Prostaglandin E2 binding proteins and uses thereof

1. A humanized antibody or antigen binding fragment thereof wherein the antibody or antigen binding fragment is capable of binding prostaglandin E 2 , and the antibody or antigen binding fragment comprises a variable heavy (VH) and a variable light (VL) domain sequence selected from the group consisting of:

a) SEQ ID NOs: 60 and 61;

b) SEQ ID NOs: 62 and 63;

c) SEQ ID NOs: 64 and 65;

d) SEQ ID NOs: 66 and 67;

e) SEQ ID NOs: 68 and 69;

f) SEQ ID NOs: 70 and 71;

g) SEQ ID NOs: 72 and 73;

h) SEQ ID NOs: 74 and 75;

i) SEQ ID NOs: 76 and 77;

j) SEQ ID NOs: 78 and 79;

k) SEQ ID NOs: 78 and 81;

l) SEQ ID NOs: 80 and 79; and

m) SEQ ID NOs: 80 and 81.

2. A humanized antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment is capable of binding prostaglandin E 2 , and the antibody or antigen binding fragment comprises complementarity determining region (CDR) sequences: GYTFTKYWLG (SEQ ID NO: 54), DIYPGYDYTHYNEKFKD (SEQ ID NO: 55), SDGSSTY (SEQ ID NO: 56), TSSQNIVHSNGNTYLE (SEQ ID NO: 57), KVSNRFSG (SEQ ID NO: 58), and FQVSHVPYT (SEQ ID NO: 59) and human framework sequences SEQ ID NOs: 72 and 73 modified by at least one framework region amino acid substitution in the heavy chain variable region selected from a substitution:

a) at position 48, from the human residue methionine to murine residue isoleucine;

b) at position 68, from the human residue valine to murine residue alanine; and

c) at position 72, from the human residue threonine to murine residue valine.

3. A humanized antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment is capable of binding prostaglandin E 2 , and the antibody or antigen binding fragment comprises complementarity determining region (CDR) sequences: GYTFTKYWLG (SEQ ID NO: 54), DIYPGYDYTHYNEKFKD (SEQ ID NO: 55), SDGSSTY (SEQ ID NO: 56), TSSQNIVHSNGNTYLE (SEQ ID NO: 57), KVSNRFSG (SEQ ID NO: 58), and FQVSHVPYT (SEQ ID NO: 59) and human framework sequences SEQ ID NOs: 72 and 73 modified by one framework amino acid substitution at a residue adjacent to a CDR, a glycosylation site residue, a residue capable of interacting with prostaglandin E 2 , a residue capable of interacting with a CDR, a residue within a Vernier zone, or a residue in a region that overlaps between a Chothia-defined variable heavy chain CDR1 and a Kabat-defined first heavy chain framework.

4. The antibody or antigen binding fragment of any one of claims 1 , 2 , and 3 , further comprising a linker polypeptide or an immunoglobulin constant domain.

5. The antibody or antigen binding fragment of any one of claims 1 , 2 , and 3 , wherein the antibody or antigen binding fragment is an immunoglobulin molecule, a disulfide linked Fv, a monoclonal antibody, a scFv, a single domain antibody, a diabody, a multispecific antibody, a Fab, a dual specific antibody, a Fab′, a bispecific antibody, a F(ab′)2, and/or a Fv.

6. The antibody or antigen binding fragment of claim 4 , wherein the antibody or antigen binding fragment is an immunoglobulin molecule, a disulfide linked Fv, a monoclonal antibody, a scFv, a single domain antibody, a diabody, a humanized antibody, a multispecific antibody, a Fab, a dual specific antibody, a Fab′, a bispecific antibody, a F(ab′)2, and/or a Fv.

7. The antibody or antigen binding fragment of claim 4 , wherein the antibody or antigen binding fragment comprises a human IgM heavy chain constant domain, a human IgG4 heavy chain constant domain, a human IgG1 heavy chain constant domain, a human IgE heavy chain constant domain, a human IgG2 heavy chain constant domain, a human IgG3 heavy chain constant domain, and/or a human IgA heavy chain constant domain.

8. The antibody or antigen binding fragment of claim 4 , wherein the antibody or antigen binding fragment comprises an immunoglobulin constant domain comprising SEQ ID No: 1, SEQ ID No: 2, SEQ ID No: 3, or SEQ ID No: 4.

9. The antibody or antigen binding fragment of claim 4 , wherein said antibody or antigen binding fragment is a crystallized antibody or antigen binding fragment.

10. The antibody or antigen binding fragment of claim 9 , wherein said crystallized antibody or antigen binding fragment is a carrier-free pharmaceutical controlled release crystallized antibody or antigen binding fragment,

11. The antibody or antigen binding fragment of claim 9 , wherein said antibody or antigen binding fragment has a greater half-life in vivo than the soluble counterpart of said antibody or antigen binding fragment.

12. An antibody conjugate comprising the antibody or antigen binding fragment of claim 4 , the antibody conjugate further comprising an immunoadhesion molecule, an imaging agent, a therapeutic agent, or a cytotoxic agent.

13. The antibody conjugate of claim 12 , wherein the imaging agent is a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, or biotin.

14. The antibody conjugate of claim 13 , wherein the radiolabel is 3 H, 14 C, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 177 Lu, 166 Ho, or 153 Sm.

15. The antibody conjugate of claim 12 , wherein the therapeutic or cytotoxic agent is an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, a toxin, or an apoptotic agent.

16. A composition for the release of an antibody or antigen binding fragment, the composition comprising:

(a) a formulation, wherein the formulation comprises a crystallized antibody or antigen binding fragment, according to claim 9 ;

(b) an ingredient; and

(c) at least one polymeric carrier.

17. The composition of claim 16 , wherein the polymeric carrier is a poly (acrylic acid), a poly (cyanoacrylate), a poly (amino acid), a poly (anhydride), a poly (depsipeptide), a poly (ester), a poly (lactic acid), a poly (lactic-co-glycolic acid) or PLGA, a poly (b-hydroxybutryate), poly (caprolactone), a poly (dioxanone); a poly (ethylene glycol), a poly ((hydroxypropyl) methacrylamide), a poly (organo) phosphazene), a poly (ortho ester), a poly (vinyl alcohol), a poly (vinylpyrrolidone), a maleic anhydride-alkyl vinyl ether copolymer, a pluronic polyol, albumin, alginate, cellulose, a cellulose derivative, collagen, fibrin, gelatin, hyaluronic acid, an oligosaccharide, a glycaminoglycan, a sulfated polysaccharide, or a blend and/or a copolymer thereof.

18. The composition of claim 16 , wherein the ingredient is albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol, or polyethylene glycol.

19. A pharmaceutical composition comprising the antibody or antigen binding fragment any one of claims 1 , 2 , and 3 , and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19 , wherein the pharmaceutically acceptable carrier is hyaluronidase.

21. The pharmaceutical composition of claim 19 , further comprising an imaging agent, a cytotoxic agent, an angiogenesis inhibitor, a kinase inhibitor, a co-stimulation molecule blocker, an adhesion molecule blocker, an anti-cytokine antibody or functional fragment thereof, methotrexate, cyclosporine, rapamycin, FK506, a detectable label or reporter, a TNF antagonist, an anti-rheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an oral steroid, an epinephrine or analog thereof, a cytokine, or a cytokine antagonist.

22. A pharmaceutical composition comprising the antibody or antigen binding fragment of claim 4 and a pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22 , further comprising at least one additional therapeutic agent for treating a disorder in which prostaglandin E 2 activity is detrimental.