Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
4.7
4.6
Journals
Pharmaceuticals
Special Issues
Antibody-Drug Conjugates (ADC): 2021
share announcement

Antibody-Drug Conjugates (ADC): 2021

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Biopharmaceuticals".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 56839

Special Issue Editors

Dr. Nicolas Joubert

E-Mail Website
Guest Editor
1. EA 7501 GICC, Team IMT, Université de Tours - UFR de Médecine, Bâtiment Vialle, 7ème étage, 10 Bd Tonnellé, BP 3223, CEDEX 01, 37032 Tours, France
2. UMR1100 CEPR INSERM Université de Tours, Team Proteolytic mechanisms in inflammation, UFR de Médecine, 10 Bd Tonnellé, CEDEX, 37032 Tours, France
Interests: antibody–drug conjugates; bioconjugation; chemical biology; chemistry; breast cancer; anticancer drugs
Special Issues, Collections and Topics in MDPI journals
Dr. Caroline Denevault-Sabourin

E-Mail Website
Guest Editor
1. EA 7501 GICC, Team IMT, Université de Tours - UFR de Médecine, Bâtiment Vialle, 7ème étage, 10 Bd Tonnellé, BP 3223, CEDEX 01, 37032 Tours, France
2. UMR1100 CEPR INSERM Université de Tours, Team Proteolytic mechanisms in inflammation, UFR de Médecine, 10 Bd Tonnellé, CEDEX, 37032 Tours, France
Interests: medicinal chemistry; targeted therapies; antibody–drug conjugates; heterocyclic kinase inhibitors; anticancer drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The design of innovative anticancer chemotherapies with superior antitumor efficacy and reduced toxicity continues to be a challenging endeavor. More than a century ago, Paul Ehrlich, who won the Nobel Price of Medicine in 1908, came up with an original concept known as “the magic bullet”. His vision was to link a cytotoxic payload to an entity with selective affinity for a tumor, with the aim of achieving selective delivery of chemotherapeutic agents in the tumor environment and reducing systemic toxicity. Although this concept seems to be quite simple, its fine-tuning is fairly elaborate and still challenging today. Antibody–drug conjugates (ADCs) appear to be the ideal embodiment of Paul Ehrlich’s “magic bullet” vision—the combination of a potent cytotoxic agent (drug) with a therapeutic monoclonal antibody (mAb) via a suitably constructed spacer arm (linker). An ADC (or armed antibody) is thus a vectorized chemotherapy, harnessing both the high potency of the drug against the malignancy and the high specificity of the mAb for its target.

In the last decade, the ADC field of research has experienced a surge of interest, exploring various ADC features from the drug, its mechanism of action, its release mechanism, to the hydrophilic nature or the (site-specific) conjugation abilities of the linker, and the target or the format of the antibody. Currently, there are around 80 ADCs in clinical development, and even more in preclinical studies. With two approvals by the FDA at the end of 2019 and in 2020, there are now 9 ADCs successfully implemented in the clinic.

This Special Issue of Pharmaceuticals aims to collect contributions on recent trends and advances in the field of ADCs, specifically addressing novel strategies in bioconjugation, cancer therapy, targeting, mechanisms of release, payload mechanism, or antibody formats. We will propose a review spanning the last ten years of ADC research. We solicit contributions, research papers or reviews, on all topics connected to this research area, including, but not limited to:

  • Design, synthesis, analysis, and biological evaluations of antibody–drug conjugates;
  • Design, synthesis, analysis, and biological evaluations of protein–drug conjugates;
  • Design, synthesis, analysis, and biological evaluations of small molecule–drug conjugates;
  • Design, synthesis, analysis, and biological evaluations of radioimmunconjugates
  • New bioconjugation methods;
  • New mechanisms of action;
  • New format of conjugates;
  • New strategies to overcome resistance;
  • Case study on an ADC preferentially approved in 2019 or 2020 (e.g. Enhertu® or Polivy®)

Recently, the success of Adcetris®, Kadcyla®, Mylotarg®, Besponsa®, Polivy®, Padcev®, and Enhertu® have made antibody–drug conjugates (ADCs) serious contenders to reach the envied status of Paul Ehrlich's “magic bullet”. New strategies in development are promising a bright future for this exciting area of research.

