ANTI-CD3 ANTIBODY FORMULATIONS
This invention relates to therapeutic, diagnostic and/or prophylactic formulations and dosages and dosing regimens of anti-CD3 antibodies, as well as to methods for using such formulations and dosages and dosing regimens.
1 . A method of treating or alleviating a symptom of autoimmune disease, an inflammatory disorder, a neurodegenerative disease or cancer comprising orally administering to a subject in need thereof an anti-CD3 antibody formulation comprising a heavy chain amino acid sequence comprising the amino acid sequence of SEQ ID NO: 10 and a light chain amino acid sequence comprising the amino acid sequence of SEQ ID NO: 11, sodium acetate, trihydrate, sodium chloride, polysorbate 80, trehalose and methionine.
2 . The method of claim 1 , wherein the autoimmune disease is nonalcoholic steatohepatitis (NASH), Crohn's disease, primary biliary cirrhosis (PBC), Type 1 diabetes, Type 2 diabetes, or ulcerative colitis (UC).
3 . The method of claim 1 , wherein the formulation further comprises EDTA.
4 . The method of claim 1 , wherein the formulation is a liquid.
5 . The method of claim 1 , wherein the formulation is a lyophilized powder.
6 . The method of claim 5 , wherein the liquid is in an enteric coated oral capsule.
7 . The method of claim 4 , wherein the lyophilized powder is in an enteric coated oral capsule.
8 . The method of claim 1 , wherein the formulation comprising a unit dose of the anti-CD3 antibody.
9 . The method of claim 8 , wherein, the unit dose is about 0.1 mg to 10 mg.
10 . The method of claim 9 , wherein, the unit dose is 0.5 mg, 2.5 mg or 5.0 mg.
11 . The method of claim 4 , wherein the concentration of:
a. sodium acetate trihydrate is about 10 mM to 500 mM;
b. sodium chloride is about 10 mM to 500 mM;
c. polysorbate 80 is about 0.01% to 1% (w/v);
d. trehalose is about 5% to 50% (w/v); and
e. methionine is 0.01% to 1% (w/v).
12 . The method of claim 11 , where the concentration of EDTA is about 0.01% to 1% (w/v).
13 . The method of claim 11 , wherein the liquid is at a pH in the range of 4 to 6.
14 . The method of claim 4 , wherein the formulation comprises a unit dose of anti-CD3 antibody, 20% trehalose (w/v), and 0.1% methionine (w/v).
15 . The method of claim 4 , wherein the formulation comprises a unit dose of about 0.1 mg to 10 mg of an anti-CD3 antibody or antigen binding fragment thereof, 25 mM sodium acetate trihydrate, 125 mM sodium chloride, 0.02% polysorbate 80 (w/v), 20% trehalose (w/v), and 0.1% methionine (w/v).
16 . The method of claim 14 , wherein the formulation further comprising 0.1% EDTA (w/v).
17 . The method of claim 14 , wherein the unit dose is 0.5 mg, 2.5 mg or 5.0 mg.
18 . The method of claim 5 , wherein the ratio of anti-CD3 antibody to:
a. polysorbate 80 is about 1:0.01 to 0.1 (w/w);
b. trehalose is about 1:10 to 50 (w/w);
c. methionine about 1:0.1 to 0.5 (w/w);
d. sodium acetate trihydrate is about 1:0.1 to 1.0 (w/w); and
e. sodium chloride is about 1:0.5 to 2.0 (w/w).
19 . The method of claim 18 , where the ratio of anti-CD3 antibody to EDTA is about 1:0.1 to 0.5 (w/w).
20 . The method of claim 5 , wherein the formulation comprises unit dose of about 0.1 mg to 10 mg of an anti-CD3 antibody and about 0.58 mg of sodium acetate trihydrate, 1.25 mg sodium chloride, 0.034 mg polysorbate 80, 34 mg trehalose and 0.17 mg methionine per 1 mg of anti-CD3 antibody.
21 . The method of claim 20 , wherein the formulation further comprising 0.17 mg EDTA per 1 mg of anti-CD3 antibody.
22 . The method of claim 20 , wherein the unit dose is 0.5 mg, 2.5 mg or 5.0 mg.
23 . The method of claim 1 , wherein the formulation comprises an antibody lyophilized formulation comprising a unit dose of antibody and about 34 mg trehalose and 0.17 mg methionine per mg of anti-CD3 antibody.
24 . The method of claim 1 , further comprising administering to the subject at least one additional active agent selected from the group consisting of: an NF-kB inhibitor, a GLP-1 or a beta cell resting compound, mesalamine or another 5-ASA drug, pentoxifylline, ursodeoxycholic acid, a PPARγ agonist, All Trans Retinoic Acid (ATRA), DPP-4 (gliptins-sitagliptin), a fatty acid synthesis inhibitor (e.g., cerulenin, quercetin, C7, apigenin, AICAR), a FXR agonist (e.g., bile salt activators, chenodeoxycholic acid, Obeticholic acid (OIBA, Ocaliva), fexaramine, cafestol, bile Acid Sequestrants (cholestyramine, cholestipol, coleserelam), SGLT2 inhibitors (ex-dapagliflozin (reduce HbA1c levels), an anti-IL-6R mAb, anti-TNF antibody (Remicade® (Infliximab), and Humira® (Adalimumab), Enbrel® (Etanercept) anti-inflammatory and/or immunosuppressive compounds (e.g., methotrexate, cyclosporin A cyclosporin microemulsion), tacrolimus, corticosteroids, statins, interferon beta, glatiramer acetate (Copaxone), interferon beta-1a (Avonex), interferon beta-1a (Rebif), interferon beta-lb (Betaseron or Betaferon), mitoxantrone (Novantrone), dexamethasone (Decadron), methylprednisolone (Depo-Medrol), prednisone (Deltasone) and an anti-obesity drug.
25 . The method of claim 1 , wherein the antibody has an IgG1 isotype.
26 . The method of claim 1 , wherein the formulation further comprises mannitol.