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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.
J Immunother. 2010 Jun; 33(5):500-9.JI

Abstract

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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20463597

Citation

Liu, Rong, et al. "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." Journal of Immunotherapy (Hagerstown, Md. : 1997), vol. 33, no. 5, 2010, pp. 500-9.
Liu R, Jiang W, Yang M, et al. 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. J Immunother. 2010;33(5):500-9.
Liu, R., Jiang, W., Yang, M., Guo, H., Zhang, Y., Wang, J., Zhu, H., Shi, R., Fan, D., Yang, C., Zhu, Z., Xie, Y., & Xiong, D. (2010). 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. Journal of Immunotherapy (Hagerstown, Md. : 1997), 33(5), 500-9. https://doi.org/10.1097/CJI.0b013e3181d75c20
Liu R, et al. 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. J Immunother. 2010;33(5):500-9. PubMed PMID: 20463597.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Liu,Rong, AU - Jiang,Wenguo, AU - Yang,Ming, AU - Guo,Hongxing, AU - Zhang,Yanjun, AU - Wang,Jinhong, AU - Zhu,Huifang, AU - Shi,Ruizan, AU - Fan,Dongmei, AU - Yang,Chunzheng, AU - Zhu,Zhenping, AU - Xie,Yong, AU - Xiong,Dongsheng, PY - 2010/5/14/entrez PY - 2010/5/14/pubmed PY - 2010/9/24/medline SP - 500 EP - 9 JF - Journal of immunotherapy (Hagerstown, Md. : 1997) JO - J. Immunother. VL - 33 IS - 5 N2 - 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. SN - 1537-4513 UR - https://www.unboundmedicine.com/medline/citation/20463597/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_ L2 - http://dx.doi.org/10.1097/CJI.0b013e3181d75c20 DB - PRIME DP - Unbound Medicine ER -