# US 2013/0156698 A1 · Tissue targeting

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- Number: US 2013/0156698 A1
- Document ID: US20130156698A1
- Status: Published application
- Kind: A1
- Application number: 13/641,278
- Filed: 2011-04-15
- Published: 2013-06-20
- Earliest claimed: 2010-04-16
- Assignees: Momenta Pharmaceuticals, Inc.
- Inventors: He Zhou; Edward Cochran; Takashi Kei Kishimoto
- Web page: https://patentgrep.com/patent/US20130156698A1

## CPC

- A61K 51/065: {conjugates with carriers being macromolecules}
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/727: Heparin; Heparan
- A61K 47/61: the organic macromolecular compound being a polysaccharide or a derivative thereof
- A61K 49/0054: {Macromolecular compounds, i.e. oligomers, polymers, dendrimers}
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

## Abstract

Methods and compositions related to targeting agents to tumor tissue are described.

## Claims

### Claim 1

A method of targeting a therapeutic or imaging agent to a tumor tissue of a patient, the method comprising (a) identifying a patient with a tumor tissue, wherein the patient is in need of administration of a therapeutic or imaging agent to treat or image the tumor; (b) providing a conjugate of the therapeutic or imaging agent and a LMWH composition; and (c) administering the conjugate to the patient, wherein the LMWH is selected from the group consisting of:
(a) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 8,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) greater than 5% and less than 50% glycol split uronic acid residues;
(b) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg;
(iii) a polysaccharide chain having a glycol split uronic acid residue (UG); and
(iv) polysaccharide chains each having no more than 3 glycol split uronic acid residues (UG);
(c) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) polysaccharide chains having on average between 0.2 and 3 glycol split uronic acid residues (UG) per polysaccharide chain;
(d) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) polysaccharide chains having greater than 40% U2SHNS,6S disaccharide residues;
(e) a LMWH having the following characteristics:
a polysaccharide preparation lacking substantial anticoagulant activity, wherein the preparation consists essentially of polysaccharides that include Formula I:
[Uw-Hx,y,z]m{tilde over ( )}[UG-Hx,y,z]n
wherein U indicates a uronic acid residue and H indicates a hexosamine residue;
wherein m and n are integers such that
m=4-16, and
n=1-4:
w=−2OS or −2OH;
x=—NS or —NAc;
y=−3OS or −3OH;
z=−6OS or −6OH;
and
wherein the symbol {tilde over ( )} indicates that the units marked m and n are distributed along the polysaccharide chain and are not necessarily in sequence, wherein w, x, y, and z are each the same or different on each unit marked m, and wherein x, y, and z are each the same or different on each unit marked n;
(f) a LMWH having the following characteristics:
lacks substantial anticoagulant activity, has antimetastatic activity and consists essentially of polysaccharides that include Formula II:
[Uw-Hx,y,z]m-[UG-Hx,y,z]n-[Uw-Hx,y,z]o-[UG-Hx,y,z]p-[Uw-Hx,y,z]q
wherein U indicates a uronic acid residue and H indicates a hexosamine residue;
wherein m-q are integers such that:
m=0-10;
n=0-3.
o=0-10;
p=0-3;
q=0-10;
w, for each occurrence, is independently −2OS or −2OH;
x, for each occurrence, is independently —NS or —NAc;
y, for each occurrence, is independently −3OS or −3OH;
z, for each occurrence, is independently −6OS or −6OH;
and UG=;
wherein w, x, y, and z are each the same or different on each unit marked m, n, o, p, or q, to thereby target the agent to the tumor tissue.

### Claim 2 (depends on 1)

The method of claim 1, wherein the agent is selected from a radioactive agent, a fluorescent agent, a cytotoxic agent, a tyrosine kinase inhibitor, a proteasome inhibitor, a protease inhibitor, an anti-angiogenic agent, an anti-metastatic agent, a steroid, a biologic immunomodulator, a monoclonal antibody, an antibody fragment, an aptamer, an siRNA, an antisense molecule, a fusion protein, a cytokine, a cytokine receptor, a bronchodialator, a statin, an anti-inflammatory agent, a microtubule inhibitor, a topoisomerase inhibitor, an antimetabolite, a protein synthesis and degradation inhibitor, a mitotic inhibitor, an alkylating agent, a platinating agent, an inhibitors of nucleic acid synthesis, a histone deacetylase and DNA methyltransferase inhibitor, a nitrogen mustard, a nitrosourea, an ethylenimine, an alkyl sulfonate, a triazene, a folate analog, a nucleoside analog, a ribnucleotide reductase inhibitor, a vinca alkaloid, a taxane, an epothilone, an intercalating agent, a signal transduction inhibitor, an apoptosis inducer, a cytokine, a chemokine, and a vaccine.

