Daratumumab Immunopolymersome-Enabled Safe and CD38-Targeted Chemotherapy and Depletion of Multiple Myeloma
Na Yu1, Yifan Zhang1, Jiaying Li2, Wenxing Gu1, Shujing Yue1, Bin Li2, Fenghua Meng1, Huanli Sun1,*（孙欢利）, Rainer Haag3, Jiandong Yuan4, and Zhiyuan Zhong1,*（钟志远）
1 Biomedical Polymers Laboratory ,College of Chemistry Chemical Engineering and Materials Science ,State Key Laboratory of Radiation Medicine and Protection,Soochow University,Suzhou 215123, P. R. China
2 Department of Orthopaedic Surgery Orthopaedic Institute The First Affiliated Hospital,Soochow University,Suzhou 215007, P. R. China
3 Department of Biology Chemistry and Pharmacy Institute for Chemistry and Biochemistry,Freie University Berlin,14195 Berlin, Germany
4 BrightGene Bio-Medical Technology Co, Ltd Suzhou 215123, P. R. China
Adv. Mater. 2021, 2007787
Multiple myeloma (MM) is a second ranking hematological malignancy. Despite the fast advancement of new treatments such as bortezormib and daratumumab, MM patients remain incurable and tend to eventually become relapsed and drug-resistant. Development of novel therapies capable of depleting MM cells is strongly needed. Here, daratumumab immunopolymersomes carrying vincristine sulfate (Dar-IPs-VCR) are reported for safe and high-efficacy CD38-targeted chemotherapy and depletion of orthotopic MM in vivo. Dar-IPs-VCR made by postmodification via strain-promoted click reaction holds tailored antibody density (2.2, 4.4 to 8.7 Dar per IPs), superb stability, small size (43–49 nm), efficacious VCR loading, and glutathioneresponsive VCR release. Dar4.4-IPs-VCR induces exceptional anti-MM activity with an IC50 of 76 × 10−12 m to CD38-positive LP-1 MM cells, 12- and 20-fold enhancement over nontargeted Ps-VCR and free VCR controls, respectively. Intriguingly, mice bearing orthotopic LP-1-Luc MM following four cycles of i.v. administration of Dar4.4-IPs-VCR at 0.25 mg VCR equiv. kg−1 reveal complete depletion of LP-1-Luc cells, superior survival rate to all controls, and no body weight loss. The bone and histological analyses indicate bare bone and organ damage. Dar-IPs-VCR appears as a safe and targeted treatment for CD38-overexpressed hematological malignancies.
链接：https://onlinelibrary.wiley.com/doi/epdf/10.1002/adma.202007787