Efficient inhibition of human B-cell lymphoma in SCID mice by synergistic antitumor effect of human 4-1BB ligand/anti-CD20 fusion proteins and anti-CD3/anti-CD20 diabodies.
Here we constructed and produced a recombinant human 4-1BB ligand (4-1BBL)/anti-CD20 fusion protein and examined its antitumor activity, alone and in combination with an anti-CD3/anti-CD20 bispecific diabody. The 4-1BBL/anti-CD20 fusion protein retained both the costimulatory activity of 4-1BBL on T cells and the tumor targeting ability of CD20 antibody on B cells. The fusion protein bound as efficiently to 4-1BB- and CD20-positive cells as its respective parental antibodies, and was capable of cross-linking human T lymphocytes and CD20-positive tumor cells. Combination treatment with 4-1BBL/anti-CD20 fusion protein and anti-CD3/anti-CD20 diabody led to significantly increased T-cell cytotoxicity to human B-lymphoma cells in vitro and drastically more potent tumor inhibitory activity in vivo in xenografted B-cell lymphoma in severe combined immunodeficiency disease mice. Mechanistic studies revealed that the combination treatment remarkably inhibited apoptosis of human peripheral blood lymphocytes, accompanied by upregulation of Bcl-XL and Bf1-1, perforin and granzyme B mRNA, and increased interleukin-2 production. Taken together, these results suggest that targeted delivery of 4-1BBL to the tumor site, when combined with anti-CD3/anti-CD20 diabody, could strongly potentiate the antitumor activity of the diabody, thus may have significant clinical application in the treatment of human CD20-positive B-cell malignancies.
Liu
Rong
R
State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Disease, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, People's Republic of China.
Jiang
Wenguo
W
Yang
Ming
M
Guo
Hongxing
H
Zhang
Yanjun
Y
Wang
Jinhong
J
Zhu
Huifang
H
Shi
Ruizan
R
Fan
Dongmei
D
Yang
Chunzheng
C
Zhu
Zhenping
Z
Xie
Yong
Y
Xiong
Dongsheng
D
D053330:4-1BB Ligand / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017252:CD3 Complex / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D000069283:Rituximab; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051020:bcl-X Protein / Q000096:biosynthesis* / Q000235:genetics
D053330:4-1BB Ligand; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D017252:CD3 Complex; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D000069283:Rituximab