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Publication Number
US-10688186-B2
Publication Date
2020-06-23
Expiration Date
Abstract
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.
Core Innovation
The document discloses anti-CD3 antibody formulations comprising an anti-CD3 antibody with a heavy chain amino acid sequence comprising SEQ ID NO: 10 and a light chain amino acid sequence comprising SEQ ID NO: 11. The formulations include sodium acetate trihydrate, sodium chloride, polysorbate 80, trehalose, and methionine, with optional excipients including EDTA, and are provided in liquid formulation, lyophilized powder, and enteric coated oral capsule formats.
The formulations define unit dose ranges of about 0.1 mg to 10 mg of an anti-CD3 antibody, including about 0.5 mg, 2.5 mg, and 5.0 mg, and constrain solution properties including a pH of between about 4 and 6. For particular formulations, the document specifies component concentration ranges or defined excipient amounts per 1 mg of anti-CD3 antibody.
The document further describes enteric delivery concepts using an enteric coated oral capsule containing an anti-CD3 antibody lyophilized formulation or an anti-CD3 antibody liquid formulation. It also outlines combination-therapy concepts by stating that additional active agents can be included selected from anti-inflammatory and immunomodulatory drugs, including NF-κB inhibitors, GLP-1/beta-cell related compounds, mesalamine/5-ASA, PPARγ agonists, FXR agonists such as obeticholic acid, anti-IL-6R mAb, and anti-TNF antibodies.
Claims Coverage
The document includes four independent claims, each centered on a different formulation format: a base formulation, a liquid formulation, a powder formulation, and an enteric coated oral capsule containing a liquid formulation. Across these independent claims, the inventive features include specific anti-CD3 heavy- and light-chain amino acid sequences (SEQ ID NO: 10 and SEQ ID NO: 11) combined with a defined excipient set featuring sodium acetate trihydrate, sodium chloride, polysorbate 80, trehalose, and methionine, with additional format- and dose-specific constraints.
Anti-CD3 formulation with defined excipients and sequences
A formulation comprising an anti-CD3 antibody comprising a heavy chain amino acid sequence comprising SEQ ID NO: 10 and a light chain amino acid sequence comprising SEQ ID NO: 11, sodium acetate trihydrate, sodium chloride, polysorbate 80, trehalose, and methionine.
Liquid formulation with defined unit dose and component concentrations
A liquid formulation comprising a unit dose of about 0.1 mg to 10 mg of an anti-CD3 antibody comprising SEQ ID NO: 10 and SEQ ID NO: 11, 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).
Powder formulation with defined unit dose and per-mg excipient amounts
A powder formulation comprising a unit dose of about 0.1 mg to 10 mg of an anti-CD3 antibody comprising SEQ ID NO: 10 and SEQ ID NO: 11 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.
Enteric coated oral capsule containing liquid formulation with defined unit dose and component concentrations
An enteric coated oral capsule containing an anti-CD3 antibody liquid formulation comprising a unit dose of about 0.1 mg to 10 mg of an anti-CD3 antibody comprising SEQ ID NO: 10 and SEQ ID NO: 11, 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).
Across the independent claims, the coverage is directed to anti-CD3 formulations that combine a specific anti-CD3 antibody defined by SEQ ID NO: 10 and SEQ ID NO: 11 with defined buffer/excipient systems including sodium acetate trihydrate, sodium chloride, polysorbate 80, trehalose, and methionine, further limited by formulation format and by enteric coated oral capsule delivery for capsule-based claims.
Stated Advantages
Improved purity and stability of trehalose+methionine (±EDTA) formulations over controls, supported by analytical outcomes including SEC-HPLC, SDS-PAGE under reduced and non-reduced conditions, IEF/cIEF, and moisture/osmolality together with glass transition temperature.
Documented Applications
Therapeutic/prophylactic use of anti-CD3 antibody formulations for autoimmune/inflammatory diseases, including PBC, NASH, ulcerative colitis, Crohn’s disease, multiple sclerosis, and type 1 diabetes.
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