MHC class I epitope delivering polypeptides

Patent metadata

Field	Value
Publication number	US-11312751-B2
Application number	US-202117231526-A
Country	US
Kind code	B2
Filing date	Apr 15, 2021
Priority date	Jan 27, 2014
Publication date	Apr 26, 2022
Grant date	Apr 26, 2022

Abstract

The present invention is directed to T-cell epitope delivering polypeptides which deliver one or more CD8+ T-cell epitopes to the MHC class I presentation pathway of a cell, including toxin-derived polypeptides which comprise embedded T-cell epitopes and are de-immunized. The present invention provides cell-targeted, CD8+ T-cell epitope delivering molecules for the targeted delivery of cytotoxicity to certain cells, e.g., infected or malignant cells, for the targeted killing of specific cell types, and the treatment of a variety of diseases, disorders, and conditions, including cancers, immune disorders, and microbial infections. The present invention also provides methods of generating polypeptides capable of delivering one or more heterologous T-cell epitopes to the MHC class I presentation pathway, including polypeptides which are 1) B-cell and/or CD4+ T-cell de-immunized, 2) comprise embedded T-cell epitopes, and/or 3) comprises toxin effectors which retain toxin functions.

First claim

The invention is claimed as follows:

1. A Shiga toxin effector polypeptide comprising an amino acid sequence having at least 90% identity to amino acids 1 to 251 of SEQ ID NO: 1;
wherein the amino acid sequence comprises at least four endogenous B-cell epitope regions, and comprises:
amino acid substitutions V54I, R55L, I57F, P59F, E60T, and E61L in SEQ ID NO: 1,
wherein the endogenous B-cell epitope regions are natively positioned in a wild-type Shiga toxin A Subunit within amino acid residues: 39-48 of SEQ ID NO:1; 94-115 of SEQ ID NO:1; 179-190 of SEQ ID NO:1; and 243-251 of SEQ ID NO:1; and
wherein the amino acid sequence comprises an asparagine at the amino acid residue corresponding to position 75 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 77 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1, a glutamate at the amino acid residue corresponding to position 167 of SEQ ID NO: 1, an arginine at the amino acid residue corresponding to position 170 of SEQ ID NO: 1, an arginine at the amino acid residue corresponding to position 176 of SEQ ID NO: 1, and a tryptophan at the amino acid residue corresponding to position 203 of SEQ ID NO: 1.

2. The Shiga toxin effector polypeptide according to claim 1 , wherein the amino acid sequence has at least 95% sequence identity to amino acids 1 to 251 of SEQ ID NO: 1.

3. The Shiga toxin effector polypeptide according to claim 1 , wherein the amino acid sequence has at least 95% sequence identity to SEQ ID NO: 16.

Assignees

• Molecular Templates Inc

Inventors

• Poma Eric
• Willert Erin

Classifications

• C07K16/1145

  Env proteins, e.g. gp41, gp110/120, gp160, V3, principal neutralising domain [PND] or CD4-binding site · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K14/25 Primary

  Shigella (G) · CPC title

• C07K16/32

  against translation products of oncogenes · CPC title

• C07K2319/33

  fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies · CPC title