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

Li HF, Wu C, Chen T, Zhang G, Zhao H, Ke CH, Xu Z - Int J Nanomedicine (2015)

Bottom Line: Comparing with free mAbs, PPRT nanocomb possesses a comparable binding ability and reduced "off-rate" to surface CD20 of NHL 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.

View Article: PubMed Central - PubMed

Affiliation: International Joint Cancer Institute, Translation Medicine Institute, the Second Military Medical University, Shanghai, People's Republic of China ; Planning Division, Scientific Research Department, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, People's Republic of China ; Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, People's Republic of China.

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.

No MeSH data available.


Related in: MedlinePlus

In vitro NHL-suppressing ability of PPRT nanocomb.Notes: (A) CDC activity against NHL cells. (B) ADCC activity against NHL cells. (C) PCD-mediating ability against NHL cells. Data are expressed as mean ± standard deviation (n=3). **P<0.01.Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; NHL, non-Hodgkin lymphoma; NT, no treatment; PCD, programmed cell death; PPB, polyethylenimine polymer–BSA; PPRT, polyethylenimine polymer–RTX–Tos; RT, rituximab+tositumomab; RTX, rituximab; Tos, tositumomab.
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f3-ijn-10-4783: In vitro NHL-suppressing ability of PPRT nanocomb.Notes: (A) CDC activity against NHL cells. (B) ADCC activity against NHL cells. (C) PCD-mediating ability against NHL cells. Data are expressed as mean ± standard deviation (n=3). **P<0.01.Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; NHL, non-Hodgkin lymphoma; NT, no treatment; PCD, programmed cell death; PPB, polyethylenimine polymer–BSA; PPRT, polyethylenimine polymer–RTX–Tos; RT, rituximab+tositumomab; RTX, rituximab; Tos, tositumomab.

Mentions: Figure 3A and B reveal that RTX (type I) but not Tos (type II) exhibits potent ability to mediate CDC. Just as per our expectation, the abilities of PPRT nanocomb to mediate both CDC and ADCC are not affected when compared with parental mAbs (RTX + Tos) or PPRT nanocomb components (PPB + RTX + Tos) (P>0.05). Figure 3C demonstrates that PPRT nanocomb can elicit a significantly higher level of PCD (characterized by annexin V+ subsets) than that induced by combination treatment with PPRT nanocomb components (PPB + RTX + Tos, P<0.01) in all the three NHL cell lines. Because PPB control treatment was unable to induce significant cell death, this excellent PCD-inducing ability has nothing to do with the PEI polymer.


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

Li HF, Wu C, Chen T, Zhang G, Zhao H, Ke CH, Xu Z - Int J Nanomedicine (2015)

In vitro NHL-suppressing ability of PPRT nanocomb.Notes: (A) CDC activity against NHL cells. (B) ADCC activity against NHL cells. (C) PCD-mediating ability against NHL cells. Data are expressed as mean ± standard deviation (n=3). **P<0.01.Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; NHL, non-Hodgkin lymphoma; NT, no treatment; PCD, programmed cell death; PPB, polyethylenimine polymer–BSA; PPRT, polyethylenimine polymer–RTX–Tos; RT, rituximab+tositumomab; RTX, rituximab; Tos, tositumomab.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525799&req=5

f3-ijn-10-4783: In vitro NHL-suppressing ability of PPRT nanocomb.Notes: (A) CDC activity against NHL cells. (B) ADCC activity against NHL cells. (C) PCD-mediating ability against NHL cells. Data are expressed as mean ± standard deviation (n=3). **P<0.01.Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; NHL, non-Hodgkin lymphoma; NT, no treatment; PCD, programmed cell death; PPB, polyethylenimine polymer–BSA; PPRT, polyethylenimine polymer–RTX–Tos; RT, rituximab+tositumomab; RTX, rituximab; Tos, tositumomab.
Mentions: Figure 3A and B reveal that RTX (type I) but not Tos (type II) exhibits potent ability to mediate CDC. Just as per our expectation, the abilities of PPRT nanocomb to mediate both CDC and ADCC are not affected when compared with parental mAbs (RTX + Tos) or PPRT nanocomb components (PPB + RTX + Tos) (P>0.05). Figure 3C demonstrates that PPRT nanocomb can elicit a significantly higher level of PCD (characterized by annexin V+ subsets) than that induced by combination treatment with PPRT nanocomb components (PPB + RTX + Tos, P<0.01) in all the three NHL cell lines. Because PPB control treatment was unable to induce significant cell death, this excellent PCD-inducing ability has nothing to do with the PEI polymer.

Bottom Line: Comparing with free mAbs, PPRT nanocomb possesses a comparable binding ability and reduced "off-rate" to surface CD20 of NHL 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.

View Article: PubMed Central - PubMed

Affiliation: International Joint Cancer Institute, Translation Medicine Institute, the Second Military Medical University, Shanghai, People's Republic of China ; Planning Division, Scientific Research Department, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, People's Republic of China ; Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, People's Republic of China.

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.

No MeSH data available.


Related in: MedlinePlus