Characterization of Maleimide Linkers in Antibody Drug Conjugates PDF Download

Author: Martyna Pawlikowska
Publisher:
ISBN:
Category : Antibody-drug conjugates
Languages : en
Pages : 164

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Book Description
Antibody Drug Conjugates (ADC's) are an emerging class of therapeutics that combine the targeting capability of a monoclonal antibody with the efficacy of a small molecule drug attached by a chemical linker. The two most common conjugation chemistries for attaching the linker-drug to the antibody are maleimide-to-hinge-region cysteines or activated ester-to-surface lysines. ... We assessed the rate of maleimide hydrolysis, aggregation of ADC's, and the efficacy of ADC's in various bioassays. Our results indicated that addition of the basic group to the MP linker and hydrolysis at pH9 with arginine is the optimal linker to move forward with in ADC development.

Author: Laurent Ducry
Publisher: Humana
ISBN: 9781493960262
Category : Medical
Languages : en
Pages : 0

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Book Description
Antibody-drug conjugates (ADCs) represent a promising therapeutic approach for cancer patients by combining the antigen-targeting specificity of monoclonal antibodies (mAbs) with the cytotoxic potency of chemotherapeutic drugs. In Antibody-Drug Conjugates, expert researchers provide detailed protocols for many of the key ADC techniques necessary for working in the field. These chapters and methodologies are aimed at the key tasks necessary to identify a suitable target, properly design the mAb, the linker and the payload, as well as to conjugate them in a reproducible and scalable fashion. Written in the highly successful Methods in Molecular BiologyTM format, these detailed chapters include the kind of practical implementation advice that guarantees quality results. Authoritative and timely, Antibody-Drug Conjugates aims to further drive ADC development and thus help toward improving cancer treatments of the future.

Author: Jeffrey Wang
Publisher: Springer
ISBN: 3319130811
Category : Medical
Languages : en
Pages : 248

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Book Description
This authoritative volume provides a holistic picture of antibody-drug conjugates (ADCs). Fourteen comprehensive chapters are divided into six sections including an introduction to ADCs, the ADC construct, development issues, landscape, IP and pharmacoeconomics, case studies, and the future of the field. The book examines everything from the selection of the antibody, the drug, and the linker to a discussion of developmental issues such as formulations, bio-analysis, pharmacokinetic-pharmacodynamic relationships, and toxicological and regulatory challenges. It also explores pharmacoecomonics and intellectual properties, including recently issued patents and the cost analysis of drug therapy. Case studies are presented for the three ADCs that have received FDA approval: gemtuzumab ozogamicin (Mylotarg®), Brentuximab vedotin (Adcetris®), and ado-trastuzumab emtansine (Kadcyla®), as well as an ADC in late-stage clinical trials, glembatumumab vedotin (CDX-011). Finally, the volume presents a perspective by the editors on the future directions of ADC development and clinical applications. Antibody-Drug Conjugates is a practical and systematic resource for scientists, professors, and students interested in expanding their knowledge of cutting-edge research in this exciting field.

Author: Kenneth J. Olivier, Jr.
Publisher: John Wiley & Sons
ISBN: 1119060842
Category : Medical
Languages : en
Pages : 567

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Book Description
Providing practical and proven solutions for antibody-drug conjugate (ADC) drug discovery success in oncology, this book helps readers improve the drug safety and therapeutic efficacy of ADCs to kill targeted tumor cells. • Discusses the basics, drug delivery strategies, pharmacology and toxicology, and regulatory approval strategies • Covers the conduct and design of oncology clinical trials and the use of ADCs for tumor imaging • Includes case studies of ADCs in oncology drug development • Features contributions from highly-regarded experts on the frontlines of ADC research and development

Author: Marc Damelin
Publisher: Springer
ISBN: 3319781545
Category : Medical
Languages : en
Pages : 358

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Book Description
Antibody-drug conjugates (ADCs) stand at the verge of a transformation. Scores of clinical programs have yielded only a few regulatory approvals, but a wave of technological innovation now empowers us to overcome past technical challenges. This volume focuses on the next generation of ADCs and the innovations that will enable them. The book inspires the future by integrating the field’s history with novel strategies and cutting-edge technologies. While the book primarily addresses ADCs for solid tumors, the last chapter explores the emerging interest in using ADCs to treat other diseases. The therapeutic rationale of ADCs is strong: to direct small molecules to the desired site of action (and away from normal tissues) by conjugation to antibodies or other targeting moieties. However, the combination of small and large molecules imposes deep complexity to lead optimization, pharmacokinetics, toxicology, analytics and manufacturing. The field has made significant advances in all of these areas by improving target selection, ADC design, manufacturing methods and clinical strategies. These innovations will inspire and educate scientists who are designing next-generation ADCs with the potential to transform the lives of patients.

