Antibody-drug conjugates (ADCs) have emerged as powerful targeted therapeutics, yet their clinical performance remains constrained by the limited payload capacity achievable with conventional small-molecule drugs. Here we introduce antibody-oligonucleotide drug conjugates (AODCs), a programmable conjugate modality enabled by oligonucleotide prodrug architectures. Distinct from conventional antibody-oligonucleotide conjugates, in which sequence-specific oligonucleotides serve as gene-regulatory therapeutic cargos, our AODCs use noncoding oligonucleotide-like chains as multivalent chemotherapeutic prodrug scaffolds, thereby expanding payload capacity while preserving controlled antibody conjugation and receptor-mediated targeting. Using the nucleoside analogue gemcitabine as a model payload, we synthesized structurally defined oligonucleotide-like prodrug polymers by solid-phase chemistry and engineered their backbone composition to balance metabolic stability with productive intracellular drug release. Conjugation of these architectures to antibodies targeting HER2 or CD38 generated high-capacity AODCs carrying multiple prodrug chains while maintaining antigen recognition and efficient cellular uptake, resulting in sustained tumor accumulation and enhanced intratumoral drug deposition across both solid and hematological tumor models. Importantly, intracellular release of gemcitabine from the oligonucleotide prodrug architectures induced hallmarks of immunogenic cell death, promoted dendritic-cell activation and antigen presentation, and remodeled the tumor immune microenvironment to support adaptive antitumor responses. These chemo-immunostimulatory effects translated into markedly enhanced therapeutic efficacy in combination with PD-1 blockade. Together, these results support AODCs as a programmable high-capacity payload platform that converts targeted antibody delivery into an integrated chemo-immunotherapy modality and define a generalizable strategy for expanding the chemical space of therapeutics compatible with antibody-based cancer immunotherapy.
Immune checkpoint inhibitors and antibody-drug conjugates have rapidly expanded treatment options for gynecologic malignancies, although the magnitude of benefit varies substantially across tumor types and biomarker-defined populations. This narrative review summarizes the biologic rationale, predictive biomarkers, pivotal clinical trials, regulatory approvals, guideline-supported strategies, and emerging directions for immune checkpoint blockade and antibody-drug conjugates in endometrial, cervical, and ovarian cancers. In endometrial cancer, molecular classification and mismatch repair status have transformed treatment selection, with PD-1 or PD-L1 blockade now integrated into first-line chemoimmunotherapy and recurrent disease management. HER2-directed and TROP-2-directed antibody-drug conjugates are also emerging as biomarker-directed strategies. In cervical cancer, human papillomavirus-driven tumor biology, PD-L1 expression, and tissue factor expression support the use of checkpoint inhibitors, antibody-drug conjugates, and therapeutic vaccine approaches across locally advanced and recurrent or metastatic settings. In ovarian cancer, single-agent checkpoint blockade has shown limited activity in unselected populations, but recent advances include biomarker-selected chemoimmunotherapy in platinum-resistant disease and clinically meaningful activity of folate receptor alpha-directed and HER2-directed antibody-drug conjugates. Across gynecologic cancers, key challenges include refining predictive biomarkers, optimizing sequencing after prior immunotherapy exposure, managing overlapping toxicities, and designing trials that enrich for biologically responsive subgroups. Future progress will depend on integrating molecular classification, immune contexture, ADC target expression, and patient-specific clinical factors into treatment selection.
