Antibody–Drug Conjugates in Contemporary Oncology: A Clinical Perspective on Dose Optimization, Sequencing, and Combination Strategies

Recent advances in function-enhanced antibody-drug conjugates: Antibody optimization and payload combination.

Antibody–drug conjugates in non-small cell lung cancer: current landscape and future directions

Antibody–drug conjugates (ADCs) represent a transformative therapeutic class in non-small cell lung cancer (NSCLC), moving precision oncology beyond traditional targeted therapies. These agents, composed of a monoclonal antibody, linker, and potent cytotoxic payload, enable targeted drug delivery to tumor cells expressing specific antigens like TROP2, HER2, and c-MET. Recent clinical trials have demonstrated remarkable efficacy of ADCs, both as monotherapy in molecularly defined populations and in combination with immunotherapy, offering new hope for patients with advanced disease. This review summarizes the latest clinical progress of ADCs in NSCLC, highlighting key agents and their impact, while also addressing the associated challenges and future directions for optimizing this promising treatment modality.

Beyond ADCs: Antibody-encapsulated drug for targeted cancer therapy

Antibody-drug conjugates (ADCs) have transformed cancer treatment by covalently linking the monoclonal antibody with cytotoxic payload, yet their clinical potential remains constrained by intrinsic limitations: heterogeneous drug-to-antibody ratios, linker instability, manufacturing complexity, and drug resistance. These challenges highlight the need for fundamentally different drug formulation and delivery platforms. Antibody-encapsulated drugs (AEDs) leverage the single protein encapsulation technology to enable one antibody to noncovalently encapsulate a predefined number of payload molecules. AEDs allow for a fixed drug-to-antibody ratio, mitigate premature drug release, simplify manufacturing, and expand the range of compatible payloads and protein molecules. Preclinical investigation of trastuzumab-encapsulated actinomycin D, a HER2-targeted AED, has demonstrated potent antitumor activity across cancer models with varying HER2 expression levels, alongside a favorable toxicity profile in animal models. The broader translational feasibility of the single protein encapsulation platform is further supported by ongoing clinical trials of albumin-encapsulated therapeutics. Together, these advances position AED as a promising next-generation targeted cancer therapy that complements and potentially extends beyond conventional ADCs, offering a compelling strategy to overcome existing resistance mechanisms and therapeutic limitations.

Antibody–Drug Conjugates and Peptide–Drug Conjugates: Current Understandings and Future Perspectives

Antibody–drug conjugates (ADCs) and peptide–drug conjugates (PDCs) are modular targeted therapeutics in which molecular recognition is coupled with controlled payload delivery. Owing to their high specificity and precision, they have been regarded as a transformative paradigm for cancer therapy. In this review, current understandings and future perspectives of ADCs and PDCs are synthesized across rational design principles, historical evolution, clinical translation, and emerging formats, aiming to improve practical comprehension and application in oncology. Key determinants of performance: target selection, antibody or peptide carrier attributes, linker stability and cleavage mechanisms, payload classes, and conjugation strategies, are additionally discussed. Milestone advances achieved spanning hematologic malignancies and solid tumors are emphatically summarized to provide a framework by which future conjugate development may be contextualized. In parallel, the expansion of PDCs as complementary platforms is outlined, and advantages are highlighted, while limitations are also considered. ADCs and PDCs still face challenges such as toxicity, resistance, and poor stability. However, through breakthroughs including linker optimization, novel payloads, bispecific designs, and AI‐driven approaches, future conjugated drugs will continue to evolve toward personalization, combination therapies, and broader indications. This article provides a systematic synthesis of extant research, thereby facilitating the future advancement of targeted conjugate drugs toward greater precision and individualization. It holds significant academic value as a reference resource and offers practical guidance for the development of novel antineoplastic therapeutics.

Linker Design in Antibody-Drug Conjugates: Balancing Stability and Drug Release

Antibody–drug conjugates (ADCs) have emerged as a powerful class of targeted therapeutics in many clinical areas, such as in oncology. Despite their efficacy, the onset of adverse events has been a major drawback in their clinical use. Among other explanations, the clinical performance of the ADCs has been associated with the chemistry of the linker connecting the antibody and payload. Linkers determine plasma stability, intracellular activation, and payload diffusibility, thereby influencing the therapeutic index, off-tumour toxicity, and by-stander activity. Mechanistic insights increasingly show that linker–payload properties govern catabolite permeability and intratumoral distribution, particularly in antigen-heterogeneous settings. Current developments include enzyme-cleavable and tumour-selective linkers, polarity-modulating masking strategies, alternative self-immolative spacers, and dual-trigger systems designed to enhance selectivity and decouple efficacy from toxicity. In parallel, linker behaviour intersects with broader mechanisms of tumour resistance. This review focuses on understanding these processes, which are essential for designing the next generation of linkers capable of improving stability, safety, and long-term therapeutic effectiveness across diverse tumour contexts.

Antibody–Drug Conjugates in Lung Cancer: Promise, Progress, and Persistent Challenges

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.