# US 2016/0355591 A1 · Subcutaneous anti-hla-dr monoclonal antibody for treatment of hematologic malignancies

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- Number: US 2016/0355591 A1
- Document ID: US20160355591A1
- Status: Published application
- Kind: A1
- Application number: 15/240,052
- Filed: 2016-08-18
- Published: 2016-12-08
- Earliest claimed: 2011-05-02
- Assignees: Immunomedics, Inc.
- Applicants: Immunomedics, Inc.
- Inventors: David M. Goldenberg; William A. Wegener
- Web page: https://patentgrep.com/patent/US20160355591A1

## CPC

- C07K 16/2833: {against MHC-molecules, e.g. HLA-molecules}
- 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
- C07K 16/065: {Purification, fragmentation}
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2851: {against the lectin superfamily, e.g. CD23, CD72}
- 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 16/3069: {Reproductive system, e.g. ovaria, uterus, testes, prostate}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/552: {Veterinary vaccine}
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- 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 2317/53: Hinge
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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)
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES

## Abstract

The present invention concerns compositions and methods of use of anti-HLA-DR antibodies or fragments thereof. In preferred embodiments, the antibodies are subcutaneously administered to a human patient with a hematologic cancer or autoimmune disease. The subcutaneously administered anti-HLA-DR antibody is effective to treat hematologic cancer or autoimmune disease in patients that have relapsed from or are refractory to standard therapies for hematologic cancer or autoimmune disease, such as administration of anti-CD20 antibodies, such as rituximab.

## Claims

### Claim 1

A method of treating hematologic cancer comprising administering a dosage of anti-HLA-DR antibody or antigen-binding fragment thereof to a human patient with a hematologic cancer by parenteral injection.

### Claim 2 (depends on 1)

The method of claim 1, wherein the administration is by subcutaneous injection.

### Claim 3 (depends on 1)

The method of claim 1, wherein administration by subcutaneous injection does not induce infusion-related toxicity.

### Claim 4 (depends on 2)

The method of claim 2, wherein the patient has failed at least one prior therapy for the hematologic cancer.

### Claim 5 (depends on 4)

The method of claim 4, wherein the patient has failed therapy with an anti-CD20 antibody, prior to administration of the anti-HLA-DR antibody.

### Claim 6 (depends on 5)

The method of claim 5, wherein the patient has failed therapy with rituximab, prior to administration of the anti-HLA-DR antibody.

### Claim 7 (depends on 4)

The method of claim 4, wherein the patient who has failed at least one prior therapy responds to the subcutaneous anti-HLA-DR antibody.

### Claim 8 (depends on 1)

The method of claim 1, wherein the cancer is recurrent or relapsed NHL (non-Hodgkin's lymphoma) or CLL (chronic lymphocytic leukemia).

### Claim 9 (depends on 1)

The method of claim 1, wherein the dosage of anti-HLA-DR antibody administered to the patient is 200 mg.

### Claim 10 (depends on 9)

The method of claim 9, wherein the dosage is administered once, twice or three times a week.

### Claim 11 (depends on 1)

The method of claim 1, wherein the cancer is selected from the group consisting of DLBCL (diffuse large B-cell lymphoma), follicular lymphoma, SLL (small lymphocytic lymphoma), mantle cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, CLL, ALL (acute lymphocytic leukemia), CML (chronic myeloid leukemia), Burkitt lymphoma, hairy cell leukemia and marginal zone lymphoma.

### Claim 12 (depends on 1)

The method of claim 1, wherein the anti-HLA-DR antibody comprises a human heavy chain γ4 constant region sequence with a Ser241Pro substitution.

### Claim 13 (depends on 1)

The method of claim 1, wherein the anti-HLA-DR antibody is a chimeric, humanized or human antibody.

### Claim 14 (depends on 13)

The method of claim 13, wherein the anti-HLA-DR antibody comprises the heavy chain complementarity determining region (CDR) sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44).

