US2023256018A1PendingUtilityA1

T cell receptors and engineered cells expressing same

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Assignee: JUNO THERAPEUTICS INCPriority: Apr 5, 2018Filed: Jun 30, 2022Published: Aug 17, 2023
Est. expiryApr 5, 2038(~11.7 yrs left)· nominal 20-yr term from priority
Inventors:Stephen J. GoldflessBrian J. BelmontCameron S. BrandtAlexandra CroftDavid Jeffrey Huss
A61K 40/46A61K 40/42A61K 40/32A61K 40/11A61K 2239/38A61K 2239/31A61K 2239/46C07K 14/025C12N 5/0636A61K 39/0011A61P 31/20A61K 35/17A61P 35/00C07K 14/7051C07K 16/084C12N 15/86C07K 16/2833C07K 2317/565C07K 2317/24C07K 2317/622C12N 2740/16043C12N 2510/00A61K 2039/505
65
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Claims

Abstract

Provided herein are binding molecules, such as those that recognize or bind a peptide epitope of a cancer antigen, such as expressed on a cancer cell, including cells infected with human papilloma virus (HPV) or that contain HPV DNA sequences and/or those that recognize or bind a peptide epitope of HPV 16 E6 or E7, in the context of a major histocompatibility complex (MHC) molecule. Among the provided binding molecules are T cell receptors (TCRs) or antibodies, including antigen-binding fragments thereof, that bind or recognize such peptide epitopes. The present disclosure further relates to engineered cells comprising such binding molecules, e.g., TCRs or antibodies (and chimeric antigen receptors containing the antibodies), and uses thereof in adoptive cell therapy.

Claims

exact text as granted — not AI-modified
1 - 157 . (canceled) 
     
     
         158 . A recombinant T cell receptor (TCR) or antigen-binding fragment thereof that binds to or recognizes a peptide epitope of human papillomavirus (HPV) 16 E7 in the context of an MHC molecule, comprising an alpha chain comprising a variable alpha (Vα) region and a beta chain comprising a variable beta (Vβ) region, wherein:
 the Vα region comprises a complementarity determining region 1 (CDR-1), a CDR-2, and a CDR-3, respectively comprising the CDR-1, the CDR-2, and the CDR-3 amino acid sequences contained within a Vα region amino acid sequence set forth in SEQ ID NO: 47; and 
 the Vβ region comprises a complementarity determining region 1 (CDR-1), a CDR-2, and a CDR-3, respectively comprising the CDR-1, the CDR-2, and the CDR-3 amino acid sequences contained within a Vβ region amino acid sequence set forth in SEQ ID NO: 60. 
 
     
     
         159 . The recombinant TCR or antigen-binding fragment thereof of  claim 158 , wherein the alpha chain further comprises an alpha constant (Cα) region and the beta chain further comprises a beta constant (Cβ) region. 
     
     
         160 . The recombinant TCR or antigen-binding fragment thereof of  claim 159 , wherein the Cα and/or Cβ regions comprise one or more amino acid replacements to introduce one or more cysteine residues capable of forming one or more non-native disulfide bridges between the alpha chain and beta chain. 
     
     
         161 . The recombinant TCR or antigen-binding fragment thereof of  claim 160 , wherein the Vα region comprises the amino acid sequence set forth in SEQ ID NO: 47 or an amino acid sequence that has at least 90% sequence identity thereto, and the Vβ region comprises the amino acid sequence set forth in SEQ ID NO: 60, or an amino acid sequence that has at least 90% sequence identity thereto. 
     
     
         162 . The recombinant TCR or antigen-binding fragment thereof of  claim 160 , wherein the Vα and Vβ regions comprise the amino acid sequences of SEQ ID NOs: 47 and 60, respectively. 
     
     
         163 . The recombinant TCR or antigen-binding fragment thereof of  claim 161 , wherein the Cα region comprises the amino acid sequence of SEQ ID NO: 14, or an amino acid sequence having at least 90% sequence identity thereto; and the Cβ region comprises the amino acid sequence of SEQ ID NO: 350, or an amino acid sequence having at least 90% sequence identity thereto. 
     
     
         164 . The recombinant TCR or antigen-binding fragment thereof of  claim 162 , wherein the Cα region comprises the amino acid sequence of SEQ ID NO: 14, or an amino acid sequence having at least 90% sequence identity thereto; and the Cβ region comprises the amino acid sequence of SEQ ID NO: 350, or an amino acid sequence having at least 90% sequence identity thereto. 
     
