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Pharmaceutics
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Advancements and Innovations in Antibody Drug Conjugates
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Advancements and Innovations in Antibody Drug Conjugates

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: 30 November 2025 | Viewed by 4715

Special Issue Editors

Dr. Murali Mohan Yallapu

E-Mail Website1 Website2
Guest Editor
Department of Immunology and Microbiology, College of Medicine, University of Texas Rio Grade Valley, McAllen, TX 78503, USA
Interests: cancer therapy; drug delivery; drug targeting; infectious disease; micelle; nanoparticles; nanotechnology; polymers; targeted therapies; HIV; antibody engineering; antibody–drug conjugates
Special Issues, Collections and Topics in MDPI journals
Dr. Shivaji Edupuganti

E-Mail Website
Guest Editor
Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD 21702, USA
Interests: C-H activation; self-immolative linkers; antibody drug conjugates; organic chemistry
Dr. Ebaston Thankarajan

E-Mail Website
Guest Editor
Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD 21702, USA
Interests: medicinal chemistry; antibody drug conjugates; fluorescence imaging; targeted drug delivery; photodynamic therapy

Special Issue Information

Dear Colleagues,

Antibody–drug conjugates (ADCs) represent a groundbreaking advancement in targeted cancer therapy, merging the specificity of monoclonal antibodies with a highly potent cytotoxic small-molecule drug. ADCs aim to improve efficacy by reducing side effects through the specific targeting of cancer cells, sparing healthy tissues. Recent innovations in ADC development have focused on optimizing antibody engineering, bispecific antibodies, combination therapies, linker stability, and the choice of payloads to enhance the therapeutic index. Improved conjugation techniques, payload delivery mechanisms, and linker chemistries are advancing the field towards greater efficacy and safety profiles.

This Special Issue highlights the latest advancements and innovations in ADC technology including recent antibody-based drug delivery systems, approved ADCs, clinical development, cytotoxic payload, drug linker design, cleavable linker design, site-specific conjugation, biodistribution, pharmacokinetics, and molecular imaging.

Dr. Murali Mohan Yallapu
Dr. Shivaji Edupuganti
Dr. Ebaston Thankarajan
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
  • monoclonal antibodies
  • targeted therapies
  • linker technologies
  • site-specific conjugation
  • bioimaging
  • pharmacokinetics
  • therapeutic index
  • next-generation ADCs
  • drug resistance
  • bispecific antibodies
  • combination therapies
  • off-target toxicity
  • efficacy and safety
  • tumor-specific antigens

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Published Papers (4 papers)