### Claim 15 (depends on 14)

The method of claim 14, wherein the anti-HLA-DR antibody is a humanized antibody comprising light chain murine L243 FR residues R37, K39, V48, F49, and G100 and heavy chain murine L243 FR residues F27, K38, K46, A68, and F91.

### Claim 16 (depends on 1)

The method of claim 1, wherein the anti-HLA-DR antibody binds to the same epitope of HLA-DR as a murine antibody comprising the heavy chain CDR sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44).

### Claim 17 (depends on 1)

The method of claim 1, wherein the anti-HLA-DR antibody competes for binding to HLA-DR with a murine antibody comprising the heavy chain CDR sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44).

### Claim 18 (depends on 1)

The method of claim 1, wherein the anti-HLA-DR antibody is a naked antibody.

### Claim 19 (depends on 1)

The method of claim 1, wherein the anti-HLA-DR antibody is attached to at least one therapeutic agent.

### Claim 20 (depends on 19)

The method of claim 19, wherein the therapeutic agent is selected from the group consisting of a drug, a toxin, an enzyme, a radioisotope, an immunomodulator, a cytokine, a hormone, a antibody or fragment thereof, an anti-angiogenic agent, a cytotoxic agent, a pro-apoptosis agent, an oligonucleotide, an siRNA and a photodynamic agent.

### Claim 21 (depends on 20)

The method of claim 20, wherein the drug is selected from the group consisting of 5-fluorouracil, aplidin, azaribine, anastrozole, anthracyclines, bendamustine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatinum, Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, estramustine, epipodophyllotoxin, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, gemcitabine, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, lenolidamide, leucovorin, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, nitrosurea, plicomycin, procarbazine, paclitaxel, pentostatin, PSI-341, raloxifene, semustine, streptozocin, tamoxifen, temazolomide, transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinorelbine, vinblastine, vincristine and vinca alkaloids.

### Claim 22 (depends on 20)

The method of claim 20, wherein the toxin is selected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), ranpirnase, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin and Pseudomonas endotoxin.

### Claim 23 (depends on 20)

The method of claim 20, wherein the anti-angiogenic agent is selected from the group consisting of angiostatin, baculostatin, canstatin, maspin, anti-VEGF antibodies, anti-P1GF peptides and antibodies, anti-vascular growth factor antibodies, anti-Flk-1 antibodies, anti-Flt-1 antibodies and peptides, anti-Kras antibodies, anti-cMET antibodies, anti-MIF (macrophage migration-inhibitory factor) antibodies, laminin peptides, fibronectin peptides, plasminogen activator inhibitors, tissue metalloproteinase inhibitors, interferons, interleukin-12, IP-10, Gro-β, thrombospondin, 2-methoxyoestradiol, proliferin-related protein, carboxiamidotriazole, CM101, Marimastat, pentosan polysulphate, angiopoietin-2, interferon-alpha, herbimycin A, PNU145156E, 16K prolactin fragment, Linomide (roquinimex), thalidomide, pentoxifylline, genistein, TNP-470, endostatin, paclitaxel, accutin, angiostatin, cidofovir, vincristine, bleomycin, AGM-1470, platelet factor 4 and minocycline.

### Claim 24 (depends on 20)

The method of claim 20, wherein the immunomodulator is selected from the group consisting of erythropoietin, thrombopoietin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α, interferon-β, interferon-γ, “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, tumor necrosis factor-α, tumor necrosis factor-β, 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-25, LIF, kit-ligand, angiostatin, thrombospondin, endostatin, tumor necrosis factor and LT.

### Claim 25 (depends on 20)

The method of claim 20, wherein the radionuclide is selected from the group consisting of 18F, 32P, 33P, 45Ti, 47Sc, 52Fe, 59Fe, 62CU, 64Cu, 67Cu, 67Ga, 68Ga, 75Se, 77As, 86Y, 89Sr, 89Zr, 90Y, 94Tc, 94mTc, 99Mo, 99mTc, 105Pd, 105Rh, 111Ag, 111In, 123I, 124I, 125I, 131I, 142Pr, 143Pr, 149Pm, 153Sm, 154-158Gd, 161Tb, 166Dy, 166Ho, 169Er, 175Lu, 177Lu, 186Re, 188Re, 189Re, 194Ir, 198Au 199Au, 211At, 211Pb 212Bi, 212Pb, 213Bi, 223Ra, 227Th and 225Ac.

