Targeted chimeric antigen receptor modified T cells for treatment of IL13Rα2 positive malignancies
Inventors
Brown, Christine E. • Stern, Lawrence • Yang, Xin • Garcia, K. Christopher • Gonzalez, Ignacio Moraga
Assignees
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Publication Number
US-12419954-B2
Publication Date
2025-09-23
Expiration Date
Abstract
Chimeric antigen receptor molecules that include a variant IL-13. The variant IL-13 are more selective for IL13Rα2 than IL13Rα1 by virtue of weaker binding to IL13Rα1. The chimeric antigen receptors can be used to treat IL13Rα2 expressing cancers.
Core Innovation
The disclosure describes IL13Rα2-targeted chimeric antigen receptor (CAR) constructs that use IL-13 variants as CAR targeting domains. The CAR targeting domains include amino acid sequences selected from IL-13 variants, including IL13 C4 and D7 variants, that bind IL13Rα2 in a more selective manner than IL13Rα1. The nucleic acid and CAR embodiments are provided for use with human T cells.
The CAR architecture includes optional spacer regions, transmembrane domain options, and costimulatory and signaling components. The spacer region includes an IgG4 Fc hinge, including mutated IgG4 Fc linker elements such as L235E and N297Q. Costimulatory domain options include 4-1BB/41BB and CD28, and the intracellular signaling domain includes a CD3ζ signaling domain.
The disclosure reports selectivity and functional performance for IL13-variant CAR T cells. IL13 C4 and D7 variants show reduced IL13Rα1 signaling and strongly IL13Rα2-selective binding, while IL13-variant CAR T cells demonstrate comparable IL13Rα2-dependent in vitro effector function and tumor killing across variants. In vivo, the IL13-variant CAR T cells show improved survival in human glioma xenografts and reduced activity against tumors expressing IL13Rα1.
Claims Coverage
The partial claim set includes two independent claims covering a nucleic molecule encoding a CAR and the CAR itself. The independent claims are grounded on at least 98% identical CAR amino-acid sequences selected from specified SEQ ID NOs, with targeting-domain specificity for the nucleic molecule claim.
Nucleic molecule encoding a targeted CAR with defined identity and IL-13 variant targeting domain
A nucleic molecule comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises or consists of an amino acid sequence selected from the group consisting of an amino acid sequence that is at least 98% identical to an amino acid sequence selected from SEQ ID NOs: 29, 30, 32, 33, 35, 36, 38 and 39 and comprises a targeting domain comprising or consisting of an amino acid sequence identical to SEQ ID NO: 26 or 27.
CAR with defined amino-acid identity selected from enumerated SEQ ID NOs
A chimeric antigen receptor comprising or consisting of an amino acid sequence selected from the group consisting of an amino acid sequence that is at least 98% identical to an amino acid sequence selected from SEQ ID NOs: 29, 30, 32, 33, 35, 36, 38 and 39.
The independent claims primarily cover CARs and a nucleic molecule encoding them that are defined by amino-acid sequence identity relative to enumerated SEQ ID NOs, and, for the nucleic molecule claim, by the CAR targeting domain being identical to SEQ ID NO: 26 or 27.
Stated Advantages
Improved in vivo survival in human glioma xenografts.
Reduced activity against IL13Rα1-expressing tumors.
IL13Rα2-selective binding with reduced IL13Rα1 signaling.
Comparable IL13Rα2-dependent in vitro effector function and tumor killing across IL13-variant CAR T cell variants.
Documented Applications
Treatment of a cancer patient whose cancer expresses IL-13Rα2 by administering autologous or allogeneic human T cells transduced with a vector containing the nucleic acid molecule of the claim.
Cancer types explicitly listed for treatment include glioblastoma, pancreatic ductal adenocarcinoma, melanoma, ovarian carcinoma, renal cell carcinoma, breast cancer, and lung cancer.
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