Her2-targeting molecules comprising de-immunized, shiga toxin a subunit scaffolds

Abstract

Provided herein are HER2-targeting molecules comprising Shiga toxin A Subunit derived polypeptides having 1) de-immunization and 2) reduced, protease-cleavage sensitivity while retaining Shiga toxin function(s), such as, e.g., potent cytotoxicity via ribosome inhibition. Certain HER2-targeting molecules of the present invention exhibit reduced immunogenic potential in mammals and are well-tolerated by mammals while retaining aforementioned features. The HER2-targeting molecules of the present invention have uses for selectively killing specific cells (e.g., HER positive tumor cells); for selectively delivering cargos to specific cells (e.g., HER positive tumor cells), and as therapeutic and/or diagnostic molecules for treating and diagnosing a variety of conditions, including cancers and tumors involving the expression or over-expression of cell-surface HER2.

1 . A method of treating a disease, disorder, or condition involving HER2-expressing cells in a patient, the method comprising the step of administering to a patient in need thereof a therapeutically effective amount of a monovalent, monomeric HER2-targeting molecule comprising the polypeptide sequence of SEQ ID NO: 29 or SEQ ID NO: 102. 
     
     
         2 . The method of  claim 1 , wherein the polypeptide sequence consists of SEQ ID NO: 29 or SEQ ID NO: 102. 
     
     
         3 . The method of  claim 1  or  claim 2 , wherein the monovalent, monomeric HER2-targeting molecule is in the form of a pharmaceutically acceptable solvate or salt. 
     
     
         4 . The method of any one of  claims 1-3 , wherein the monovalent, monomeric HER2-targeting molecule is administered with at least one pharmaceutically acceptable excipient or carrier. 
     
     
         5 . The method of any one of  claims 1-4 , wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of an additional HER2-targeting therapeutic agent. 
     
     
         6 . The method of any one of  claims 1-5 , wherein the patient has been previously treated with at least one other HER2-targeting therapeutic agent.