### Claim 26 (depends on 1)

The method of claim 1, further comprising administering to the patient an anti-CD20 antibody or fragment thereof, wherein administration of the anti-HLA-DR antibody and the anti-CD20 antibody inhibits proliferation of the hematologic cancer more than either anti-HLA-DR antibody or anti-CD20 antibody alone.

### Claim 27 (depends on 18)

The method of claim 18, further comprising administering at least one therapeutic agent to the patient.

### Claim 28

A method of treating an autoimmune or immune dysfunction disease comprising administering a dosage of anti-HLA-DR antibody or antigen-binding fragment thereof to a human patient with an autoimmune disease by subcutaneous injection.

### Claim 29 (depends on 28)

The method of claim 28, wherein the autoimmune or immune dysfunction 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 spondylitis, Goodpasture's syndrome, thromboangitis obliterans, Sjogren's syndrome, primary biliary cirrhosis, Hashimoto's thyroiditis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, pemphigus vulgaris, Wegener's granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis, psoriasis, fibrosing alveolitis, GVHD (graft-versus-host disease) and organ transplant rejection.

### Claim 30 (depends on 29)

The method of claim 29, wherein the patient has failed at least one prior therapy for the autoimmune disease.

### Claim 31 (depends on 30)

The method of claim 30, wherein the patient has failed therapy with an anti-CD20 antibody, prior to administration of the anti-HLA-DR antibody.

### Claim 32 (depends on 28)

The method of claim 28, wherein the dosage of anti-HLA-DR antibody is 200 mg.

### Claim 33 (depends on 32)

The method of claim 32, wherein the dosage is administered once, twice or three times a week.

### Claim 34 (depends on 28)

The method of claim 28, wherein the anti-HLA-DR antibody comprises a human heavy chain γ4 constant region sequence with a Ser241Pro substitution.

### Claim 35 (depends on 28)

The method of claim 28, wherein the anti-HLA-DR antibody is a chimeric, humanized or human antibody.

### Claim 36 (depends on 35)

The method of claim 35, wherein the anti-HLA-DR antibody comprises the heavy chain complementarity determining region (CDR) sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44).

### Claim 37 (depends on 36)

The method of claim 36, wherein the anti-HLA-DR antibody is a humanized antibody comprising light chain murine L243 FR residues R37, K39, V48, F49, and G100 and heavy chain murine L243 FR residues F27, K38, K46, A68, and F91.

### Claim 38 (depends on 28)

The method of claim 28, wherein the anti-HLA-DR antibody binds to the same epitope of HLA-DR as a murine antibody comprising the heavy chain CDR sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44).

### Claim 39 (depends on 28)

The method of claim 28, wherein the anti-HLA-DR antibody competes for binding to HLA-DR with a murine antibody comprising the heavy chain CDR sequences NYGMN (SEQ ID NO: 39), WINTYTREPTYADDFKG (SEQ ID NO: 40), and DITAVVPTGFDY (SEQ ID NO: 41) and the light chain CDR sequences RASENIYSNLA (SEQ ID NO: 42), AASNLAD (SEQ ID NO: 43), and QHFWTTPWA (SEQ ID NO: 44).

### Claim 40 (depends on 28)

The method of claim 28, wherein the anti-HLA-DR antibody is a naked antibody.

### Claim 41 (depends on 28)

The method of claim 28, wherein the anti-HLA-DR antibody is attached to at least one therapeutic agent selected from the group consisting of a drug, an enzyme, an immunomodulator, a cytokine, a hormone, an antibody or fragment thereof, an oligonucleotide, an siRNA and a photodynamic agent.