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Anti-CD20 multivalent HPMA copolymer-Fab' conjugates for the direct induction of apoptosis.

ABSTRACT: A hybrid biomimetic system comprising high-molecular-weight, linear copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) grafted with multiple Fab' fragments of anti-CD20 monoclonal antibody (mAb) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization followed by attachment of Fab' fragments via thioether bonds. Exposure of human non-Hodgkin's lymphoma (NHL) Raji B cells to the multivalent conjugates resulted in crosslinking of CD20 receptors and commencement of apoptosis. Five conjugates with varying molecular weight and valence (amount of Fab' per polymer chain) were synthesized. One of the copolymers contained enzyme degradable peptide sequences (GFLG) in the backbone. The multivalency led to higher avidity and apoptosis induction compared to unconjugated whole mAb. Time-dependent studies showed that the cytotoxicity of conjugates exhibited a slower onset at shorter exposure times than mAb hyper-crosslinked with a secondary Ab; however, at longer time intervals the HPMA copolymer conjugates achieved significantly higher biological efficacies. In addition, study of the relationship between the structure of conjugates and Raji B cell apoptosis revealed that both valency and polymer molecular weight influenced biological activities, while insertion of peptide sequences into the backbone was not a factor in vitro.

SUBMITTER: Chu TW

PROVIDER: S-EPMC3572842 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Anti-CD20 multivalent HPMA copolymer-Fab' conjugates for the direct induction of apoptosis.

Chu Te-Wei TW Yang Jiyuan J Kopeček Jindřich J

Biomaterials 20120712 29

A hybrid biomimetic system comprising high-molecular-weight, linear copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) grafted with multiple Fab' fragments of anti-CD20 monoclonal antibody (mAb) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization followed by attachment of Fab' fragments via thioether bonds. Exposure of human non-Hodgkin's lymphoma (NHL) Raji B cells to the multivalent conjugates resulted in crosslinking of CD20 receptors and commencement ...[more]

PMID: 22795544

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Project description:Recently, we developed 2nd generation backbone degradable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates which contain enzymatically cleavable sequences (GFLG) in both polymeric backbone and side-chains. This design allows using polymeric carriers with molecular weights above renal threshold without impairing their biocompatibility, thereby leading to significant improvement in therapeutic efficacy. For example, 2nd generation HPMA copolymer-epirubicin (EPI) conjugates (2P-EPI) demonstrated complete tumor regression in the treatment of mice bearing ovarian carcinoma. To obtain a better understanding of the in vivo fate of this system, we developed a dual-labeling strategy to simultaneously investigate the pharmacokinetics and biodistribution of the polymer carrier and drug EPI. First, we synthesized two different types of dual-radiolabeled conjugates, including 1) (111)In-2P-EPI-(125)I (polymeric carrier 2P was radiolabeled with (111)In and drug EPI with (125)I), and 2) (125)I-2P-EPI-(111)In (polymeric carrier 2P was radiolabeled with (125)I and drug EPI with (111)In). Then, we compared the pharmacokinetics and biodistribution of these two dual-labeled conjugates in female nude mice bearing A2780 human ovarian carcinoma. There was no significant difference in the blood circulation between polymeric carrier and payload; the carriers ((111)In-2P and (125)I-2P) showed similar retention of radioactivity in both tumor and major organs except kidney. However, compared to (111)In-labeled payload EPI, (125)I-labeled EPI showed lower radioactivity in normal organs and tumor at 48h and 144h after intravenous administration of conjugates. This may be due to different drug release rates resulting from steric hindrance to the formation of enzyme-substrate complex as indicated by cleavage experiments with lysosomal enzymes (Tritosomes). A slower release rate of EPI(DTPA)(111)In than EPI(Tyr)(125)I was observed. It may be also due to in vivo catabolism and subsequent iodine loss as literature reported. Nevertheless, tumor-to-tissue uptake ratios of both radionuclides were comparable, indicating that drug-labeling strategy does not affect the tumor targeting ability of HPMA copolymer conjugates.

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Anti-CD20 multivalent HPMA copolymer-Fab' conjugates for the direct induction of apoptosis.

Publications

Anti-CD20 multivalent HPMA copolymer-Fab' conjugates for the direct induction of apoptosis.

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