Dr. Nicolas Joubert
Dr. Caroline Denevault-Sabourin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antibody–drug conjugates
  • protein-drug conjugates
  • small molecule–drug conjugates
  • targeted delivery
  • controlled release
  • cancer research

Related Special Issues

Published Papers (5 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

13 pages, 2874 KiB  
Article
State-of-the-Art Native Mass Spectrometry and Ion Mobility Methods to Monitor Homogeneous Site-Specific Antibody-Drug Conjugates Synthesis
by Evolène Deslignière, Anthony Ehkirch, Bastiaan L. Duivelshof, Hanna Toftevall, Jonathan Sjögren, Davy Guillarme, Valentina D’Atri, Alain Beck, Oscar Hernandez-Alba and Sarah Cianférani
Pharmaceuticals 2021, 14(6), 498; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060498 - 24 May 2021
Cited by 17 | Viewed by 4573
Abstract
Antibody-drug conjugates (ADCs) are biotherapeutics consisting of a tumor-targeting monoclonal antibody (mAb) linked covalently to a cytotoxic drug. Early generation ADCs were predominantly obtained through non-selective conjugation methods based on lysine and cysteine residues, resulting in heterogeneous populations with varying drug-to-antibody ratios (DAR). [...] Read more.
Antibody-drug conjugates (ADCs) are biotherapeutics consisting of a tumor-targeting monoclonal antibody (mAb) linked covalently to a cytotoxic drug. Early generation ADCs were predominantly obtained through non-selective conjugation methods based on lysine and cysteine residues, resulting in heterogeneous populations with varying drug-to-antibody ratios (DAR). Site-specific conjugation is one of the current challenges in ADC development, allowing for controlled conjugation and production of homogeneous ADCs. We report here the characterization of a site-specific DAR2 ADC generated with the GlyCLICK three-step process, which involves glycan-based enzymatic remodeling and click chemistry, using state-of-the-art native mass spectrometry (nMS) methods. The conjugation process was monitored with size exclusion chromatography coupled to nMS (SEC-nMS), which offered a straightforward identification and quantification of all reaction products, providing a direct snapshot of the ADC homogeneity. Benefits of SEC-nMS were further demonstrated for forced degradation studies, for which fragments generated upon thermal stress were clearly identified, with no deconjugation of the drug linker observed for the T-GlyGLICK-DM1 ADC. Lastly, innovative ion mobility-based collision-induced unfolding (CIU) approaches were used to assess the gas-phase behavior of compounds along the conjugation process, highlighting an increased resistance of the mAb against gas-phase unfolding upon drug conjugation. Altogether, these state-of-the-art nMS methods represent innovative approaches to investigate drug loading and distribution of last generation ADCs, their evolution during the bioconjugation process and their impact on gas-phase stabilities. We envision nMS and CIU methods to improve the conformational characterization of next generation-empowered mAb-derived products such as engineered nanobodies, bispecific ADCs or immunocytokines. Full article
(This article belongs to the Special Issue Antibody-Drug Conjugates (ADC): 2021)
►▼ Show Figures

Graphical abstract

17 pages, 2084 KiB  
Article
Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform
by Louise Conilh, Guy Fournet, Eric Fourmaux, Angélique Murcia, Eva-Laure Matera, Benoît Joseph, Charles Dumontet and Warren Viricel
Pharmaceuticals 2021, 14(3), 247; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030247 - 09 Mar 2021
Cited by 27 | Viewed by 13932
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Antibody-Drug Conjugates (ADC): 2021)
►▼ Show Figures

