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Advances in Antibody–Drug Conjugates (ADCs) in Cancers

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Drug Development".

Deadline for manuscript submissions: closed (20 March 2026) | Viewed by 8607

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Special Issue Editor

Prof. Dr. Jayanth Panyam

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Professor and Dean, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA
Interests: targeted drug delivery; nanoparticles; antibody-drug conjugates; controlled release; chemoprevention; immunotherapy; cancer vaccine
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Special Issue Information

Dear Colleagues,

Antibody–drug conjugates (ADCs) are targeted anticancer therapeutics comprising an antibody conjugated to a cytotoxic payload through a linker. This composition confers ADCs with improved specificity and less potential for side-effects than traditional chemotherapy regimens. Several ADCs have been approved for the treatment of both hematological malignancies and solid tumors, and numerous more are in clinical trials. While the composition of ADCs is straightforward, many factors, including antigen affinity/avidity/specificity, hydrophobicity of the construct, stability of the linker, atypical glycosylation patterns, and the presence of specific amino acid residues in the complementarity-determining region, impact the in vivo disposition and therapeutic efficacy of ADCs. This Special Issue will focus on the drug delivery aspects of ADCs and the relationship between the structural features and in vivo disposition of ADCs.

Prof. Dr. Jayanth Panyam
Guest Editor

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Keywords

antibody–drug conjugates (ADCs)
therapeutic efficacy
drug delivery
structural features
disposition
linker design
payload optimization

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Published Papers (6 papers)

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Research

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17 pages, 4658 KB

Open AccessArticle

In Vitro Characterization of Internalization Pathways and Cytotoxic Activity of Anti-HSPG2 Antibody–Drug Conjugates in MDA-MB-231-LM2 Cells

by Zekun Shao, Lauren Morelli, Benjamin E. Blass, Andrey Efimov and Jayanth Panyam

Cancers 2026, 18(10), 1638; https://doi.org/10.3390/cancers18101638 - 19 May 2026

Viewed by 144

Abstract

Background/objectives: This study presents a mechanistic assessment of an anti-HSPG2 monoclonal antibody (AM6) as an antibody–drug conjugate (ADC) carrier in vitro. Methods: Using live-cell confocal imaging with pathway inhibitors, we qualitatively characterized AM6 internalization and trafficking and compared linker/payload configurations for intracellular delivery and in vitro cytotoxicity. Results: AM6 exhibited rapid cellular entry in MDA-MB-231-LM2 cells, with contributions from clathrin-mediated endocytosis and macropinocytosis, followed by accumulation in endo-lysosomal compartments. Consistent with these trafficking observations, AM6 ADCs bearing cleavable linkers and a potent payload (MMAE) produced more pronounced antiproliferative effects in MDA-MB-231-LM2 and other HSPG2-positive tumor cells than non-cleavable constructs, whereas doxorubicin-based ADCs showed limited activity and greater aggregation risk. Conclusions: Overall, the data inform linker/payload selection and highlight considerations for future work, including quantitative internalization, antigen-negative or knockdown controls, and in vivo pharmacology. Full article

(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs) in Cancers)

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18 pages, 6360 KB

Open AccessArticle

Poliovirus Receptor as a Potential Target in Gastric Signet-Ring Cell Carcinoma for Antibody-Drug Conjugate Development

by Yinxia Zhao, Hanfei Xie, Xuefei Tian, Li Yuan, Can Hu, Yujie Dai, Shengjie Zhang, Peng Guo and Xiangdong Cheng

