Immunoconjugate formulations
The present invention provides an immunoconjugate formulation that is substantially free of particles, the immunoconjugate formulation comprising: an immunoconjugate and one or more excipients selected from the group consisting of: sucrose, polysorbate 20, polysorbate 80, cyclodextrin, dextrose, glycerol, polyethylene glycol, mannitol, sodium chloride, and an amino acid, wherein the formulation is a buffered aqueous solution having a pH of 4.5 to 7.6. The present invention also provides an immunoconjugate formulation that is substantially free of aggregates, the immunoconjugate formulation comprising: an immunoconjugate and one or more excipients selected from the group consisting of histidine, sucrose, glycine and sodium chloride, wherein the formulation is a buffered aqueous solution having a pH of 4.5 to 7.6. The present invention further provides an immunoconjugate formulation that is substantially free of both particles and aggregates.
1. An immunoconjugate liquid formulation comprising:
(i) an immunoconjugate, which is an antibody comprising one or more covalently linked hydrophobic cytotoxic drugs,
(ii) 5-20 mM histidine,
(iii) 100-300 mM glycine,
(iv) 0.1-12% sucrose, and
(v) 0.5-2% beta-cyclodextrin,
wherein the pH of the formulation is 4.5 to 7.6.
2. The formulation of claim 1 , wherein:
said immunoconjugate is present in an amount of 0.5-20 mg/ml.
3. The formulation of claim 1 , wherein:
said immunoconjugate is present in an amount of 0.5-20 mg/ml,
said histidine is present in an amount of 10-15 mM,
said glycine is present in an amount of 130-250 mM,
said sucrose is present in an amount of 5-10%, and
said beta-cyclodextrin is present in an amount of 0.5-1%.
4. The formulation of claim 3 , wherein the formulation further comprises polysorbate 80 or polysorbate 20 in an amount of 0.005-0.2%.
5. The formulation of claim 4 , wherein:
said sucrose is present in an amount of 5%,
said histidine is present in an amount of 10 mM, and
said glycine is present in an amount of 130 mM.
6. The formulation of claim 1 , wherein the pH is from 5-7.
7. The formulation of claim 1 , wherein the pH is from 5-6.
8. The formulation of claim 1 , wherein said antibody is a humanized antibody selected from the group consisting of huMy 9-6, huN901, huC242, huB4, DS6, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab.
9. The formulation of claim 1 , wherein said antibody is huC242.
10. The formulation of claim 1 , wherein said antibody is huN901.
11. The formulation of claim 1 , wherein the cytotoxic drug is selected from the group consisting of a maytansinoid, a taxane, and a CC-1065.
12. The formulation of claim 10 , wherein the cytotoxic drug is a maytansinoid.
13. The formulation of claim 11 , wherein the cytotoxic drug is a maytansinoid.
14. The formulation of claim 11 , wherein the cytotoxic drug is N 2 ′-deacetyl-N 2 ′-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N 2 ′-deacetyl-N 2 ′-(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4).
15. The formulation of claim 5 , wherein:
said immunoconjugate is a humanized N901-DM1 immunoconjugate and is present in an amount of 0.5-10 mg/ml.
16. The formulation of claim 5 , wherein:
said cytotoxic drug is N 2 ′-deacetyl-N 2 ′-(4-methyl-4-mercapto -1-oxopentyl) -maytansine(DM4) and said immunoconjugate is present in an amount of 0.5-10 mg/ml.
17. The formulation of claim 5 , wherein:
said immunoconjugate is a humanized C242-DM4 immunoconjugate and is present in an amount of 0.5-10 mg/ml.
18. An immunoconjugate liquid formulation comprising:
(i) an immunoconjugate, which is an antibody comprising one or more covalently linked hydrophobic cytotoxic drugs,
(ii) 100-300 mM glycine,
(iii) 0.1-12% sucrose, and
(iv) 0.5-2% beta-cyclodextrin,
wherein the formulation is a buffered aqueous solution having a pH of 4.5 to 7.6.
19. The formulation of claim 18 , wherein the formulation further comprises polysorbate 20 or polysorbate 80 in an amount of 0.005-1%.
20. The formulation of claim 18 , wherein:
said immunoconjugate is present in an amount of 0.5-20 mg/ml.
21. The formulation of claim 18 , wherein the pH is from 5-7.
22. The formulation of claim 18 , wherein the pH is from 5-6.
23. The formulation of claim 18 , wherein said antibody is a humanized antibody selected from the group consisting of huMy9-6, huN901, huC242, huB4, DS6, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab.
24. The formulation of claims 23 , wherein said antibody is huN901 or huC242.
25. The formulation of claim 18 , wherein the cytotoxic drug is selected from the group consisting of a maytansinoid, a taxane, and a CC-1065.
