# US 9,518,123 B2 · Compositions and methods for treatment of cancer

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- Number: US 9,518,123 B2
- Document ID: US9518123B2
- Status: Granted
- Kind: B2
- Application number: 14/997,042
- Filed: 2016-01-15
- Published: 2016-07-07
- Granted: 2016-12-13
- Earliest claimed: 2010-12-09
- Assignees: The Trustees of the University of Pennsylvania
- Applicants: The Trustees of the University of Pennsylvania
- Inventors: Carl H. June; Bruce L. Levine; David L. Porter; Michael D. Kalos; Michael C. Milone
- Web page: https://patentgrep.com/patent/US9518123B2

## CPC

- C12N 5/0636: {T lymphocytes}
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/4211: {CD19 or B4}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/075: Adenoviridae
- C07K 14/525: Tumour necrosis factor [TNF]
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 14/70517: {CD8}
- C07K 14/70521: {CD28, CD152}
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C07K 14/70596: {Molecules with a "CD"-designation not provided for elsewhere}
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 16/30: from tumour cells
- C07K 16/3061: {Blood cells}
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- C12N 15/85: for animal cells
- C12N 15/861: Adenoviral vectors
- A61K 2039/505: {comprising antibodies}
- A61K 2039/5256: {expressing foreign proteins}
- A61K 2039/585: {wherein the target is cancer}
- A61K 2239/31: characterized by the route of administration
- A61K 2239/38: characterised by the dose, timing or administration schedule
- A61K 2239/48: Blood cells, e.g. leukemia or lymphoma
- C07K 2317/53: Hinge
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/80: remaining in the (producing) cell, i.e. intracellular antibodies or intrabodies
- C07K 2319/00: Fusion polypeptide
- C07K 2319/02: containing a signal sequence
- C07K 2319/03: containing a transmembrane segment
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- C07K 2319/74: containing a fusion for binding to a cell surface receptor
- C12N 2501/51: B7 molecules, e.g. CD80, CD86, CD28 (ligand), CD152 (ligand)
- C12N 2501/515: CD3, T-cell receptor complex
- C12N 2510/00: Genetically modified cells
- C12N 2740/15034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2740/15043: viral genome or elements thereof as genetic vector
- C12N 2740/15071: Demonstrated in vivo effect
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention provides compositions and methods for treating cancer in a human. The invention includes relates to administering a genetically modified T cell to express a CAR wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain.

## Claims

### Claim 1

A human T cell comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain comprising, from the amino to the carboxy terminus, a light chain variable region and a heavy chain variable region of SEQ ID NO:20, wherein the CAR further comprises a transmembrane domain, a 4-1BB costimulatory signaling region, and a CD3 zeta signaling domain, wherein the T cells is from a human having cancer.

### Claim 2 (depends on 1)

The human T cell of claim 1, wherein said antigen binding fragment is a scFv.

### Claim 3 (depends on 2)

The human T cell of claim 2, wherein the scFv comprises the amino acid sequence of SEQ ID NO:20.

### Claim 4 (depends on 1)

The human T cell of claim 1, wherein the transmembrane domain is CD8α transmembrane domain.

### Claim 5 (depends on 4)

The human T cell of claim 4, wherein the CD8α transmembrane domain comprises the amino acid sequence of SEQ ID NO: 22.

### Claim 6 (depends on 1)

The human T cell of claim 1, wherein the CAR further comprises a hinge domain.

### Claim 7 (depends on 6)

The human T cell of claim 6, wherein the hinge domain is a CD8α hinge domain.

### Claim 8 (depends on 7)

The human T cell of claim 7, wherein the CD8α hinge domain comprises the amino acid sequence of SEQ ID NO:21.

### Claim 9 (depends on 1)

The human T cell of claim 1, wherein the 4-1BB costimulatory signaling region comprises the amino acid sequence of SEQ ID NO:23.

### Claim 10 (depends on 1)

The human T cell of claim 1, wherein the CD3 zeta signaling domain comprises the amino acid sequence of SEQ ID NO: 24.

### Claim 11 (depends on 1)

The human T cell of claim 1, wherein the CD19 antigen binding domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 14.

### Claim 12 (depends on 5)

The human T cell of claim 5, wherein the CD8α transmembrane domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 16.

### Claim 13 (depends on 8)

The human T cell of claim 8, wherein the CD8α hinge domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 15.

### Claim 14 (depends on 9)

The human T cell of claim 9, wherein the 4-1BB costimulatory signaling region is encoded by a nucleic acid sequence comprising SEQ ID NO: 17.

### Claim 15 (depends on 10)

The human T cell of claim 10, wherein the CD3 zeta signaling domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 18.

### Claim 16 (depends on 1)

The human T cell of claim 1, wherein the CAR comprises the amino acid sequence of SEQ ID NO:12.

### Claim 17 (depends on 16)

The human T cell of claim 16, wherein the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO:8.

### Claim 18 (depends on 1)

The human T cell of claim 1, wherein the CAR further comprises a CD28 costimulatory signaling region.

### Claim 19 (depends on 1)

The human T cell of claim 1, wherein the cancer is a hematological cancer.

### Claim 20 (depends on 1)

The human T cell of claim 1, wherein the T cell comprises a vector that comprises the nucleic acid sequence.

### Claim 21 (depends on 20)

The human T cell of claim 20, wherein the vector is a lentiviral vector.

### Claim 22 (depends on 21)

The human T cell of claim 21, wherein the vector further comprises a promoter.

### Claim 23 (depends on 22)

The human T cell of claim 22, wherein the promoter is an EF-1α promoter.

### Claim 24 (depends on 1)

The human T cell of claim 1, wherein the cell is isolated from a blood sample obtained from a human before the human is treated with a modality selected from the group consisting of an antiviral agent, chemotherapy, radiation, an immunosuppressive agent and an antibody.

### Claim 25 (depends on 24)

The human cell of claim 24, wherein the antibody is selected from the group consisting of anti-CD3 antibody, natalizumab and efalizumab.

### Claim 26 (depends on 24)

The human cell of claim 24, wherein the immunosuppressive agent is selected from the group consisting of cyclosporin, azathioprine, methotrexate, mycophenolate, FK506, CAMPATH, cytoxan, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, a steroid, and FR901228.