Antibody polymer drug conjugates with increased drug to antibody ratio: CD38-targeting nanomedicines for innovative therapy of relapsed lymphomas
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
40409372
DOI
10.1016/j.jconrel.2025.113876
PII: S0168-3659(25)00496-1
Knihovny.cz E-resources
- Keywords
- Active targeting, Anti-CD38, Antibody polymer drug conjugates, Daratumumab, Diffuse large B-cell lymphoma, Monomethyl auristatin E, Non-Hodgkin lymphoma,
- MeSH
- Acrylamides chemistry MeSH
- Aminobenzoates administration & dosage chemistry MeSH
- ADP-ribosyl Cyclase 1 * immunology MeSH
- Lymphoma, B-Cell * drug therapy MeSH
- Immunoconjugates * administration & dosage chemistry therapeutic use MeSH
- Humans MeSH
- Antibodies, Monoclonal * administration & dosage chemistry therapeutic use pharmacokinetics MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Nanomedicine MeSH
- Oligopeptides MeSH
- Polymers * chemistry MeSH
- Antineoplastic Agents * administration & dosage therapeutic use chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acrylamides MeSH
- Aminobenzoates MeSH
- ADP-ribosyl Cyclase 1 * MeSH
- daratumumab MeSH Browser
- Immunoconjugates * MeSH
- Antibodies, Monoclonal * MeSH
- monomethyl auristatin E MeSH Browser
- N-(2-hydroxypropyl)methacrylamide MeSH Browser
- Oligopeptides MeSH
- Polymers * MeSH
- Antineoplastic Agents * 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.
References provided by Crossref.org
