HER2-targeting molecules comprising de-immunized, Shiga toxin A subunit scaffolds

Patent metadata

Field	Value
Publication number	US-11225509-B2
Application number	US-202017072562-A
Country	US
Kind code	B2
Filing date	Oct 16, 2020
Priority date	Apr 17, 2018
Publication date	Jan 18, 2022
Grant date	Jan 18, 2022

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.

First claim

The invention claimed is:

1. A method of treating a disease, disorder, or condition involving HER2-expressing cells in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a HER2-targeting molecule comprising a polypeptide sequence of SEQ ID NO: 29 or SEQ ID NO: 102, and at least one pharmaceutically acceptable excipient or carrier, wherein the patient is refractory to treatment with at least one dual tyrosine kinase inhibitor or anti-HER2 monoclonal antibody prior to administration of the HER2-targeting molecule.

2. The method of claim 1 , wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional dual tyrosine kinase inhibitor or anti-HER2 monoclonal antibody, wherein the at least one additional dual tyrosine kinase inhibitor or anti-HER2 monoclonal antibody is administered simultaneously or sequentially with the HER2-targeting molecule.

3. The method of claim 2 , wherein the at least one anti-HER2 monoclonal antibody binds an antigenic determinant in HER2 that does not overlap with the antigenic determinant in HER2 bound by the HER2-targeting molecule.

4. The method of claim 1 , wherein the at least one pharmaceutically acceptable excipient or carrier is selected from citrate, sorbitol, polysorbate 20, chloride, and sodium.

5. The method of claim 1 , wherein the at least one dual tyrosine kinase inhibitor or anti-HER2 monoclonal antibody is selected from lapatinib, neratinib, trastuzumab, and pertuzumab.

6. The method of claim 2 , wherein the at least one dual tyrosine kinase inhibitor or anti-HER2 monoclonal antibody is selected from lapatinib, neratinib, trastuzumab, and pertuzumab.

Assignees

• Molecular Templates Inc

Inventors

• Poma Eric
• Willert Erin
• Higgins Jack

Classifications

• A61K39/0011

  Cancer antigens · CPC title

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title