Transformative therapeutic innovation should not begin with a molecule-or even a molecular target. It should begin with a clearly defined unmet clinical need. Here, we present a seven-step Translational Therapeutic Development Roadmap that systematically connects an unmet medical need to a developable drug candidate through the disciplined sequence of (i) defining the need, (ii) understanding disease and resistance biology, (iii) building a mechanistic hypothesis, (iv) defining a target product profile (TPP), (v) molecular design and experimental validation, (vi) developability and manufacturability assessment, and (vii) clinical translation. A central conclusion emerging from this review is that resistance biology should be viewed not merely as a cause of therapeutic failure, but as a primary design input for next-generation therapeutic innovation. Our analysis identifies continuous alignment among unmet clinical needs, resistance biology, mechanistic hypothesis, molecular design, developability, and clinical translation as the defining characteristic of successful therapeutic development. We use dual-payload antibody-drug conjugates (ADCs) as a contemporary and highly illustrative case study of this resistance-informed therapeutic development approach. Single-payload ADCs such as trastuzumab deruxtecan and sacituzumab govitecan have transformed treatment across multiple solid tumors, yet most patients ultimately relapse through antigen loss, defective intracellular trafficking, drug efflux, payload-target alterations, and tumor heterogeneity, creating an emerging post-ADC treatment gap. Dual-payload ADCs, which deliver two mechanistically distinct warheads from a single antibody, represent a form of molecular combination therapy designed to increase the barrier to resistance and address multiple escape pathways simultaneously, as well as provide a clinically relevant model for resistance-informed therapeutic design. Using dual-payload ADCs as a worked example, we demonstrate how resistance biology directly informs payload pairing, molecular architecture, conjugation strategy, experimental validation, and developability. Our analysis indicates that successful dual-payload ADC design depends not simply on combining two cytotoxic payloads, but on selecting complementary mechanisms with non-overlapping resistance liabilities while satisfying predefined target product profiles and manufacturability requirements. We further summarize resistance-guided payload pairing strategies, including topoisomerase I plus tubulin inhibitors, topoisomerase I plus DNA-damage-response inhibitors, cytotoxic plus immunomodulatory payloads, and cell-permeable plus non-permeable combinations; the conjugation chemistries that enable defined dual-payload products; the preclinical validation, pharmacological optimization, and developability hurdles that separate promising biology from viable therapeutics; and the rapidly expanding clinical landscape, including the first-in-human program KH815 and emerging bispecific dual-payload constructs. Finally, we demonstrate that the same translational roadmap extends beyond ADCs to radiopharmaceutical conjugates, multispecific antibodies, targeted protein degraders, and cell and gene therapies, indicating that it represents a general framework for therapeutic innovation rather than an ADC-specific strategy. Collectively, this review supports the concept that therapeutic innovation is most successful when unmet clinical needs, resistance biology, molecular design, developability, and clinical translation are considered as an integrated continuum rather than as independent stages of drug discovery. This Translational Therapeutic Development Roadmap provides an organizing framework for guiding the rational development of next-generation targeted therapeutics across diverse therapeutic modalities.
Integrins represent a large family of cell surface receptors that exist as heterodimers with essential roles in key biological processes such as cellular adhesion, motility, and cytokinesis. Among them, integrin beta-6 (IB6), which exclusively dimerizes with integrin alpha-v, has emerged as a clinically relevant target due to its restricted expression in normal adult epithelial tissues and elevated levels in solid tumors. High expression of IB6 is correlated with poor prognosis across multiple solid tumor types. PF-08046876 is an investigational antibody-drug conjugate (ADC) consisting of the anti-IB6 monoclonal antibody conjugated to a camptothecin-class topoisomerase I (TOP1) inhibitor, AMDCPT, using a traceless enzyme-cleavable glucuronide linker. The AMDCPT payload has been optimized for differentiation from other TOP1 inhibitors with improved potency, enhanced bystander activity, and reduced susceptibility to multidrug resistance (MDR) efflux mechanisms. PF-08046876 leverages the same antibody backbone from sigvotatug vedotin (SV) and binds IB6 without cross-reactivity to other alpha-v integrin complexes. In preclinical studies, PF-08046876 has demonstrated significant antitumor activity both in vitro and in vivo across multiple tumor models with IB6 expression, including non-small cell lung (NSCLC), head and neck squamous cell (HNSCC), urothelial (UC), pancreatic (PDAC), and esophageal (ESCA) carcinomas. These findings support further clinical development of PF-08046876 as a promising therapeutic candidate for the treatment of IB6-expressing solid tumors.