### Claim 3 (depends on 1)

The method of claim 1, wherein the agent is selected from the group consisting of: cisplatin, cyclophosphamide, dacarbazine, methotrexate, fluorouracil, gemcitabine, capecitabine, hydroxyurea, topotecan, irinotecan, azacytidine, vorinostat, ixabepilone, bortezomib, taxanes (paclitaxel, docetaxel), cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, vinorelbine, colchicin, anthracyclines (doxorubicin and epirubicin) daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, adriamycin, 1-dehydrotestosterone, glucocorticoid, procaine, tetracaine, lidocaine, propranolol, puromycin, ricin, and maytansinoids, Gefitinib, Erlotinib, Lapatinib, Sorafenib, Sunitinib, Imatinib, Dasatinib, Nilotinib, temsirolimus, everolimus, rapamycin, Trastuzumab, Cetuximab, Panitumumab, Bevacizumab, Rituximab, and Tositumomab.

### Claim 4 (depends on 1)

The method of claim 1, wherein the tumor is a solid tumor.

### Claim 5 (depends on 1)

The method of claim 1, wherein the tumor is a carcinoma or sarcoma of the head, neck, pharynx, thyroid, lung, breast, lymph, blood, gastrointestinal system, genitals and genitourinary tract, CNS, or skin.

### Claim 6 (depends on 1)

The method of claim 1, wherein the tumor is a primary cancer site or a metastasis site.

### Claim 7 (depends on 1)

The method of claim 1, further comprising one or more of the following steps: biopsing the tumor tissue, imaging the tumor tissue, and evaluating the effect of the administration on the tumor tissue.

### Claim 8 (depends on 1)

The method of claim 1, wherein the conjugate is administered intravenously, subcutaneously, intra-muscularly, intra-peritoneally, or orally.

### Claim 9

(canceled)

### Claim 10

A method of treating a subject, the method comprising:
(a) identifying a subject who has a tumor, and
(b) administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a conjugate of an anti-tumor agent and a LMWH composition, wherein the LMWH is selected from the group consisting of:
(a) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 8,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) greater than 5% and less than 50% glycol split uronic acid residues;
(b) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg;
(iii) a polysaccharide chain having a glycol split uronic acid residue (UG); and
(iv) polysaccharide chains each having no more than 3 glycol split uronic acid residues (UG);
(c) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) polysaccharide chains having on average between 0.2 and 3 glycol split uronic acid residues (UG) per polysaccharide chain;
(d) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) polysaccharide chains having greater than 40% U2SHNS,6S disaccharide residues;
(e) a LMWH having the following characteristics:
a polysaccharide preparation lacking substantial anticoagulant activity, wherein the preparation consists essentially of polysaccharides that include Formula I:
[Uw-Hx,y,z]m{tilde over ( )}[UG-Hx,y,z]n
wherein U indicates a uronic acid residue and H indicates a hexosamine residue;
wherein m and n are integers such that
m=4-16, and
n=1-4:
w=−2OS or −2OH;
x=—NS or —NAc;
y=−3OS or −3OH;
z=−6OS or −6OH;
and
wherein the symbol {tilde over ( )} indicates that the units marked m and n are distributed along the polysaccharide chain and are not necessarily in sequence, wherein w, x, y, and z are each the same or different on each unit marked m, and wherein x, y, and z are each the same or different on each unit marked n;
(f) a LMWH having the following characteristics:
lacks substantial anticoagulant activity, has antimetastatic activity and consists essentially of polysaccharides that include Formula II:
[Uw-Hx,y,z]m-[UG-Hx,y,z]n-[Uw-Hx,y,z]o-[UG-Hx,y,z]p-[Uw-Hx,y,z]q
wherein U indicates a uronic acid residue and H indicates a hexosamine residue;
wherein m-q are integers such that:
m=0-10;
n=0-3.
o=0-10;
p=0-3;
q=0-10;
w, for each occurrence, is independently −2OS or −2OH;
x, for each occurrence, is independently —NS or —NAc;
y, for each occurrence, is independently −3OS or −3OH;
z, for each occurrence, is independently −6OS or −6OH;
and
wherein w, x, y, and z are each the same or different on each unit marked m, n, o, p, or q.

