Construction and characterization of an anti-CD20 mAb nanocomb with exceptionally excellent lymphoma-suppressing activity

Abstract

The CD20-directed monoclonal antibody rituximab (RTX) established a new era in the treatment of non-Hodgkin lymphoma (NHL); however, suboptimal response and/or resistance to RTX still limit its clinical merits. Although four effector mechanisms are validated to participate in CD20-based immunotherapy, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, caspase-dependent apoptosis, and lysosome-mediated programmed cell death (PCD), they could hardly be synchronously activated by any anti-CD20 mAb or mAb derivative until now. Herein, a novel mAb nanocomb (polyethylenimine polymer–RTX–tositumomab [PPRT nanocomb]) was firstly constructed through mass arming two different anti-CD20 mAbs (RTX and tositumomab) to one polymer by nanotechnology. Comparing with free mAbs, PPRT nanocomb possesses a comparable binding ability and reduced “off-rate” to surface CD20 of NHL cells. When treated by PPRT nanocomb, the caspase-dependent apoptosis was remarkably enhanced except for concurrently eliciting complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and lysosome-mediated PCD. Besides, “cross-cell link”-assisted homotypic adhesion by PPRT nanocomb further enhanced the susceptibility to PCD of lymphoma cells. Pharmacokinetic assays revealed that PPRT nanocomb experienced a relatively reduced clearance from peripheral blood compared with free antibodies. With the cooperation of all the abovementioned superiorities, PPRT nanocomb exhibits exceptionally excellent in vivo antitumor activities in both disseminated and localized human NHL xenotransplant models.

Rituximab (anti-CD20)-modified AZD-2014-encapsulated nanoparticles killing of B lymphoma cells

“…The reason that Ab-NPs-AZD-2014 induced apoptosis was not simply due to the increased uptake of AZD-2014. Many studies have shown that cross-linking of CD20 on the surface of NHL cells may be important in inducing apoptosis/death of cells [32,33]. Compared with CD20-based monoclonal antibodies, CD20 monoclonal antibody-modified nanoparticles have stronger binding to cell surface CD20 molecules, reduce the "dissociation rate" of CD20 on the surface of NHL cells, and promote translocation of the cellular CD20 into lipid rafts; these effects inhibit P38 MAPK and ERK1/2 survival pathways and activation of caspase cascades [34].…”

Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia

“…PF-06747143 was added to CLL-B cells (1 × 10 6 /mL) in RPMI media with 5% active human serum [ 28 , 29 ] or inactivated human serum, which was incubated at 56 °C for 30 min. The heat-inactivated/normal human serum-treated cells were incubated for 4 h at 37 °C with increasing concentrations of PF-06747143.…”

Drug delivery methods for cancer immunotherapy

“…Significant prophylactic effect with reduced growth of tumor cells [ 69 ] Poly(propylene sulfide)-based nanoparticles OVA and CpG adjuvant (cancer vaccine) Potent CD8 + -based immune responses, significant tumor regression and enhanced survival [ 70 ] Polyethylenimine-based polymer conjugate Lymphoma Rituximab and tositumomab Binding affinity with reduced off-target effects and minimal bold clearance. Long-term survival with significant tumor growth inhibition [ 71 ] Targeted CXCL13-zwitterionic particles (2-methacryloyloxy-ethyl phosphorylcholine monomers and glycerol dimethacrylate crosslinkers) Rituximab Ability to cross BBB and reach the CNS. pH-responsive sustained release.…”

“…This nanoconjugate possesses the same binding affinity to non-Hodgkin lymphoma cells as the free antibodies but with reduced off-target effects and minimal blood clearance. The intravenous administration of this formulation in non-Hodgkin lymphoma-bearing mice results in a long-term survival with a significant inhibition of the tumor growth [ 71 ]. In the case of the central nervous system (CNS) lymphoma, Wen et al encapsulated the monoclonal antibody rituximab in zwitterionic polymeric particles, which were synthesized using 2-methacryloyloxyethyl phosphorylcholine (MPC) monomers and glycerol dimethacrylate (GDMA) crosslinkers, to cross the blood–brain barrier and reach the CNS.…”