Gastric cancer is a highly prevalent malignancy of the digestive tract in China. Conventional chemotherapeutic drugs and human epidermal growth factor receptor 2 (HER2)‑targeted agents such as trastuzumab remain limited by significant challenges in the treatment of GC, including high rates of drug resistance, significant toxicity and adverse effects, and suboptimal tolerability. The advent of antibody-drug conjugates (ADCs) has marked a paradigm shift in the therapeutic landscape. This review systematically summarises the structural design, mechanisms of action, and current clinical applications of ADCs in HER2-positive or HER2-low advanced gastric cancer. The present review focuses on key clinical trial data for new-generation ADCs, specifically trastuzumab deruxtecan (T-DXd) and disitamab vedotin (RC48), drawing from the DESTINY-Gastric series and the RC48-C008 study. The review systematically synthesised data on efficacy, safety profiles, resistance mechanisms, and future therapeutic directions. New-generation ADCs have demonstrated significant improvements in objective response rates (ORR) and overall survival (OS) compared with traditional chemotherapy in later-line treatment settings. Emerging evidence also suggests the presence of activity in HER2-low-expressing populations. A systematic assessment of adverse drug reactions highlights both common events (e.g. gastrointestinal reactions, haematologic toxicity) and distinctive adverse events (e.g. interstitial lung disease), with corresponding management strategies. A comprehensive analysis of multiple resistance mechanisms, including HER2 heterogeneity, endocytic barriers, drug efflux, and target mutations, is conducted. The present study demonstrates that ADCs represent a transformative therapeutic modality for HER2-positive or HER2-low cases. Ongoing advancements in ADC structural optimisation, combination strategies with immune checkpoint inhibitors show great promise in terms of further improving clinical outcomes. The objective of this review is to furnish clinicians and researchers with a detailed reference for future clinical practice and investigation.
The rational generation of antibody-drug conjugate (ADC) linkers remains challenging due to the need to balance linker stability, payload release, and compatibility with antibody-payload components. We propose MolT5-Linker, a Transformer-based generative framework conditioned on antibody sequences and payload molecular structures. In the encoder stage, the model integrates a GAT-based Attachment Site Attention Network that infers putative attachment sites from antibody and payload representations. This site-related information guides the decoder to generate chemically compatible linker candidates, improving compatibility between generated linkers and ADC components. Following fine-tuning on a self-constructed ADC data set, MolT5-Linker achieves a generation validity of 0.8986 while maintaining a balance between molecular recovery (0.5802) and uniqueness (0.5438). Furthermore, the generated linker candidates exhibit medicinal chemistry property distributions─including molecular weight, lipophilicity, and topological polar surface area (TPSA)─consistent with ground-truth ADC linkers. These results highlight MolT5-Linker as a computational framework for ADC linker candidate generation.
Antibody-drug conjugates (ADCs) are a promising class of cancer therapeutics that enable the targeted delivery of highly cytotoxic payloads to cancer cells. Mesothelin (MSLN) is an attractive therapeutic target in cancer treatment. Lidamycin (LDM), an enediyne-containing antibiotic with potent antitumor effects, has potential as ADC payload. To generate an ADC targeting MSLN, we first produced a novel anti-MSLN antibody, 3B7A, using hybridoma technology. We then obtained the humanized version, h3B7A, via complementarity-determining region (CDR) grafting. This was followed by fusion with LDM through genetic recombination and molecular assembly to create the ADC h3B7A-LDM. h3B7A-LDM undergoes efficient internalization and lysosomal trafficking in MSLN-positive cancer cells. It demonstrates strong tumor-targeting capability and long-term persistence in tumor-bearing mice. In vitro, it exhibits potent antitumor effects, suppressing the proliferation and migration of cancer cells with sub-nanomolar half maximal inhibitory concentration (IC50) values. Mechanistically, h3B7A-LDM induces cell cycle arrest and apoptosis, triggers immunogenic cell death (ICD), and may elicit antitumor immunity. In vivo, h3B7A-LDM significantly inhibits tumor growth in multiple cancer xenograft models. Together, these findings support h3B7A-LDM as a promising drug candidate for treating MSLN-positive cancer.
