Aug 2026· Expert Opinion on Drug Delivery· pp. 1-14· 0 citations· 77 references
Medicine
TL;DR
This review synthesizes literature spanning 1990-2026 on advances in ADC design and their clinical and translational implementation in breast cancer to support reframing antigen selection as a system-level challenge, supported by delivery-focused engineering, precision-medicine-driven trial design, and adaptive methodology.
Abstract
INTRODUCTION
Breast cancer remains a leading cause of mortality among women worldwide, with diagnoses projected to reach 3.5 million annually by 2050. Therapeutic progress is hindered by marked molecular heterogeneity and distinct biological and clinical subtypes. Antibody - drug conjugates (ADCs) have emerged as a promising strategy for treatment‑resistant disease, combining targeted delivery with potent cytotoxic payloads.
AREAS COVERED
This review synthesizes literature spanning 1990-2026 on advances in ADC design and their clinical and translational implementation in breast cancer. Primary research articles were then inputted into Research Rabbit to identify additional original research articles and maximize data retrieval.
EXPERT OPINION
The success of ADCs is limited less by payload potency than by delivery biology. Efficacy depends on patient context, tumor site - specific factors, and bystander effects in antigen‑heterogeneous environments. However, current development often overlooks systemic antigen sinks, metastatic microenvironments, and evolving resistance. Future progress requires reframing antigen selection as a system‑level challenge, supported by delivery‑focused engineering and adaptive trial design. Traditional ADCs rely on a narrow range of tumor antigens and payloads, restricting therapeutic index and applicability. Future progress requires reframing antigen selection as a system-level challenge, supported by delivery-focused engineering, precision-medicine-driven trial design, and adaptive methodology.
Lung cancer is currently the most frequently diagnosed malignancy worldwide, accounting for approximately 12.4% of all cancers and, despite major advances in molecularly targeted therapies and immunotherapy, represents the leading cause of cancer-related mortality, In recent years, antibody–drug conjugates (ADCs) have emerged as a novel therapeutic strategy, combining the specificity of monoclonal antibodies with the potent cytotoxic activity of highly active payloads to selectively target tumor cells while limiting systemic toxicity. This narrative review summarizes the current role of ADCs in lung cancer, with particular focus on their structural components, mechanisms of action, and the biological features that determine treatment efficacy. We discuss the rationale for targeting established and emerging antigens in non-small cell and small cell lung cancer, including HER2, TROP2, c-MET, HER3, CEACAM5, DLL3, and other promising targets currently under clinical investigation. The principal mechanisms of primary and acquired resistance are also reviewed, including antigen modulation, altered intracellular trafficking, lysosomal dysfunction, drug efflux, tumor microenvironment-mediated immune suppression, and intratumor heterogeneity. In addition, we provide an overview of the safety profile of ADCs, highlighting the most clinically relevant adverse events and their underlying biological mechanisms. We also examine the evolving landscape of predictive biomarkers beyond antigen expression, including genomic, transcriptomic, proteomic, and liquid biopsy-based approaches, together with emerging spatial and single-cell technologies that may improve patient selection. Finally, we discuss future directions in the field, including novel payloads, next-generation linker technologies, bispecific ADCs, combination strategies, and personalized ADC development. Overall, ADCs are rapidly reshaping the therapeutic landscape of lung cancer. Continued optimization of drug design, biomarker-driven patient selection, and a deeper understanding of resistance mechanisms will be essential to fully realize their clinical potential.
P. Paliogiannis, G. Fara, A. Zinellu et al.· Current Issues in Molecular...· 0 citations
Antibody-drug conjugates (ADCs) are rapidly evolving from conventional cytotoxic delivery systems into multifunctional, immune-integrated therapeutic platforms. Highlights from the 2026 American Association for Cancer Research (AACR) Annual Meeting demonstrate significant advances in ADC design, including dual- and multi-payload constructs, multispecific targeting strategies, and immunostimulatory payloads. These innovations aim to overcome key limitations such as tumor heterogeneity, resistance, and systemic toxicity. Novel approaches targeting the tumor microenvironment, including depletion of regulatory T cells and tumor-associated macrophages, further expand the therapeutic scope of ADCs beyond direct tumor cell killing. In parallel, integration with emerging modalities such as engineered CD16-enhanced natural killer T (NKT) cells underscores the potential for synergy between ADCs and cellular immunotherapies. Advances in AI-guided target discovery and antibody engineering are also enhancing tumor selectivity and internalization. Collectively, these developments highlight a paradigm shift toward precision, multi-mechanistic ADCs with the potential to improve clinical outcomes across diverse cancer types.
Antibody-drug conjugates (ADCs) represent an emerging class of targeted therapeutics with considerable potential in the management of colorectal cancer (CRC). By delivering highly potent cytotoxic agents to cancer cells via specific antibodies, ADCs enable precise tumor targeting while minimizing off-target toxicity. Recent advancements have identified several promising targets for ADC development in CRC, including human epidermal growth factor receptor 2 (HER2), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), mesenchymal-epithelial transition factor (c-MET), epidermal growth factor receptor (EGFR), cadherin-17 (CDH17), and trophoblast cell surface antigen 2 (Trop-2). Clinical trials have demonstrated encouraging objective response rates and survival benefits with ADCs such as trastuzumab deruxtecan (T-DXd) and disitamab vedotin in patients with advanced CRC. Nonetheless, the clinical application of ADCs faces several challenges, including tumor heterogeneity leading to variable target expression, the emergence of diverse resistance mechanisms that limit long-term efficacy, and manageable but significant safety concerns. Future research should prioritize tumor-selective linker design, novel payload development, bispecific and dual-payload ADC platforms, and rational combination strategies to overcome resistance and further improve the therapeutic index of ADCs in CRC.
