IP Library Granted Patent US 12,404,314
Granted Patent B2
US 12,404,314 · App. 16/408,923 · Granted Sep 2, 2025

Switch costimulatory receptors

Inventors: Carl H. June (Merion Station, PA); Yangbing Zhao (Lumberton, NJ)
Assignee: The Trustees of the University of Pennsylvania
C07K14/70503A61K38/1774A61K40/11A61K40/31A61K40/421A61K40/4211C07K14/7051C07K14/70521A61K38/00A61K48/005A61K2239/17C07K2319/00C07K2319/03
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Quick Facts
Patent No.
US 12,404,314
App. No.
16/408,923
Granted
Sep 2, 2025
Kind
B2
Abstract

The present invention relates generally to a fusion protein that when displayed on a cell can convert a negative signal into a positive signal in the cell. The fusion protein is a chimeric protein in that the protein comprises at least two domains, wherein the first domain is a polypeptide that is associated with a negative signal and the second domain is a polypeptide that is associated with a positive signal. Thus, the invention encompasses switch receptors that are able to switch negative signals to positive signals for enhancement of an immune response.

Claims (25)

1. A modified immune cell engineered to express:

(a) a fusion protein comprising an extracellular domain, a transmembrane domain, and an intracellular domain, wherein:

(i) the extracellular domain is an extracellular domain of an inhibitory polypeptide that is associated with a negative signal, and wherein the inhibitory polypeptide that is associated with a negative signal is selected from the group consisting of PD-1 and BTLA; and

(ii) the intracellular domain is an intracellular domain of a stimulatory polypeptide that is associated with a positive signal that activates immune cells, and wherein the stimulatory polypeptide that is associated with a positive signal is selected from the group consisting of CD28 and ICOS; and

(b) a chimeric antigen receptor (CAR) comprising an antigen recognition domain that specifically targets a cancer antigen and an intracellular domain of a CD3-zeta chain;

wherein, when the fusion protein and the CAR are bound to their respective ligands, IL-2 and IFN-γ secretion is enhanced at least three times as compared to IL-2 and IFN-γ secretion in (i) a modified immune cell only expressing the CAR or (ii) a modified immune cell expressing a CAR comprising the antigen recognition domain that specifically targets a cancer antigen, a costimulatory domain, and an intracellular domain of a CD3-zeta chain; and

wherein the modified immune cell is polarized to secrete IL-17 and IFN-γ, and wherein the modified immune cell is a modified T cell.

2. The modified immune cell of claim 1 , wherein the fusion protein is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 2, 4, 6-9 and 10-11.

3. The modified immune cell of claim 2 , wherein the modified immune cell is autologous.

4. The modified immune cell of claim 1 , wherein the polypeptide that is associated with a negative signal is BTLA.

5. The modified immune cell of claim 1 , wherein the polypeptide that is associated with a negative signal is PD-1.

6. The modified immune cell of claim 1 , wherein the polypeptide that is associated with a positive signal is CD28.

7. The modified immune cell of claim 1 , wherein the polypeptide that is associated with a positive signal is ICOS.

8. The modified immune cell of claim 1 , wherein the transmembrane domain is the transmembrane domain of the inhibitory polypeptide that is associated with the negative signal.

9. The modified immune cell of claim 1 , wherein the transmembrane domain is the transmembrane domain of the stimulatory polypeptide that is associated with the positive signal.

10. The modified immune cell of claim 1 , wherein the polypeptide that is associated with a negative signal is PD-1, and the polypeptide that is associated with a positive signal is CD28.

11. The modified immune cell of claim 1 , wherein the CAR comprises an antigen recognition domain that specifically targets CD19.

12. A population of modified immune cells engineered to express:

(a) a fusion protein comprising an extracellular domain, a transmembrane domain, and an intracellular domain, wherein the extracellular domain is an extracellular domain of PD-1, and wherein the intracellular domain is an intracellular domain of CD28; and

(b) a chimeric antigen receptor (CAR) comprising an antigen recognition domain that specifically targets a cancer antigen and an intracellular domain of a CD3-zeta chain; and

wherein, when the fusion protein and the CAR are bound to their respective ligands, IL-2 and IFN-γ secretion is enhanced at least three times as compared to IL-2 and IFN-γ secretion in modified immune cells only expressing the CAR; and

wherein the population of modified immune cells comprise modified CD4 + T cells and modified CD8 + T cells, and wherein the fusion protein enhances TNFα, IL2 and IFNγ secretion in CD4 + T cells, thereby enhancing the CD4 + T cells antitumor response.

13. The population of modified immune cell of claim 12 , wherein the fusion protein-induced TNFα, IL2 and IFNγ secretion in CD4 + T cells is at least 2-fold higher than the fusion protein-induced TNFα, IL2 and IFNγ secretion in CD8 + T cells.

14. The population of modified immune cell of claim 12 , wherein the fusion protein enhances CD8 + T cells proliferation.

15. The population of modified immune cell of claim 12 , wherein the CAR comprises an antigen recognition domain that specifically targets CD19.

Continuity (3)
Division 14232557
Provisional Application 61513259 · Jul 29, 2011
Related Publication 20190345219A1 · Nov 14, 2019
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