# US 8,784,824 B2 · Compositions and methods for treatment of angiogenesis in pathological lesions

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- Number: US 8,784,824 B2
- Document ID: US8784824B2
- Status: Granted
- Kind: B2
- Application number: 12/835,854
- Filed: 2010-07-14
- Published: 2010-12-16
- Granted: 2014-07-22
- Earliest claimed: 2000-02-24
- Assignees: Philogen S.P.A.
- Applicants: Luciano Zardi; Dario Neri; Barbara Carnemolla; Fredrik Nilsson; Lorenzo Tarli; Laura Borsi; Cornelia Halin
- Inventors: Luciano Zardi; Dario Neri; Barbara Carnemolla; Fredrik Nilsson; Lorenzo Tarli; Laura Borsi; Cornelia Halin
- Web page: https://patentgrep.com/patent/US8784824B2

## CPC

- A61K 38/217: {IFN-gamma}
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 38/1709: {from mammals}
- A61K 38/191: {Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta}
- A61K 38/2013: {IL-2}
- A61K 38/208: {IL-12}
- A61K 47/62: the modifying agent being a protein, peptide or polyamino acid
- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- A61K 47/6813: {the drug being a peptidic cytokine, e.g. an interleukin or interferon}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07K 14/475: Growth factors; Growth regulators
- C07K 14/525: Tumour necrosis factor [TNF]
- C07K 14/5434: {IL-12}
- C07K 14/55: IL-2
- C07K 14/57: IFN-gamma
- C07K 14/70596: {Molecules with a "CD"-designation not provided for elsewhere}
- C07K 16/18: against material from animals or humans
- A61K 2039/505: {comprising antibodies}
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2319/00: Fusion polypeptide
- 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

Treatment of lesions of pathological angiogenesis, especially tumors, rheumatoid arthritis, diabetic retinopathy, age-related muscular degeneration, and angiomas. A conjugate is used comprising a molecule that exerts a biocidal or cytotoxic effect on target cells in the lesions and an antibody directed against an extracellular matrix component which is present in such lesions. The antibody may be directed against fibronectin-2 (IL-2), doxorubicin, interleukin-12 (IL-12), Interferon-γ (IFN-γ), Tumor Necrosis Factor α (TNFα) or Tissue Factor protein (which may be truncated).

## Claims

### Claim 1

A conjugate of
(i) an antibody, or an antigen binding fragment thereof, which is specific for fibronectin ED-B comprising the
VH domain and/or the VL domain of antibody L19
and
(ii) TNF-α.

### Claim 2 (depends on 1)

A conjugate according to claim 1 wherein said antibody is the L19 antibody.

### Claim 3 (depends on 1)

A conjugate according to claim 1 wherein the antibody or an antigen binding fragment thereof is a single-chain.

### Claim 4

A conjugate of
(i) an antibody or an antigen binding fragment thereof which is specific for fibronectin ED-B comprising the
VH domain and/or the VL domain of antibody L19 which has respectively the VH and/or VL amino acid sequence encoded by the DNA insert of ATCC deposit no. PTA-9529
and
(ii) TNF-α.

### Claim 5

A conjugate of
(i) an antibody or an antigen binding fragment thereof which is specific for fibronectin ED-B comprising the domain having the sequence
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFSMSWVRQAPGKGLEWVSSISGSSGTT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPFPYFDYWGQGTLVTV SS (SEQ ID NO: 34) and/or the domain having the sequence EIVLTQSPGTLSLSPGERATLSCRASQSVSSSFLAWYQQKPGQAPRLLIYYASSRATGI PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQTGRIPPTFGQGTKVEIK (SEQ ID NO: 35);
and
(ii) TNF-α.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a conjugate of claim 1 and a pharmaceutically acceptable carrier.

### Claim 7 (depends on 2)

A pharmaceutical composition comprising a conjugate of claim 2 and a pharmaceutically acceptable carrier.

### Claim 8 (depends on 4)

A pharmaceutical composition comprising a conjugate of claim 4 and a pharmaceutically acceptable carrier.

### Claim 9 (depends on 5)

A pharmaceutical composition comprising a conjugate of claim 5 and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 1)

A method of treating angiogenesis in pathological lesions in a patient in need of said treatment, comprising administering a conjugate according to claim 1.

### Claim 11 (depends on 10)

A method according to claim 10, wherein the pathological lesion is a tumor.

### Claim 12 (depends on 2)

A method of treating angiogenesis in pathological lesions in a patient in need of said treatment, comprising administering a conjugate according to claim 2.

### Claim 13 (depends on 12)

A method according to claim 12 wherein said pathological lesion is a tumor.

### Claim 14 (depends on 4)

A method of treating angiogenesis in pathological lesions in a patient in need of said treatment, comprising administering a conjugate according to claim 4.

### Claim 15 (depends on 14)

A method according to claim 14 wherein said pathological lesion is a tumor.

### Claim 16 (depends on 1)

A method for suppressing tumor growth in a patient in need of said treatment, comprising administering a conjugate according to claim 1.

### Claim 17 (depends on 16)

A method according to claim 16 wherein said antibody or antigen-binding fragment thereof is L19 antibody.

### Claim 18 (depends on 10)

A method of claim 10 further comprising administering another treatment for said pathological lesion.

### Claim 19 (depends on 18)

A method according to claim 18, wherein the pathological lesion is a tumor.

### Claim 20 (depends on 19)

A method according to claim 19 wherein said antibody or antigen-binding fragment thereof is L19 antibody.

### Claim 21 (depends on 14)

A method of claim 14 further comprising administering another treatment for said pathological lesion.

### Claim 22 (depends on 16)

A method of claim 16 further comprising administering another treatment for said pathological lesion.

### Claim 23 (depends on 5)

A method of treating angiogenesis in pathological lesions in a patient in need of said treatment, comprising administering a conjugate according to claim 5.

### Claim 24 (depends on 23)

A method of claim 23 further comprising administering another treatment for said pathological lesion.