# US 9,364,504 B2 · Compostition and therapeutic anti-tumour vaccine

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- Number: US 9,364,504 B2
- Document ID: US9364504B2
- Status: Granted
- Kind: B2
- Application number: 12/672,094
- Filed: 2008-08-08
- Published: 2012-01-12
- Granted: 2016-06-14
- Earliest claimed: 2007-08-08
- Assignees: Erytech Pharma
- Applicants: Yann Godfrin; Alice Banz
- Inventors: Yann Godfrin; Alice Banz
- Web page: https://patentgrep.com/patent/US9364504B2

## CPC

- A61K 35/18: Erythrocytes (haemoglobin A61K38/42)
- A61K 39/0011: {Cancer antigens}
- A61K 39/001106: {Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4}
- A61K 39/001122: {Ephrin Receptors [Eph]}
- A61K 39/001139: {Colony stimulating factors [CSF]}
- A61K 39/001149: {Cell cycle regulated proteins, e.g. cyclin, CDC, CDK or INK-CCR}
- A61K 39/00115: {Apoptosis related proteins, e.g. survivin or livin}
- A61K 39/001151: {p53}
- A61K 39/001153: {Wilms tumor 1 [WT1]}
- A61K 39/001156: {Tyrosinase and tyrosinase related proteinases [TRP-1 or TRP-2]}
- A61K 39/001157: {Telomerase or TERT [telomerase reverse transcriptase]}
- A61K 39/001159: {Matrix metalloproteinases [MMP]}
- A61K 39/001162: {Kinases, e.g. Raf or Src}
- A61K 39/001164: {GTPases, e.g. Ras or Rho}
- A61K 39/001166: {Adhesion molecules, e.g. NRCAM, EpCAM or cadherins}
- A61K 39/00117: {Mucins, e.g. MUC-1}
- A61K 39/001184: {Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE}
- A61K 39/001186: {MAGE}
- A61K 39/001188: {NY-ESO}
- A61K 39/001189: {PRAME}
- A61K 39/001191: {Melan-A/MART}
- A61K 39/001192: {Glycoprotein 100 [Gp100]}
- A61K 39/001193: {Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR}
- A61K 39/001197: {Breakpoint cluster region-abelson tyrosine kinase [BCR-ABL]}
- A61K 47/02: Inorganic compounds
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- C07K 16/2806: {against CD2}
- A61K 2039/5154: {Antigen presenting cells [APCs], e.g. dendritic cells or macrophages}
- A61K 2039/5156: {expressing foreign proteins}
- A61K 2039/55522: {Cytokines; Lymphokines; Interferons}
- A61K 2039/55561: {CpG containing adjuvants; Oligonucleotide containing adjuvants}
- A61K 2039/572: {cytotoxic response}
- A61K 2039/6056: {Antibodies}
- 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 invention relates to a composition which induces, in a host, a cytotoxic cell response directed against cells expressing an antigen, in particular tumor cells, and which comprises red blood cells containing said antigen. These red blood cells may be in the form of an immune complex with an immunoglobulin, in particular IgG, which recognizes an epitope at the surface of the red blood cells, and/or be heat-treated or chemically treated so as to promote phagocytosis of said red blood cells by dendritic cells. As a variant, the red blood cells may be xenogenic red blood cells. The invention also relates to a therapeutic especially anti-tumor vaccine containing such a composition.

## Claims

### Claim 1

A pharmaceutically acceptable injectable or infusible pharmaceutical comprising a non-naturally-occurring suspension of red blood cells containing a tumor antigen inside of said red blood cells, wherein the suspension comprises the red blood cells at a haematocrit level of between 40 and 70%, a pharmaceutically acceptable injectable or infusible saline buffer comprising NaCl and an ingredient selected from the group consisting of adenine, glucose and mannitol, and a pharmaceutically acceptable adjuvant for activating dendritic cell maturation, wherein said composition is capable of inducing a cytotoxic cellular response against tumor cells in a host.

### Claim 2 (depends on 1)

Composition according to claim 1, wherein the red blood cells (1) contain an antigen and (2) are in the form of an immune complex with an immunoglobulin which recognizes an epitope at the surface of the red blood cells, so as to promote phagocytosis of said red blood cells by dendritic cells.

### Claim 3 (depends on 2)

Composition according to claim 2, wherein the red blood cells form an immune complex with an anti-rhesus or anti-glycophorin A or anti-CR1 antibody.

