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Pharmaceutics
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Antibody Drug Conjugates: Unlocking the Future of Immunotherapies
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Antibody Drug Conjugates: Unlocking the Future of Immunotherapies

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biologics and Biosimilars".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 31562

Special Issue Editors

Prof. Dr. Deyarina Gonzalez

E-Mail Website
Guest Editor
Medical School, Swansea University, Singleton Park, Swansea SA2 8PP, UK
Interests: targetted therapies; antibody drug conjugates; oncology; female infertily; functional genomics; 3D patient-derived multicellular models; exosomes; tumor microenvironment; drug development characterisation platforms
Prof. Dr. R. Steven Conlan

E-Mail Website
Guest Editor
Medical School, Swansea University, Singleton Park, Swansea SA2 8PP, UK
Interests: cancer drug discovery; epigenomics; nanomedicines; antibody drug conjugates; exosomes; pre-clinical models; AI; functional genomics; nanosensors

Special Issue Information

Dear Colleagues,

Antibody Drug Conjugates (ADC) are quintessential example of advanced biopharmaceutical therapies. These targeted nanomedicines use the specificity of monoclonal antibodies to guide highly potent cytotoxic payloads to specific target cell. The resulting ADCs have a broader therapeutic window than their potent payloads while sparing healthy cells. Currently there are 12 ADCs approved for the treatment of haematological and solid tumour malignancies including: ado-trastuzumab emtansine (Kadcyla™), brentuximab vedotin (Adcetris™), inotuzumab ozogamicin (Besponsa™), gemtuzumab ozogamicin (Mylotarg™) , Moxetumomab pasudotox (Lumoxiti™), polatuzumab vedotin-piiq (Polivy™), Enfortumab vedotin (Padcev™), Sacituzumab govitecan (Trodelvy), Trastuzumab deruxtecan (Enhertu™), belantamab mafodotin-blmf (Blenrep™) , loncastuximab tesirine-lpyl (ZYNLONTA™), and totoaba vedotin-tftv (Tivdak). The field of ADC development is further growing in strength with more than 100 ADCs currently being investigated at either preclinical phase or at clinical trials. 

Despite growing interest in this complex biopharmaceutical modality challenges remain to improve ADC quality, safety, and efficacy.

This Special Issue of Pharmaceutics will focus on recent advances in ADC development from ADC design including identification of new targets, antibody selection, development of new conjugation and linker chemistry technologies, novel payloads and mechanism of action, ADC characterisation platforms, to ADC preclinical characterisation including pharmacokinetics, pharmacodynamics, biodistribution, toxicity and efficacy studies and clinical studies looking at oncology and non-oncology applications. In addition, studies looking at development of small molecular conjugates and bispecifics and the use of artificial intelligence (AI) to drive the development of ADC technologies are encouraged. Review articles should be focused in addressing limitations in the field and discussing successful and discontinued ADCs as lessons learned.

Prof. Dr. Deyarina Gonzalez
Prof. Dr. R. Steven Conlan
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. Pharmaceutics 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
  • bispecifics
  • target antigens
  • conjugation technologies
  • artificial intelligence
  • ADC payloads
  • clinical trials
  • preclinical development

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Published Papers (6 papers)