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.
Triple-negative breast cancer (TNBC) is an aggressive and chemotherapy-resistant subtype characterized by high metastatic potential and frequent recurrence, making monotherapies largely ineffective. This study evaluates a combination strategy utilizing a CD276 (B7-H3)-targeted antibody-drug conjugate (ADC) alongside mitochondria-targeted gene therapy. The anti-CD276 monoclonal antibody-mertansine conjugate substantially reduces tumor burden at a low dose. It exhibits strong synergy with the cmLumiOpto platform, enhancing cytotoxicity across three TNBC cell lines, impairing mitochondrial function, and elevating the tumoral immune response. Furthermore, the ADC/cmLumiOpto combination suppresses TNBC metastasis in mouse models and inhibits tumor growth by 95%-100% in patient-derived xenograft models. Mechanistic investigations reveal downregulated metastatic signaling, tumor microenvironment remodeling, increased apoptosis, and upregulated tumoral immunity. Histological and body weight analyses indicate minimal systemic toxicity. These findings highlight the translational potential of combining CD276-targeted ADC with mitochondrial gene therapy to treat aggressive TNBC.
Pancreatic cancer remains one of the most aggressive and lethal malignancies, characterized by late-stage diagnosis, profound molecular heterogeneity, and limited responsiveness to conventional cytotoxic therapies. Recent advances in molecular diagnostics and biomarker-driven treatment stratification have accelerated the development of precision therapeutic approaches aimed at improving outcomes in selected patient populations. This review highlights three mechanistically distinct yet complementary therapeutic strategies that illustrate the evolving landscape of personalized pancreatic cancer management. Adagrasib represents targeted inhibition of oncogenic KRAS G12C signaling, reflecting recent progress in directly targeting historically "undruggable" driver mutations. Dostarlimab illustrates the tissue-agnostic application of immune checkpoint blockade in pancreatic cancers harboring mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H), highlighting the growing importance of biomarker-defined immunotherapy-responsive subsets despite the limited pancreatic cancer-specific clinical evidence currently available. Trastuzumab deruxtecan represents a next-generation HER2-directed antibody-drug conjugate (ADC) and demonstrates the potential of HER2-targeted therapy in the small subgroup of patients with HER2-positive pancreatic cancer, although the available evidence is derived primarily from basket trials and tumor-agnostic clinical development. Collectively, these therapeutic approaches underscore the expanding role of biomarker-guided treatment strategies integrating targeted inhibition, immunotherapy, and precision cytotoxic payload delivery. This review summarizes the molecular rationale, available clinical evidence, therapeutic limitations, and resistance mechanisms associated with these approaches while discussing emerging directions in translational research, rational combination strategies, liquid biopsy applications, and precision oncology that may further refine individualized treatment algorithms for pancreatic cancer.
Telisotuzumab Vedotin (Teliso-V), previously known as ABBV-399, is a novel, first-in-class antibodydrug conjugate developed by AbbVie. It combines an anti-c-Met monoclonal antibody (ABT-700) with monomethyl auristatin E (MMAE), a potent microtubule-disrupting agent, via a cleavable linker. This design allows selective delivery of the cytotoxic payload to c-Met-overexpressing tumour cells, thereby bypassing reliance on MET signalling for efficacy. Preclinical studies demonstrated that ABBV-399 effectively inhibited the growth of xenograft tumors refractory to other MET-targeted inhibitors. In early Phase I trials, the agent showed a favourable safety profile and elicited objective tumour responses in c-Met-expressing non-small cell lung cancer (NSCLC) patients. In the Phase II LUMINOSITY study, which served as the basis for accelerated FDA approval, Teliso-V demonstrated an overall response rate (ORR) of 35% and a median duration of response (DOR) of 9 months in patients with high c-Met protein overexpression. Continued approval may depend on confirmatory Phase III data.
