US2021269534A1PendingUtilityA1

Flt3 directed car cells for immunotherapy

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Assignee: CYTOIMMUNE THERAPEUTICS INCPriority: Sep 23, 2015Filed: Mar 11, 2021Published: Sep 2, 2021
Est. expirySep 23, 2035(~9.2 yrs left)· nominal 20-yr term from priority
Inventors:Jianhua YuMichael A. CaligiuriSteven T. Devine
A61K 40/11A61K 40/4211A61K 40/31A61K 40/15A61K 40/4202A61K 2239/38A61K 2239/31A61K 2239/48A61K 2039/505A61K 2039/5158A61K 2039/5156C12N 2740/16043C07K 2319/02C07K 2319/33C07K 2317/622C07K 2319/60C07K 2319/50A61K 35/17C12N 9/6472C07K 14/70578C07K 2317/565C07K 2317/53C07K 2319/03C07K 16/2863C07K 14/70521A61P 35/02C07K 14/7051C07K 2319/00A61P 35/00C07K 2317/56A61K 35/00
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Claims

Abstract

CAR cells targeting FLT3 relevant antigens are described as a new method of cancer treatment. It is proposed that FLT3 CAR cells are safe and effective in patients and can be used to treat human tumors and cancer.

Claims

exact text as granted — not AI-modified
1 . A method of treating a blood or bone marrow cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a cell expressing a chimeric antigen receptor (CAR) comprising: (a) an antigen binding domain of a FLT3 antibody, (b) a hinge domain, (c) a transmembrane domain, and (d) an intracellular domain, and hematopoietic stem cells (HSCs). 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the antigen binding domain of the FLT3 antibody comprises a FLT3 heavy chain variable region, a FLT3 light chain variable region, and a linker polypeptide located between the FLT3 heavy chain variable region and the FLT3 light chain variable region. 
     
     
         4 . The method of  claim 3 , wherein the linker polypeptide comprises the peptide of SEQ ID NO: 46. 
     
     
         5 . The method of  claim 1 , wherein the CAR further comprises a suicide switch. 
     
     
         6 . The method of  claim 5 , wherein the suicide switch is an iCasp suicide switch comprising the peptide encoded by SEQ ID NO: 40. 
     
     
         7 . The method of  claim 1 , wherein the cancer is leukemia. 
     
     
         8 . The method of  claim 7 , wherein the leukemia is acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). 
     
     
         9 . The method of  claim 1 , wherein the subject is a mammal. 
     
     
         10 . The method of  claim 9 , wherein the mammal is a human. 
     
     
         11 . The method of  claim 1 , wherein the CAR-expressing cell is a eukaryotic cell selected from a T-cell, a B cell, an NK cell, a dendritic cell, a myeloid cell, or a leukocyte derived from HSC. 
     
     
         12 . The method of  claim 1 , wherein the CAR-expressing cell is allogeneic or autologous to the subject. 
     
     
         13 . The method of  claim 1 , wherein the cancer expresses FLT3. 
     
     
         14 . The method of  claim 1 , wherein the HSCs express FLT3. 
     
     
         15 . The method of  claim 1 , wherein the HSCs differentiate to cells not expressing CD34 in the subject. 
     
     
         16 . The method of  claim 1 , wherein the HSCs express CD34 and CD90 but not CD38 or CD45RA. 
     
     
         17 . The method of  claim 1 , wherein the HSCs are allogeneic to the subject. 
     
     
         18 . The method of  claim 1 , wherein the CAR-expressing cell is administered before the HSCs. 
     
     
         19 . The method of  claim 1 , wherein the CAR-expressing cell is administered after the administration of the HSCs. 
     
     
         20 . The method of  claim 1 , wherein the CAR-expressing cell is administered concurrently with the HSCs. 
     
     
         21 . The method of  claim 1 , wherein the CAR-expressing cell is an NK cell that is administered prior to the administration of the HSCs. 
     
     
         22 . The method of  claim 1 , wherein the CAR-expressing cell is a T cell or an NK cell, and is administered after the administration of the HSCs. 
     
     
         23 . The method of  claim 1 , wherein the CAR-expressing cell is an allogenic T cell or an allogeneic NK cell, and is administered after the administration of the HSCs. 
     