### Claim 4 (depends on 2)

Composition according to claim 2, wherein the immunoglobulin is an IgG.

### Claim 5 (depends on 1)

Composition according to claim 1, wherein the red blood cells (1) contain an antigen and (2) are heat-treated or chemically treated so as to promote phagocytosis of said red blood cells by dendritic cells.

### Claim 6 (depends on 2)

Composition according to claim 2 wherein the red blood cells in the form of an immune complex are heat-treated or chemically treated.

### Claim 7 (depends on 1)

Composition according to claim 1, wherein the red blood cells are xenogenic red blood cells.

### Claim 8 (depends on 1)

Composition according to claim 1, wherein the adjuvant is present in the red blood cells, at their surface and/or outside the red blood cells.

### Claim 9 (depends on 8)

Composition according to claim 8, wherein the adjuvant is a TLR (Toll-like receptor) ligand or a cytokine.

### Claim 10 (depends on 9)

Composition according to claim 9, wherein the TLR ligand is selected from imidazoquinolines belonging to the group consisting of imidazoquinoline, imiquimod, resiquimod, CpG oligodeoxynucleotides LPSs (lipopolysaccharides) or poly(inosinic acid)-poly(cytidylic acid).

### Claim 11 (depends on 9)

Composition according to claim 9, wherein the cytokine is selected from the group consisting of interferon alpha, IL-2(interleukin 2), IFNγ (interferon gamma), GM-CSF (Granulocyte Monocyte-Colony Stimulating Factor), IL-12(interleukin 12) or TNFα (Tumor Necrosis Factor alpha).

### Claim 12 (depends on 1)

Composition according to claim 1, comprising at least two tumour antigens representative of the tumour to be treated.

### Claim 13 (depends on 1)

Composition according to claim 1, wherein the tumour antigen is selected from the group consisting of the following antigens: alpha-actinin-4; ARTC1; BCR-ABL fusion protein (b3a2); B-RAF; CASP-5; CASP-8; beta-catenin; Cdc27; CDK4; CDKN2A; COA-1; dek-can fusion protein; EFTUD2; Elongation factor 2; ETV6-AML1 fusion protein; FN1; GPNMB; LDLR-fucosyltransferaseAS fusion protein; HLA-A2d; HLA-A11d; hsp70-2; KIAAO205; MART2; ME1; MUM-1f; MUM-2; MUM-3; neo-PAP; Myosin class I; NFYC; OGT; OS-9; pml-RARalpha fusion protein; PRDX5; PTPRK; K-ras; N-ras; RBAF600; SIRT2; SNRPD1; SYT-SSX1 or -SSX2 fusion protein; Triosephosphate Isomerase; BAGE-1; GAGE-1,2,8; GAGE-3,4,5,6,7; GnTVf; HERV-K-MEL; KK-LC-1; KM-HN-1; LAGE-1; MAGE-A1; MAGE-A2; MAGE-A3; MAGE-A4; MAGE-A6; MAGE-A9; MAGE-A10; MAGE-A12; MAGE-C2; mucin k; NA-88; NY-ESO-1/LAGE-2; SAGE; Sp17; SSX-2; SSX-4; TRAG-3; TRP2-INT2g; CEA; gp100/Pme117; Kallikrein 4; mammaglobin-A; Melan-A/MART-1; NY-BR-1; OA1; PSA; RAB38/NY-MEL-1; TRP-1/gp75; TRP-2; tyrosinase; adipophilin; AIM-2; BING-4; CPSF; cyclin D1; Ep-CAM; EphA3; FGF5; G250/MN/CAIX; HER-2/neu; IL13Ralpha2; Intestinal carboxyl esterase; alpha-foetoprotein; M-CSF; mdm-2; MMP-2; MUC1; p53; PBF; PRAME; PSMA; RAGE-1; RNF43; RU2AS; secernin 1; SOX10; STEAP1; survivin; Telomerase; WT1; FLT3-ITD; BCLX(L); DKK1; ENAH(hMena); MCSP; RGS5; Gastrin-17; Human Chorionic Gonadotropin, EGFRvIII, HER2, HER2/neu, P501, Guanylyl Cyclase C, PAP.

### Claim 14 (depends on 1)

Therapeutic anti-tumour vaccine, comprising an effective amount of a composition according to claim 1.

### Claim 15 (depends on 1)

Composition according to claim 1, for use as a therapeutic anti-tumour vaccine.

