Abstract
The recent approval of trastuzumab emtansine (Kadcyla®) and brentuximab vedotin (Adcetris ®) has spurred tremendous investment in new approaches for the targeted delivery of pharmaceutical agents. Targeted delivery approaches, such as Antibody Drug Conjugates (ADCs), typically rely on an endogenous or exogenous “trigger” that results in the release of the pharmacologically active agent at the intended site of action. Lysosomal and intracellular triggers include proteolytic cleavage, glycolytic cleavage, phosphatase cleavage, hydrolytic cleavage, and reductive cleavage. Recent work has also illustrated that exogenous triggers and extracellular enzymes can be harnessed to result in linker cleavage at the site of action. As these linker technologies have grown, so also has our understanding of the biophysical parameters that drive exposure and stability. The growth in targeted delivery approaches has also driven advancement in bioanalytical strategies for assessing the distribution, processing, and metabolism of these agents. This review provides a systematic overview of each of these areas, particularly focusing on recent advancements in the field that has the potential to expand the scope of therapeutic areas that ADCs and other targeted delivery approaches can be designed to address.
Keywords: Brentuximab vedotin, antibody drug conjugates, glycolytic cleavage, phosphatase cleavage, hydrolytic cleavage, reductive cleavage.
Current Topics in Medicinal Chemistry
Title:ADME Considerations for the Development of Biopharmaceutical Conjugates Using Cleavable Linkers
Volume: 17 Issue: 32
Author(s): L. Nathan Tumey*Sean Han
Affiliation:
- School of Pharmacy and Pharmaceutical Sciences, Binghamton University, PO Box 6000, Binghamton, NY 13902- 6000,United States
Keywords: Brentuximab vedotin, antibody drug conjugates, glycolytic cleavage, phosphatase cleavage, hydrolytic cleavage, reductive cleavage.
Abstract: The recent approval of trastuzumab emtansine (Kadcyla®) and brentuximab vedotin (Adcetris ®) has spurred tremendous investment in new approaches for the targeted delivery of pharmaceutical agents. Targeted delivery approaches, such as Antibody Drug Conjugates (ADCs), typically rely on an endogenous or exogenous “trigger” that results in the release of the pharmacologically active agent at the intended site of action. Lysosomal and intracellular triggers include proteolytic cleavage, glycolytic cleavage, phosphatase cleavage, hydrolytic cleavage, and reductive cleavage. Recent work has also illustrated that exogenous triggers and extracellular enzymes can be harnessed to result in linker cleavage at the site of action. As these linker technologies have grown, so also has our understanding of the biophysical parameters that drive exposure and stability. The growth in targeted delivery approaches has also driven advancement in bioanalytical strategies for assessing the distribution, processing, and metabolism of these agents. This review provides a systematic overview of each of these areas, particularly focusing on recent advancements in the field that has the potential to expand the scope of therapeutic areas that ADCs and other targeted delivery approaches can be designed to address.
Export Options
About this article
Cite this article as:
Tumey Nathan L. *, Han Sean, ADME Considerations for the Development of Biopharmaceutical Conjugates Using Cleavable Linkers, Current Topics in Medicinal Chemistry 2017; 17 (32) . https://dx.doi.org/10.2174/1568026618666180118154017
DOI https://dx.doi.org/10.2174/1568026618666180118154017 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
From Natural Products to Small Molecule Ketone Histone Deacetylase Inhibitors: Development of New Class Specific Agents
Current Pharmaceutical Design A Modified Teaching-Learning-Based Optimization (mTLBO) for Global Search
Recent Patents on Computer Science The Pilot Phase of the NIH Chemical Genomics Center
Current Topics in Medicinal Chemistry Post-Translational Protein Modifications of Rare and Unconventional Types: Implications in Functions and Diseases
Current Medicinal Chemistry Plasma Proteins Interaction with Curcumin Nanoparticles: Implications in Cancer Therapeutics
Current Drug Metabolism Antipsoriatic Drug Development: Challenges and New Emerging Therapies
Recent Patents on Inflammation & Allergy Drug Discovery The Importance and Evolution of Radiation Dose in DCIS
Current Cancer Therapy Reviews Meet Our Editorial Board Member
Combinatorial Chemistry & High Throughput Screening The Role of Drug Transporters in the Pharmacokinetics of Antibiotics
Current Drug Metabolism Design and Green Synthesis of Thieno[2,3-d]pyrimidine Analogues as Potential Antiproliferative Agents
Anti-Cancer Agents in Medicinal Chemistry Migration and Function of Th17 Cells
Inflammation & Allergy - Drug Targets (Discontinued) Chemoprevention of Skin Cancer: Effect of Lawsonia inermis L. (Henna) Leaf Powder and its Pigment Artifact, Lawsone in the Epstein- Barr Virus Early Antigen Activation Assay and in Two-Stage Mouse Skin Carcinogenesis Models
Anti-Cancer Agents in Medicinal Chemistry Glucosamine Protects Rat Bone Marrow Cells Against Cisplatin-induced Genotoxicity and Cytotoxicity
Anti-Cancer Agents in Medicinal Chemistry Synthesis and Evaluation of Cytotoxic Activity of Some Pyrroles and Fused Pyrroles
Anti-Cancer Agents in Medicinal Chemistry Potential Anticancer Agents. I. Synthesis of Isoxazole Moiety Containing Quinazoline Derivatives and Preliminarily in vitro Anticancer Activity
Anti-Cancer Agents in Medicinal Chemistry Development of Hedgehog Pathway Inhibitors (HPI) in Treatment of Cancer
Current Chemical Biology Modulation of Cellular Function by TAT Mediated Transduction of Full Length Proteins
Current Protein & Peptide Science Molecular Bases of Liver Cancer Refractoriness to Pharmacological Treatment
Current Medicinal Chemistry Label-Free Cell Phenotypic Drug Discovery
Combinatorial Chemistry & High Throughput Screening Anthracyclines Still Prove Effective in Anticancer Therapy
Mini-Reviews in Medicinal Chemistry