TREATMENT OF CANCER USING HUMANIZED ANTI-EGFRvIII CHIMERIC ANTIGEN RECEPTOR

Patent metadata

Field	Value
Publication number	US-2024238396-A1
Application number	US-202318505864-A
Country	US
Kind code	A1
Filing date	Nov 9, 2023
Priority date	Feb 20, 2013
Publication date	Jul 18, 2024
Grant date	—

Abstract

The invention provides compositions and methods for treating diseases associated with expression of EGFRvIII. The invention also relates to chimeric antigen receptor (CAR) specific to EGFRvIII, vectors encoding the same, and recombinant T cells comprising the anti-EGFRvIII CAR. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises an anti-EGFRvIII binding domain.

First claim

1 . An isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein said CAR comprises an anti-EGFRvIII binding domain, a transmembrane domain, and an intracellular signaling domain comprising a primary signaling domain, and wherein said anti-EGFRvIII binding domain comprises one or more of a light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and light chain complementarity determining region 3 (LC CDR3) of any anti-EGFRvIII light chain binding domain amino acid sequence listed in Table 2 or SEQ ID NO:11, and one or more of a heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3) of any anti-EGFRvIII heavy chain binding domain amino acid sequence listed in Table 2 or SEQ ID NO:11.

2 - 4 . (canceled)

5 . The isolated nucleic acid molecule of claim 1 , comprising (a) any light chain variable region listed in Table 2 or SEQ ID NO:11; (b) any heavy chain variable region listed in Table 2 or SEQ ID NO:11; or (c) any light chain variable region listed in Table 2 or SEQ ID NO:11 and any heavy chain variable region listed Table 2 or SEQ ID NO.:11.

6 - 10 . (canceled)

11 . The isolated nucleic acid molecule of claim 1 , wherein the anti-EGFRvIII binding domain comprises a sequence selected from a group consisting of SEQ ID NO:38, SEQ ID NO:44, SEQ ID NO:50, SEQ ID NO:56, SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:80, and SEQ ID NO:86, or a sequence with 95-99% identify thereof.

12 . The isolated nucleic acid molecule of claim 1 , wherein the nucleic acid sequence encoding the anti-EGFRvIII binding domain comprises a sequence selected from a group consisting of SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:51, SEQ ID NO:57, SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:75, SEQ ID NO:81 and SEQ ID NO:98, or a sequence with 95-99% identify thereof.

13 . The isolated nucleic acid molecule of claim 1 , wherein the encoded CAR comprises a transmembrane domain that comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154.

14 .- 19 . (canceled)

20 . The isolated nucleic acid molecule of claim 1 , further comprising a sequence encoding a costimulatory domain.

21 . The isolated nucleic acid molecule of claim 20 , wherein the encoded costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of OX40, CD27, CD28, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), and 4-1BB (CD137).

22 .- 32 . (canceled)

33 . An isolated polypeptide molecule encoded by the nucleic acid molecule of claim 1 .

34 . The isolated polypeptide molecule of claim 33 comprising a sequence selected from the group consisting of SEQ ID NO:43, SEQ ID NO:49, SEQ ID NO:55, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:73, SEQ ID NO:79, SEQ ID NO:85 and SEQ ID NO:90, or a sequence with 95-99% identify thereof.

35 - 36 . (canceled)

37 . An isolated chimeric antigen receptor (CAR) molecule comprising an anti-EGFRvIII binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the anti-EGFRvIII binding domain comprises one or more light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and light chain complementarity determining region 3 (LC CDR3) of any anti-EGFRvIII binding domain listed in Table 2 or SEQ ID NO:11, and one or more heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3) of any anti-EGFRvIII binding domain listed in Table 2 or SEQ ID NO:11.

38 . The isolated CAR molecule of claim 37 , wherein the intracellular signaling domain comprises a costimulatory domain and a primary signaling domain.

39 .- 65 . (canceled)

66 . An anti-EGFRvIII binding domain comprising one or more light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and light chain complementarity determining region 3 (LC CDR3) of an anti-EGFRvIII binding domain in SEQ ID NO:38, 44, 50, 56, 62, 68, 74 or 80, and one or more heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3) of an anti-EGFRvIII binding domain in SEQ ID NO:38, 44, 50, 56, 62, 68, 74 or 80.

67 - 71 . (canceled)

72 . The anti-EGFRvIII binding domain of claim 66 , comprising a sequence selected from the group consisting of SEQ ID NO:38, SEQ ID NO:44, SEQ ID NO:50, SEQ ID NO:56, SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:80, and SEQ ID NO:86, or a sequence with 95-99% identify thereof.

73 . A vector comprising a nucleic acid molecule of claim 1 .

74 .- 80 . (canceled)

81 . A cell comprising the vector of claim 73 .

82 .- 84 . (canceled)

85 . A method of making a cell comprising transducing a T cell with a vector of claim 73 .

86 . A method of generating a population of RNA-engineered cells comprising introducing an in vitro transcribed RNA or synthetic RNA into a cell, where the RNA comprises the nucleic acid molecule of claim 1 .

87 . A method of providing an anti-tumor immunity in a mammal comprising administering to the mammal an effective amount of the cell of claim 81 .

88 - 90 . (canceled)

91 . A method of treating a mammal having a disease associated with expression of EGFRvIII comprising administering to the mammal an effective amount of the cell of claim 81 .

92 . (canceled)

93 . The method of claim 91 , wherein the disease associated with expression of EGFRvIII is a cancer selected from the group consisting of glioblastoma multiforme (GBM), anaplastic astrocytoma, giant cell glioblastoma, gliosarcoma, anaplastic oligodendroglioma, anaplastic ependymoma, choroid plexus carcinoma, anaplastic ganglioglioma, pineoblastoma, medulloepithelioma, ependymoblastoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, atypical teratoid/rhabdoid tumor, lung cancer (e.g., non-small cell lung carcinomas) breast, prostate, ovarian, colorectal and bladder carcinoma and any combination thereof, and metastases of any of the cancers.

94 - 98 . (canceled)

Assignees

• Novartis Ag
• Univ Pennsylvania
• Univ Pittsburgh Commonwealth Sys Higher Education

Inventors

• Brogdon Jennifer
• Johnson Laura Alexandra
• June Carl H
• Loew Andreas
• Maus Marcela
• Scholler John
• Okada Hideho

Classifications

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• A61K40/31

  Chimeric antigen receptors [CAR] · CPC title

• A61K40/4255

  Mesothelin [MSLN] · CPC title

• A61K40/4204

  Epidermal growth factor receptors [EGFR] · CPC title

• A61K2239/38

  characterised by the dose, timing or administration schedule · CPC title