Nanomedicine (London, England) · 2011
Multivalent rituximab lipid nanoparticles as improved lymphoma therapies: indirect mechanisms of action and in vivo activity.
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Popov Jesse, Kapanen Anita I, Turner Christopher, Ng Rebecca, Tucker Catherine, Chiu Gigi, Klasa Richard, Bally Marcel B, Chikh Ghania
Аннотация
AIMS: The activity of therapeutic antibodies can be enhanced by creating multivalent constructs, such as antibody lipid nanoparticles (LNPs). Here, we examine differences between rituximab (Ritux) and Ritux-LNPs in terms of their indirect mechanisms of action: complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).
MATERIALS & METHODS: We employed two mantle-cell lymphoma cell lines, Z138 and JVM2, which exhibit different in vivo sensitivities to Ritux along with variable expression levels of cell-surface proteins that regulate ADCC and CDC.
RESULTS: In both cell lines, CDC and ADCC were found to be significantly enhanced after treatment with Ritux-LNPs compared with Ritux. In vivo efficacy studies, however, suggested that the therapeutic activities of Ritux and Ritux-LNPs were equivalent, which was subsequently explained in part by pharmacokinetic studies indicating rapid elimination of Ritux-LNP.
CONCLUSION: Although indirect and direct mechanisms of multivalent Ritux are enhanced, its further development requires methods to improve its circulation lifetime.
MATERIALS & METHODS: We employed two mantle-cell lymphoma cell lines, Z138 and JVM2, which exhibit different in vivo sensitivities to Ritux along with variable expression levels of cell-surface proteins that regulate ADCC and CDC.
RESULTS: In both cell lines, CDC and ADCC were found to be significantly enhanced after treatment with Ritux-LNPs compared with Ritux. In vivo efficacy studies, however, suggested that the therapeutic activities of Ritux and Ritux-LNPs were equivalent, which was subsequently explained in part by pharmacokinetic studies indicating rapid elimination of Ritux-LNP.
CONCLUSION: Although indirect and direct mechanisms of multivalent Ritux are enhanced, its further development requires methods to improve its circulation lifetime.