2. Academic Validation
  3. Antibody polymer drug conjugates with increased drug to antibody ratio: CD38-targeting nanomedicines for innovative therapy of relapsed lymphomas

Antibody polymer drug conjugates with increased drug to antibody ratio: CD38-targeting nanomedicines for innovative therapy of relapsed lymphomas

  • J Control Release. 2025 Aug 10:384:113876. doi: 10.1016/j.jconrel.2025.113876.
Ondřej Lidický 1,  Nicol Renešová 2,  Júlia Kudláčová 1,  Marcela Filipová 1,  Tereza Běláková 1,  Petra Kovaříková 3,  Dmitry Manakov 2,  Jan Pankrác 4,  Alexandra Dolníková 2,  Eva Pokorná 2,  Pavel Klener 3,  Tomáš Etrych 5
Affiliations

Affiliations

  • 1 Institute of Macromolecular Chemistry of the Czech Academy of Sciences, v.v.i., Heyrovského nám. 2, 162 00, Prague 6, Czech Republic.
  • 2 Institute of Pathological Physiology, First Faculty of Medicine, Charles University, U Nemocnice 5, 128 53, Prague 2, Czech Republic.
  • 3 Institute of Pathological Physiology, First Faculty of Medicine, Charles University, U Nemocnice 5, 128 53, Prague 2, Czech Republic; First Department of Internal Medicine-Department of Hematology, General University Hospital in Prague and First Faculty of Medicine, Charles University, U Nemocnice 2, 128 08, Prague 2, Czech Republic.
  • 4 Center for Advanced Preclinical Imaging (CAPI), First Faculty of Medicine, Charles University, Salmovská 3, Prague 2, 120 00, Czech Republic.
  • 5 Institute of Macromolecular Chemistry of the Czech Academy of Sciences, v.v.i., Heyrovského nám. 2, 162 00, Prague 6, Czech Republic. Electronic address: etrych@imc.cas.cz.
PMID: 40409372 DOI: 10.1016/j.jconrel.2025.113876
Abstract

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.

Keywords

Active targeting; Anti-CD38; Antibody polymer drug conjugates; Daratumumab; Diffuse large B-cell lymphoma; Monomethyl auristatin E; Non-Hodgkin lymphoma.

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