Author: David E Thurston
Publisher: Royal Society of Chemistry
ISBN: 1788018451
Category : Medical
Languages : en
Pages : 502

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Book Description
Antibody–drug conjugates (ADCs) represent one of the most promising and exciting areas of anticancer drug discovery. Five ADCs are now approved in the US and EU [i.e., ado-trastuzumab emtansine (KadcylaTM), brentuximab vedotin (AdcetrisTM), inotuzumab ozogamicin (BesponsaTM), gemtuzumab ozogamicin (MylotargTM) and moxetumomab pasudotox-tdfk (Lumoxiti®)] and over 70 others are in various stages of clinical development, with impressive interim results being reported for many. The technology is based on the concept of delivering a cytotoxic payload selectively to cancer cells by attaching it to an antibody targeted to antigens on the cell surfaces. This approach has several advantages including the ability to select patients as likely responders based on the presence of antigen on the surface of their cancer cells and a wider therapeutic index, given that ADC targeting enables a more efficient delivery of cytotoxic agents to cancer cells than can be achieved by conventional chemotherapy, thus minimising systemic toxicity. Although there are many examples of antibodies that have been developed for this purpose, along with numerous linker technologies used to attach the cytotoxic agent to the antibody, there is presently a relatively small number of payload molecules in clinical use. The purpose of this book is to describe the variety of payloads used to date, along with a discussion of their advantages and disadvantages and to provide information on novel payloads at the research stage that may be used clinically in the future.

Author: Wenkui Li
Publisher: John Wiley & Sons
ISBN: 111927429X
Category : Science
Languages : en
Pages : 384

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Book Description
Revised and Expanded Handbook Provides Comprehensive Introduction and Complete Instruction for Sample Preparation in Vital Category of Bioanalysis Following in the footsteps of the previously published Handbook of LC-MS Bioanalysis, this book is a thorough and timely guide to all important sample preparation techniques used for quantitative Liquid Chromatography–Mass Spectrometry (LC-MS) bioanalysis of small and large molecules. LC-MS bioanalysis is a key element of pharmaceutical research and development, post-approval therapeutic drug monitoring, and many other studies used in human healthcare. While advances are continually being made in key aspects of LC-MS bioanalysis such as sensitivity and throughput, the value of research/study mentioned above is still heavily dependent on the availability of high-quality data, for which sample preparation plays the critical role. Thus, this text provides researchers in industry, academia, and regulatory agencies with detailed sample preparation techniques and step-by-step protocols on proper extraction of various analyte(s) of interest from biological samples for LC-MS quantification, in accordance with current health authority regulations and industry best practices. The three sections of the book with a total of 26 chapters cover topics that include: Current basic sample preparation techniques (e.g., protein precipitation, liquid-liquid extraction, solid-phase extraction, salting-out assisted liquid-liquid extraction, ultracentrifugation and ultrafiltration, microsampling, sample extraction via electromembranes) Sample preparation techniques for uncommon biological matrices (e.g., tissues, hair, skin, nails, bones, mononuclear cells, cerebrospinal fluid, aqueous humor) Crucial aspects of LC-MS bioanalytical method development (e.g., pre-analytical considerations, derivation strategies, stability, non-specific binding) in addition to sample preparation techniques for challenging molecules (e.g., lipids, peptides, proteins, oligonucleotides, antibody-drug conjugates) Sample Preparation in LC-MS Bioanalysis will prove a practical and highly valuable addition to the reference shelves of scientists and related professionals in a variety of fields, including pharmaceutical and biomedical research, mass spectrometry, and analytical chemistry, as well as practitioners in clinical pharmacology, toxicology, and therapeutic drug monitoring.