### Claim 16 (depends on 1)

Composition according to claim 1, wherein the red blood cells encapsulating a tumor antigen have been prepared by lysis-resealing in order to encapsulate the antigen.

### Claim 17 (depends on 1)

Composition according to claim 1, wherein the suspension comprises the red blood cells at a haematocrit level of between 45 and 55%.

### Claim 18 (depends on 1)

Composition according to claim 1, wherein the suspension comprises the red blood cells at a haematocrit level of 50%.

### Claim 19 (depends on 1)

Composition according to claim 1, which is packaged in a volume of 10 to 250 ml.

### Claim 20

A pharmaceutically acceptable injectable or infusible composition comprising a non-naturally-occurring suspension of red blood cells containing a tumor antigen inside of said red blood cells, a pharmaceutically acceptable injectable or infusible saline buffer comprising NaCl and an ingredient selected from the group consisting of adenine glucose and mannitol, and a pharmaceutically acceptable adjuvant for activating dendritic cell maturation, and a injectable buffer, wherein said composition is capable of inducing a cytotoxic cellular response against tumor cells in a host.

### Claim 21 (depends on 20)

Composition according to claim 20, wherein the injectable buffer is a NaCl glucose buffer.

### Claim 22 (depends on 20)

Composition according to claim 20, comprising the red blood cells at a haematocrit level of between 40 and 70%.

### Claim 23 (depends on 20)

Composition according to claim 20, comprising the red blood cells at a haematocrit level of between 45 and 55%.

### Claim 24 (depends on 20)

Composition according to claim 20, comprising the red blood cells at a haematocrit level of 50%.

### Claim 25 (depends on 20)

Composition according to claim 20, which is packaged in a volume of 10 to 250 ml.

### Claim 26 (depends on 1)

Composition according to claim 1, wherein the adjuvant is outside the red blood cells.

### Claim 27 (depends on 1)

Composition according to claim 1, wherein the red blood cells encapsulating the tumor antigen have been prepared by lysis in a dialysis element and resealing.

### Claim 28 (depends on 20)

Composition according to claim 20, wherein the adjuvant is outside the red blood cells.

### Claim 29 (depends on 20)

Composition according to claim 20, wherein the red blood cells encapsulating the tumor antigen have been prepared by lysis in a dialysis element and resealing.

### Claim 30

A pharmaceutically acceptable injectable or infusible composition comprising a non-naturally-occurring suspension of red blood cells containing a tumor antigen inside of said red blood cells, and a pharmaceutically acceptable injectable or infusible saline buffer comprising NaCl and an ingredient selected from the group consisting of adenine, glucose and mannitol.

### Claim 31 (depends on 30)

The composition as claimed in claim 30, wherein the pharmaceutically acceptable injectable or infusible saline buffer comprises NaCl, adenine, glucose and mannitol.

### Claim 32 (depends on 30)

The composition as claimed in claim 30, wherein the pharmaceutically acceptable injectable or infusible saline buffer is a NaCl glucose buffer.

### Claim 33 (depends on 1)

The composition as claimed in claim 1, wherein the pharmaceutically acceptable injectable or infusible saline buffer comprises NaCl, adenine, glucose and mannitol.

### Claim 34 (depends on 1)

The composition as claimed in claim 1, wherein the composition is packaged into a blood bag suitable for blood transfusion.

### Claim 35 (depends on 34)

The composition as claimed in claim 34, wherein the blood bag contains the amount of encapsulated tumour antigen corresponding to the medical prescription.

### Claim 36 (depends on 1)

The composition as claimed in claim 1, wherein the adjuvant is encapsulated inside the red blood cells encapsulating the tumor antigen.

### Claim 37 (depends on 1)

The composition as claimed in claim 1, wherein the adjuvant is encapsulated inside red blood cells.

### Claim 38 (depends on 1)

The composition as claimed in claim 1, wherein the red blood cells originates from a donor.

### Claim 39 (depends on 20)

The composition as claimed in claim 20, wherein the pharmaceutically acceptable injectable or infusible saline buffer comprises NaCl, adenine, glucose and mannitol.

### Claim 40 (depends on 20)

The composition as claimed in claim 20, wherein the adjuvant is encapsulated inside the red blood cells encapsulating the tumor antigen.

### Claim 41 (depends on 20)

The composition as claimed in claim 20, wherein the adjuvant is encapsulated inside red blood cells.

### Claim 42 (depends on 20)

The composition as claimed in claim 20, wherein the red blood cells originates from a donor.