Cancers 2026, 18(2), 270; https://doi.org/10.3390/cancers18020270 - 15 Jan 2026

Viewed by 715

Abstract

Background: Gastric signet-ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer characterized by unique biological features, leading to low rates of early diagnosis, poor prognosis, and limited response to chemotherapy and immunotherapy. Effective targeted therapies for GSRCC remain scarce. Given these treatment challenges and the potential efficacy of antibody-drug conjugates (ADCs) in clinical settings, this study focuses on identifying novel ADCs with significant potential to improve the treatment outcomes of GSRCC. Methods: We conducted a comprehensive bioinformatics analysis of GSRCC using multi-omics data (including transcriptomics and proteomics) and identified the poliovirus receptor (PVR) as a potential therapeutic target for GSRCC. We selected deruxtecan (DXd) as an effective carrier for developing an ADC targeting GSRCC. The synthesized PVR monoclonal antibody-DXd complex (PVR-DXd) has a drug-to-antibody ratio (DAR) of 4. Results: PVR-DXd demonstrated potent antitumor activity in a human GSRCC xenograft model, effectively eliminating tumors while sparing normal tissue, highlighting its potential as a novel and impactful targeted therapy for this aggressive subtype of gastric signet ring cell carcinoma. Conclusions: This preliminary study supports the further development of PVR-DXd as a candidate therapy for advanced GSRCC. Full article

(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs) in Cancers)

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15 pages, 975 KB

Open AccessArticle

Integrating In Vitro Analytics for Improved Antibody–Drug Conjugate Candidate Selection

by Virginia del Solar, Ali Saleh, Annarita Di Tacchio, Lena Sokol Becciolini, Gyoung Dong Kang, Bianka Jackowska, Yan Hu, Chao Gong, Angel Zhang, Leigh Hostetler, Maximilliam Lee, Akbar H. Khan, Abhisek Mitra, Mahammad Ahmed, David Tickle and Balakumar Vijayakrishnan

Cancers 2026, 18(1), 164; https://doi.org/10.3390/cancers18010164 - 3 Jan 2026

Viewed by 1539

Abstract

Background/Objectives: The development of antibody–drug conjugates (ADCs) presents significant scientific and operational challenges, from optimising conjugation chemistry and linker stability to establishing robust analytical controls. Advanced analytical methods, particularly the combination of plasma stability assays with enzymatic studies, are essential for early screening and characterisation of ADC candidates. Integrating these in vitro assays with powerful data analysis software accelerates structure–activity relationship assessments and the identification of stable compounds in plasma. Methods: This article examines how combined analytical and computational approaches enhance candidate selection by offering valuable insights into the metabolic fate and stability risks of ADCs. Results: Our research shows correlation between in vitro stability profiles and in vivo pharmacokinetic (PK) data, demonstrating the predictive power of early-stage analytical studies. Implementation of software-driven visualisation and analysis enables faster, data-informed decision making, streamlining the triage process to prioritise candidates with optimal PK and pharmacodynamics (PD) characteristics. Conclusions: These findings highlight the critical need for integrated in vitro analytics and computational tools in efficient ADC development, supporting the selection of candidates with the greatest potential for clinical success and facilitating a more effective and accelerated path from discovery to clinical application. Full article

(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs) in Cancers)

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15 pages, 2550 KB

Open AccessArticle

Characterisation of mAb104 Antibody–Drug Conjugates Targeting a Tumour-Selective HER2 Epitope

by Sagun Parakh, Nhi Huynh, Laura D. Osellame, Diana D. Cao, Angela Rigopoulos, Benjamin Gloria, Nancy Yanan Guo, Fiona E. Scott, Zhanqi Liu, Hui K. Gan and Andrew M. Scott

Cancers 2025, 17(18), 2995; https://doi.org/10.3390/cancers17182995 - 13 Sep 2025

Cited by 1 | Viewed by 1462

Abstract

Background: The novel anti-HER2 antibody 104 (mAb104) targets a unique tumour-specific epitope, lacks normal tissue binding and can internalise into tumour cells, thus supporting its development into antibody drug conjugates (ADCs). Methods: We now describe the binding properties and preclinical activity of mAb104-ADCs developed through the conjugation of mAb104 via linkers to the anti-microtubule drug maytansoinoid ematansine (DM1-SMCC; DM1), topoisomerase I inhibitor, exatecan derivative (MC-GGFG-DX8951; DX8951) or microtubule disruptor monomethyl auristatin E (MC-vc-PAB-MMAE; MMAE). Results: Mab104-ADCs demonstrate dose-dependent cytotoxicity in vitro. The safety of single-dose mAb104-DX8951 was demonstrated in vivo at doses up to 10 mg/kg. MAb104-ADCs also demonstrated potent and prolonged anti-tumour activity in a range of tumour types with variable HER2 expression. Mab104-DX8951 showed significant responses in trastuzumab-resistant HER2-positive breast cancer, low HER2-expressing cancers, as well as HER2-overexpressing cancers. Conclusion: These findings indicate the potential for tumour-specific targeting of HER2-expressing tumours with mAb104-ADCs. Full article