26. The formulation of claim 18 , wherein:
said immunoconjugate is a humanized N901-DM1 immunoconjugate and is present
in an amount of 0.5-10 mg/ml.
27. An immunoconjugate liquid formulation comprising:
(i) an immunoconjugate, which is an antibody comprising one or more covalently linked hydrophobic cytotoxic drugs,
(ii) 100-300 mM glycine,
(iii) 2-8% glycerol,
(iv) 0.5-2% beta-cyclodextrin, and
(v) 0.005-1.0% polysorbate 20 or polysorbate 80,
wherein the formulation is a buffered aqueous solution having a pH of 4.5-7.6.
28. The formulation of claim 27 , wherein:
said immunoconjugate is present in an amount of 0.5-20 mg/ml,
said glycine is present in an amount of 130-250 mM,
said glycerol is present in an amount of 2-5%,
said beta-cyclodextrin is present in an amount of 0.5-1%, and
said is polysorbate 80 or polysorbate 20 is present in an amount of 0.005-0.2%.
29. The formulation of claim 27 , wherein the pH is from 5-7.
30. The formulation of claim 27 , wherein the pH is from 5-6.
31. The formulation of claim 27 , wherein said antibody is a humanized antibody selected from the group consisting of huMy9-6, huN901, huC242, huB4, DS6, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab.
32. The formulation of claim 27 , wherein the cytotoxic drug is selected from the group consisting of a maytansinoid, a taxane, and a CC-1065.
33. The formulation of claim 27 , wherein said cytotoxic drug is N 2 ′-deacetyl-N 2 ′-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N 2 ′-deacetyl-N 2 ′-(4-methyl-4 -merecapto-1 -oxopentyl)-maytansine (DM4).
34. An immunoconjugate liquid formulation comprising:
(i) an immunoconjugate, which is an antibody comprising one or more covalently linked hydrophobic cytotoxic drugs,
(ii) 2-8% mannitol,
(iii) 0.1-12% sucrose,
(iv) 0.5-2% beta-cyclodextrin, and
(v) 0.005-1.0% polysorbate 20 or polysorbate 80,
wherein the formulation is a buffered aqueous solution having a pH of 4.5-7.6.
35. The formulation of claim 34 , wherein:
said immunoconjugate is present in an amount of 0.5-20 mg/ml,
said mannitol is present in and amount of 3-5%,
said sucrose is present in an amount of 5-10%, and
said is polysorbate 80 or polysorbate 20 is present in an amount of 0.005-0.2%.
36. The formulation of claim 34 , wherein the pH is from 5-7.
37. The formulation of claim 34 , wherein the pH is from 5-6.
38. The formulation of claim 34 , wherein said antibody is a humanized antibody selected from the group consisting of huMy9-6, huN901, huC242, huB4, DS6, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab.
39. The formulation of claim 34 , wherein the cytotoxic drug is selected from the group consisting of a maytansinoid, a taxane, and a CC-1065.
40. The formulation of claim 18 , wherein the buffered aqueous solution contains one or more of histidine, succinate, citrate, phosphate, and acetate.
41. The formulation of claim 40 , wherein the buffered aqueous solution contains succinate.
42. The formulation of claim 40 , wherein the buffered aqueous solution contains citrate.
43. The formulation of claim 18 , wherein
said immunoconjugate is present in an amount of 0.5-20 mg/ml,
said glycine is present in an amount of 130-250 mM,
said sucrose is present in an amount of 5-10%, and
said beta-cyclodextrin is present in an amount of 0.5-1%.
44. The formulation of claim 43 , wherein the formulation further comprises polysorbate 80 or polysorbate 20 in an amount of 0.005-0.2%.
45. The formulation of claim 18 , wherein said cytotoxic drug is N 2′ -deacetyl-N 2′ -(3-mercapto-1-oxopropyl)-maytansine (DM1) or N 2′ -deacetyl-N 2′ -(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4).
46. The formulation of claim 27 , wherein the buffered aqueous solution contains one or more of histidine, succinate, citrate, phosphate, and acetate.
47. The formulation of claim 46 , wherein the buffered aqueous solution contains succinate.
48. The formulation of claim 27 , wherein:
said immunoconjugate is present in an amount of 0.5-20 mg/ml.
49. The formulation of claim 34 , wherein the buffered aqueous solution contains one or more of histidine, succinate, citrate, phosphate, and acetate.
50. The formulation of claim 49 , wherein the buffered aqueous solution contains succinate.
51. The formulation of claim 34 , wherein:
said immunoconjugate is present in an amount of 0.5-20 mg/ml.
52. The formulation of claim 34 , wherein said cytotoxic drug is N 2′ -deacetyl-N 2 ′-(3-mercapto -1 -oxopropyl)-maytansine (DM1) or N 2′ -deacetyl-N 2′ -(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4).