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J. Biol. Chem., Vol. 283, Issue 3, 1572-1579, January 18, 2008

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A Chimera of Interleukin 2 and a Binding Variant of Aerolysin Is Selectively Toxic to Cells Displaying the Interleukin 2 Receptor^*

From the Protox Therapeutics Incorporated, Vancouver, British Columbia V6C 3E8, Canada

Aerolysin is a bacterial toxin that binds to glycosylphosphatidylinositol-anchored proteins (GPI-AP) on mammalian cells and oligomerizes, inserting into the target membranes and forming channels that cause cell death. We have made a variant of aerolysin, R336A, that has greatly reduced the ability to bind to GPI-AP, and as a result it is only very weakly active. Fusion of interleukin 2 (IL2) to the N terminus of R336A-aerolysin results in a hybrid that has little or no activity against cells that do not have an IL2 receptor because it cannot bind to the GPI-AP on the cells. Strikingly, the presence of the IL2 moiety allows this hybrid to bind to cells displaying high affinity IL2 receptors. Once bound, the hybrid molecules form insertion-competent oligomers. Cell death occurs at picomolar concentrations of the hybrid, whereas the same cells are insensitive to much higher concentrations of R336A-aerolysin lacking the IL2 domain. The targeted channel-forming hybrid protein may have important advantages as a therapeutic agent.

Received for publication, August 3, 2007 , and in revised form, October 30, 2007.

^* 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.

¹ To whom correspondence should be addressed: Protox Therapeutics Inc., 1210-885 West Georgia St., Vancouver, British Columbia V6C 3E8, Canada. Tel.: 250-598-6822; Fax: 250-598-6877; E-mail: tbuckley{at}protoxtherapeutics.com.

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