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Research

14 pages, 10805 KB  
Article
Non-Competitive Binding of Isatuximab and Daratumumab to CD38: Implications for Targeted Therapy in Multiple Myeloma
by Rubén Osuna-Gómez, Jordi López-Pardo, Maria Mulet, Josep Nomdedéu, Elisabet Cantó, Rosa Ortin, Ángela Sánchez Cayuela, Ma Àngels Ortiz, Albert Guinart-Cuadra and Silvia Vidal
Pharmaceutics 2025, 17(10), 1278; https://doi.org/10.3390/pharmaceutics17101278 - 30 Sep 2025
Viewed by 263
Abstract
Background/Objectives: CD38-targeting monoclonal antibodies isatuximab and daratumumab have revolutionized multiple myeloma (MM) treatment, but a deeper understanding of their distinct mechanisms is crucial for therapeutic optimization. Methods: We used flow cytometry to assess isatuximab and daratumumab binding competition in MM cell [...] Read more.
Background/Objectives: CD38-targeting monoclonal antibodies isatuximab and daratumumab have revolutionized multiple myeloma (MM) treatment, but a deeper understanding of their distinct mechanisms is crucial for therapeutic optimization. Methods: We used flow cytometry to assess isatuximab and daratumumab binding competition in MM cell lines and patient-derived bone marrow cells. The dynamics of CD38 expression were evaluated at different time points before and after antibody-mediated removal. The effects of IMiDs (pomalidomide, lenalidomide) on CD38 expression and isatuximab-induced apoptosis, either alone or in combination with IMiDs, were also examined. Moreover, MM cell migration was assessed through CXCR4-mediated assays, and cell adhesion was evaluated via CD49d-dependent assays. Results: Isatuximab and daratumumab did not compete for CD38 binding, confirming distinct epitope recognition. Following depletion with either antibody, CD38 expression on the MM cell surface began to recover within 2 h, suggesting a dynamic regulation of CD38 availability. While daratumumab lacked direct apoptosis, isatuximab induced significant direct cell death. Pomalidomide enhanced isatuximab-induced apoptosis by increasing CD38 expression, whereas lenalidomide had no significant effect. Additionally, both antibodies effectively inhibited MM cell migration and significantly reduced cell adhesion. Conclusions: Their non-competitive binding and shared impact on cell dynamics suggest opportunities for optimizing treatment strategies through combinatorial or sequential approaches in MM therapy. Full article
(This article belongs to the Special Issue Advancements and Innovations in Antibody Drug Conjugates)
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19 pages, 6473 KB  
Article
Identification of Variable Lymphocyte Receptors That Target the Human Blood–Brain Barrier
by Moriah E. Katt, Elizabeth A. Waters, Benjamin D. Gastfriend, Brantley R. Herrin, Max D. Cooper and Eric V. Shusta
Pharmaceutics 2025, 17(9), 1179; https://doi.org/10.3390/pharmaceutics17091179 - 10 Sep 2025
Viewed by 559
Abstract
Background/Objectives: Receptor-mediated transcytosis utilizing the native transporters at the blood–brain barrier (BBB) is a growing strategy for the delivery of therapeutics to the brain. One of the major challenges in identifying appropriate human transcytosis targets is that there is a species-specific transporter [...] Read more.
Background/Objectives: Receptor-mediated transcytosis utilizing the native transporters at the blood–brain barrier (BBB) is a growing strategy for the delivery of therapeutics to the brain. One of the major challenges in identifying appropriate human transcytosis targets is that there is a species-specific transporter expression profile at the BBB, complicating translation of successful preclinical candidates into humans. In an effort to overcome this obstacle and identify proteins capable of binding human-relevant BBB ligands, we generated and screened a BBB-targeting library against human-induced pluripotent stem cell-derived brain microvascular endothelial-like cells (iPSC-derived BMEC-like cells). As targeting molecules, we used lamprey antibodies, known as variable lymphocyte receptors (VLRs), and generated a VLR library by immunizing lamprey with iPSC-derived BMEC-like cells, and inserting the resultant VLR repertoire into the yeast surface display system. Methods: The yeast displayed VLR library was then panned against human iPSC-derived BMEC-like cells and lead VLRs were validated using human in vitro models and mouse and human ex vivo brain tissue sections. Results: Finally, brain uptake for a set of VLRs was validated in mice. Of the 15 lead VLR candidates, 14 bound to human BBB antigens, and 10 bound to the murine BBB. Pharmacodynamic testing using the neuroactive peptide neurotensin indicated that the lead candidate, VLR2G, could cross the mouse BBB after intravenous injection and deliver sufficient neurotensin payload to generate a pharmacological response and lower systemic body temperature. Conclusions: Together, these results demonstrate the application of a novel screening technique capable of identifying a VLR with human relevance that can cross the BBB and deliver a payload. Full article
(This article belongs to the Special Issue Advancements and Innovations in Antibody Drug Conjugates)
