US2023029341A1PendingUtilityA1

Nucleic acid encoding lilrb1-based chimeric antigen receptor

71
Assignee: A2 BIOTHERAPEUTICS INCPriority: Dec 11, 2019Filed: Dec 11, 2020Published: Jan 26, 2023
Est. expiryDec 11, 2039(~13.4 yrs left)· nominal 20-yr term from priority
Inventors:Carl Alexander KambAgnes Eva HamburgerBreanna E. DiandrethMark DarisKiran Deshmukh
C07K 2317/92C07K 16/2803C07K 14/70521C07K 14/70503A61P 35/00C07K 16/2833C07K 2317/76A61K 2039/505C07K 2317/622C07K 14/70578C07K 14/7051C07K 2319/03A61K 40/31A61K 40/11A61K 40/42A61K 35/17A61K 40/4269A61K 40/4268A61K 40/4211A61K 2239/17A61K 2239/21C12N 5/0636A61K 2300/00A61K 2121/00C07K 2319/00C07K 16/3053C12N 2510/00C07K 16/3069
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Claims

Abstract

Provided are polynucleotides comprising nucleic acid sequences encoding chimeric antigen receptors having the hinge, transmembrane region, and/or intracellular domain of LILRB1, or functional fragments or variants thereof. Also provided herein are vectors and immune cells comprising said polynucleotides.

Claims

exact text as granted — not AI-modified
1 - 90 . (canceled) 
     
     
         91 . A polynucleotide comprising a nucleic acid sequence encoding an inhibitory receptor comprising a polypeptide comprising:
 a) an LILRB1 hinge domain or functional fragment or variant thereof;   b) a transmembrane domain; and   c) an LILRB1 intracellular domain comprising at least one immunoreceptor tyrosine-based inhibitory motif (ITIM) selected from the group consisting of NLYAAV (SEQ ID NO: 8, VTYAEV (SEQ ID NO: 9), VTYAQL (SEQ ID NO: 10), and SIYATL (SEQ ID NO: 11).   
     
     
         92 . The polynucleotide of  claim 91 , comprising an antigen binding domain. 
     
     
         93 . The polynucleotide of  claim 91 , wherein the intracellular domain is encoded by a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 34. 
     
     
         94 . The polynucleotide of  claim 91 , wherein the transmembrane domain comprises a LILRB1 transmembrane domain or a functional fragment or variant thereof. 
     
     
         95 . The polynucleotide of  claim 94 , wherein the LILRB1 transmembrane domain or functional fragment or variant thereof comprises a sequence at least 95% identical to SEQ ID NO: 5. 
     
     
         96 . The polynucleotide of  claim 91 , wherein the LILRB1 hinge domain or functional fragment or variant thereof comprises a sequence at least 95% identical to SEQ ID NO: 4, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 80, SEQ ID NO:81, SEQ ID NO: 82, SEQ ID NO: 83 or SEQ ID NO: 84. 
     
     
         97 . The polynucleotide of  claim 91 , wherein the LILRB1 hinge and transmembrane comprise a sequence at least 95% identical to SEQ ID NO: 20. 
     
     
         98 . The polynucleotide of  claim 91 , wherein the LILRB1 transmembrane and intracellular domain comprise a sequence at least 95% identical to SEQ ID NO: 21. 
     
     
         99 . The polynucleotide of  claim 91 , wherein the LILRB1 hinge, transmembrane and intracellular domains are encoded by a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 126. 
     
     
         100 . The polynucleotide of  claim 91 , wherein the LILRB1 hinge, transmembrane and intracellular domains comprise SEQ ID NO: 2. 
     
     
         101 . The polynucleotide of  claim 92 , wherein the antigen binding domain is specific to an antigen that is lost in a cancer cell through loss of heterozygosity. 
     
     
         102 . The polynucleotide of  claim 92 , wherein the antigen binding domain is specific to a minor histocompatibility antigen (MiHA) or an antigen that is lost in a cancer cell through loss of Y chromosome. 
     
     
         103 . The polynucleotide of  claim 92 , wherein the antigen binding domain is specific to a major histocompatibility class I allele. 
     
