perspectives; References; Chapter 5: Enzyme-Based Strategies to Generate Site-Specifically Conjugated Antibody Drug Conjugates; 5.1 Introduction; 5.2 Enzymatic Conjugation Technologies Used for the Generation of Site-Specifically Conjugated ADCs.

5.2.1 Strategies Involving Bacterial Transglutaminase (BTG) Enzyme5.2.2 Use of Sortase Enzymes for Generating Homogeneous ADCs; 5.2.3 Formyl-glycine Converting Enzyme (FGE) Approach; 5.2.4 Split Inteins for Generating Site-Specifically Conjugated ADCs; 5.2.5 Glycan-Remodeling Approaches to Create Handles for Site-Specific Conjugation; 5.2.6 Other Enzymatic Approaches; 5.3 Conclusions; References; Chapter 6: Substance P-Saporin for the Treatment of Intractable Pain; 6.1 Introduction; 6.2 Animal and Human Tests of SP-SAP; 6.2.1 The Substance-P and Saporin Molecules.

Chapter 3: Stable and Homogeneous Drug Conjugation by Sequential Bis-Alkylation at Disulphide Bonds Using Bis-Sulphone Reagents3.1 Introduction; 3.2 Bis-Sulphone Reagents for Disulphide Bridging Conjugation; 3.3 Reagent; 3.4 ADC Characterisation; 3.4.1 ADC Stability; 3.5 In Vitro Potency; 3.6 In Vivo Efficacy; 3.7 Antibody Fragments; 3.8 Fab Drug Conjugates; 3.9 Imaging Applications; 3.10 Conclusion; References; Chapter 4: Calicheamicin Antibody-Drug Conjugates for Liquid and Solid Tumor Indications; 4.1 Mechanism of Action of Calicheamicin as an ADC Payload.

This book describes the newest developments in antibody drug conjugates and immunotoxins, paving their way to clinical application. Lessons learned from the current state of the art are used to further improve our understanding of their mechanisms of action and off target activities. The book introduces scientists to all of the prerequisites that must be properly addressed, including identification of the right target, specific traits of target binding antibodies, proper selection of the toxic payload, internalization induced by binding, and next generation conjugation and linker technologies. These knowledge-based, revolutionary new drug principles will form the cornerstone of the future standard of care and will lead to major advances in application, as well as improved quality of life and patient survival rates. This book will be of interest to biotech companies and researchers working in the fields of immunology, pharmacology, and oncology.