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21 pages, 3228 KB  
Article
CUSP06, a Novel CDH6-Targeted Antibody-Drug Conjugate, Demonstrates Antitumor Efficacy in Multiple CDH6-Expressing Human Cancer Models
by Wei Lu, Jing Shi, Wentao Zhang, Nicole Covino, Amy Penticoff, Robert Phillips, John Cogswell, Laurie Tatalick, Stephanie Pasas-Farmer, Jianjian Zhang, Caiwei Chen, Yixuan Wang, Huiyan Shi, Shuhui Liu, Xun Meng and Eric Slosberg
Pharmaceutics 2025, 17(8), 1049; https://doi.org/10.3390/pharmaceutics17081049 - 13 Aug 2025
Viewed by 1215
Abstract
Background/Objectives: Cadherin-6 (CDH6), also known as K-cadherin, is a type II classic cadherin molecule that plays an important role in the embryonic development of the kidney but has very limited expression in adult tissues. It is overexpressed in several human malignancies, primarily in [...] Read more.
Background/Objectives: Cadherin-6 (CDH6), also known as K-cadherin, is a type II classic cadherin molecule that plays an important role in the embryonic development of the kidney but has very limited expression in adult tissues. It is overexpressed in several human malignancies, primarily in ovarian cancer, renal cell carcinoma, as well as, less frequently, cholangiocarcinoma, uterine serous carcinoma, glioma, lung, pancreatic and thyroid cancers. The characteristic of limited expression in normal tissues, high expression in tumor tissues, and rapid internalization upon antibody binding makes CDH6 a well-suited antibody-drug conjugate (ADC) target. Methods: We developed a novel CDH6-targeting ADC, CUSP06, consisting of a proprietary humanized antibody selective for CDH6, a protease cleavable linker, and an exatecan payload, with a drug-to-antibody ratio (DAR) of 8. We further characterized the pharmacological activities of CUSP06 in multiple in vitro and in vivo models. Results: CUSP06 was selectively bound to cell surface CDH6 and was efficiently internalized into CDH6-positive ovarian cancer cells, and led to the induction of DNA damage and apoptosis of CDH6-positive cancer cells. CUSP06 exhibited strong antiproliferative activity against several CDH6-positive cancer cell lines and demonstrated strong bystander cell killing effect in the cell mixing experiments in vitro. CUSP06 exhibits excellent in vivo antitumor efficacy in CDH6-high or -low cell line-derived xenograft (CDX) or patient-derived xenograft (PDX) models from human ovarian, renal and uterine cancers, as well as cholangiocarcinoma. CUSP06 demonstrated a favorable safety profile in GLP-compliant toxicology studies in Sprague Dawley rats and cynomolgus monkeys. Conclusions: The preclinical data highlighted the therapeutic potential of CUSP06 in multiple CDH6-positive human cancers. Full article
(This article belongs to the Special Issue Advancements and Innovations in Antibody Drug Conjugates)
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19 pages, 2002 KB  
Article
A Dual-Payload Bispecific ADC Improved Potency and Efficacy over Single-Payload Bispecific ADCs
by Nicole A. Wilski, Peter Haytko, Zhengxia Zha, Simin Wu, Ying Jin, Peng Chen, Chao Han and Mark L. Chiu
Pharmaceutics 2025, 17(8), 967; https://doi.org/10.3390/pharmaceutics17080967 - 25 Jul 2025
Viewed by 2080
Abstract
Background/Objectives: All current FDA-approved antibody–drug conjugates (ADCs) are single-target and single-payload molecules that have limited efficacy in patients due to drug resistance. Therefore, our goal was to generate a novel ADC that was less susceptible to single points of resistance to reduce the [...] Read more.
Background/Objectives: All current FDA-approved antibody–drug conjugates (ADCs) are single-target and single-payload molecules that have limited efficacy in patients due to drug resistance. Therefore, our goal was to generate a novel ADC that was less susceptible to single points of resistance to reduce the likelihood of patient relapse. Methods: We developed a dual-targeting, dual-payload ADC by conjugating a bispecific EGFR x cMET antibody to two payloads (MMAF and SN38) that had separate mechanisms of action using a novel tri-functional linker. This dual-payload ADC was tested for potency and efficacy in dividing and nondividing in vitro cell models using multiple tumor cell types. Efficacy of the dual-payload ADC was confirmed using in vivo models. Results: Our ADC with dual MMAF and SN38 payloads was more efficacious in inhibiting cell proliferation than single-payload ADCs across multiple cancer cell lines. In addition, the dual-payload molecule inhibited nondividing cells, which were more resistant to traditional ADC payloads. The dual-payload ADC also exhibited more potent tumor growth inhibition in vivo compared to that of single-payload ADCs. Conclusions: Overall, the bispecific antibody conjugated with both the MMAF and SN38 payloads inhibited tumor growth more strongly than ADCs conjugated with MMAF or SN38 alone. Developing dual-payload ADCs could limit the impact of acquired resistance in patients as well as lower the effective dose of each payload. Full article
(This article belongs to the Special Issue Advancements and Innovations in Antibody Drug Conjugates)
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