Anti-KK-LC-1 T cell receptors
Inventors
Stevanovic, Sanja • Hinrichs, Christian S.
Assignees
United States Of American REPRESENTED BY SECRETARY Department Of Health And Human Service AS • US Department of Health and Human Services
Publication Number
US-11352410-B2
Publication Date
2022-06-07
Expiration Date
2037-04-17
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Abstract
Disclosed is an isolated or purified T cell receptor (TCR) having antigenic specificity for Kita-Kyushu Lung Cancer Antigen 152-60 (KK-LC-152-60). Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions are also provided. Also disclosed are methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal.
Core Innovation
The invention provides isolated or purified T cell receptors (TCRs) with antigenic specificity for Kita-Kyushu Lung Cancer Antigen 152-60 (KK-LC-152-60). These TCRs, as well as related polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, cell populations, and pharmaceutical compositions, are described. The invention also includes methods for detecting cancer presence in mammals and methods for treating or preventing cancer using these TCRs and related materials.
A specific embodiment includes TCRs that recognize KK-LC-1 in a major histocompatibility complex (MHC) class I-dependent manner, preferably presented by HLA-A1 molecules. The TCRs comprise variable regions with complementarity determining regions (CDRs) specific for KK-LC-1, particularly for the peptide sequence NTDNNLAVY (SEQ ID NO: 2). The TCRs may also include human or murine constant regions, including modified murine constant regions with amino acid substitutions enhancing TCR pairing, surface expression, and anti-tumor activity. The invention further covers functional variants, fragments, fusion proteins, and nucleic acids encoding these TCRs.
The problem addressed by the invention arises from challenges in adoptive cell therapy (ACT) for cancer treatment, including the difficulty in generating human T cells with anti-tumor potential and the toxicity of transferred T cells to normal tissues. There is a need for immunological compositions and methods that better target cancer cells while minimizing damage to healthy cells. The TCRs of the invention aim to overcome these obstacles by targeting the KK-LC-1 antigen, a cancer-testis antigen expressed in multiple human cancers but largely absent from normal tissues except for non-MHC expressing germ cells, thereby providing specificity and reducing toxicity.
Claims Coverage
The patent claims encompass 25 inventive features focusing on isolated nucleic acids encoding TCRs specific for KK-LC-152-60, the structure and modifications of these TCRs, recombinant vectors, host cells, compositions, and therapeutic and diagnostic methods.
Nucleic acid encoding TCR with antigenic specificity for KK-LC-152-60 presented by HLA-A1
A single isolated or purified nucleic acid encoding a TCR that specifically recognizes KK-LC-152-60 presented by HLA-A1, wherein the TCR comprises the amino acid sequences of SEQ ID NOs: 3-8.
TCR comprising a murine constant region
The TCR encoded by the nucleic acid includes murine constant regions in the alpha and beta chains.
TCR variable region amino acid sequences
The TCR includes alpha and beta chain variable regions comprising SEQ ID NO: 9 and SEQ ID NO: 10 respectively, with the residue at position 2 of SEQ ID NO: 10 being Ala or Gly.
TCR with substituted murine constant regions
The TCR includes murine constant regions with amino acid substitutions specified at positions 48, 112, 114, and 115 of the alpha chain (SEQ ID NO: 13) and position 57 of the beta chain (SEQ ID NO: 14), allowing for cysteine or other hydrophobic amino acid substitutions enhancing pairing and expression.
Full-length TCR alpha and beta chain amino acid sequences
The TCR comprises full-length alpha and beta chain amino acid sequences as recited in SEQ ID NOs: 15 and 16 respectively.
Polypeptide comprising TCR alpha and beta chain CDRs
A polypeptide comprising the TCR alpha chain amino acid sequences of SEQ ID NOs: 3-5 and the TCR beta chain amino acid sequences of SEQ ID NOs: 6-8.
Linker peptide inclusion
The polypeptide or protein may further comprise a linker amino acid sequence (SEQ ID NO: 17) linking the TCR beta and alpha chains for coordinated expression and cleavage.
Recombinant expression vectors and vector configuration
Vectors comprising nucleic acids encoding the TCR are claimed, specifically recombinant expression vectors where the beta chain encoding sequence is positioned 5′ of the alpha chain encoding sequence to enhance expression and functionality.
Host cells and populations expressing the recombinant TCR
Host cells and populations of cells transformed or transduced with recombinant vectors for expressing the TCR are claimed, including pharmaceutical compositions comprising these cells.
Methods for detecting and treating cancer using TCRs specific for KK-LC-152-60
Methods are claimed for detecting cancer by contacting a sample with cells expressing the TCR and detecting complexes; and methods for treating cancer by administering cells expressing the TCR specific for KK-LC-152-60 presented by HLA-A1.
The claims comprehensively cover nucleic acids encoding TCRs specific for KK-LC-152-60 presented by HLA-A1, protein and polypeptide forms of such TCRs including variable and constant region sequences, recombinant expression vectors with defined configurations, host cells and populations expressing these TCRs, pharmaceutical compositions, and methods for cancer detection and treatment using these TCR materials.
Stated Advantages
The TCRs specifically target KK-LC-1, a cancer-testis antigen expressed in multiple cancers but not in normal tissues, minimizing toxicity to healthy cells.
The TCRs enable adoptive cell therapy to treat or prevent multiple types of cancer expressing KK-LC-1, including cancers resistant to chemotherapy, surgery, or radiation.
Modified constant regions (murine with cysteine and hydrophobic substitutions) improve TCR pairing, surface expression, and anti-tumor activity.
High functional avidity of the TCRs allows recognition of unmanipulated tumor cells presenting KK-LC-1 naturally.
Documented Applications
Detecting the presence of cancer in a mammal by contacting a sample with TCR-expressing cells and detecting TCR-antigen complexes.
Treating or preventing cancer in a mammal by administering cells expressing TCRs specific for KK-LC-1 antigen (KK-LC-152-60 peptide) presented by HLA-A1.
Use in adoptive cell therapy to transfer T cells with anti-tumor potential against various carcinomas including bladder, uterine cervix, stomach, breast, lung, colon, rectum, and pancreas cancers.
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