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.
Abstract
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.
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 are discussed.
P. Paliogiannis, G. Fara, A. Zinellu et al.· Current Issues in Molecular...· 0 citations
Prostate-specific membrane antigen (PSMA) is a well-characterized cell-surface antigen with 100- to 1000-fold increased expression in prostate cancer relative to normal prostate tissue, establishing it as a compelling therapeutic target in metastatic castration-resistant prostate cancer (mCRPC). Decades of clinical investigation across radioligand therapy, antibody-drug conjugates (ADCs), chimeric antigen receptor T-cell (CAR-T) therapy, and bispecific T-cell engagers (BiTEs) have validated PSMA as a clinically actionable target. However, across these modalities, antigen expression heterogeneity, the immunosuppressive tumor microenvironment, and construct-level limitations have consistently emerged as the primary determinants of therapeutic outcome. The approval of ¹⁷⁷Lu-PSMA-617 (lutetium-177 vipivotide tetraxetan; Pluvicto) established proof-of-concept for PSMA-directed therapy in mCRPC, yet a substantial proportion of patients derive limited or no durable benefit, and early immunotherapeutic platforms encountered recurring challenges including cytokine release syndrome, immunogenicity, and insufficient T-cell persistence. Next-generation bispecific constructs incorporating tumor-conditional activation via molecular masking, exemplified by VIR-5500, have demonstrated markedly improved tolerability and encouraging anti-tumor activity in Phase 1 evaluation. This review traces the clinical and biological insights that have guided successive generations of PSMA-targeted therapeutic design and discusses the combination strategies and molecular profiling tools that will be essential for extending durable benefit across the broader mCRPC population.
Jasmine A. Anderson, Haolong Li· Serican Journal of Medicine· 0 citations
Antibody-drug conjugates (ADCs) are one of the most significant advancements in modern cancer therapeutics. Combining the target selectivity of monoclonal antibodies with the cytotoxic potential of payloads, ADCs effectively kill cancer cells and offer hope to patients with even refractory cancer types. Beyond simply increasing the number of therapeutic options available for cancer patients, ADCs have become a powerful frontline agent in overcoming multidrug resistance (MDR). As one of the most challenging obstacles to effective cancer care, MDR is mediated by ATP-binding cassette (ABC) transporter-mediated drug efflux, target-based mutations, and dysregulated apoptosis. The clinical success of ADCs specifically engineered to overcome MDR, including in heterogeneous tumors and cancer cells that exhibit bypass signaling, is well established. This is especially evident with trastuzumab deruxtecan (T-DXd) in HER2-low, HER2-positive, and HER2-mutant cancers; sacituzumab govitecan (SG) in TROP2-expressing triple-negative breast cancer (TNBC) and urothelial carcinoma; and enfortumab vedotin in Nectin-4-positive bladder cancer. By overcoming MDR, ADCs have enabled more effective treatment algorithms across multiple malignancies. Most importantly, the clinical application of ADCs has become inextricably linked to cancer genomics. HER2 testing has evolved from a two-tiered system to a continuous spectrum including HER2-ultralow, HER2-low, HER2-positive, and ERBB2-mutant categories. Each of these categories exhibits different eligibility guidelines for ADC patient selection. As cancer cells continue to evolve and develop resistance to even ADCs through mutations and variants, researchers and clinicians have used pharmacogenomics to predict ADC response and resistance. To define the genomic architecture of ADC-resistant tumor subpopulations, single-cell transcriptomic studies and liquid biopsy approaches are being used to enable real-time examination of the tumor genome during ADC therapy, thereby optimizing treatment and circumventing resistance driven by emerging mutations and variants. This review provides a comprehensive analysis of the molecular structure of ADCs, the pharmacological principles underlying their potent cytotoxic activity against MDR cancer cells, the genomic and transcriptomic biomarkers that guide ADC patient selection, and the emerging resistance mechanisms that will shape the next generation of promising ADC development.
Ryan Li, Xiang Chen, Qinguo Huang et al.· Cancer Letters· 0 citations
Continued translational research is therefore essential to identify predictive biomarkers and to optimize novel combination strategies to overcome resistance, 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, V. O. Costa et al.· Therapeutic Advances in Medi...· 0 citations
Human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (Trop-2) are tumor-associated antigens widely overexpressed in multiple malignant tumors, which drive malignant proliferation, invasion, metastasis, and therapeutic resistance by activating key downstream signaling pathways. Antibody–drug conjugates (ADCs) targeting HER2 and Trop-2 leverage their antigen-specific binding capacity to achieve precise targeted delivery of cytotoxic drugs, representing a significant breakthrough in solid tumor therapy. This review systematically outlines the biological functions and carcinogenic mechanisms of HER2 and Trop-2, focusing on the latest research and development progress of related ADCs. We also summarize and analyze key clinical data and application prospects in breast cancer (BC), gastric cancer (GC), non-small cell lung cancer (NSCLC), and urothelial carcinoma (UC), while also delving into the challenges and future directions within this field.
Introduction: Antibody–drug conjugates (ADCs) direct chemotherapeutic payloads to tumors using antibodies targeting tumor-associated proteins. Despite this, ADC efficacy remains constrained by toxicity, some of which is driven by ADC binding to non-tumor tissues expressing the ADC’s target. For example, anti-human epidermal growth factor receptor 2 (HER2) ADCs can induce serious cardiac toxicity related to HER2 expression in the heart, and glembatumumab vedotin causes severe rash plausibly due to expression of its target, glycoprotein non-metastatic melanoma protein B (gpNMB), in the skin. Improving the selectivity of ADCs for tumors relative to non-tumor tissue could widen the therapeutic window of these drugs. Here we show that with careful optimization, bispecific ADCs (bsADCs) can improve tumor selectivity.
Materials and methods: To investigate the impact of dual targeting on improving the tumor selectivity of bsADCs, we developed a mechanistic pharmacokinetic/receptor occupancy (PK/RO) model that accounts for antibody affinity and avidity. This model quantitatively predicts on-tumor and off-tumor target binding for bsADCs as a function of bsADC pharmacokinetics, target properties, and antibody binding affinity.
Results: Bispecific antibodies can only enhance tumor selectivity of ADCs compared to healthy target-expressing tissues when the affinities for both targets are properly optimized. The extent of bsADC tumor selectivity depends on the on- and off-rates for target binding. This four-dimensional search space is best explored using a computational model, as we have developed here. Improvements in ADC tumor selectivity remain robust to an order of magnitude of variation in target expression levels.
Conclusions: Bispecific antibodies may improve targeting specificity of ADCs, but it is critical to optimize affinities for the two tumor-associated antigens with the aid of mathematical modeling. This can improve the ratio of target-mediated on-tumor to off-tumor ADC engagement compared to single-target ADCs. The approach presented here provides a practical method of model-guided optimization of dual targeting, which may have broader applicability across antibody-based therapeutics.
M. Stoddard, Sheetal K Panday, H. Gardner et al.· Academia Drug Development an...· 0 citations
