Ultrafiltration concentration of allotype selected antibodies for small-volume administration

Patent metadata

Field	Value
Publication number	US-9468689-B2
Application number	US-201314132549-A
Country	US
Kind code	B2
Filing date	Dec 18, 2013
Priority date	May 2, 2011
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

Abstract

Disclosed are methods, compositions and uses of high concentration antibody or immunoglobulin formulations for subcutaneous, intramuscular, transdermal or other local (regional) administration, in a volume of than 3, less than 2 or less than 1 ml. Preferably, the formulation contains a high concentration formulation (HCF) buffer comprising phosphate, citrate, polysorbate 80 and mannitol at a pH of about 5.2. The formulation more preferably comprises at least 100, 150, 200, 250 mg/ml or 300 mg/ml of antibody. The methods for preparing the high concentration formulation include ultrafiltration and diafiltration to concentrate the antibody and exchange the medium for HCF buffer. Other embodiments concern use of non-G1m1 (nG1m1) allotype antibodies, such as G1m3 and/or a nG1m1,2 antibodies. The nG1m1 antibodies show decreased immunogenicity compared to G1m1 antibodies.

First claim

What is claimed is:

1. A method of subcutaneous, intramuscular or transdermal administration of a therapeutic antibody or immunoglobulin comprising
a) purifying the antibody or immunoglobulin by sequential column chromatography on Protein-A resin, an anion exchange resin and a cation exchange resin;
b) concentrating the antibody or immunoglobulin by ultrafiltration, wherein the antibody or immunoglobulin is concentrated to at least 200 mg/ml;
c) using the concentrated antibody or immunoglobulin to prepare a high concentration formulation of the antibody or immunoglobulin, wherein the formulation comprises citrate, phosphate, sodium chloride, polysorbate 80 and mannitol; and
d) administering the concentrated antibody or immunoglobulin formulation to a patient by subcutaneous, intramuscular or transdermal delivery;

wherein the volume of concentrated antibody solution administered is selected from the group consisting of 3 ml or less, 2 ml or less and 1 ml or less.

2. The method of claim 1 , wherein the antibody or immunoglobulin is concentrated to at least 225 mg/ml, at least 250 mg/ml or at least 300 mg/ml.

3. The method of claim 1 , wherein the amount of antibody or immunoglobulin administered is selected from the group consisting of 40 mg, 80 mg, 160 mg, 240 mg and 320 mg.

4. The method of claim 1 , wherein the administration is repeated.

5. The method of claim 1 , wherein subcutaneously, intramuscularly or transdermally administered antibody is effective at a lower dose than the same antibody administered intravenously.

6. The method of claim 1 , wherein the high concentration formulation is at a pH of 5.2.

7. The method of claim 1 , wherein the high concentration formulation comprises 6.2 mM citric acid monohydrate, 105 mM sodium chloride, 1.2 mM sodium citrate dihydrate, 8.7 mM sodium phosphate dibasic, 5.5 mM sodium phosphate monobasic, 0.1% polysorbate 80 and 66 mM mannitol.

8. The method of claim 1 , wherein the high concentration formulation further comprises arginine and glutamic acid.

9. The method of claim 1 , wherein the polysorbate 80 is added to the concentrated antibody or immunoglobulin solution after the antibody or immunoglobulin is concentrated.

10. The method of claim 9 , wherein addition of polysorbate 80 after the antibody or immunoglobulin is concentrated reduces the amount of precipitate formed during concentration.

11. The method of claim 1 , wherein the antibody is a non-G1m1 (nG1 m1) antibody, wherein the nG1m1 allotype is characterized by glutamate at Kabat residue 356 and methionine at Kabat residue 358 of the antibody heavy chain.

12. The method of claim 11 , wherein the antibody has a G1m3 heavy chain allotype, wherein the G1m3 allotype is characterized by arginine at Kabat residue 214 of the antibody heavy chain.

13. The method of claim 12 , wherein the antibody has a nG1 m1,2 heavy chain null allotype, wherein the nG1 m1,2 allotype is characterized by glutamate at Kabat residue 356, methionine at Kabat residue 358 and alanine at Kabat residue 431 of the antibody heavy chain.

14. The method of claim 11 , wherein the antibody has a Km3 light chain allotype, wherein the Km3 allotype is characterized by alanine at Kabat residue 153 and valine at Kabat residue 191 of the antibody light chain.

15. The method of claim 11 , wherein the antibody comprises heavy chain constant region amino acid residues arginine-214, glutamic acid-356, methionine-358 and alanine-431.

16. The method of claim 12 , wherein the G1m3 allotype antibody is less immunogenic than a G1m1 allotype antibody when administered to the patient.

17. The method of claim 1 , wherein the antibody is selected from the group consisting of a monoclonal antibody, an antigen-binding fragment of a monoclonal antibody, a bispecific antibody, a multispecific antibody, an immunoconjugate and an antibody fusion protein.

18. The method of claim 17 , wherein the immunoconjugate comprises at least one non-cytotoxic therapeutic or diagnostic agent.

19. The method of claim 18 , wherein the therapeutic agent is selected from the group consisting of an immunomodulator, a cytokine, a chemokine, a tyrosine kinase inhibitor, a growth factor, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interleukin (IL), an interferon (IFN), a hormone and an enzyme.

20. The method of claim 19 , wherein the therapeutic agent is selected from the group consisting of erythropoietin, thrombopoietin tumor necrosis factor-α (TNF), TNF-β, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α, interferon-β, interferon-γ, stem cell growth factor designated “S1 factor”, human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, NGF-β, platelet-growth factor, TGF-α, TGF-β, insulin-like growth factor-I, insulin-like growth factor-II, macrophage-CSF (M-CSF), IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, IL-23, IL-25, LIF, FLT-3, angiostatin, thrombospondin, endostatin and LT.

21. The method of claim 1 , wherein the antibody is a naked antibody.

22. The method of claim 21 , further comprising administering at least one therapeutic agent to said individual.

23. The method of claim 22 , wherein the therapeutic agent is selected from the group consisting of a drug, a prodrug, a toxin, an enzyme, a tyrosine kinase inhibitor, a sphingosine inhibitor, an immunomodulator, a cytokine, a hormone, a second antibody, a second antibody fragment, an immunoconjugate, a radionuclide, an antisense oligonucleotide, an RNAi, an anti-angiogenic agent, a pro-apoptosis agent and a cytotoxic agent.

24. The method of claim 1 , wherein the antibody is selected from the group consisting of epratuzumab, veltuzumab, milatuzumab, hL243 (anti-HLA-DR) and hL243 IgG4P (anti-HLA-DR).

25. The method of claim 1 , wherein the patient has a disease selected from the group consisting of autoimmune disease, immune dysregulation disease, infectious disease, carcinoma, sarcoma, lymphoma, leukemia, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma, non-Hodgkin's lymphoma, Alzheimer's disease, type-2 diabetes, type-1 diabetes, amyloidosis, cardiovascular disease, neurological disease and metabolic disease.

26. The method of claim 25 , wherein the autoimmune disease is selected from the group consisting of acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu's arteritis, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spon

Assignees

• Immunomedics Inc

Inventors

• Zeng Li
• Mitra Rohini
• Rossi Edmund A
• Hansen Hans J
• Goldenberg David M

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title