### Claim 11 (depends on 10)

The method of claim 10, wherein the anti-tumor agent is selected from a radioactive agent, a cytotoxic agent, a tyrosine kinase inhibitor, a proteasome inhibitor, a protease inhibitor, an anti-angiogenic agent, an anti-metastatic agent, a steroid, a biologic immunomodulator, a monoclonal antibody, an antibody fragment, an aptamer, an siRNA, an antisense molecule, a fusion protein, a cytokine, a cytokine receptor, a bronchodialator, a statin, an anti-inflammatory agent, a microtubule inhibitor, a topoisomerase inhibitor, an antimetabolite, a protein synthesis and degradation inhibitor, a mitotic inhibitor, an alkylating agent, a platinating agent, an inhibitors of nucleic acid synthesis, a histone deacetylase and DNA methyltransferase inhibitor, a nitrogen mustard, a nitrosourea, an ethylenimine, an alkyl sulfonate, a triazene, a folate analog, a nucleoside analog, a ribnucleotide reductase inhibitor, a vinca alkaloid, a taxane, an epothilone, an intercalating agent, a signal transduction inhibitor, an apoptosis inducer, a cytokine, a chemokine, and a vaccine.

### Claim 12 (depends on 10)

The method of claim 10, wherein the anti-tumor agent is selected from the group consisting of: cisplatin, cyclophosphamide, dacarbazine, methotrexate, fluorouracil, gemcitabine, capecitabine, hydroxyurea, topotecan, irinotecan, azacytidine, vorinostat, ixabepilone, bortezomib, taxanes (paclitaxel, docetaxel), cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, vinorelbine, colchicin, anthracyclines (doxorubicin and epirubicin) daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, adriamycin, 1-dehydrotestosterone, glucocorticoid, procaine, tetracaine, lidocaine, propranolol, puromycin, ricin, and maytansinoids, Gefitinib, Erlotinib, Lapatinib, Sorafenib, Sunitinib, Imatinib, Dasatinib, Nilotinib, temsirolimus, everolimus, rapamycin, Trastuzumab, Cetuximab, Panitumumab, Bevacizumab, Rituximab, and Tositumomab.

### Claim 13 (depends on 10)

The method of claim 10, wherein the tumor is a solid tumor.

### Claim 14 (depends on 10)

The method of claim 10, wherein the tumor is a carcinoma of the head, neck, pharynx, thyroid, lung, breast, lymph, gastrointestinal system, genitals and genitourinary tract, CNS or skin.

### Claim 15 (depends on 10)

The method of claim 10, further comprising one or more of the following steps: biopsing the tumor tissue, imaging the tumor tissue, and evaluating the effect of the administration on the tumor tissue.

### Claim 16 (depends on 10)

The method of claim 10, wherein the conjugate is administered intravenously.

### Claim 17

(canceled)

### Claim 18

A pharmaceutical composition comprising a conjugate of a therapeutic or imaging agent and a LMWH composition, wherein the LMWH is selected from the group consisting of:
(a) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 8,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) greater than 5% and less than 50% glycol split uronic acid residues;
(b) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg;
(iii) a polysaccharide chain having a glycol split uronic acid residue (UG); and
(iv) polysaccharide chains each having no more than 3 glycol split uronic acid residues (UG);
(c) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) polysaccharide chains having on average between 0.2 and 3 glycol split uronic acid residues (UG) per polysaccharide chain;
(d) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) polysaccharide chains having greater than 40% U2SHNS,6S disaccharide residues;
(e) a LMWH having the following characteristics:
a polysaccharide preparation lacking substantial anticoagulant activity, wherein the preparation consists essentially of polysaccharides that include Formula I:
[Uw-Hx,y,z]m{tilde over ( )}[UG-Hx,y,z]n
wherein U indicates a uronic acid residue and H indicates a hexosamine residue;
wherein m and n are integers such that
m=4-16, and
n=1-4:
w=−2OS or −2OH;
x=—NS or —NAc;
y=−3OS or −3OH;
z=−6OS or −6OH;
and
wherein the symbol {tilde over ( )} indicates that the units marked m and n are distributed along the polysaccharide chain and are not necessarily in sequence, wherein w, x, y, and z are each the same or different on each unit marked m, and wherein x, y, and z are each the same or different on each unit marked n;
(f) a LMWH having the following characteristics:
lacks substantial anticoagulant activity, has antimetastatic activity and consists essentially of polysaccharides that include Formula II:
[Uw-Hx,y,z]m-[UG-Hx,y,z]n-[Uw-Hz,y,z]o-[UG-Hx,y,z]p-[Uw-Hx,y,z]q
wherein U indicates a uronic acid residue and H indicates a hexosamine residue;
wherein m-q are integers such that:
m=0-10;
n=0-3.
o=0-10;
p=0-3;
q=0-10;
w, for each occurrence, is independently −2OS or −2OH;
x, for each occurrence, is independently —NS or —NAc;
y, for each occurrence, is independently −3OS or −3OH;
z, for each occurrence, is independently −6OS or −6OH;
and
wherein w, x, y, and z are each the same or different on each unit marked m, n, o, p, or q.