     
         104 . The polynucleotide of  claim 103 , wherein the major histocompatibility class I allele comprises HLA-A, HLA-B, -HLA-C allele or HLA-E allele. 
     
     
         105 . The polynucleotide of  claim 104 , wherein the HLA-A allele is HLA-A*02. 
     
     
         106 . The polynucleotide of  claim 92 , wherein the antigen binding domain comprises a single chain variable fragment (scFv). 
     
     
         107 . The polynucleotide of  claim 106 , wherein the scFv comprises complementarity determined regions (CDRs) comprising SEQ ID NOS: 22-27 or SEQ ID NOS: 28-33. 
     
     
         108 . The polynucleotide of  claim 106 , wherein the scFv comprises a sequence at least 95% identical to any one of SEQ ID NOS: 35-46 or 125. 
     
     
         109 . The polynucleotide of  claim 91 , wherein the inhibitory receptor comprises an amino acid sequence at least 95% identical to any one of SEQ ID NOS: 48-50, 52-53, 55-56, 59-65, 67-68, 77, 120 or 122. 
     
     
         110 . The polynucleotide of  claim 91 , wherein the inhibitory receptor comprises an amino acid sequence of SEQ ID NOS: 48-50, 52-53, 55-56, 59-65, 67-68, 77, 120 or 122. 
     
     
         111 . The polynucleotide of  claim 91 , wherein the inhibitory receptor comprises an amino acid sequence at least 95% identical to SEQ ID NO: 122 or SEQ ID NO: 89. 
     
     
         112 . The polynucleotide of  claim 106 , wherein the scFv is encoded by a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 127. 
     
     
         113 . The polynucleotide of  claim 91 , wherein the inhibitory receptor is encoded by a nucleic acid sequence that is at least 95% identical to any one of SEQ ID NOS: 111, 112, 113, 114, 121, or 123. 
     
     
         114 . The polynucleotide of  claim 91 , comprising a promoter operably linked to the nucleic acid sequence encoding the inhibitory receptor. 
     
     
         115 . The polynucleotide of  claim 114 , wherein the promoter is an immediate early cytomegalovirus (CMV) promoter sequence, Elongation Growth Factor-1a (EF-1a) promoter sequence, simian virus 40 (SV40) early promoter sequence, an Epstein-Barr virus immediate early promoter sequence, a Rous sarcoma virus promoter sequence, an actin promoter sequence, a myosin promoter sequence, or a creatine kinase promoter sequence. 
     
     
         116 . The polynucleotide of  claim 114 , wherein the promoter is mouse mammary tumor virus (MMTV) promoter sequence, human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter sequence, MoMuLV promoter sequence, an avian leukemia virus promoter sequence, or a hemoglobin promoter sequence. 
     
     
         117 . The polynucleotide of  claim 114 , wherein the promoter is Elongation Growth Factor-1a (EF-1a). 
     
     
         118 . The polynucleotide of  claim 114 , wherein the promoter is immediate early cytomegalovirus (CMV). 
     
     
         119 . The polynucleotide of  claim 114 , wherein the polynucleotide comprises a nucleic acid sequence encoding an activator receptor. 
     
     
         120 . The polynucleotide of  claim 119 , wherein the activating receptor comprises a CD3 intracellular domain. 
     
     
         121 . The polynucleotide of  claim 120 , wherein the activating chimeric antigen receptor comprises one or more of a CD28 intracellular domain and 4-1BB intracellular domain. 
     
     
         122 . The polynucleotide of  claim 120 , wherein the polynucleotide encoding the activating receptor is responsive to a target antigen. 
     
     
         123 . A vector comprising the polynucleotide of  claim 91 . 
     
     
         124 . The vector of  claim 123 , wherein the polynucleotide comprises a nucleic acid sequence encoding an activating receptor. 
     
     
         125 . The vector of  claim 124 , wherein the vector is a lentiviral vector. 
     
     
         126 . An immune cell comprising the polynucleotide of  claim 91 . 
     
     
         127 . The immune cell of  claim 126 , wherein the immune cell is a T cell. 
     
     
         128 . The immune cell of  claim 127 , wherein the polynucleotide comprises an activating receptor.

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