US 12,404,314 B2
Switch costimulatory receptors
Carl H. June, Merion Station, PA (US); and Yangbing Zhao, Lumberton, NJ (US)
Assigned to The Trustees of the University of Pennsylvania, Philadelphia, PA (US)
Filed by The Trustees of the University of Pennsylvania, Philadelphia, PA (US)
Filed on May 10, 2019, as Appl. No. 16/408,923.
Application 16/408,923 is a division of application No. 14/232,557, granted, now 10,981,969, previously published as PCT/US2012/048543, filed on Jul. 27, 2012.
Claims priority of provisional application 61/513,259, filed on Jul. 29, 2011.
Prior Publication US 2019/0345219 A1, Nov. 14, 2019
Int. Cl. A61K 40/30 (2025.01); A61K 38/17 (2006.01); A61K 40/11 (2025.01); A61K 40/31 (2025.01); A61K 40/42 (2025.01); C07K 14/705 (2006.01); C07K 14/725 (2006.01); A61K 38/00 (2006.01); A61K 48/00 (2006.01)
CPC C07K 14/70503 (2013.01) [A61K 38/1774 (2013.01); A61K 40/11 (2025.01); A61K 40/31 (2025.01); A61K 40/421 (2025.01); A61K 40/4211 (2025.01); C07K 14/7051 (2013.01); C07K 14/70521 (2013.01); A61K 38/00 (2013.01); A61K 48/005 (2013.01); A61K 2239/17 (2023.05); C07K 2319/00 (2013.01); C07K 2319/03 (2013.01)] 15 Claims
 
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.