     
         165 . The recombinant TCR or antigen-binding fragment thereof of  claim 160 , wherein the Cα region comprises the amino acid sequence of SEQ ID NO: 14, and the Cβ region comprises the amino acid sequence of SEQ ID NO: 350. 
     
     
         166 . The recombinant TCR or antigen-binding fragment thereof of  claim 161 , wherein the Cα region comprises the amino acid sequence of SEQ ID NO: 14, and the Cβ region comprises the amino acid sequence of SEQ ID NO: 350. 
     
     
         167 . The recombinant TCR or antigen-binding fragment thereof of  claim 160 , wherein the TCR or antigen-binding fragment thereof is encoded by a polynucleotide that encodes the amino acid sequence of SEQ ID NO: 362, or a sequence having at least 90% sequence identity thereto. 
     
     
         168 . A nucleic acid molecule(s) encoding the recombinant TCR or antigen-binding fragment thereof of  claim 160 , or an alpha or a beta chain thereof. 
     
     
         169 . A vector comprising the nucleic acid molecule(s) of  claim 168 . 
     
     
         170 . An isolated engineered cell comprising the recombinant TCR or antigen-binding fragment thereof of  claim 160 . 
     
     
         171 . The isolated engineered cell of  claim 170 , wherein the cell comprises a genetic disruption of a T cell receptor alpha constant (TRAC) gene and/or a T cell receptor beta constant (TRBC) gene. 
     
     
         172 . An isolated engineered cell comprising the recombinant TCR or antigen-binding fragment thereof of  claim 161 . 
     
     
         173 . The isolated engineered cell of  claim 172 , wherein the cell comprises a genetic disruption of a TRAC gene and/or a TRBC gene. 
     
     
         174 . An isolated engineered cell comprising the recombinant TCR or antigen-binding fragment thereof of  claim 162 . 
     
     
         175 . The isolated engineered cell of  claim 174 , wherein the cell comprises a genetic disruption of a TRAC gene and/or a TRBC gene. 
     
     
         176 . An isolated engineered cell comprising the recombinant TCR or antigen-binding fragment thereof of  claim 163 . 
     
     
         177 . The isolated engineered cell of  claim 176 , wherein the cell comprises a genetic disruption of a TRAC gene and/or a TRBC gene. 
     
     
         178 . An isolated engineered cell comprising the recombinant TCR or antigen-binding fragment thereof of  claim 164 . 
     
     
         179 . The isolated engineered cell of  claim 178 , wherein the cell comprises a genetic disruption of a TRAC gene and/or a TRBC gene. 
     
     
         180 . A composition comprising engineered cells of  claim 170 , wherein the cells are T cells or natural killer (NK) cells. 
     
     
         181 . A composition comprising engineered cells of  claim 171 , wherein the cells are T cells or NK cells. 
     
     
         182 . A composition comprising engineered cells of  claim 172 , wherein the cells are T cells or NK cells. 
     
     
         183 . A composition comprising engineered cells of  claim 174 , wherein the cells are T cells or NK cells. 
     
     
         184 . A composition comprising engineered cells of  claim 175 , wherein the cells are T cells or NK cells. 
     
     
         185 . A composition comprising engineered cells of  claim 178 , wherein the cells are T cells or NK cells. 
     
     
         186 . A composition comprising engineered cells of  claim 179 , wherein the cells are T cells or NK cells. 
     
     
         187 . A method of treatment, comprising administering the composition of  claim 180  to a subject having a disease or disorder associated with HPV 16. 
     
     
         188 . A method of treatment, comprising administering the composition of  claim 181  to a subject having a disease or disorder associated with HPV 16. 
     
     
         189 . A method of treatment, comprising administering the composition of  claim 182  to a subject having a disease or disorder associated with HPV 16. 
     
     
         190 . A method of treatment, comprising administering the composition of  claim 183  to a subject having a disease or disorder associated with HPV 16. 
     
     
         191 . A method of treatment, comprising administering the composition of  claim 184  to a subject having a disease or disorder associated with HPV 16. 
     
     
         192 . A method of treatment, comprising administering the composition of  claim 185  to a subject having a disease or disorder associated with HPV 16. 
     
     
         193 . A method of treatment, comprising administering the composition of  claim 186  to a subject having a disease or disorder associated with HPV 16.

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