(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs) in Cancers)

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Review

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21 pages, 1455 KB

Open AccessReview

Biophysical and Structural Characterization of Antibody–Drug Conjugates

by Isabel P. Mariano and Abhinav Nath

Cancers 2026, 18(6), 917; https://doi.org/10.3390/cancers18060917 - 12 Mar 2026

Viewed by 1498

Abstract

Antibody–drug conjugates (ADCs) comprise a monoclonal antibody covalently bound to a cytotoxic payload by a linker. ADCs minimize off-target effects on healthy tissues, leveraging the specificity of monoclonal antibodies to deliver cytotoxic drugs to the intended tumor site. ADCs can be prone to poor behavior, including aggregation and misfolding, leading to poor efficacy, impaired pharmacokinetics, and immunogenicity. It is advantageous to understand the developability and potential liabilities of a protein candidate prior to costly in vivo studies or clinical trials. This review summarizes biophysical and structural techniques used to characterize ADCs and introduces emerging techniques aimed at accurately assessing the developability of protein candidates. Stability is commonly assayed using techniques like differential scanning calorimetry (DSC), differential scanning fluorimetry (DSF), or spectroscopic probes such as circular dichroism and intrinsic fluorescence. Drug-to-antibody ratio (DAR) is a critical parameter that can be measured using absorbance spectroscopy or chromatographic analysis. Aggregation and self-association can be probed using scattering techniques such as dynamic light scattering (DLS), static light scattering (SLS), and size exclusion chromatography–multi-angle light scattering (SEC-MALS), as well as more specialized approaches such as fluorescence correlation spectroscopy (FCS) and analytical ultracentrifugation (AUC). Mass spectrometry (MS) provides extremely valuable insight into stability, covalent modifications, and, through approaches like hydrogen–deuterium exchange (HDX-MS), structural dynamics of ADCs. Looking forward, the use of biophysical assays in ex vivo matrices and strategic use of artificial intelligence/machine learning (AI/ML) approaches are likely to advance the efficient and rapid development of ADCs and other next-generation protein therapeutics. Full article

(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs) in Cancers)

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17 pages, 2036 KB

Open AccessReview

Pharmacokinetic and Pharmacodynamic Modeling of Antibody-Drug Conjugates

by Patrick M. Glassman

Cancers 2026, 18(1), 5; https://doi.org/10.3390/cancers18010005 - 19 Dec 2025

Cited by 5 | Viewed by 2361

Abstract

Antibody-drug conjugates (ADCs) have risen in prominence over the past 15 years, with numerous regulatory approvals in oncology. A complicating factor in the development of ADCs is the presence of numerous analytes with unique pharmacologic properties. Following administration, ADCs are present in the body as the intact ADC, unconjugated antibody, and liberated payload. Due to heterogeneity in conjugation and in vivo deconjugation rates, the drug-to-antibody ratio (DAR) changes with time. Each of these molecular species has unique pharmacokinetic (PK) and pharmacodynamic (PD) properties that should be understood and characterized. One approach that is frequently applied is the development of in silico mathematical models to characterize and predict the PK/PD of ADCs. In this review, we summarize key mechanisms controlling the PK/PD of ADCs. This provides context for a detailed discussion of the array of PK/PD models that have been applied for ADCs, ranging from empirical compartmental models all the way through system-level models, such as physiologically based pharmacokinetics (PBPK) and cell-level PK/PD models. We provide a critical discussion of the strengths, weaknesses, and utility of each of these model structures. Full article

(This article belongs to the Special Issue Advances in Antibody–Drug Conjugates (ADCs) in Cancers)

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