# US 2014/0193359 A1 · Ultrafiltration Concentration of Allotype Selected Antibodies for Small-Volume Administration

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- Number: US 2014/0193359 A1
- Document ID: US20140193359A1
- Status: Published application
- Kind: A1
- Application number: 14/163,443
- Filed: 2014-01-24
- Published: 2014-07-10
- Earliest claimed: 2011-05-02
- Assignees: Immunomedics, Inc.
- Applicants: Immunomedics, Inc.
- Inventors: Li Zeng; Rohini Mitra; Edmund A. Rossi; Hans J. Hansen; David M. Goldenberg
- Web page: https://patentgrep.com/patent/US20140193359A1

## CPC

- C07K 16/2851: {against the lectin superfamily, e.g. CD23, CD72}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/39591: {Stabilisation, fragmentation}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6869: {the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate}
- A61K 47/6879: {the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin}
- A61K 47/6897: {Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies}
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- A61K 51/1027: {against receptors, cell-surface antigens or cell-surface determinants}
- A61K 51/1045: {against animal or human tumor cells or tumor cell determinants}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- C07K 16/065: {Purification, fragmentation}
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2833: {against MHC-molecules, e.g. HLA-molecules}
- C07K 16/2887: {against CD20}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 16/30: from tumour cells
- C07K 16/3007: {Carcino-embryonic Antigens}
- C07K 16/3069: {Reproductive system, e.g. ovaria, uterus, testes, prostate}
- C07K 16/3092: {against tumour-associated mucins}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/55505: {Inorganic adjuvants}
- A61K 2039/55511: {Organic adjuvants}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES

## 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.

## Claims

### Claim 1

A composition for subcutaneous, intramuscular or trandermal administration comprising an antibody in high concentration formulation buffer, wherein the buffer is pH 5.2 and comprises citrate, phosphate, sodium chloride, polysorbate 80 and mannitol, wherein the antibody is a chimeric, humanized or human antibody of nG1m1 allotype, wherein the nG1m1 allotype is characterized by glutamate at Kabat residue 356 and methionine at Kabat residue 358 of the antibody heavy chain.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the high concentration formulation buffer 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.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

The composition of claim 1, wherein the antibody is at a concentration of at least 100 mg/ml, at least 150 mg/ml, at least 200 mg/ml, at least 250 mg/ml or at least 300 mg/ml.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the antibody has a G1m3 heavy chain allotype, wherein the G1m3 allotype is characterized by an arginine at Kabat position 214 of the antibody heavy chain.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the antibody has a nG1m1,2 heavy chain null allotype wherein the nG1m1,2 allotype is characterized by a glutamate at Kabat position 356, methionine at Kabat position 358 and alanine at Kabat position 431 of the antibody heavy chain.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the antibody has a Km3 light chain allotype, wherein the Km3 allotype is characterized by valine at Kabat position 153 and leucine at Kabat position 191 of the antibody light chain.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the antibody comprises heavy chain constant region amino acid residues arginine-214, glutamic acid-356, methionine-358 and alanine-11.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the amino acid sequence of the antibody heavy chain constant region is SEQ ID NO:33 or SEQ ID NO:38.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the amino acid sequence of the antibody light chain constant region is SEQ ID NO:40.

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 1)

The composition of claim 1, wherein the antibody is conjugated to at least one non-cytotoxic therapeutic or diagnostic agent.

### Claim 13 (depends on 12)

The composition of claim 12, wherein the therapeutic agent is selected from the group consisting of an antibody, an antibody fragment, 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.

### Claim 14 (depends on 13)

The composition of claim 13, 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-13, 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 lymphotoxin.

### Claim 15 (depends on 1)

The composition of claim 1, wherein the antibody binds to an antigen selected from the group consisting of carbonic anhydrase IX, CCCL19, CCCL21, CSAp, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, IGF-1R, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67, CD70, CD70L, CD74, CD79a, CD80, CD83, CD95, CD126, CD132, CD133, CD138, CD147, CD154, AFP, PSMA, CEACAM5, CEACAM-6, B7, ED-B of fibronectin, Factor H, FHL-1, Flt-3, folate receptor, GROB, HMGB-1, hypoxia inducible factor (HIF), HM1.24, insulin-like growth factor-1 (ILGF-1), IFN-γ, IFN-α, IFN-13, IL-2, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, MAGE, mCRP, MCP-1, MIP-IA, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, MUC5, PAM4 antigen, NCA-95, NCA-90, Ia, HM1.24, EGP-1, EGP-2, HLA-DR, tenascin, Le(y), RANTES, T101, TAC, Tn antigen, Thomson-Friedenreich antigens, tumor necrosis antigens, TNF-α, TRAIL receptor (R1 and R2), VEGFR, EGFR, PlGF, complement factors C3, C3a, C3b, C5a, C5, and an oncogene product.

### Claim 16 (depends on 1)

The composition of claim 1, wherein the antibody is selected from the group consisting of hR1 (anti-IGF-1R), hPAM4 (anti-mucin), hA20 (anti-CD20), GA101 (anti-CD20), hA19 (anti-CD19), hIMMU31 (anti-AFP), hLL1 (anti-CD74), hLL2 (anti-CD22), hMu-9 (anti-CSAp), hL243 (anti-HLA-DR), hL243 IgG4P (anti-HLA-DR), hMN-14 (anti-CEACAM5), hMN-15 (anti-CEACAM6), hRS7 (anti-EGP-1), hMN-3 (anti-CEACAM6), hRFB4 (anti-CD22), Ab124 (anti-CXCR4) and Ab125 (anti-CXCR4).

### Claim 17 (depends on 1)

The composition 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).

### Claim 18 (depends on 1)

The composition of claim 1, wherein the antibody is epratuzumab.

### Claim 19 (depends on 1)

The composition of claim 1, wherein the antibody is veltuzumab.

### Claim 20 (depends on 1)

The composition of claim 1, wherein the antibody is milatuzumab.

### Claim 21 (depends on 1)

The composition of claim 1, wherein the antibody is clivatuzumab.

### Claim 22 (depends on 1)

The composition of claim 1, wherein the antibody is labetuzumab.

### Claim 23 (depends on 1)

The composition of claim 1, wherein the antibody is hRS7.

### Claim 24 (depends on 1)

The composition of claim 1, wherein the antibody is a bispecific antibody.

### Claim 25 (depends on 24)

The composition of claim 24, wherein the bispecific antibody binds to two different antigens, each antigen selected from the group consisting of CD19, CD20, CD22, CD74, CD79a, CD40L, ILGF-R1, TROP2, CEACAM5, CECAM6, HLA-DR, IFNa, IL-6 and TNF-α.