Antibody-drug conjugates (antibody drug conjugates, ADCs) are a leading class of targeted cancer therapeutics that couple a tumour-associated antigen-specific antibody to a toxic payload, enabling selective delivery of cytotoxic therapy. They have advanced rapidly in oncology, with over 430 ADCs reaching early-to-late clinical studies over the past two decades and 14 FDA-approved agents for clinical cancer use. Mechanistically, ADC performance depends on antigen targeting, internalization, payload release, and resistance biology, and recent work highlights how the tumor microenvironment can constrain delivery and activity. Clinically, ADCs are being applied across breast cancer, relapsed/refractory multiple myeloma, non-small cell lung cancer, bladder cancer, and several oncofusion-driven sarcomas and lymphomas. Current development includes next-generation constructs targeting b7 h3, cmet, gd2, gpc2, il1rap, trop 2, and trophoblast cell surface antigen 2, with AI/ML approaches such as xgboost used to prioritize favorable half-life profiles in mice. Recent literature also emphasizes resistance mechanisms in breast cancer and emerging activity in EGFR-mutant NSCLC after third-generation EGFR TKI resistance.
Cancer
- ADCs have revolutionized the treatment landscape of breast cancer, with recent reviews focusing on resistance mechanisms and strategies to overcome them. (PMID:41874465)
- In non small cell lung cancer, ADCs targeting trop 2 and cmet are entering clinical trials, including settings with acquired resistance to third-generation EGFR TKIs. (PMID:41945491; PMID:41730505)
- ADCs are being evaluated as systemic therapies in bladder cancer clinical trials, reflecting broader oncology adoption. (PMID:41964855)
- The field has expanded to next-generation targets including b7 h3, gd2, gpc2, and trophoblast cell surface antigen 2. (PMID:41855081)
Hematologic malignancy
- ADCs are described as one of the backbones of treatment for relapsed refractory multiple myeloma. (PMID:41842719)
- Engineered ADCs targeting il1rap showed potent activity against primary and metastatic disease in multiple oncofusion-driven cancers. (PMID:41973074)
- il1rap-targeting ADCs blocked growth of anaplastic large cell lymphoma xenografts. (PMID:41973074)
- il1rap-targeting ADCs also induced durable regression in ewing sarcoma models and suppressed syngeneic sarcoma growth. (PMID:41973074)
Drug design, resistance, and optimization
- A state-of-the-art review summarizes ADC design and mechanism of action, emphasizing antibody specificity plus toxic payload delivery as the core therapeutic principle. (PMID:41855081)
- Resistance in breast cancer is a major focus, with biological mechanisms and analytical frameworks proposed to overcome ADC failure. (PMID:41874465)
- Tumor microenvironmental factors are recognized as constraints on ADC delivery and activity, contributing to resistance. (PMID:41874465)
- A multi-modal machine learning framework using xgboost prioritized ADCs with favorable half-life in C57BL/6 mice. (PMID:41996252)