     
         24 . The method of  claim 1 , wherein the antigen binding domain of the FLT3 antibody comprises a FLT3 heavy chain variable region and a FLT3 light chain variable region, and wherein the FLT3 heavy chain variable region comprises:
 CDRH1 having the peptide of SEQ ID NO: 29 (NYGLH) or SEQ ID NO: 21 (SYWMH),   CDRH2 having the peptide of SEQ ID NO: 30 (VIWSGGSTDYNAAFIS) or SEQ ID NO: 22 (EIDPSDSYKDYNQKFKD), and   CDRH3 having the peptide of SEQ ID NO: 31 (GGIYYANHYYAMDY) or SEQ ID NO: 23 (AITTTPFDF),   
       and the FLT3 light chain variable region comprises:
 CDRL1 having the peptide of SEQ ID NO: 32 (KSSQSLLNSGNQKNYM) or SEQ ID NO: 24 (RASQSISNNLH), 
 CDRL2 having the peptide of SEQ ID NO: 33 (GASTRES) or SEQ ID NO: 25 (YASQSIS), and 
 CDRL3 having the peptide of SEQ ID NO: 34 (QNDHSYPLT) or SEQ ID NO: 26 (QQSNTWPYT). 
 
     
     
         25 . The method of  claim 24 , wherein the antigen binding domain of the FLT3 antibody comprises:
 a FLT3 heavy chain variable region comprising the peptide encoded by the polynucleotide of SEQ ID NO: 19 and a FLT3 light chain variable region comprising the peptide encoded by the polynucleotide of SEQ ID NO: 20, or an equivalent of each thereof; or   a FLT3 heavy chain variable region comprising the peptide encoded by the polynucleotide of SEQ ID NO: 27 and a FLT3 light chain variable region comprising the peptide encoded by the polynucleotide of SEQ ID NO: 28, or an equivalent of each thereof.   
     
     
         26 . The method of  claim 1 , wherein the antigen binding domain of the FLT3 antibody comprises:
 a FLT3 heavy chain variable region comprising CDRH1 having the peptide of SEQ ID NO: 29, CDRH2 having the peptide of SEQ ID NO: 30, and CDRH3 having the peptide of SEQ ID NO: 31; and   a FLT3 light chain variable region comprising CDRL1 having the peptide of SEQ ID NO: 32, CDRL2 having the peptide of SEQ ID NO: 33, and CDRL3 having the peptide of SEQ ID NO: 34.   
     
     
         27 . The method of  claim 1 , wherein the antigen binding domain of the FLT3 antibody comprises:
 a FLT3 heavy chain variable region comprising CDRH1 having the peptide of SEQ ID NO: 21, CDRH2 having the peptide of SEQ ID NO: 22, and CDRH3 having the peptide of SEQ ID NO: 23; and   a FLT3 light chain variable region comprising CDRL1 having the peptide of SEQ ID NO: 24, CDRL2 having the peptide of SEQ ID NO: 25, and CDRL3 having the peptide of SEQ ID NO: 26.   
     
     
         28 . The method of  claim 1 , wherein the transmembrane domain comprises a CD28 transmembrane domain and the intracellular domain comprises a CD3 zeta signaling domain and one or more costimulatory regions selected from a CD28 costimulatory signaling region, a 4-1BB costimulatory signaling region, an ICOS costimulatory signaling region, or an OX40 costimulatory region. 
     
     
         29 . The method of  claim 1 , wherein the CAR further comprises a detectable marker or a purification marker attached to the CAR. 
     
     
         30 . The method of  claim 1 , wherein the CAR-expressing cell comprises a nucleic acid sequence encoding the CAR or its complement. 
     
     
         31 . The method of  claim 30 , wherein the nucleic acid sequence further comprises a promoter located upstream of a polynucleotide encoding the antigen binding domain of the FLT3 antibody. 
     
     
         32 . The method of  claim 31 , wherein the promoter is selected from a CMV promoter, an MND promoter, or an EF1 alpha promoter. 
     
     
         33 . The method of  claim 30 , wherein the nucleic acid sequence further comprises an inducible caspase (iCasp) encoding polynucleotide sequence located upstream or downstream of the polynucleotide encoding the antigen binding domain of the FLT3 antibody. 
     
     
         34 . The method of  claim 30 , wherein the nucleic acid sequence further comprises a 2A peptide (T2A) encoding polynucleotide sequence located upstream of a polynucleotide encoding the antigen binding domain of the FLT3 antibody. 
     
     
         35 . The method of  claim 30 , wherein the nucleic acid sequence further comprises a signal peptide encoding polynucleotide sequence located upstream of a polynucleotide encoding the antigen binding domain of the FLT3 antibody. 
     
     
         36 . The method of  claim 1 , further comprising treating the subject with one or more of the following: an anti-cancer therapeutics, a cytokine, an immunoregulatory cell population, or a cytoreductive therapy. 
     
     
         37 . A kit comprising a cell expressing a chimeric antigen receptor (CAR) comprising: (a) an antigen binding domain of a FLT3 antibody, (b) a hinge domain, (c) a transmembrane domain, and (d) an intracellular domain, or a vector comprising a nucleic acid encoding the CAR, and hematopoietic stem cells (HSCs).

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