US 12,077,785 B2
Chimeric antigen receptor polypeptides in combination with trans metabolism molecules modulating Krebs cycle and therapeutic uses thereof
Kathleen McGinness, Cambridge, MA (US); Seth Ettenberg, Cambridge, MA (US); Luke Barron, Cambridge, MA (US); Michael Fray, Cambridge, MA (US); Charles Wilson, Cambridge, MA (US); and Gregory Motz, Cambridge, MA (US)
Assigned to SOTIO BIOTECH INC., Boston, MA (US)
Appl. No. 17/268,345
Filed by SOTIO BIOTECH INC., Boston, MA (US)
PCT Filed Aug. 14, 2019, PCT No. PCT/US2019/046550
§ 371(c)(1), (2) Date Feb. 12, 2021,
PCT Pub. No. WO2020/037066, PCT Pub. Date Feb. 20, 2020.
Claims priority of provisional application 62/718,579, filed on Aug. 14, 2018.
Claims priority of provisional application 62/718,491, filed on Aug. 14, 2018.
Prior Publication US 2021/0332334 A1, Oct. 28, 2021
Int. Cl. C12N 9/04 (2006.01); A61K 35/17 (2015.01); A61K 48/00 (2006.01); A61P 35/00 (2006.01); C07K 14/705 (2006.01); C07K 14/725 (2006.01); C07K 16/30 (2006.01); C12N 9/06 (2006.01); C12N 9/10 (2006.01); C12N 9/80 (2006.01); C12N 9/88 (2006.01)
CPC C12N 9/0006 (2013.01) [A61K 35/17 (2013.01); A61P 35/00 (2018.01); C07K 14/7051 (2013.01); C07K 14/70517 (2013.01); C07K 14/70521 (2013.01); C07K 14/70578 (2013.01); C07K 16/303 (2013.01); C12N 9/0016 (2013.01); C12N 9/1096 (2013.01); C12N 9/80 (2013.01); C12N 9/88 (2013.01); C12Y 101/01037 (2013.01); C12Y 101/01042 (2013.01); C12Y 104/01002 (2013.01); C12Y 206/01001 (2013.01); C12Y 206/01002 (2013.01); C12Y 206/01052 (2013.01); C12Y 305/01002 (2013.01); C12Y 401/01032 (2013.01); A61K 48/00 (2013.01); C07K 2319/02 (2013.01); C07K 2319/03 (2013.01)] 23 Claims
 
1. A genetically engineered hematopoietic cell, which has a modulated Krebs cycle as compared with a native hematopoietic cell of the same hematopoietic cell type;
wherein the genetically engineered hematopoietic cell expresses:
(i) a Krebs cycle modulating polypeptide, which is glutamic-oxaloacetic transaminase (GOT), isocitrate dehydrogenase (IDH), malate dehydrogenase (MDH), phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1), glutamate dehydrogenase (GDH1), glutamate-pyruvate transaminase 1 (GPT1), or glutaminase (GLS); and
(ii) a chimeric receptor polypeptide, which comprises
(a) an extracellular target binding domain;
(b) a transmembrane domain; and
(c) a cytoplasmic signaling domain; and
wherein the Krebs cycle modulating polypeptide is encoded by an exogenous nucleic acid; and wherein the transmembrane domain is from a membrane protein selected from the group consisting of CD8α, CD8β, CD137, CD27, CD28, CD34, CD4, FcεR1γ, CD16, CD134, CD32, CD64, CD45, CD5, CD9, CD22, CD37, CD80, CD86, CD40, CD154, VEGFR2, FAS, and FDFR2B.