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J. Biol. Chem., Vol. 282, Issue 39, 28301-28308, September 28, 2007

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Specific Targeting to Murine Myeloma Cells of Cyt1Aa Toxin from Bacillus thuringiensis Subspecies israelensis^*

Shmuel Cohen, Rivka Cahan¹, Eitan Ben-Dov^¶, Marina Nisnevitch, Arieh Zaritsky¹, and Michael A. Firer¹²

From the Department of Life Sciences, Ben-Gurion University of the Negev, P. O. 653, Be'er-Sheva 84105, Israel, Department of Chemical Engineering and Biotechnology, College of Judea and Samaria, Ariel 44837, Israel, and ^¶Achva Academic College, MP Shikmim 79800, Israel

Multiple myeloma is currently an incurable cancer of plasma B cells often characterized by overproduction of abnormally high quantities of a patient-specific, clonotypic immunoglobulin "M-protein." The M-protein is expressed on the cell membrane and secreted into the blood. We previously showed that ligand-toxin conjugates (LTC) incorporating the ribosome-inactivating Ricin-A toxin were very effective in specific cytolysis of the anti-ligand antibody-bearing target cells used as models for multiple myeloma. Here, we report on the incorporation of the membrane-disruptive Cyt1Aa toxin from Bacillus thuringiensis subsp. israelensis into LTCs targeted to murine myeloma cells. Proteolytically activated Cyt1Aa was conjugated chemically or genetically through either its amino or carboxyl termini to the major peptidic epitope VHFFKNIVTPRTP (p87–99) of the myelin basic protein. The recombinant fusion-encoding genes were cloned and expressed in acrystalliferous B. thuringiensis subsp. israelensis through the shuttle vector pHT315. Both chemically conjugated and genetically fused LTCs were toxic to anti-myelin basic protein-expressing murine hybridoma cells, but the recombinant conjugates were more active. LTCs comprising the Cyt1Aa toxin might be useful anticancer agents. As a membrane-acting toxin, Cyt1Aa is not likely to induce development of resistant cell lines.

Received for publication, April 30, 2007 , and in revised form, June 28, 2007.

^* This work was supported in part by Grant 2001-042 from the United States-Israel Binational Science Foundation, Jerusalem, Israel (to A. Z. and Sammy Boussiba). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 972-3-9066212; Fax: 972-3-9066323; E-mail: firer{at}research.yosh.ac.il.

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				R. Cahan, H. Friman, and Y. Nitzan Antibacterial activity of Cyt1Aa from Bacillus thuringiensis subsp. israelensis Microbiology, November 1, 2008; 154(11): 3529 - 3536. [Abstract] [Full Text] [PDF]