ANTI-ANGIOGENIC COMPOUNDS

• US 20100003267A1
• Filed: 04/29/2009
• Published: 01/07/2010
• Est. Priority Date: 05/05/2008
• Status: Active Grant

• Current Assignee: CovX Technologies Ireland Ltd. (Pfizer Inc.)
• Original Assignee: CovX Technologies Ireland Ltd. (Pfizer Inc.)
• Inventors: Oates, Bryan Douglas, Bhat, Abhijit Suresh, Lai, Jing-Yu, Desharnais, Joel, Bradshaw, Curt William, Doppalapudi, Venkata Ramana, Liu, Dingguo, Fu, Yanwen, Chen, Gang, Liu, Bin
• Granted Patent: US 8,293,714 B2
• Time in Patent Office: Days
• US Class Current: 424/179.1
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61K 47/6835 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/71 for growth factors; for growth regulators

Abstract

The present invention provides VEGF binding peptides. In addition, the invention provides VEGF peptides conjugated to antibodies alone and in conjunction with other anti-angiogenic molecules. Various uses of the peptides and compounds are provided, including methods to treat disorders associated with abnormal angiogenesis.

Claims

1. A compound of the formula:

R¹-[VEGF-Peptide]-R² wherein [VEGF-Peptide] is a peptide having the sequence;

X¹—

X²—

P³—

N⁴—

C⁵—

X⁶—

X⁷—

X⁸—

V⁹—

X¹⁰—

X¹¹—

X¹²—

W¹³—

X¹⁴—

C¹⁵—

F¹⁶-E¹⁷-R¹⁸—

X¹⁹—

X^20-X²¹—

X²²—

X²³ (SEQ ID NO;

131) wherein R¹ is absent, CH₃, C(O)CH₃, C(O)CH₃, C(O)CH₂CH₃, C(O)CH₂CH₂CH₃, C(O)CH(CH₃)CH₃, C(O)CH₂CH₂CH₂CH₃, C(O)CH(CH₃)CH₂CH₃, C(O)C₆H₅, C(O)CH₂CH₂(CH₂CH₂O)_1-5Me, amido-2-PEG, or an N-acyl or N-alkyl amino protecting group, a lipid fatty acid group or a carbohydrate; and

R² is absent, OH, NH₂, NH(CH₃), NHCH₂CH₃, NHCH₂CH₂CH₃, NHCH(CH₃)CH₃, NHCH₂CH₂CH₂CH₃, NHCH(CH₃)CH₂CH₃, NHC₆H₅, NHCH₂CH₂OCH₃, NHOCH₃, NHOCH₂CH₃, a carboxy protecting group, a lipid fatty acid group or a carbohydrate, and X¹ is a hydrophobic amino acid residue, X² is a negatively charged residue, X⁶ is a negatively charged residue, X⁷ is a hydrophobic amino acid residue, X⁸ is a residue comprising a ring structure, X¹⁰ may be a hydrophobic amino acid, X¹¹ is an aromatic amino acid, X¹² is selected from the group consisting of V, E and Kac, X¹⁴ is E or V, X¹⁹ may be any hydrophobic amino acid residue, or D-isomer thereof, X²⁰ may be absent, or may be any neutral, hydrophobic or aromatic amino acid or D-isomer thereof, X²¹ may be absent, or may be any positively charged residue or any aliphatic non-polar residue or D-isoform thereof, X²² may be absent, or may be selected from the group consisting of G, V, L, I, P, S, T, W, F, E, Kac, or D-isomers thereof, X²³ may be absent, or is selected from the group consisting of G, A, I, L, Q, E, F, T, W, S, Y, and Kac and D-isomers thereof, and wherein one of the group-consisting of X¹, X², P³, N⁴, V⁹, X¹⁰, X¹², X¹⁴, E¹⁷ and the C-terminus residue may substituted with a linking residue comprising a nucleophilic side chain or the N-terminus amino group or C-terminus carboxle group covalently linked to the combining site of an antibody directly or via an intermediate linker, the linking residue being selected from the group consisting of K, R, Y, C, T, S, homologs of lysine, homocysteine, homoserine, Dap, Dab, the N-terminus residue and the C-terminus residue, or a pharmaceutically acceptable salt thereof.

2. The compound or salt according to claim 1, wherein the [VEGF-Peptide] includes a sequence selected from the group consisting of SEQ ID NOs:

34-136, and SEQ ID NOs;

192-195.

3. The compound or salt according to claim 1, wherein the R¹-[VEGF-Peptide]-R² comprises the formula (SEQ ID NO:

195);

4. The compound or salt according to claim 1, wherein a linking residue is present, and wherein a linear or branched linker is covalently linked to the side chain of the linking residue.

