2025/05/21 by Ondřej Lidický, Nicol Renešová, Júlia Kudláčová +9 · 1 voice
Medicine · Chemistry · #HER2/EGFR in Cancer Research #Monoclonal and Polyclonal Antibodies Research #Synthesis and Biological Evaluation
paper · doi:10.1016/j.jconrel.2025.113876
openalex publication_date 2025/05/21 · openalex created_date 2025/10/10 · openalex updated_date 2026/06/24
The current frontline therapy for B-cell non-Hodgkin lymphomas (B-NHL), the most frequent hematologic malignancy in the Western hemisphere, is based on immunochemotherapy (ICT), i.e., a combination of genotoxic cytostatics and the anti-CD20 monoclonal antibody (mAb) rituximab. The treatment of relapsed or refractory (R/R) B-NHL remains an unmet medical need. Here, we developed and preclinically characterized a tailored hybrid mAb-polymer-drug conjugate (APDC) composed of the anti-CD38 mAb daratumumab (clinically approved for multiple myeloma therapy) and biocompatible N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymers conjugated with a cytotoxic payload monomethyl auristatine E (MMAE) via a Val-Cit-para-amino benzyl carbamate spacer cleavable by lysosomal enzymes. This innovative APDC design results in a significantly higher drug-to-antibody ratio (DAR) while maintaining a degree-of-conjugation (DOC) comparable to that of standard antibody-drug conjugates (ADCs). The enhanced anti-lymphoma efficacy of the new APDC nanotherapeutics, compared to standard ADCs, was confirmed in vivo using patient-derived lymphoma xenografts from a patient with R/R B-NHL. These APDC nanomedicines show promise as a personalized targeted chemotherapy approach.