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Methods and compositions for modification of a HLA locus

  • US 10,072,062 B2
  • Filed: 01/05/2015
  • Issued: 09/11/2018
  • Est. Priority Date: 07/21/2010
  • Status: Active Grant
First Claim
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1. A genetically modified mammalian cell comprising an endogenous human leukocyte antigen (HLA) class I gene comprising a sequence selected from the group consisting of any one of the nucleotides of SEQ ID NOs:

  • 97 to 111 and an endogenous HLA class II gene comprising a sequence selected from the group consisting of any one of the nucleotides of SEQ ID NOs;

    112 to 115, the genetically modified cell comprising;

    (i) a first genomic modification comprising an integrated exogenous nucleotide sequence encoding a chimeric antigen receptor (CAR) or T-cell receptor gene, and(ii) a second genomic modification comprising an inactivated HLA gene following zinc finger nuclease-mediated cleavage of the active HLA class I gene and/or HLA class II gene with a pair of zinc finger nucleases, each zinc finger nuclease comprising a cleavage domain and the recognition helix regions of the zinc finger proteins designated 18889, which binds to a target site within SEQ ID NO;

    97;

    11881, which binds to a target site within SEQ ID NO;

    98;

    24859, which binds to a target site within SEQ ID NO;

    99;

    25191, which binds to a target site within SEQ ID NO;

    100;

    25190, which binds to a target site within SEQ ID NO;

    101;

    25316, which binds to a target site within SEQ ID NO;

    102;

    25317, which binds to a target site within SEQ ID NO;

    103;

    15267, which binds to a target site within SEQ ID NO;

    104;

    15265, which binds to a target site within SEQ ID NO;

    105;

    17454, which binds to a target site within SEQ ID NO;

    106;

    17456, which binds to a target site within SEQ ID NO;

    107;

    15296, which binds to a target site within SEQ ID NO;

    108;

    15298, which binds to a target site within SEQ ID NO;

    109;

    25588, which binds to a target site within SEQ ID NO;

    110;

    25589, which binds to a target site within SEQ ID NO;

    111;

    15872, which binds to a target site within SEQ ID NO;

    112;

    15873, which binds to a target site within SEQ ID NO;

    113;

    15909, which binds to a target site within SEQ ID NO;

    114;

    or 15910, which binds to a target site within SEQ ID NO;

    115,wherein the pair of zinc finger nucleases includes 18889 and 18881;

    18889 and 24859;

    25191 and 25190;

    25316 and 25317;

    15267 and 15265;

    17454 and 17456;

    15296 and 15298;

    25588 and 25589;

    15872 and 15873;

    or 15909 and 15910;

    and wherein the HLA gene is inactivated by the second genomic modification.

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