Author: Greg T. Hermanson
Publisher: Academic Press
ISBN: 0080568726
Category : Science
Languages : en
Pages : 1233

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Book Description
Bioconjugate Techniques, 2nd Edition, is the essential guide to the modification and cross linking of biomolecules for use in research, diagnostics, and therapeutics. It provides highly detailed information on the chemistry, reagent systems, and practical applications for creating labeled or conjugate molecules. It also describes dozens of reactions with details on hundreds of commercially available reagents and the use of these reagents for modifying or cross linking peptides and proteins, sugars and polysaccharides, nucleic acids and oligonucleotides, lipids, and synthetic polymers. A one-stop source for proven methods and protocols for synthesizing bioconjugates in the lab Step-by-step presentation makes the book an ideal source for researchers who are less familiar with the synthesis of bioconjugates More than 600 figures that visually describe the complex reactions associated with the synthesis of bioconjugates Includes entirely new chapters on the latest areas in the field of bioconjugation as follows: Microparticles and nanoparticlesSilane coupling agentsDendrimers and dendronsChemoselective ligationQuantum dotsLanthanide chelatesCyanine dyesDiscrete PEG compoundsBuckyballs,fullerenes, and carbon nanotubesMass tags and isotope tagsBioconjugation in the study of protein interactions

Author: Yanyan Li
Publisher: Springer
ISBN: 1493910108
Category : Medical
Languages : en
Pages : 113

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Book Description
Lasso peptides form a growing family of fascinating ribosomally-synthesized and post-translationally modified peptides produced by bacteria. They contain 15 to 24 residues and share a unique interlocked topology that involves an N-terminal 7 to 9-residue macrolactam ring where the C-terminal tail is threaded and irreversibly trapped. The ring results from the condensation of the N-terminal amino group with a side-chain carboxylate of a glutamate at position 8 or 9, or an aspartate at position 7, 8 or 9. The trapping of the tail involves bulky amino acids located in the tail below and above the ring and/or disulfide bridges connecting the ring and the tail. Lasso peptides are subdivided into three subtypes depending on the absence (class II) or presence of one (class III) or two (class I) disulfide bridges. The lasso topology results in highly compact structures that give to lasso peptides an extraordinary stability towards both protease degradation and denaturing conditions. Lasso peptides are generally receptor antagonists, enzyme inhibitors and/or antibacterial or antiviral (anti-HIV) agents. The lasso scaffold and the associated biological activities shown by lasso peptides on different key targets make them promising molecules with high therapeutic potential. Their application in drug design has been exemplified by the development of an integrin antagonist based on a lasso peptide scaffold. The biosynthesis machinery of lasso peptides is therefore of high biotechnological interest, especially since such highly compact and stable structures have to date revealed inaccessible by peptide synthesis. Lasso peptides are produced from a linear precursor LasA, which undergoes a maturation process involving several steps, in particular cleavage of the leader peptide and cyclization. The post-translational modifications are ensured by a dedicated enzymatic machinery, which is composed of an ATP-dependent cysteine protease (LasB) and a lactam synthetase (LasC) that form an enzymatic complex called lasso synthetase. Microcin J25, produced by Escherichia coli AY25, is the archetype of lasso peptides and the most extensively studied. To date only around forty lasso peptides have been isolated, but genome mining approaches have revealed that they are widely distributed among Proteobacteria and Actinobacteria, particularly in Streptomyces, making available a rich resource of novel lasso peptides and enzyme machineries towards lasso topologies.

Author: L. Nathan Tumey
Publisher:
ISBN: 9781493999316
Category : Immunoglobulins
Languages : en
Pages : 373

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Book Description
This volume looks at key methodologies that are commonly used across antibody drug conjugates (ADCs) programs. The chapters in this book cover topics such as conjugations to endogenous cysteine residues; click chemistry conjugations; antibody conjugations via glycosyl remodeling; analysis of ADCs by native mass spectrometry; characterization of ADCs by capillary electrophoresis; LC/MS methods for studying lysosomal ADC catabolism; and determination of ADC concentration by ligand-binding assays. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and practical, Antibody-Drug Conjugates: Methods and Protocols is a valuable resource that aims to lower the "activation barrier" when undertaking a new discipline, and provides a "toolbox" for the next generation of ADC scientists.