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Abstract

The method of the present invention employs a hybrid reagent comprising a first portion (i.e., a cell-targeting portion) which binds to cell surfaces coupled to a second portion (i.e., a toxin-binding portion) which binds to, or has bound to it, an endosomally active domain of DT and releases the endosomally active domain of DT in response to the low pH in endosomal vesicles of cells. Thus, the second portion of the hybrid reagent binds an endosomally active domain directly (e.g., an antibody which binds to all or a portion of the T domain of DT) or indirectly (e.g., an antibody which binds to the R domain of a moiety in which the R domain of DT is coupled to the T domain of DT). A second endosomally active domain of DT, which is different from the first endosomally active domain of DT, is delivered to the same endosomal vesicles separately. The independent endosomally active domains of DT are not toxic to cells until they meet within the endosomes. Thus, the therapeutic window of the binary toxin described herein is much greater than current toxin delivery systems, which generally retain collateral toxicity, even when undelivered.

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First Claim