Loncastuximab tesirine is a cysteine-linked antibody-drug conjugate composed of an anti-CD19 monoclonal antibody linked to the PBD dimer payload SG3249 via a protease-cleavable linker, enabling targeted release of a highly cytotoxic DNA cross-linking agent. NAC-SG3249, a thiol adduct formed with N-acetylcysteine, serves as an important indicator of payload release and ADC stability. In this study, mass spectrometry techniques were employed to systematically investigate the stability and related small-molecule impurities of this ADC. Quantitative analysis of the free payload showed good linearity over 0.05-100 ng/mL (R² ≥ 0.991), with an LLOQ of 0.05 ng/mL, accuracy of 80%-120%, and precision below 5%, and the results were consistent between HRMS and TQMS, both methods can achieve effective quantification. Potential payload-related impurities were further characterized based on predicted hydrolysis pathways using targeted MRM analysis. Forced degradation studies under acidic, alkaline, photolytic, and thermal conditions revealed multiple degradation products using a highly sensitive nanoLC-HRMS method, with alkaline conditions producing the greatest number of impurities. Clinical trial number: not applicable.
Antibody-drug conjugate (ADC) efficacy in solid tumors is often limited by low or heterogeneous antigen expression. Here, we investigated low-dose radiotherapy (LDRT) as a noninvasive sensitization strategy to enhance tumor surface antigen expression and improve ADC activity. Transcriptomic profiling and flow cytometry identified ICAM1 as the most strongly radiation-inducible antigen after 2 Gy irradiation, showing an approximately 4-fold increase and exceeding several established ADC targets. Mechanistic studies revealed that radiation-induced reactive oxygen species (ROS) and oxidative stress signaling upregulated ICAM1, enhanced antibody internalization, and improved ICAM1-targeted ADC delivery. In xenograft models, LDRT combined with ICAM1-targeted ADCs achieved >70% tumor growth inhibition with minimal toxicity. Transcriptomic and immunohistochemical (IHC) staining analyses further showed that LDRT induced recruitment of immunosuppressive CCL8high M2-like tumor-associated macrophages, whereas ADC-mediated bystander killing attenuated this adaptive feedback and promoted a more immunoactive tumor microenvironment. Together, these findings support LDRT as a clinically translatable strategy to increase ICAM1 expression, overcome antigen-low barriers, and enhance ADC efficacy in refractory solid tumors.
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.
Immune checkpoint inhibitors have transformed cancer treatment; however, resistance, on-target toxicity, and limited efficacy in autoimmune disorders have motivated next-generation immunotherapies. T cell engagers (TCEs) redirect cytotoxic T cells to kill pathogenic cells independently of MHC restriction, whereas antibody-drug conjugates (ADCs) deliver potent payloads directly into target cells via receptor-mediated internalization. This review synthesizes preclinical and clinical data on TCEs and ADCs in oncology and immune-mediated inflammatory disorders (IMIDs). The CD47/SIRPα innate immune checkpoint is briefly examined as a case study in next-generation immunopharmacology, with agents like evorpacept and BYON4228 showing encouraging objective response rates (50% ORR) in non-hodgkin lymphoma when combined with rituximab, with next-generation designs reducing hematologic toxicity. Recent compassionate use findings in autoimmunity demonstrate that CD19 × CD3 TCE (blinatumomab) and (B-cell maturation antigen) BCMA × CD3 TCE (teclistamab) elicit rapid clinical improvement in refractory antisynthetase syndrome and systemic sclerosis, accompanied by cytokine release syndrome (CRS) (grade 3 in 40% and 100% of patients, respectively) and no neurotoxicity. In engineered TCEs with attenuated CD3 affinity, grade 1-2 CRS occurs in < 20% of patients. Beyond cell-depleting strategies, bispecific antibodies targeting OX40L/TNFα and anti-TL1A antibodies are advancing in hidradenitis suppurativa and rheumatic diseases. Conversely, ADC strategies have yielded mixed results; an anti-TNF-glucocorticoid receptor modulator ADC failed to outperform adalimumab in a phase 2b trial. Safety profiles differ: TCEs predominantly cause cytokine release syndrome, whereas ADCs pose off-target payload toxicity risks. Emerging dual-targeting TCEs, half-life-extended formats, and rational combinations illustrate key immunopharmacological principles that may broaden the therapeutic landscape for cancer and autoimmune diseases.
