Multivalent rituximab lipid nanoparticles as improved lymphoma therapies: indirect mechanisms of action and in vivo activity.
OBJECTIVE
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).


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.


CONCLUSIONS
Although indirect and direct mechanisms of multivalent Ritux are enhanced, its further development requires methods to improve its circulation lifetime.
Department of Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Ave., Vancouver BC, V5Z 1L3, Canada.
Jesse
J
Popov
Anita I
AI
Kapanen
Christopher
C
Turner
Rebecca
R
Ng
Catherine
C
Tucker
Gigi
G
Chiu
Richard
R
Klasa
Marcel B
MB
Bally
Ghania
G
Chikh
D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008223:Lymphoma / Q000188:drug therapy*; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D000069283:Rituximab
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008055:Lipids; D000069283:Rituximab