TREATMENT OF CANCER USING HUMANIZED ANTI-EGFRvIII CHIMERIC ANTIGEN RECEPTOR

• US 20170008963A1
• Filed: 06/15/2016
• Published: 01/12/2017
• Est. Priority Date: 02/20/2013
• Status: Active Grant

• Current Assignee: Novartis Ag, Trustees Of The University Of Pennsylvania (University of Pennsylvania), University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Brogdon, Jennifer, Johnson, Laura Alexandra, June, Carl H., Loew, Andreas, Maus, Marcela, Scholler, John, Okada, Hideho
• Granted Patent: US 10,308,717 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2239/47 Brain; Nervous system
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4631 Chimeric Antigen Receptors [CAR]
• CPC Class Codes: A61K 39/464404 Epidermal growth factor receptors [EGFR]
• CPC Class Codes: A61K 39/464468 Mesothelin [MSLN]
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/3053 Skin, nerves, brain
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/03 : containing a transmembrane segment
• CPC Class Codes: C07K 2319/33 : fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

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.

Claims

1-65. -65. (canceled)

66. A humanized anti-EGFRvIII binding domain comprising one or more light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary 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 complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary 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. The humanized anti-EGFRvIII binding domain of claim 66, comprising LC CDR1, LC CDR2 and LC CDR3 of an anti-EGFRvIII light chain binding domain amino acid sequence in SEQ ID NO:

38, 44, 50, 56, 62, 68, 74 or 80.

68. The humanized anti-EGFRvIII binding domain of claim 66, comprising HC CDR1, HC CDR2, and HC CDR3 of an anti-EGFRvIII heavy chain binding domain amino acid sequence in SEQ ID NO:

38, 44, 50, 56, 62, 68, 74 or 80.

73. A vector comprising a nucleic acid molecule encoding the humanized anti-EGFRvIII binding domain of claim 66.

81. A cell comprising the vector of claim 73.

69-72. -72. (canceled)

74-80. -80. (canceled)

82-98. -98. (canceled)

99. A humanized anti-EGFRvIII binding domain comprising:

(a) a heavy chain immunoglobulin variable region comprising;

(i) a CDR1 comprising the sequence DYYIH (SEQ ID NO;

     22);

(ii) a CDR2 comprising the sequence RIDPENDETKYGPIFQG (SEQ ID NO;

     23); and

(iii) a CDR3 comprising the sequence RGGVY (SEQ ID NO;

     24); and

(b) a light chain immunoglobulin variable region comprising;

(i) a CDR1 comprising the sequence KSSQSLLDSDGKTYLN (SEQ ID NO;

     26);

(ii) a CDR2 comprising the sequence LVSKLDS (SEQ ID NO;

     27); and

(iii) a CDR3 comprising the sequence WQGTHFPGT (SEQ ID NO;

     28).

100. The humanized anti-EGFRvIII binding domain of claim 99, wherein the humanized anti-EGFRvIII binding domain comprises an amino acid sequence with 99% sequence identity to SEQ ID NO:

68.

101. The humanized anti-EGFRvIII binding domain of claim 99, wherein the humanized anti-EGFRvIII binding domain comprises an amino acid sequence with 100% sequence identity to SEQ ID NO:

68.

102. The humanized anti-EGFRvIII binding domain of claim 99, wherein the humanized anti-EGFRvIII binding domain comprises an scFv domain.

103. The humanized anti-EGFRvIII binding domain of claim 99, wherein the humanized anti-EGFRvIII binding domain comprises a Fab domain.

104. An isolated nucleic acid molecule encoding a humanized anti-EGFRvIII binding domain comprising:

(a) a heavy chain immunoglobulin variable region comprising;

(i) a CDR1 comprising the sequence DYYIH (SEQ ID NO;

     22);

(ii) a CDR2 comprising the sequence RIDPENDETKYGPIFQG (SEQ ID NO;

     23); and

(iii) a CDR3 comprising the sequence RGGVY (SEQ ID NO;

     24); and

(b) a light chain immunoglobulin variable region comprising;

(i) a CDR1 comprising the sequence KSSQSLLDSDGKTYLN (SEQ ID NO;

     26);

(ii) a CDR2 comprising the sequence LVSKLDS (SEQ ID NO;

     27); and

(iii) a CDR3 comprising the sequence WQGTHFPGT (SEQ ID NO;

     28).

105. The isolated nucleic acid molecule of claim 104, wherein the humanized anti-EGFRvIII binding domain comprises an amino acid sequence with 99% sequence identity to SEQ ID NO:

68.

106. The isolated nucleic acid molecule of claim 104, wherein the humanized anti-EGFRvIII binding domain comprises an amino acid sequence with 100% sequence identity to SEQ ID NO:

68.

107. The isolated nucleic acid molecule of claim 104, wherein the nucleic acid sequence encoding the humanized anti-EGFRvIII binding domain comprises a nucleotide sequence with greater than 99% sequence identity to SEQ ID NO:

69.

108. The isolated nucleic acid molecule of claim 104, wherein the nucleic acid sequence encoding the humanized anti-EGFRvIII binding domain comprises a nucleotide sequence with 100% sequence identity to SEQ ID NO:

69.

109. The isolated nucleic acid molecule of claim 104, wherein the humanized anti-EGFRvIII binding domain comprises an scFv domain.

110. The isolated nucleic acid molecule of claim 104, wherein the humanized anti-EGFRvIII binding domain comprises a Fab domain.