Toxin-derived delivery constructs

Abstract

The present disclosure relates to isolated non-naturally occurring delivery constructs comprising a bacterial toxin-derived delivery construct coupled to a biologically active therapeutic cargo; wherein the delivery construct is capable of delivering the biologically active cargo via transcytosis transport across an epithelial cell; and wherein the delivery construct does not comprise a bacterial toxin-derived translocation domain or a bacterial toxin-derived catalytic (cytotoxic) domain.

1 .- 280 . (canceled) 
     
     
         281 . A delivery construct comprising:
 a carrier consisting of a domain I of a  Pseudomonas  exotoxin and optionally an N-terminal methionine; and   an antibody coupled to the carrier; wherein the carrier is configured to deliver the antibody across a polarized epithelial cell in a subject via transcytosis.   
     
     
         282 . The delivery construct of  claim 281 , wherein the antibody is a therapeutic antibody. 
     
     
         283 . The delivery construct of  claim 281 , wherein the antibody is a diagnostic antibody. 
     
     
         284 . The delivery construct of  claim 281 , wherein the antibody comprises a diabody, a minibody, a single-chain variable fragment, or a combination thereof. 
     
     
         285 . The delivery construct of  claim 282 , wherein the therapeutic antibody is an anti-TNFa antibody. 
     
     
         286 . The delivery construct of  claim 285 , wherein the anti-TNFa antibody is adalimumab or infliximab. 
     
     
         287 . The delivery construct of  claim 281 , wherein the carrier has at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 137. 
     
     
         288 . The delivery construct of  claim 281 , wherein the carrier is covalently coupled to the antibody. 
     
     
         289 . The delivery construct of  claim 288 , wherein the carrier is coupled to the antibody via a spacer. 
     
     
         290 . A pharmaceutical composition comprising the delivery construct of  claim 281  and a pharmaceutically acceptable excipient. 
     
     
         291 . The pharmaceutical composition of  claim 290 , wherein the pharmaceutical composition is formulated for pulmonary administration. 
     
     
         292 . The pharmaceutical composition of  claim 290 , wherein the pharmaceutical composition is formulated into an aerosol. 
     
     
         293 . A method for delivering an antibody across a polarized epithelial cell in a subject via transcytosis, the method comprising administering the delivery construct of  claim 281  to the subject. 
     
     
         294 . The method of  claim 293 , wherein the antibody is a therapeutic antibody. 
     
     
         295 . The method of  claim 293 , wherein the antibody is a diagnostic antibody. 
     
     
         296 . The method of  claim 293 , wherein the antibody comprises a diabody, a minibody, a single-chain variable fragment, or a combination thereof. 
     
     
         297 . The method of  claim 294 , wherein the therapeutic antibody is an anti-TNFa antibody. 
     
     
         298 . The method of  claim 297 , wherein the anti-TNFa antibody is adalimumab or infliximab. 
     
     
         299 . The method of  claim 293 , wherein the carrier is covalently coupled to the heterologous cargo. 
     
     
         300 . The method of  claim 293 , wherein the carrier is coupled to the heterologous cargo via a spacer. 
     
     
         301 . The method of  claim 293 , wherein the carrier has at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 137. 
     
     
         302 . The method of  claim 293 , wherein the subject has an infectious disease. 
     
     
         303 . The method of  claim 302 , wherein the infectious disease is a systemic microbial infection. 
     
     
         304 . The method of  claim 302 , wherein the infectious disease is a viral disease. 
     
     
         305 . The method of  claim 293 , wherein the delivery construct is in a pharmaceutical composition. 
     
     
         306 . The method of  claim 305 , wherein the pharmaceutical composition is formulated for pulmonary delivery. 
     
     
         307 . The method of  claim 305 , wherein the pharmaceutical composition is formulated into an aerosol.