Lili Zeng, Yuanlin Zhu, Ke Zhang et al.· Biochemical Pharmacology· 0 citations
, Breast cancer remains the most frequently diagnosed malignancy in women worldwide, with over 2.3 million new cases annually [1]. despite the success of endocrine therapies, chemotherapy, and monoclonal antibodies (e.g., trastuzumab, pertuzumab), a significant therapeutic gap persists for advanced, metastatic, and treatment-refractory cases [2]. resistance mechanisms and tumor heterogeneity necessitate the development of next-generation biologics [3]. Bispecific antibodies (BsAbs) offer a transformative approach by simultaneously engaging two different epitopes, thereby redirecting immune effector cells (t/NK cells) to the tumor microenvironment or dual-inhibiting compensatory signaling pathways [4]. here, we present a systematic landscape analysis of global BsAb clinical trials in breast cancer to identify emerging trends and strategic development gaps. data was extracted from trialtrove, a curated clinical trial intelligence platform that combines records from Clinicaltrials.gov, Who iCtrP, and eU Clinical trials register [5,6]. We focused on the period from 2015 to october 14, 2025. the year 2015 was selected as the starting point to mark the “modern era” of bispecific antibody (BsAb) research and development, a booming wave driven by the FdA approval of the first t-cell engager on december 3, 2014 [7]. We queried for drug type: Bispecific Antibody disease: Breast until october 14th, 2025, and found 164 records. We searched interventional clinical trials related to breast cancer and BsAbs, then manually screened records for eligibility. inclusion criteria were: (i) breast cancer as the target disease; (ii) an interventional design evaluating a BsAb either as monotherapy or in combination; (iii) any clinical phase; and (iv) any geographic region. exclusion criteria were observational studies, preclinical studies, duplicate records, and withdrawn records without usable trial information. We excluded 3 observational studies, 15 trials before 2015, and 22 single target investigations, resulting in 124 valid BsAb trials. two reviewers independently verified target combinations, clinical phase, sponsor type, and geographic distribution, with discrepancies resolved by discussion.
Breast cancer is one of the most common causes of death in women and requires therapies that are both more precise and less toxic. Recently, antibody–drug conjugates (ADCs) have emerged as a promising strategy by selectively direct cytotoxic agents to tumor cells. The aim of this review was to investigate the efficacy, safety, and limitations of these antibodies in breast cancer treatment, and discuss their future perspectives and clinical challenges such as resistance and toxicity. This narrative review is based on a search of Pubmed, Scielo, Science Direct and INCA databases, including clinical and preclinical studies and reviews that have investigated the mechanisms of action, efficacy, and safety of ADCs over the last 15 years. Evidence from clinical trials suggests that therapy may prolong survival and reduce toxicity compared to conventional treatments, as demonstrated in clinical trials in HER2+ and TNBC patients. However, the occurrence of adverse events, resistance to therapy, and challenges in conjugating the components point to the need for optimized approaches. Overall, the results suggest that despite the challenges, this technology represents a significant advance in breast cancer therapy and that the integration of combined and personalized strategies may enhance antibody efficacy, overcome current barriers and contribute to better clinical outcomes.
Andrezza Furquim Da Cruz, M. Lima, Bárbara Sentanin et al.· International Journal of Adv...· 0 citations
Antibody-drug conjugates (ADCs) have emerged as a major therapeutic advance in ovarian cancer, particularly when platinum-based chemotherapy is not a treatment option. By selectively delivering potent cytotoxic payloads to tumor cells, ADCs such as mirvetuximab soravtansine (MIRV), targeting FRα, and trastuzumab deruxtecan (T-DXd), targeting HER2, have demonstrated clinically meaningful activity in selected populations. However, resistance to ADCs inevitably develops through diverse mechanisms, including payload resistance and target antigen downregulation. Continued translational research is therefore essential to identify predictive biomarkers and to optimize novel combination strategies. Beyond ADCs, other systemic approaches have demonstrated survival improvements in PROC even in biomarker-unselected populations, including the addition of the glucocorticoid receptor antagonist relacorilant to nab-paclitaxel and immune–chemotherapy combinations such as pembrolizumab plus paclitaxel with or without bevacizumab. Future directions aim to prioritize synergistic combinations to overcome resistance. This includes pairing ADCs with replication stress inhibitors like ATR inhibitors and WEE1 inhibitors or integrating them with next-generation immuno-oncology platforms such as bispecifics, T-cell engagers, and cancer vaccines, as well as the integration of dynamic biomarkers and quantitative tools to define optimal treatment sequencing and improve patient outcomes in this challenging disease setting.
M. Noronha, L. F. Costa de Almeida, Valbert Oliveira Costa et al.· Therapeutic Advances in Medi...· 0 citations