Expression of chimeric polypeptide with variable lymphocyte receptors on immune cells and uses for treating cancer

Patent metadata

Field	Value
Publication number	US-10323077-B2
Application number	US-201515117811-A
Country	US
Kind code	B2
Filing date	Feb 9, 2015
Priority date	Feb 10, 2014
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

This disclosure relates to recombinant cellular expression of chimeric proteins with peptide sequences derived from lymphocyte receptors and uses for treating cancer. In certain embodiments, the disclosure relates to a recombinant vector comprising a nucleic acid that encodes a chimeric protein with a segment with a targeting moiety based on a variable lymphocyte receptor (VLR) capable of binding a tumor associated antigen and a segment with a T cell signal transduction subunit. In certain embodiments, the recombinant vectors are used in immune based cancer treatments.

First claim

What is claimed is:

1. A recombinant vector comprising a nucleic acid that encodes a chimeric polypeptide comprising a targeting sequence of a variable lymphocyte receptor domain, a transmembrane domain, a T cell costimulatory molecule domain, and a signal-transduction component of a T-cell antigen receptor domain, wherein the variable lymphocyte receptor has SEQ ID NO: 4, 6, or 8.

2. The recombinant vector of claim 1 , wherein the nucleic acid has SEQ ID NO: 3, 5, or 7 or a sequence with greater than 95% identity thereto.

3. The recombinant vector of claim 1 , wherein the costimulatory molecule is selected from CD28, CD80, CD86 or variant or fragment thereto.

4. The recombinant vector of claim 1 , wherein the signal-transduction component of the T-cell antigen comprises sequence YXXLXXXXXXXXYXXL (SEQ ID NO: 15) wherein X is any amino acid, L is leucine or isoleucine, and one or two X are optionally deleted.

5. The recombinant vector of claim 1 , wherein the chimeric polypeptide further comprises an interleukin signal sequence.

6. The recombinant vector of claim 1 , wherein the chimeric polypeptide further comprises CD8.

7. The recombinant vector of claim 1 , further encoding an enzyme that confers resistance to cellular damage in the presence of a chemotherapy agent.

8. The recombinant vector of claim 1 , further encoding methylguanine methyltransferase (MGMT), dihydrofolate reductase (DHFR), cytidine deaminase (CD), and/or multidrug resistant protein (MDR-1) or variant thereof.

9. An isolated cell comprising the recombinant vector of claim 1 .

10. The cell of claim 9 , selected from T helper cell, cytotoxic T cell, natural killer T cell, or γδ T cell.

11. A recombinant vector comprising a nucleic acid that encodes a chimeric polypeptide comprising a targeting sequence of a variable lymphocyte receptor domain, a transmembrane domain, a T cell costimulatory molecule domain, and a signal-transduction component of a T-cell antigen receptor domain, wherein the variable lymphocyte receptor has SEQ ID NO: 10 encoded by SEQ ID NO: 9.

Assignees

• Univ Emory
• Childrens Healthcare Atlanta Inc
• Childrens Healthcare Of Atlanta

Inventors

• Spencer H Trent
• Doering Christopher B
• Herrin Brantley R
• Cooper Max Dale

Classifications

• C07K2319/02

  containing a signal sequence · 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

• C07K14/70521 Primary

  CD28, CD152 · CPC title

• C07K2319/70

  containing domain for protein-protein interaction · CPC title

• C07K14/461

  from fish · CPC title