5. The compound or salt according to claim 4, wherein the linker comprises the formula L or L′

, and L is of the formula;

-[Connector]-X—

Y-Z, or —

X—

Y-Z-, and L′

is of the formula;

-[Connector]-X—

Y-Z′

, or —

X—

Y-Z′

-, wherein;

[Connector] is present where the linker is branched, and where present is covalently linked to the linking residue, and one or more additional Active Molecules,

X is a biologically compatible connecting chain including any atom selected from the group consisting of C, H, N, O, P, S, F, Cl, Br, and I, and may comprise a polymer or block co-polymer, and is covalently linked to the linking residue where the linker is linear,

Y is an optionally present recognition group comprising the optionally substituted structure;

6. The compound or salt according to claim 5, wherein X—

Y is

7. The compound or salt according to claim 5, wherein the linker is linear and the [Connector] is absent, wherein the compound is selected from the group consisting of Compounds 1001-1080 where Z is present, and Compounds 2001-2080 where Z′

is present.

9. A compound comprising the formula:

10. The compound or salt according to claim 9, wherein [Connector] comprises the formula:

-[Active Molecule-1-Spacer]-[Branch]-[Active Molecule-2-Spacer]-, and wherein [Active Molecule-1-Spacer] and [Active Molecule-2-Spacer] are each independently a biologically compatible polymer, block copolymer C, H, N, O, P, S, halogen (F, Cl, Br, I), or a salt thereof, alkyl, alkenyl, alkynyl, oxoalkyl, oxoalkenyl, oxoalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, sulfoalkyl, sulfoalkenyl, sulfoalkynyl, phosphoalkyl, phosphoalkenyl, or phosphoalkynyl group, covalently bonded to [Branch], and [Branch] is molecule with at least three reactive groups, and [Active Molecule-1-Spacer] is covalently linked to [Branch] and to the [Active Molecule-1], and [Active Molecule-2-Spacer] is covalently linked to [Branch] and to the [Active Molecule-2].

11. The compound or salt according to claim 10, wherein [Branch] is a chemical moiety comprising three orthogonal reactive groups, and is selected from the group consisting of:

a cysteine branch, diaminopropionic acid based branch, diaminobutanoic acid based branch, ornithine based branch, lysine based branch, homocysteine branch, bismaleimide branch, and maleimide-acid branch, and derivitaves and homologs thereof, and the following structures;

12. The compound or salt according to claim 11, wherein [Branch]-L is selected from the group consisting of:

13. The compound or salt according to claim 9, wherein [Active Molecule 2] is an Ang-2 binding peptide of the formula:

R³-[Ang2-peptide]-R⁴ wherein R³ is absent, CH₃, C(O)CH₃, C(O)CH₃, C(O)CH₂CH₃, C(O)CH₂CH₂CH₃, C(O)CH(CH₃)CH₃, C(O)CH₂CH₂CH₂CH₃, C(O)CH(CH₃)CH₂CH₃, C(O)C₆H₅, C(O)CH₂CH₂(CH₂CH₂O)_1-5Me, amido-2-PEG, an N-acyl or N-alkyl amino protecting group, a lipid fatty acid group or a carbohydrate; and

R⁴ is absent, OH, NH₂, NH(CH₃), NHCH₂CH₃, NHCH₂CH₂CH₃, NHCH(CH₃)CH₃, NHCH₂CH₂CH₂CH₃, NHCH(CH₃)CH₂CH₃, NHC₆H₅, NHCH₂CH₂OCH₃, NHOCH₃, NHOCH₂CH₃, a carboxy protecting group, a lipid fatty acid group or a carbohydrate, and wherein [Ang2-Peptide] comprises a sequence;

14. The compound or salt according to claim 13, wherein the [Ang2-peptide] comprises a sequence selected from the group consisting of:

SEQ ID NOs;

137-191.

15. The compound or salt according to claim 14, wherein R¹-[Ang-peptide]-R² is (SEQ ID NO:

153);

{C(O)CH₃}-Q-(Kac)-Y-Q-P-L-D-E-(Kac)-D-K-T-L-Y-D-Q-F-M-L-Q-Q-G-{NH₂} and K at position 11 is the Ang2-linking residue covalently linked to the [Connector].

16. The compound or salt according to claim 9, wherein [VEGF-Peptide] is covalently linked to [Connector] through a nucleophilic side chain or the N-terminus amino group or C-terminus carboxyl group of an VEGF-linking residue, the VEGF-linking residue being selected from the group consisting of K, R, Y, C, T, S, homologs of lysine, homocysteine, homoserine, Dap, Dab, the N-terminus residue or C-terminus residue.

17. The compound according to claim 9, wherein the compound is selected from the group consisting of:

Compound 5001-Compound 5028, and Compound 5031-Compound 5074, and Compounds 5053, 5060, 5061 and 5062;

or a pharmaceutically acceptable salt thereof.

18. The compound or salt according to claim 16, wherein the linking residue is covalently linked to the combining site of an antibody, and the compound is selected from the group consisting of:

6001-6026, 6028, 6029, and 6031-6074.

8. A compound comprising the formula of Compound 2018:

19. A compound comprising the formula of Compound 6053:

20. A compound or salt according to claim 19, wherein the Antibody is a full-length antibody, Fab, Fab′

, F(ab′

)₂, F_v, dsF_v, scF_v, V_H, V_L, diabody, minibody comprising V_H and V_L domains from h38c2, or full length antibody comprising the V_H and V_L domains from h38c2 and a constant domain selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

21. A pharmaceutical composition comprising a therapeutically effective amount of the compound or salt according to claim 19, and a pharmaceutically acceptable carrier.