Lyophilized formulation of a monoclonal antibody against transthyretin
The invention provides antibody formulations and methods useful for prophylaxis or treatment of transthyretin-related amyloidosis.
1. A pharmaceutical formulation comprising:
(a) a monoclonal antibody comprising a mature heavy chain comprising the amino acid sequence of SEQ ID NO:82 except the C-terminal lysine may be absent and a mature light chain comprising the amino acid sequence of SEQ ID NO:86, wherein the antibody is present at a concentration within the range from about 25 mg/mL to about 75 mg/mL;
(b) a histidine buffer present at a concentration of about 20 mM;
(c) sucrose present at a concentration of about 220 to about 260 mM, and
(d) poloxamer 188 (PX188) present at a concentration within the range from about 0.03% to about 0.050% by weight;
wherein the formulation is characterized by a pH within the range from about 5.5 to about 6.5.
2. The pharmaceutical formulation of claim 1 , comprising:
20 mM histidine, 240 mM sucrose and 0.04% w/w PX188.
3. The pharmaceutical formulation of claim 2 , wherein the formulation consists essentially of the antibody and
about 20 mM histidine, 240 mM sucrose and 0.04% w/w PX188.
4. The formulation of claim 1 , wherein the antibody is present at about 50 mg/ml.
5. A lyophilized formulation of an antibody prepared by lyophilizing the formulation of claim 1 .
6. The lyophilized formulation of claim 5 , which is reconstitutable with water to a pH of between about 5.5 to about 6.5.
7. A method of reconstituting the lyophilized formulation of claim 5 comprising:
combining the lyophilized formulation with sterile water to produce a liquid formulation.
8. A sterile lyophilized dosage form of an antibody formulation in a 20 ml vial, which is used for reconstituting the antibody formulation to a volume of 5.0 mL, consisting essentially of:
(i) an antibody within a range of about 225-275 mg;
(ii) histidine within a range of about 15-19 mg;
(iii) poloxamer 188 (PX188) within a range of about 2-2.5 mg; and;
(iv) sucrose within a range of about 400-490 mg;
wherein the antibody comprises a mature heavy chain comprising the amino acid sequence of SEQ ID NO:82 except the C-terminal lysine may be absent and a mature light chain comprising the amino acid sequence of SEQ ID NO:86.
9. The sterile lyophilized dosage form of claim 8 , wherein the vial has contents consisting essentially of:
(i) about 250 mg of the antibody;
(ii) about 16.8 mg of L-histidine,
(iii) about 2.2 mg of poloxamer PX188; and
(iv) about 445.3 mg of sucrose.
10. A method of preparing the lyophilized dosage form of claim 8 for administration to a subject, comprising:
(i) reconstituting the antibody formulation to a volume of about 5.0 mL with sterile water, and
(ii) diluting the reconstituted antibody formulation of step (i) in normal saline for infusion.
11. A reconstituted formulation resulting from reconstituting the lyophilized formulation of claim 5 .
12. The reconstituted formulation of claim 11 , comprising the antibody at a concentration of about 50 mg/mL, the histidine buffer at a concentration of about 20 mM, poloxamer 188 (PX188) at a concentration of about 0.04% by weight, and at pH of about 6.0.