Lidický Ondřej, Renešová Nicol, Kudláčová Júlia, Filipová Marcela, Běláková Tereza, Kovaříková Petra, Manakov Dmitry, Pankrác Jan, Dolníková Alexandra, Pokorná Eva, Klener Pavel, Etrych Tomáš
Institute of Macromolecular Chemistry of the Czech Academy of Sciences, v.v.i., Heyrovského nám. 2, 162 00, Prague 6, Czech Republic.
Institute of Pathological Physiology, First Faculty of Medicine, Charles University, U Nemocnice 5, 128 53, Prague 2, Czech Republic.
J Control Release. 2025 Aug 10;384:113876. doi: 10.1016/j.jconrel.2025.113876. Epub 2025 May 21.
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.
B细胞非霍奇金淋巴瘤（B-NHL）是西半球最常见的血液系统恶性肿瘤，目前的一线治疗方案是基于免疫化疗（ICT），即基因毒性细胞抑制剂与抗CD20单克隆抗体（mAb）利妥昔单抗联合使用。复发或难治性（R/R）B-NHL的治疗仍然是未满足的医疗需求。在此，我们研发并在临床前对一种定制的杂交单克隆抗体-聚合物-药物偶联物（APDC）进行了表征，该偶联物由抗CD38单克隆抗体达雷妥尤单抗（临床批准用于多发性骨髓瘤治疗）和生物相容性的基于N-（2-羟丙基）甲基丙烯酰胺（HPMA）的共聚物组成，通过溶酶体酶可裂解的缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯间隔物与细胞毒性载荷单甲基奥瑞他汀E（MMAE）偶联。这种创新的APDC设计在保持与标准抗体-药物偶联物（ADC）相当的偶联度（DOC）的同时，显著提高了药物与抗体的比例（DAR）。与标准ADC相比，新型APDC纳米疗法增强的抗淋巴瘤疗效在体内使用来自一名R/R B-NHL患者的患者源性淋巴瘤异种移植模型得到了证实。这些APDC纳米药物有望成为一种个性化的靶向化疗方法。
