Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Monodisperse polysarcosine-based highly-loaded antibody-drug conjugates.

ABSTRACT: Antibody-drug conjugates (ADCs) convey highly potent anticancer drugs to antigen-expressing tumor cells, thereby sparing healthy tissues throughout the body. Pharmacokinetics and tolerability of ADCs are predominantly influenced by the drug-antibody ratio (DAR) of the conjugates, which is to-date limited to a value of 3-4 drugs per antibody in ADCs under clinical investigations. Here, we report the synthesis of monodisperse (i.e. discrete) polysarcosine compounds and their use as a hydrophobicity masking entity for the construction of highly-loaded homogeneous ?-glucuronidase-responsive antibody-drug conjugates (ADCs). The highly hydrophilic drug-linker platform described herein improves drug-loading, physicochemical properties, pharmacokinetics and in vivo antitumor efficacy of the resulting conjugates.

SUBMITTER: Viricel W

PROVIDER: S-EPMC6457330 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Monodisperse polysarcosine-based highly-loaded antibody-drug conjugates.

Viricel Warren W Fournet Guy G Beaumel Sabine S Perrial Emeline E Papot Sébastien S Dumontet Charles C Joseph Benoît B

Chemical science 20190306 14

Antibody-drug conjugates (ADCs) convey highly potent anticancer drugs to antigen-expressing tumor cells, thereby sparing healthy tissues throughout the body. Pharmacokinetics and tolerability of ADCs are predominantly influenced by the drug-antibody ratio (DAR) of the conjugates, which is to-date limited to a value of 3-4 drugs per antibody in ADCs under clinical investigations. Here, we report the synthesis of monodisperse (<i>i.e.</i> discrete) polysarcosine compounds and their use as a hydrop ...[more]

PMID: 31015945

Similar Datasets

Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform.

Project description:We herein report the development and evaluation of a novel HER2-targeting antibody-drug conjugate (ADC) based on the topoisomerase I inhibitor payload exatecan, using our hydrophilic monodisperse polysarcosine (PSAR) drug-linker platform (PSARlink). In vitro and in vivo experiments were conducted in breast and gastric cancer models to characterize this original ADC and gain insight about the drug-linker structure-activity relationship. The inclusion of the PSAR hydrophobicity masking entity efficiently reduced the overall hydrophobicity of the conjugate and yielded an ADC sharing the same pharmacokinetic profile as the unconjugated antibody despite the high drug-load of the camptothecin-derived payload (drug-antibody ratio of 8). Tra-Exa-PSAR10 demonstrated strong anti-tumor activity at 1 mg/kg in an NCI-N87 xenograft model, outperforming the FDA-approved ADC DS-8201a (Enhertu), while being well tolerated in mice at a dose of 100 mg/kg. In vitro experiments showed that this exatecan-based ADC demonstrated higher bystander killing effect than DS-8201a and overcame resistance to T-DM1 (Kadcyla) in preclinical HER2+ breast and esophageal models, suggesting potential activity in heterogeneous and resistant tumors. In summary, the polysarcosine-based hydrophobicity masking approach allowsfor the generation of highly conjugated exatecan-based ADCs having excellent physicochemical properties, an improved pharmacokinetic profile, and potent in vivo anti-tumor activity.

| S-EPMC8000490 | biostudies-literature

Microtubule inhibitor-based antibody-drug conjugates for cancer therapy.

Project description:The specificity of monoclonal antibodies represents a potential therapeutic advantage, but their use as single agents in oncology has proven limited to date. The development of antibody-drug conjugates (ADCs) takes advantage of the specificity of the monoclonal antibody and potent cytotoxic effect of chemotherapy, leading to enhanced cytotoxicity in target cells and limiting toxicity to normal tissue. Microtubules represent a validated oncologic target in a range of tumor types, with a number of anti-microtubule targeting cytotoxic drugs approved for cancer use. The systemic use of potent microtubule-binding agents is limited by their effects in normal cells, which leads to toxicity including myelosuppression and peripheral neuropathy. Linking these agents to monoclonal antibodies may limit toxicity to normal tissues and increase drug concentration in target tissues, also allowing the use of more potent agents which would be too toxic to administer in their unbound form. Two such ADCs have been approved for clinical use and many others are in development. Here we review the characteristics of each of the ADC components that have led to efficacious therapies and discuss some of the tubulin inhibitor-based ADCs in development for cancer therapy.

| S-EPMC4259504 | biostudies-other

Aptamer-Drug Conjugates-loaded Bacteria for Pancreatic Cancer Synergistic Therapy

Project description:Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of Salmonella typhimurium, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose an approach to synergistic therapy that utilizes the penetrative capability of bacteria and the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 via straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer's specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 hours and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer's targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment.

2024-09-18 | GSE276051 | GEO

The Potential of Topoisomerase Inhibitor-Based Antibody-Drug Conjugates.

