Antibody polymer drug conjugates with increased drug to antibody ratio: CD38-targeting nanomedicines for innovative therapy of relapsed lymphomas
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články
PubMed
40409372
DOI
10.1016/j.jconrel.2025.113876
PII: S0168-3659(25)00496-1
Knihovny.cz E-zdroje
- Klíčová slova
- Active targeting, Anti-CD38, Antibody polymer drug conjugates, Daratumumab, Diffuse large B-cell lymphoma, Monomethyl auristatin E, Non-Hodgkin lymphoma,
- MeSH
- akrylamidy chemie MeSH
- aminobenzoáty aplikace a dávkování chemie MeSH
- antigeny CD38 * imunologie MeSH
- B-buněčný lymfom * farmakoterapie MeSH
- imunokonjugáty * aplikace a dávkování chemie terapeutické užití MeSH
- lidé MeSH
- monoklonální protilátky * aplikace a dávkování chemie terapeutické užití farmakokinetika MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nanomedicína MeSH
- oligopeptidy MeSH
- polymery * chemie MeSH
- protinádorové látky * aplikace a dávkování terapeutické užití chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- akrylamidy MeSH
- aminobenzoáty MeSH
- antigeny CD38 * MeSH
- daratumumab MeSH Prohlížeč
- imunokonjugáty * MeSH
- monoklonální protilátky * MeSH
- monomethyl auristatin E MeSH Prohlížeč
- N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
- oligopeptidy MeSH
- polymery * MeSH
- protinádorové látky * MeSH
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.
Citace poskytuje Crossref.org
