PROTEIN FORMULATIONS AND METHODS OF MAKING SAME
The invention provides an aqueous formulation comprising water and a protein, and methods of making the same. The aqueous formulation of the invention may be a high protein formulation and/or may have low levels of conductity resulting from the low levels of ionic excipients. Also included in the invention are formulations comprising water and proteins having low osmolality.
1 . An aqueous formulation comprising a protein and water, wherein the formulation has a characteristic selected from the group consisting of:
(a) a conductivity of less than about 2.5 mS/cm, wherein the protein has a molecular weight (Mw) greater than about 47 kDa;
(b) an osmolality of no more than about 30 mOsmol/kg;
(c) a hydrodynamic diameter (Dh) which is at least about 50% less than the Dh of the protein in a buffered solution at a given concentration; and
(d) a hydrodynamic diameter (D h ) of less than about 4 nm.
2 . The formulation of claim 1 , wherein the protein is an antibody, or an antigen-binding fragment thereof.
3 . The formulation of claim 2 , wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody (dAb).
4 . The formulation of claim 2 , wherein the antibody, or antigen-binding fragment thereof, is an anti-TNFα or an anti-IL-12 antibody.
5 . The formulation of claim 2 , wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of adalimumab, alemtuzumab, CEA-Scan Arcitumomab (fab fragment), cetuximab, trastuzumab, imciromab pentetate), capromab pendetide, infliximab), abciximab, rituximab, basiliximab, palivizumab, nofetumomab, omalizumab, daclizumab, ibritumomab tiuxetan, muromonab-CD3, edrecolomab, gemtuzumab ozogamicin), golimumab, certolizumab pegol, eculizumab, ustekinumab, panitumumab, tositumomab and I131 tositumomab, and bevacizumab.
6 . The formulation of claim 1 , wherein the protein is a therapeutic protein.
7 . The formulation of claim 1 , wherein the concentration of protein is 50 to 200 mg/ml.
8 . The formulation of claim 1 , further comprising a non-ionizable excipient.
9 . The formulation of claim 8 , wherein the non-ionizable excipient is a sugar or a polysorbate.
10 . A method of treating a subject having a disorder, comprising administering to the subject the formulation of claim 1 .
11 . A device comprising the formulation of claim 1 .
12 . An article of manufacture comprising the device of claim 11 .
13 . A method of preparing an aqueous formulation comprising a protein and water, the method comprising:
a) providing the protein in a first solution; and
b) subjecting the first solution to diafiltration using water as a diafiltration medium until at least a five-fold volume exchange with the water has been achieved to thereby prepare the aqueous formulation.
14 . A method of preparing an aqueous formulation of a protein, the method comprising:
a) providing the protein in a first solution;
b) subjecting the first solution to diafiltration using water as a diafiltration medium until at least a five-fold volume exchange with the water has been achieved to thereby prepare a diafiltered protein solution; and
c) concentrating the diafiltered protein solution to thereby prepare the aqueous formulation of the protein.
15 . The method of claim 13 , wherein the protein is an antibody, or an antigen-binding fragment thereof.
16 . The method of claim 15 , wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody (dAb).
17 . An aqueous formulation prepared according to the method of claim 13 .
18 . The method of claim 14 , wherein the protein is an antibody, or an antigen-binding fragment thereof.
19 . The method of claim 18 , wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody (dAb).
20 . An aqueous formulation prepared according to the method of claim 14 .