Project description:DNA topoisomerases are essential enzymes that stabilize DNA supercoiling and resolve entanglements. Topoisomerase inhibitors have been widely used as anti-cancer drugs for the past 20 years. Due to their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs. To increase accumulation of TOP1 inhibitors in cancer cells through the targeting of tumors, TOP1 inhibitor antibody-drug conjugates (TOP1-ADC) have been developed and marketed. Some TOP1-ADCs have shown enhanced therapeutic efficacy compared to prototypical anti-cancer ADCs, such as T-DM1. Here, we review various types of camptothecin-based TOP1 inhibitors and recent developments in TOP1-ADCs. We then propose key points for the design and construction of TOP1-ADCs. Finally, we discuss promising combinatorial strategies, including newly developed approaches to maximizing the therapeutic potential of TOP1-ADCs.

| S-EPMC9413092 | biostudies-literature

Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy.

Project description:Antibody-drug conjugates (ADCs) are a class of highly potent biopharmaceutical drugs generated by conjugating cytotoxic drugs with specific monoclonal antibodies through appropriate linkers. Specific antibodies used to guide potent warheads to tumor tissues can effectively reduce undesired side effects of the cytotoxic drugs. An in-depth understanding of antibodies, linkers, conjugation strategies, cytotoxic drugs, and their molecular targets has led to the successful development of several approved ADCs. These ADCs are powerful therapeutics for cancer treatment, enabling wider therapeutic windows, improved pharmacokinetic/pharmacodynamic properties, and enhanced efficacy. Since tubulin inhibitors are one of the most successful cytotoxic drugs in the ADC armamentarium, this review focuses on the progress in tubulin inhibitor-based ADCs, as well as lessons learned from the unsuccessful ADCs containing tubulin inhibitors. This review should be helpful to facilitate future development of new generations of tubulin inhibitor-based ADCs for cancer therapy.

| S-EPMC6152078 | biostudies-literature

DNA damaging agent-based antibody-drug conjugates for cancer therapy.

Project description:Currently, four antibody-drug conjugates (ADCs) are approved by the Food and Drug Administration or the European Medicine Agency to treat cancer patients. More than 60 ADCs are in clinical development for cancer therapy. More than 60% of ADCs in clinical trials employ microtubule inhibitors as their payloads. A better understanding of payloads other than microtubule inhibitors, especially DNA-damaging agents, is important for further development of ADCs. In this review, we highlight an emerging trend of using DNA-damaging agents as payloads for ADCs. This review summarizes recent advances in our understanding gained from ongoing clinical studies; it will help to define the utility of DNA-damaging payloads for ADCs as cancer therapeutics. Future directions of the development of ADCs are also discussed, focusing on targeting drug resistance and combination treatment with immunotherapy.

| S-EPMC6161754 | biostudies-literature

A Versatile Chemo-Enzymatic Conjugation Approach Yields Homogeneous and Highly Potent Antibody-Drug Conjugates.

Project description:The therapeutic efficacy of antibodies can be successfully improved through targeted delivery of potent cytotoxic drugs in the form of antibody-drug conjugates. However, conventional conjugation strategies lead to heterogeneous conjugates with undefined stoichiometry and sites, even with considerable batch-to-batch variability. In this study, we have developed a chemo-enzymatic strategy by equipping the C-terminus of anti-CD20 ofatumumab with a click handle using Sortase A, followed by ligation of the payload based on a strain-promoted azide-alkyne cycloaddition to produce homogeneous conjugates. The resulting antibody-drug conjugates fully retained their antigen binding capability and proved to be internalized and trafficked to the lysosome, which released the payload with a favorable efficacy in vitro and in vivo. Thus, this reported method is a versatile tool with maximum flexibility for development of antibody-drug conjugates and protein modification.

| S-EPMC5713254 | biostudies-literature

Antibody-Drug Conjugates in Bladder Cancer.

Project description:Urothelial carcinoma (UC) is characterized by expression of a plethora of cell surface antigens, thus offering opportunities for specific therapeutic targeting with use of antibody-drug conjugates (ADCs). ADCs are structured from two major constituents, a monoclonal antibody (mAb) against a specific target and a cytotoxic drug connected via a linker molecule. Several ADCs are developed against different UC surface markers, but the ones at most advanced stages of development include sacituzumab govitecan (IMMU-132), enfortumab vedotin (ASG-22CE/ASG-22ME), ASG-15ME for advanced UC, and oportuzumab monatox (VB4-845) for early UC. Several new targets are identified and utilized for novel or existing ADC testing. The most promising ones include human epidermal growth factor receptor 2 (HER2) and members of the fibroblast growth factor receptor axis (FGF/FGFR). Positive preclinical and early clinical results are reported in many cases, thus the next step involves further improving efficacy and reducing toxicity as well as testing combination strategies with approved agents.

| S-EPMC6087439 | biostudies-literature

Antibody-drug conjugates: Intellectual property considerations.

Project description:Antibody-drug conjugates are highly complex entities that combine an antibody, a linker and a toxin. This complexity makes them demanding both technically and from a regulatory point of view, and difficult to deal with in their patent aspects. This article discusses different issues of patent protection and freedom to operate with regard to this promising new class of drugs.

| S-EPMC4966491 | biostudies-literature

Antibody-Drug Conjugates for Cancer Therapy.

Project description:Antibody-drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.

| S-EPMC7587605 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data