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A highly effective and stable bispecific diabody for cancer immunotherapy: cure of xenografted tumors by bispecific diabody and T-LAK cells.
Cancer Immunol Immunother. 2004 Jun; 53(6):497-509.CI

Abstract

PURPOSE

In the field of cancer immunotherapy research, the targeting of effector cells with specific antibodies is a very promising approach. Recent advances in genetic engineering have made it possible to prepare immunoglobulin fragments consisting of variable domains using bacterial expression systems.

METHODS

We have produced an anti-epidermal growth-factor receptor (EGFR) x anti-CD3 bispecific diabody (Ex3 diabody) in an Escherichia coli (E. coli) expression system with refolding method. The Ex3 diabody targets lymphokine-activated killer cells with a T-cell phenotype (T-LAK cells) to EGFR positive bile duct carcinoma cells with dramatic enhancement of cytotoxicity in vitro. This specific killing of EGFR-positive cells was completely inhibited by parental mAb IgGs directed to EGFR and the CD3 antigen.

RESULTS

When T-LAK cells were cultured with EGFR-positive tumor cells in the presence of Ex3 diabody, they produced much higher levels of IFN-gamma, GM-CSF, and TNF-alpha than in its absence, this being a possible mechanism underlying specific antitumor activity. The Ex3 diabody showed good stability when tested at 37 degrees C for 48 h, and also markedly inhibited tumor growth of bile duct carcinoma xenografts in severe combined immunodeficient (SCID) mice. When Ex3 diabody (20 microg/mouse) was administrated intravenously, together with T-LAK cells and interleukin-2 (IL-2), complete cure of tumors were observed in three of six mice, and the other three showed marked retardation of tumor growth.

CONCLUSION

The Ex3 diabody can be considered a highly promising reagent for study of specific targeting immunotherapy against bile duct and other EGFR-positive carcinomas.

Authors+Show Affiliations

Division of Gastroenterological Surgery, Department of Surgery, Graduate School of Medicine, Tohoku University, Seiryomachi 1-1, Aoba-ku, 980-8574 Sendai, Japan.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 availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

14648071

Citation

Hayashi, Hiroki, et al. "A Highly Effective and Stable Bispecific Diabody for Cancer Immunotherapy: Cure of Xenografted Tumors By Bispecific Diabody and T-LAK Cells." Cancer Immunology, Immunotherapy : CII, vol. 53, no. 6, 2004, pp. 497-509.
Hayashi H, Asano R, Tsumoto K, et al. A highly effective and stable bispecific diabody for cancer immunotherapy: cure of xenografted tumors by bispecific diabody and T-LAK cells. Cancer Immunol Immunother. 2004;53(6):497-509.
Hayashi, H., Asano, R., Tsumoto, K., Katayose, Y., Suzuki, M., Unno, M., Kodama, H., Takemura, S., Yoshida, H., Makabe, K., Imai, K., Matsuno, S., Kumagai, I., & Kudo, T. (2004). A highly effective and stable bispecific diabody for cancer immunotherapy: cure of xenografted tumors by bispecific diabody and T-LAK cells. Cancer Immunology, Immunotherapy : CII, 53(6), 497-509.
Hayashi H, et al. A Highly Effective and Stable Bispecific Diabody for Cancer Immunotherapy: Cure of Xenografted Tumors By Bispecific Diabody and T-LAK Cells. Cancer Immunol Immunother. 2004;53(6):497-509. PubMed PMID: 14648071.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A highly effective and stable bispecific diabody for cancer immunotherapy: cure of xenografted tumors by bispecific diabody and T-LAK cells. AU - Hayashi,Hiroki, AU - Asano,Ryutaro, AU - Tsumoto,Kouhei, AU - Katayose,Yu, AU - Suzuki,Masanori, AU - Unno,Michiaki, AU - Kodama,Hideaki, AU - Takemura,Shin-ichi, AU - Yoshida,Hiroshi, AU - Makabe,Koki, AU - Imai,Kohzoh, AU - Matsuno,Seiki, AU - Kumagai,Izumi, AU - Kudo,Toshio, Y1 - 2003/11/25/ PY - 2003/07/10/received PY - 2003/09/24/accepted PY - 2003/12/3/pubmed PY - 2004/6/29/medline PY - 2003/12/3/entrez SP - 497 EP - 509 JF - Cancer immunology, immunotherapy : CII JO - Cancer Immunol Immunother VL - 53 IS - 6 N2 - PURPOSE: In the field of cancer immunotherapy research, the targeting of effector cells with specific antibodies is a very promising approach. Recent advances in genetic engineering have made it possible to prepare immunoglobulin fragments consisting of variable domains using bacterial expression systems. METHODS: We have produced an anti-epidermal growth-factor receptor (EGFR) x anti-CD3 bispecific diabody (Ex3 diabody) in an Escherichia coli (E. coli) expression system with refolding method. The Ex3 diabody targets lymphokine-activated killer cells with a T-cell phenotype (T-LAK cells) to EGFR positive bile duct carcinoma cells with dramatic enhancement of cytotoxicity in vitro. This specific killing of EGFR-positive cells was completely inhibited by parental mAb IgGs directed to EGFR and the CD3 antigen. RESULTS: When T-LAK cells were cultured with EGFR-positive tumor cells in the presence of Ex3 diabody, they produced much higher levels of IFN-gamma, GM-CSF, and TNF-alpha than in its absence, this being a possible mechanism underlying specific antitumor activity. The Ex3 diabody showed good stability when tested at 37 degrees C for 48 h, and also markedly inhibited tumor growth of bile duct carcinoma xenografts in severe combined immunodeficient (SCID) mice. When Ex3 diabody (20 microg/mouse) was administrated intravenously, together with T-LAK cells and interleukin-2 (IL-2), complete cure of tumors were observed in three of six mice, and the other three showed marked retardation of tumor growth. CONCLUSION: The Ex3 diabody can be considered a highly promising reagent for study of specific targeting immunotherapy against bile duct and other EGFR-positive carcinomas. SN - 0340-7004 UR - https://www.unboundmedicine.com/medline/citation/14648071/A_highly_effective_and_stable_bispecific_diabody_for_cancer_immunotherapy:_cure_of_xenografted_tumors_by_bispecific_diabody_and_T_LAK_cells_ L2 - https://dx.doi.org/10.1007/s00262-003-0465-9 DB - PRIME DP - Unbound Medicine ER -