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Research

Jump to: Review

22 pages, 4753 KiB  
Article
MiR-126-Loaded Immunoliposomes against Vascular Endothelial Inflammation In Vitro and Vivo Evaluation
by Yongyu Tang, Ying Chen, Qianqian Guo, Lidan Zhang, Huanhuan Liu, Sibu Wang, Xingjie Wu, Xiangchun Shen and Ling Tao
Pharmaceutics 2023, 15(5), 1379; https://doi.org/10.3390/pharmaceutics15051379 - 30 Apr 2023
Cited by 8 | Viewed by 2115
Abstract
Due to the accompaniment of vascular endothelial inflammation during the occurrence and development of cardiovascular diseases (CVD), treatment modalities against vascular endothelial inflammation have been intensively investigated for CVD prevention and/or treatment. Vascular cell adhesion molecule-1 (VCAM-1) is a typical transmembrane inflammatory protein [...] Read more.
Due to the accompaniment of vascular endothelial inflammation during the occurrence and development of cardiovascular diseases (CVD), treatment modalities against vascular endothelial inflammation have been intensively investigated for CVD prevention and/or treatment. Vascular cell adhesion molecule-1 (VCAM-1) is a typical transmembrane inflammatory protein specifically expressed by inflammatory vascular endothelial. By inhibiting VCAM-1 expression through the miR-126 mediated pathway, vascular endothelial inflammation can be efficiently relieved. Inspired by this, we developed a miR-126-loaded immunoliposome with VCAM-1 monoclonal antibody (VCAMab) decorated at its surface. This immunoliposome can be directly targeted to VCAM-1 at the inflammatory vascular endothelial membrane surface and achieve highly efficient treatment against inflammation response. The cellular experiment results showed the immunoliposome had a higher uptake rate towards inflammatory human vein endothelial cells (HUVECs) and can significantly downregulate the VCAM-1 expression level of inflammatory HUVECs. In vivo investigation further demonstrated that this immunoliposome displayed a higher accumulation rate at vascular inflammatory dysfunction sites than its non-VCAMab-modified counterpart. These results suggest that this novel nanoplatform can effectively deliver miR-126 to vascular inflammatory endothelium, opening a new avenue for the safe and effective delivery of miRNA for potential clinical application. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates: Unlocking the Future of Immunotherapies)
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30 pages, 5222 KiB  
Article
Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes
by Hsuan-Ping Chang, Huyen Khanh Le and Dhaval K. Shah
Pharmaceutics 2023, 15(4), 1132; https://doi.org/10.3390/pharmaceutics15041132 - 3 Apr 2023
Cited by 7 | Viewed by 10423
Abstract
We hypothesize that different routes of administration may lead to altered pharmacokinetics/pharmacodynamics (PK/PD) behavior of antibody-drug conjugates (ADCs) and may help to improve their therapeutic index. To evaluate this hypothesis, here we performed PK/PD evaluation for an ADC administered via subcutaneous (SC) and [...] Read more.
We hypothesize that different routes of administration may lead to altered pharmacokinetics/pharmacodynamics (PK/PD) behavior of antibody-drug conjugates (ADCs) and may help to improve their therapeutic index. To evaluate this hypothesis, here we performed PK/PD evaluation for an ADC administered via subcutaneous (SC) and intratumoral (IT) routes. Trastuzumab-vc-MMAE was used as the model ADC, and NCI-N87 tumor-bearing xenografts were used as the animal model. The PK of multiple ADC analytes in plasma and tumors, and the in vivo efficacy of ADC, after IV, SC, and IT administration were evaluated. A semi-mechanistic PK/PD model was developed to characterize all the PK/PD data simultaneously. In addition, local toxicity of SC-administered ADC was investigated in immunocompetent and immunodeficient mice. Intratumoral administration was found to significantly increase tumor exposure and anti-tumor activity of ADC. The PK/PD model suggested that the IT route may provide the same efficacy as the IV route at an increased dosing interval and reduced dose level. SC administration of ADC led to local toxicity and reduced efficacy, suggesting difficulty in switching from IV to SC route for some ADCs. As such, this manuscript provides unprecedented insight into the PK/PD behavior of ADCs after IT and SC administration and paves the way for clinical evaluation of these routes. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates: Unlocking the Future of Immunotherapies)
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26 pages, 4439 KiB  
Article
DOPE/CHEMS-Based EGFR-Targeted Immunoliposomes for Docetaxel Delivery: Formulation Development, Physicochemical Characterization and Biological Evaluation on Prostate Cancer Cells
by Thais da Silva Moreira, Alan Denis Olivindo Silva, Bianca Rodrigues Farias Vasconcelos, Elias da Silva Santos, Ana Carolina Cruz de Sousa, João Vito Barroso de Freitas, Yara Santiago de Oliveira, Laura Maria Teodorio Vidal, Fábio de Oliveira Silva Ribeiro, Alyne Rodrigues de Araújo, José de Brito Vieira Neto, Cláudia do Ó Pessoa, Raquel Petrilli and Josimar O. Eloy
Pharmaceutics 2023, 15(3), 915; https://doi.org/10.3390/pharmaceutics15030915 - 11 Mar 2023
Cited by 8 | Viewed by 3081
Abstract
Docetaxel (DTX) is a non-selective antineoplastic agent with low solubility and a series of side effects. The technology of pH-sensitive and anti-epidermal growth factor receptor (anti-EGFR) immunoliposomes aims to increase the selective delivery of the drug in the acidic tumor environment to cells [...] Read more.
Docetaxel (DTX) is a non-selective antineoplastic agent with low solubility and a series of side effects. The technology of pH-sensitive and anti-epidermal growth factor receptor (anti-EGFR) immunoliposomes aims to increase the selective delivery of the drug in the acidic tumor environment to cells with EFGR overexpression. Thus, the study aimed to develop pH-sensitive liposomes based on DOPE (dioleoylphosphatidylethanolamine) and CHEMS (cholesteryl hemisuccinate), using a Box–Behnken factorial design. Furthermore, we aimed to conjugate the monoclonal antibody cetuximab onto liposomal surface, as well as to thoroughly characterize the nanosystems and evaluate them on prostate cancer cells. The liposomes prepared by hydration of the lipid film and optimized by the Box–Behnken factorial design showed a particle size of 107.2 ± 2.9 nm, a PDI of 0.213 ± 0.005, zeta potential of −21.9 ± 1.8 mV and an encapsulation efficiency of 88.65 ± 20.3%. Together, FTIR, DSC and DRX characterization demonstrated that the drug was properly encapsulated, with reduced drug crystallinity. Drug release was higher in acidic pH. The liposome conjugation with the anti-EGFR antibody cetuximab preserved the physicochemical characteristics and was successful. The liposome containing DTX reached an IC50 at a concentration of 65.74 nM in the PC3 cell line and 28.28 nM in the DU145 cell line. Immunoliposome, in turn, for PC3 cells reached an IC50 of 152.1 nM, and for the DU145 cell line, 12.60 nM, a considerable enhancement of cytotoxicity for the EGFR-positive cell line. Finally, the immunoliposome internalization was faster and greater than that of liposome in the DU145 cell line, with a higher EGFR overexpression. Thus, based on these results, it was possible to obtain a formulation with adequate characteristics of nanometric size, a high encapsulation of DTX and liposomes and particularly immunoliposomes containing DTX, which caused, as expected, a reduction in the viability of prostate cells, with high cellular internalization in EGFR overexpressing cells. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates: Unlocking the Future of Immunotherapies)
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13 pages, 1426 KiB  
Article
Implementation of Systematic Bioanalysis of Antibody–Drug Conjugates for Preclinical Pharmacokinetic Study of Ado-Trastuzumab Emtansine (T-DM1) in Rats
by Eun-Jeong Jeon, Ju-Hee Han, Youjin Seo, Eun Mi Koh, Kang-Hyun Han, Kyunghwa Hwang and Kyung Jin Jung
Pharmaceutics 2023, 15(3), 756; https://doi.org/10.3390/pharmaceutics15030756 - 24 Feb 2023
Cited by 5 | Viewed by 3990
Abstract
Antibody–drug conjugates (ADCs) are composed of monoclonal antibodies covalently bound to cytotoxic drugs by a linker. They are designed to selectively bind target antigens and present a promising cancer treatment without the debilitating side effects of conventional chemotherapies. Ado-trastuzumab emtansine (T-DM1) is an [...] Read more.
Antibody–drug conjugates (ADCs) are composed of monoclonal antibodies covalently bound to cytotoxic drugs by a linker. They are designed to selectively bind target antigens and present a promising cancer treatment without the debilitating side effects of conventional chemotherapies. Ado-trastuzumab emtansine (T-DM1) is an ADC that received US FDA approval for the treatment of HER2-positive breast cancer. The purpose of this study was to optimize methods for the quantification of T-DM1 in rats. We optimized four analytical methods: (1) an enzyme-linked immunosorbent assay (ELISA) to quantify the total trastuzumab levels in all drug-to-antibody ratios (DARs), including DAR 0; (2) an ELISA to quantify the conjugated trastuzumab levels in all DARs except DAR 0; (3) an LC–MS/MS analysis to quantify the levels of released DM1; and (4) a bridging ELISA to quantify the level of anti-drug antibodies (ADAs) of T-DM1. We analyzed serum and plasma samples from rats injected intravenously with T-DM1 (20 mg/kg, single dose) using these optimized methods. Based on these applied analytical methods, we evaluated the quantification, pharmacokinetics, and immunogenicity of T-DM1. This study establishes the systematic bioanalysis of ADCs with validated assays, including drug stability in matrix and ADA assay, for future investigation on the efficacy and safety of ADC development. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates: Unlocking the Future of Immunotherapies)
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Review

