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 Blood, 15 February 2006, Vol. 107, No. 4, pp. 1564-1569.
Prepublished online as a Blood First Edition Paper on October 18, 2005; DOI 10.1182/blood-2005-07-2738.

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Submitted July 11, 2005
Accepted September 30, 2005

Use of trifunctional bispecific antibodies to prevent graft-versus-host disease induced by allogeneic lymphocytes

Shoshana Morecki*, Horst Lindhofer, Elena Yacovlev, Yael Gelfand, and Shimon Slavin

Department of Bone Marrow Transplantation & Cancer Immunotherapy, Cell Therapy & Transplantation Research Center, Hadassah University Hospital, Jerusalem, Israel
TRION Research, Martinsried, Germany

* Corresponding author; email: morecki{at}hadassah.org.il.

A trifunctional bispecific antibody (BiLu) directed against murine CD3 and human epithelial cell adhesion molecule (EpCAM) was tested for its ability to improve cell-mediated adoptive immunotherapy in a murine model of B-16 melanoma cells transfected with human EpCAM. Intraperitoneal (IP) inoculation of naive C57BL/6 (C57) splenocytes induced lethal graft-versus-host-disease (GVHD) in 85-97% of sub-lethally irradiated (BALB/c x C57BL/6)F1 (F1) hosts inoculated IP with a sub-lethal or lethal dose of melanoma cells. BiLu antibodies given IP concomitantly with alloreactive C57 cells, effectively prevented GVHD-related and tumor-related death in 16/25 F1 mice inoculated with a sub-lethal tumor cell dose and in 10/20 mice inoculated with a lethal tumor cell dose over a follow-up period of >200 days. Bilu treatment also efficiently prevented severe GVHD, which was induced by high doses of BALB/c derived splenocytes. Trifunctional bispecific antibodies capable of cross-linking T lymphocytes, natural killer, and other Fc{gamma}R+ effector cells, via their Fc-region, to the tumor cells, may be applied together with adoptive allogeneic cell therapy to maximize anti-tumor responses while acting on GVHD in patients with minimal residual disease.


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