Vobramitamab duocarmazine is an investigational antibody-drug conjugate (ADC) targeting B7 homolog 3 (B7-H3) with a cytotoxic duocarmycin-based DNA-alkylating payload. This study evaluated its safety and antitumor activity in advanced solid tumors. In this phase 1/2 trial (CP-MGC-018-01/NCT03729596), vobramitamab duocarmazine was evaluated at 0.5-4.0 mg/kg intravenously every 3 weeks. The multicohort tumor-expansion phase focused on metastatic castration-resistant prostate cancer (mCRPC), lung, breast, melanoma, and squamous head and neck carcinomas. Primary end points were safety and tolerability. Secondary end points included pharmacokinetics, immunogenicity, and antitumor activity. Across vobramitamab duocarmazine-treated patients, 97.9% (140 of 143) experienced treatment-related adverse events (TRAEs) of all grades; the grade ≥3 TRAE rate was 65.0% (93 of 143). With two dose-limiting toxicities in patients receiving 4.0 mg/kg (grade 4 afebrile neutropenia and grade 3 fatigue), the recommended dose for expansion was 3.0 mg/kg. Among all patients treated at 3.0 mg/kg, the rate of grade ≥3 TRAEs was 65.3% (79 of 121) and the confirmed objective response rate (ORR) was 7.2% (seven of 97), with a 6.3-month median duration of response (DOR). Among patients with mCRPC receiving 3.0 mg/kg, the confirmed ORR was 8.3% (two of 24), with a 5.3-month median DOR; the confirmed prostate-specific antigen with a ≥50% decline from the baseline response rate was 43.9% (18 of 41), with a 6.2-month median DOR. Vobramitamab duocarmazine demonstrated modest antitumor activity across tumor types, with the most pronounced activity in mCRPC. Treatment was limited by toxicity, particularly pleural effusions and fatigue, which restricted dosing duration. Study treatment was discontinued to refocus on mCRPC in a randomized phase 2 study (TAMARACK/NCT05551117), which was later discontinued after assessment of the vobramitamab duocarmazine safety and efficacy profile.
Non-small cell lung cancer (NSCLC) continues to be one of the leading causes of cancer death worldwide. Although targeted therapies and immune checkpoint inhibitors have meaningfully improved outcomes for some patients, many still lack targetable mutations or quickly develop resistance. Antibody-drug conjugates (ADCs), which combine tumor-specific antibodies with potent cytotoxic payloads, have become an increasingly promising option. This review looks at ADC-based combination strategies in NSCLC, grouped by key molecular targets such as Trop-2, HER2, HER3, c-Met, B7-H3, CEACAM5, and ITGβ6, along with bispecific ADCs. The literature was identified through searches of PubMed, ClinicalTrials.gov, and major oncology conference proceedings (including ASCO, ESMO, and WCLC). We examined published trial results, conference abstracts, and ongoing registered studies covering combinations with immune checkpoint inhibitors, EGFR tyrosine kinase inhibitors, chemotherapy, and other agents. ADC combinations are a fast-moving and exciting area in NSCLC. Trop-2 ADC plus ICI approaches show efficacy that appears strongly linked to PD-L1 levels, while certain EGFR-directed strategies, especially bispecific ADCs like izalontamab brengitecan with osimertinib, have demonstrated promising preliminary clinical activity. Still, success will hinge on strong single-agent activity, clear synergy, and reliable biomarkers for patient selection.