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19 pages, 879 KiB  
Review
An Overview of the Development and Preclinical Evaluation of Antibody–Drug Conjugates for Non-Oncological Applications
by Lal Bahadur Pal, Prajakta Bule, Wahid Khan and Naveen Chella
Pharmaceutics 2023, 15(7), 1807; https://doi.org/10.3390/pharmaceutics15071807 - 24 Jun 2023
Cited by 6 | Viewed by 6474
Abstract
Typically, antibody–drug conjugates (ADCs) are made up of a humanized antibody and a small-molecule medication connected by a chemical linker. ADCs’ ability to deliver cytotoxic agents to the specific site with reduced side effects showed promising results in oncology. To date, fourteen ADCs [...] Read more.
Typically, antibody–drug conjugates (ADCs) are made up of a humanized antibody and a small-molecule medication connected by a chemical linker. ADCs’ ability to deliver cytotoxic agents to the specific site with reduced side effects showed promising results in oncology. To date, fourteen ADCs have been approved by the US Food and Drug Administration, and approximately 297 ADCs are in pre-clinical/clinical stages in the oncology area. Inspired by these outcomes, a few scientists explored the potential of antibody–drug conjugates in non-oncological conditions such as arthritis, myasthenia gravis, immunological disorders, and kidney failure. However, there are limited data available on the non-oncological applications of antibody–drug conjugates. This current review focuses on the non-oncological applications of antibody–drug conjugates, their developmental studies, testing procedures, in vitro evaluations, and pre-clinical testing. Additionally, a summary of the restrictions, difficulties, and prospects for ADCs in non-oncological applications is provided. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates: Unlocking the Future of Immunotherapies)
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Graphical abstract

