T cell receptors recognizing mutated P53
Inventors
DENIGER, Drew C. • Rosenberg, Steven A. • Pasetto, Anna • Yoseph, Rami • Lo, Winifred M. • Lu, Yong-Chen • Parkhurst, Maria R. • Robbins, Paul F. • Malekzadeh, Parisa
Assignees
US Department of Health and Human Services
Publication Number
US-11939365-B2
Publication Date
2024-03-26
Expiration Date
2038-09-17
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Abstract
Disclosed is an isolated or purified T cell receptor (TCR) having antigenic specificity for mutated human p53. 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 an isolated or purified T cell receptor (TCR) having antigenic specificity for mutated human p53. The mutated human p53 has one of several human p53 mutations, including R175H, Y220C, G245S, R248Q, or R248W, defined with reference to SEQ ID NO: 1. The TCR can comprise specific amino acid sequences including complementarity-determining regions (CDRs), variable and constant regions of alpha and beta chains, or combinations thereof as detailed in numerous SEQ ID NOs.
Mutations in the p53 protein may reduce or eliminate tumor suppressor functions. These mutated p53 proteins are expressed in various human cancers such as colon cancer, melanoma, pancreatic cancer, breast cancer and others, many of which have limited treatment options when metastatic or unresectable. The invention addresses the need for additional cancer treatments by providing TCRs that specifically recognize mutated p53 in an HLA-dependent manner, allowing targeting of mutations present in a substantial fraction of tumors.
Claims Coverage
The patent includes two independent claims focused on isolated TCRs and polypeptides with antigenic specificity for mutated human p53, particularly with specific p53 mutations.
T-cell receptor with specificity for mutated p53 mutations
An isolated or purified TCR has antigenic specificity for mutated human p53 with mutations R175H, Y220C, G245S, R248Q, or R248W, defined relative to SEQ ID NO: 1, incorporating amino acid sequences of specific CDRs and constant regions as enumerated in the patent.
T-cell receptor with defined variable and constant regions
The TCR comprises an alpha chain and a beta chain with specific variable regions comprising CDR1, CDR2, and CDR3, and constant regions derived from mouse or human sequences, including murine constant region modifications such as cysteine substitutions or LVL-modifications.
Polypeptide comprising functional portions of TCR recognizing mutated p53
Isolated polypeptides comprising functional portions of TCRs that bind to mutated p53 mutations are claimed, wherein the polypeptides contain defined CDR amino acid sequences, variable regions, and optionally constant regions corresponding to the TCR sequences described.
Recombinant nucleic acids, expression vectors, and host cells encoding the TCRs
Nucleic acids encoding the TCRs or polypeptides, recombinant expression vectors comprising these nucleic acids, and host cells, including populations of such cells, are claimed as part of the invention.
Pharmaceutical compositions containing TCRs or related materials
Pharmaceutical compositions comprising the TCRs, polypeptides, proteins, nucleic acids, expression vectors, or host cells combined with pharmaceutically acceptable carriers are covered, enabling therapeutic or prophylactic use.
The claims cover isolated TCRs specific for defined mutated human p53 antigens, polypeptides and proteins comprising these TCRs or functional portions thereof, corresponding nucleic acids and vectors, host cells expressing these molecules, and pharmaceutical compositions thereof. The invention emphasizes the sequences of variable and constant regions relevant for the antigenic specificity for the specified p53 mutations.
Stated Advantages
The inventive TCRs target mutated p53 expressed by cancer cells and not by normal cells, reducing toxicity by minimizing destruction of normal cells.
They may successfully treat or prevent cancers that are resistant to other therapies such as chemotherapy, surgery, or radiation.
Inventive TCRs provide high avidity recognition of mutated p53, including unmanipulated tumor cells without prior modifications.
The frequent occurrence of conserved hotspot p53 mutations across unrelated tumors increases the number of patients eligible for treatment with these TCR-based immunotherapies.
Documented Applications
Detection of the presence of cancer in a mammal by contacting a sample with the TCRs, polypeptides, proteins, nucleic acids, host cells or pharmaceutical compositions and detecting the complex formed.
Treatment or prevention of cancer in a mammal by administering the TCRs, polypeptides, proteins, nucleic acids, recombinant expression vectors, or host cells in an effective amount.
Use of TCR-expressing cells for adoptive cell transfer therapy targeting mutated p53-positive cancers.
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