### Claim 19

A method of targeting a therapeutic or imaging agent to a fibrotic tissue or inflammatory lesion of a patient, the method comprising (a) identifying a patient with a fibrotic tissue or inflammatory lesion, wherein the patient is in need of administration of a therapeutic or imaging agent to treat or image the fibrotic tissue or inflammatory lesion; (b) providing a conjugate of the therapeutic or imaging agent and a LMWH composition; and (c) administering the conjugate to the patient, wherein the LMWH is selected from the group consisting of:
(a) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 8,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) greater than 5% and less than 50% glycol split uronic acid residues;
(b) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg;
(iii) a polysaccharide chain having a glycol split uronic acid residue (UG); and
(iv) polysaccharide chains each having no more than 3 glycol split uronic acid residues (UG);
(c) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) polysaccharide chains having on average between 0.2 and 3 glycol split uronic acid residues (UG) per polysaccharide chain;
(d) a LMWH having the following characteristics:
(i) a weight average chain molecular weight between 3,500 and 7,000 Da;
(ii) anti-Xa activity and anti-IIa activity each less than 50 IU/mg; and
(iii) polysaccharide chains having greater than 40% U2SHNS,6S disaccharide residues;
(e) a LMWH having the following characteristics:
a polysaccharide preparation lacking substantial anticoagulant activity, wherein the preparation consists essentially of polysaccharides that include Formula I:
[Uw-Hx,y,z]m{tilde over ( )}[UG-Hx,y,z]n
wherein U indicates a uronic acid residue and H indicates a hexosamine residue;
wherein m and n are integers such that
m=4-16, and
n=1-4:
w=−2OS or −2OH;
x=—NS or —NAc;
y=−3OS or −3OH;
z=−6OS or −6OH;
and
wherein the symbol {tilde over ( )} indicates that the units marked m and n are distributed along the polysaccharide chain and are not necessarily in sequence, wherein w, x, y, and z are each the same or different on each unit marked m, and wherein x, y, and z are each the same or different on each unit marked n;
(f) a LMWH having the following characteristics:
lacks substantial anticoagulant activity, has antimetastatic activity and consists essentially of polysaccharides that include Formula II:
[Uw-Hx,y,z]m-[UG-Hx,y,z]n-[Uw-Hx,y,z]o-[UG-Hx,y,z]p-[Uw-Hx,y,z]q
wherein U indicates a uronic acid residue and H indicates a hexosamine residue;
wherein m-q are integers such that:
m=0-10;
n=0-3.
o=0-10;
p=0-3;
q=0-10;
w, for each occurrence, is independently −2OS or −2OH;
x, for each occurrence, is independently —NS or —NAc;
y, for each occurrence, is independently −3OS or −3OH;
z, for each occurrence, is independently −6OS or −6OH;
and
wherein w, x, y, and z are each the same or different on each unit marked m, n, o, p, or q, to thereby target the agent to the fibrotic tissue or inflammatory lesion.

### Claim 20 (depends on 19)

The method of claim 19, wherein the agent is selected from a radioactive agent, a fluorescent agent, an anti-inflammatory agent (CD4+ T cell inhibiting agent e.g. an anti-CD4 antibody (preferably a blocking or non-depleting antibody), an anti-CD8 antibody, a TNF antagonist e.g. an anti-TNF antibody or TNF inhibitor e.g. soluble TNF receptor, or agents such as NSAIDs), and an anti-fibrotic agent (e.g., cytokines such as interferon and hepatocyte growth factor; anti-TGF-beta1, and anti-TGF-beta2 and an anti-PDGF antibody).

### Claim 21 (depends on 19)

The method of claim 19, wherein the patient has arthritis, lupus erythematosus, Hashimotos thyroiditis, multiple sclerosis, diabetes, uveitis, dermatitis, psoriasis, urticaria, nephrotic syndrome, glomerulonephritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, sjogren's syndrome, allergies, asthma, rhinitis, eczema, GVH, COPD, insulitis, bronchitis, or a fibrotic disease.

### Claim 22

(canceled)

### Claim 23

(canceled)

### Claim 24

(canceled)