Compositions and Methods for Tumor-Targeted Delivery of Effector Molecules

Abstract

The present application discloses the preparation and use of attenuated tumor-targeted bacteria vectors for the delivery of one or more primary effector molecule(s) to the site of a solid tumor. The primary effector molecule(s) of the invention is used in the methods of the invention to treat a solid tumor cancer such as a carcinoma, melanoma, lymphoma, or sarcoma. The invention relates to the surprising discovery that effector molecules, which may be toxic when administered systemically to a host, can be delivered locally to tumors by attenuated tumor-targeted bacteria with reduced toxicity to the host. The application also discloses to the delivery of one or more optional effector molecule(s) (termed secondary effector molecules) which may be delivered by the attenuated tumor-targeted bacteria in conjunction with the primary effector molecule(s).

1 - 119 . (canceled) 
     
     
         120 . An attenuated tumor-targeted bacteria comprising one or more nucleic acid molecules encoding one or more primary effector molecules and one or more secondary effector molecules operably linked to one or more promoters, wherein said attenuated tumor-targeted bacteria is a facultative aerobe or facultative anaerobe. 
     
     
         121 . The attenuated tumor-targeted bacteria of  claim 120 , wherein at least one of the effector molecules is a nucleic acid molecule. 
     
     
         122 . The attenuated tumor-targeted bacteria of  claim 121 , wherein the nucleic acid molecule is an antisense molecule or a ribozyme. 
     
     
         123 . The attenuated tumor-targeted bacteria of  claim 121 , wherein the nucleic acid molecule is an RNA molecule or a DNA molecule. 
     
     
         124 . The attenuated tumor-targeted bacteria of  claim 120 , wherein at least one of the effector molecules is a TNF family member. 
     
     
         125 . The attenuated tumor-targeted bacteria of  claim 120 , wherein at least one of the effector molecules is an immunomodulating agent, an anti-tumor protein, a prodrug converting enzyme, or an antigen. 
     
     
         126 . The attenuated tumor-targeted bacteria of  claim 120 , wherein the promoter or promoters are eukaryote or prokaryote. 
     
     
         127 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the attenuated tumor-targeted bacteria of  claim 120 . 
     
     
         128 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the attenuated tumor-targeted bacteria of  claim 121 . 
     
     
         129 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the attenuated tumor-targeted bacteria of  claim 124 . 
     
     
         130 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the attenuated tumor-targeted bacteria of  claim 125 . 
     
     
         131 . A method for delivering one or more fusion proteins for the treatment of a solid-tumor cancer to a subject in need of such treatment, comprising administering a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the attenuated tumor-targeted bacteria of  claim 120 . 
     
     
         132 . A method for delivering one or more fusion proteins for the treatment of a solid-tumor cancer to a subject in need of such treatment, comprising administering a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the attenuated tumor-targeted bacteria of  claim 121 . 
     
     
         133 . A method for delivering one or more fusion proteins for the treatment of a solid-tumor cancer to a subject in need of such treatment, comprising administering a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the attenuated tumor-targeted bacteria of  claim 124 . 
     
     
         134 . A method for delivering one or more fusion proteins for the treatment of a solid-tumor cancer to a subject in need of such treatment, comprising administering a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the attenuated tumor-targeted bacteria of  claim 125 .