Immune checkpoint B7-H3 is an emerging target for immunotherapy. DS-7300a is an advanced B7-H3-targeting antibody-drug conjugate (ADC) warheaded with the topoisomerase I inhibitor DXd. DS-7300a has demonstrated clinical activity, but molecular biomarkers to predict its therapeutic response remain elusive. TP53 is one of the most mutated tumor suppressor genes across cancers, and effective therapies are urgently needed for TP53-deficient cancers. Using prostate cancer (PCa) as a model system, we reported that DS-7300a's anti-tumor efficacy is highly dependent on functional p53 in cancer cells, and TP53 defects confer resistance to DS-7300a. Mechanistically, we found that DS-7300a and its payload, DXd, induce DNA damage and activate the ATM/ATR/CHK signaling cascade, thereby stabilizing p53 and inducing a pro-apoptotic and senescence-associated transcriptome. In contrast, TP53-deficient cells fail to sense DXd-induced DNA damage, maintain a high proliferation rate, and exhibit low levels of apoptosis and senescence, thereby conferring resistance to DS-7300a. Ferroptosis is an iron-dependent form of regulated cell death triggered by lipid peroxidation, which is mechanistically and morphologically distinct from apoptosis. Interestingly, DS-7300a treatment elevates lipid peroxidation in TP53-deficient cancer cells and upregulates glutathione peroxidase 4 (GPX4), an antioxidant enzyme that mitigates lipid peroxidation. Using isogeneic xenograft models and a newly developed humanized B7-H3 PCa model, we demonstrated that inducing ferroptosis by pharmacological inhibition of GPX4 enhances DS-7300a's efficacy in TP53-deficient tumors. Our studies demonstrate that TP53 status dictates anti-tumor responses to DS-7300a, and ferroptosis induction represents a promising therapeutic approach to overcome resistance to DS-7300a in malignancies harboring TP53 defects.
Antibody-drug conjugates (ADCs) have become an increasingly important component of the therapeutic landscape of many solid tumors. Currently, there are eight ADCs approved for solid tumors, with hundreds being developed and in clinical trials. Initially being approved in the advanced or metastatic settings, ADCs are also being incorporated as neoadjuvant or adjuvant therapies. In this review, we discuss the important components of ADC design in the context of clinical successes and failures. We further evaluate mechanisms of intrinsic and acquired resistance and strategies to overcome these barriers. Finally, we discuss the landscape of potential combination partners to increase efficacy of ADC therapies.
Antibody-drug conjugates (ADCs) have significantly advanced cancer therapy by enabling the selective delivery of cytotoxic agents to tumour cells. However, ADC efficacy remains constrained by its dependence on a single target antigen, which limits tumour targeting and promotes resistance in heterogeneous tumours with variable and low antigen expression1-6. Here we introduce an in vivo bioorthogonal ligation strategy that generates functional antibody-ADC click constructs following systemic administration. This platform provides a modular and translatable approach for enhanced targeted drug delivery in heterogeneous tumours. We conjugate therapeutic antibodies and ADCs with trans-cyclooctene and tetrazine moieties for sequential administration to enable in vivo ligation of an antibody with an ADC after systemic delivery. The antibody-ADC click approach demonstrated improved antitumour activity relative to standard ADC monotherapy or antibody plus ADC combinations in preclinical models of HER2 and EGFR co-expression. These included tumours with low, ultralow, negative or heterogeneous HER2 expression and resistant or ineligible for conventional HER2-directed ADCs. This modular strategy leverages receptor biology and bioorthogonal chemistry for optimal therapeutic efficacy and does not require extensive antibody re-engineering. Moreover, the antibody-ADC click approach can be extended to other receptor pairs, which makes it a flexible modular platform to address heterogeneity and resistance to targeted therapies across different tumour types.