21 pages, 3230 KiB  
Review
Advances in Targeted Therapy of Breast Cancer with Antibody-Drug Conjugate
by Md Abdus Subhan and Vladimir P. Torchilin
Pharmaceutics 2023, 15(4), 1242; https://doi.org/10.3390/pharmaceutics15041242 - 14 Apr 2023
Cited by 11 | Viewed by 4126
Abstract
Antibody–drug conjugates (ADCs) are a potential and promising therapy for a wide variety of cancers, including breast cancer. ADC-based drugs represent a rapidly growing field of breast cancer therapy. Various ADC drug therapies have progressed over the past decade and have generated diverse [...] Read more.
Antibody–drug conjugates (ADCs) are a potential and promising therapy for a wide variety of cancers, including breast cancer. ADC-based drugs represent a rapidly growing field of breast cancer therapy. Various ADC drug therapies have progressed over the past decade and have generated diverse opportunities for designing of state-of-the-art ADCs. Clinical progress with ADCs for the targeted therapy of breast cancer have shown promise. Off-target toxicities and drug resistance to ADC-based therapy have hampered effective therapy development due to the intracellular mechanism of action and limited antigen expression on breast tumors. However, innovative non-internalizing ADCs targeting the tumor microenvironment (TME) component and extracellular payload delivery mechanisms have led to reduced drug resistance and enhanced ADC effectiveness. Novel ADC drugs may deliver potent cytotoxic agents to breast tumor cells with reduced off-target effects, which may overcome difficulties related to delivery efficiency and enhance the therapeutic efficacy of cytotoxic cancer drugs for breast cancer therapy. This review discusses the development of ADC-based targeted breast cancer therapy and the clinical translation of ADC drugs for breast cancer treatment. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates: Unlocking the Future of Immunotherapies)
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