Figure 1

14 pages, 2540 KiB  
Article
Targeting and Efficacy of Novel mAb806-Antibody-Drug Conjugates in Malignant Mesothelioma
by Puey-Ling Chia, Sagun Parakh, Ming-Sound Tsao, Nhu-An Pham, Hui K. Gan, Diana Cao, Ingrid J. G. Burvenich, Angela Rigopoulos, Edward B. Reilly, Thomas John and Andrew M. Scott
Pharmaceuticals 2020, 13(10), 289; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13100289 - 02 Oct 2020
Cited by 9 | Viewed by 3350
Abstract
Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and [...] Read more.
Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and mAb806 epitope expressions in mesothelioma cell lines were evaluated using an array of binding assays, and the in vitro cell effects of ABT-414 and ABBV-322 were determined. In vivo therapy studies were conducted in mesothelioma xenograft and patient-derived xenograft (PDX) tumor models. We also performed biodistribution and imaging studies to allow the quantitative targeting of MM by mAb806 using a 89Zr-labeled immunoconjugate—ch806. A high EGFR expression was present in all mesothelioma cell lines evaluated and mAb806 binding present in all cell lines, except NCIH-2452. ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions. In contrast, in an EGFR-expressing PDX model that was negative for the mAb806 epitope, no growth inhibition was observed. We demonstrated the specific targeting of the mAb806 epitope expressing MM tumors using 89Zr-based PET imaging. Our data suggest that targeting EGFR in MM using specific ADCs is a valid therapeutic strategy and supports further investigation of the mAb806 epitope expression as a predictive biomarker. Full article
(This article belongs to the Special Issue Antibody-Drug Conjugates (ADC): 2021)
►▼ Show Figures

Graphical abstract

Review

Jump to: Research

16 pages, 1458 KiB  
Review
Analytical Methods for the Detection and Quantification of ADCs in Biological Matrices
by Héloïse Cahuzac and Laurent Devel
Pharmaceuticals 2020, 13(12), 462; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13120462 - 14 Dec 2020
Cited by 16 | Viewed by 5112
Abstract
Understanding pharmacokinetics and biodistribution of antibody–drug conjugates (ADCs) is a one of the critical steps enabling their successful development and optimization. Their complex structure combining large and small molecule characteristics brought out multiple bioanalytical methods to decipher the behavior and fate of both [...] Read more.
Understanding pharmacokinetics and biodistribution of antibody–drug conjugates (ADCs) is a one of the critical steps enabling their successful development and optimization. Their complex structure combining large and small molecule characteristics brought out multiple bioanalytical methods to decipher the behavior and fate of both components in vivo. In this respect, these methods must provide insights into different key elements including half-life and blood stability of the construct, premature release of the drug, whole-body biodistribution, and amount of the drug accumulated within the targeted pathological tissues, all of them being directly related to efficacy and safety of the ADC. In this review, we will focus on the main strategies enabling to quantify and characterize ADCs in biological matrices and discuss their associated technical challenges and current limitations. Full article
(This article belongs to the Special Issue Antibody-Drug Conjugates (ADC): 2021)
►▼ Show Figures

Figure 1

31 pages, 8076 KiB  
Review
Antibody–Drug Conjugates: The Last Decade
by Nicolas Joubert, Alain Beck, Charles Dumontet and Caroline Denevault-Sabourin
Pharmaceuticals 2020, 13(9), 245; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13090245 - 14 Sep 2020
Cited by 204 | Viewed by 26963
Abstract
An armed antibody (antibody–drug conjugate or ADC) is a vectorized chemotherapy, which results from the grafting of a cytotoxic agent onto a monoclonal antibody via a judiciously constructed spacer arm. ADCs have made considerable progress in 10 years. While in 2009 only gemtuzumab [...] Read more.
An armed antibody (antibody–drug conjugate or ADC) is a vectorized chemotherapy, which results from the grafting of a cytotoxic agent onto a monoclonal antibody via a judiciously constructed spacer arm. ADCs have made considerable progress in 10 years. While in 2009 only gemtuzumab ozogamicin (Mylotarg®) was used clinically, in 2020, 9 Food and Drug Administration (FDA)-approved ADCs are available, and more than 80 others are in active clinical studies. This review will focus on FDA-approved and late-stage ADCs, their limitations including their toxicity and associated resistance mechanisms, as well as new emerging strategies to address these issues and attempt to widen their therapeutic window. Finally, we will discuss their combination with conventional chemotherapy or checkpoint inhibitors, and their design for applications beyond oncology, to make ADCs the magic bullet that Paul Ehrlich dreamed of. Full article
(This article belongs to the Special Issue Antibody-Drug Conjugates (ADC): 2021)
►▼ Show Figures

Graphical abstract

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-5
Back to TopTop