# US 2010/0168085 A1 · Dopamine and agonists and antagonists thereof for modulation of suppressive activity of CD4+CD25+ regulatory T cells

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- Number: US 2010/0168085 A1
- Document ID: US20100168085A1
- Status: Published application
- Kind: A1
- Application number: 10/557,901
- Filed: 2004-05-23
- Published: 2010-07-01
- Earliest claimed: 2003-05-22
- Assignees: YESA RESEARCH AND DEVELOPMENT CO. LTD. at the Weizmann Institute of Science
- Inventors: Michal Eisenbach-Schwartz; Jonathan Kipnis
- Web page: https://patentgrep.com/patent/US20100168085A1

## CPC

- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/5513: 1,4-Benzodiazepines, e.g. diazepam {or clozapine}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- 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

Compositions and methods for modulation of the suppressive activity of CD4+CD25+regulatory T cells (Treg) on CD4+CD25− effector T cells (Teff) are provided. An agent selected from: (i) dopamine; (ii) a dopamine precursor; (iii) a D1-R agonist; (iv) a D2-R antagonist; (v) a combination of (i) and (ii); or (vi) a combination of (i), (ii) or (iii) with (iv), down-regulates the suppressive activity of Treg and is useful for treatment of cancer. An agent selected from (i) a dopamine D2-R agonist, (ii) a dopamine D1-R antagonist, and (iii) a combination of (i) and (ii), up-regulates the suppressive activity of Treg and is useful for treatment of an autoimmune disease or for controlling graft rejection in tissue/organ transplantation.

## Claims

### Claim 1

A method for modulating the suppressive effect of CD4+CD25+ regulatory T cells (Treg) on CD4+CD25− effector T cells (Teff), which comprises administering to an individual in need an agent selected from the group consisting of dopamine, a dopamine precursor, a dopamine agonist, a dopamine antagonist, and a combination thereof.

### Claim 2 (depends on 1)

A method according to claim 1 for down-regulating the suppressive effect of Treg on Teff, said method comprising administering to an individual in need an agent that down-regulates the suppressive activity of Treg on Teff, wherein said agent is selected from the group consisting of:
(i) dopamine or a pharmaceutically acceptable salt thereof;
(ii) a dopamine precursor or a pharmaceutically acceptable salt thereof;
(iii) an agonist of the dopamine receptor type 1 family (D1-R agonist) or a pharmaceutically acceptable salt thereof;
(iv) an antagonist of the dopamine receptor type 2 family (D2-R antagonist) or a pharmaceutically acceptable salt thereof;
(v) a combination of (i) and (ii); and
(vi) a combination of (i), (ii) or (iii) with (iv);
provided that said individual is need is not being treated for a neurodegenerative condition, disorder or disease.

### Claim 3 (depends on 2)

A method according to claim 2, wherein said agent is dopamine or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 2)

A method according to claim 2, wherein said agent is a combination of dopamine and the dopamine precursor levodopa, optionally in further combination with carbidopa.

### Claim 5 (depends on 2)

A method according to claim 2, wherein said agent is a dopamine D1-R agonist.

### Claim 6 (depends on 5)

The method according to claim 5, wherein said dopamine D1-R agonist is selected from the group consisting of A-77636, SKF-38393, SKF-77434, SKF-81297, SKF-82958, dihydrexidine and fenoldopam.

### Claim 7 (depends on 2)

A method according to claim 2, wherein said agent is a dopamine D2-R antagonist.

### Claim 8 (depends on 7)

The method according to claim 7, wherein said dopamine D2-R antagonist is selected from the group consisting of amisulpride, clozapine, domperidone, eticlopride, haloperidol, iloperidone, mazapertine, olanzapine, raclopride, remoxipride, risperidone, sertindole, spiperone, spiroperidol, sulpride, tropapride, zetidoline, CP-96345, LU111995, SDZ-HDC-912, and YM 09151-2.

### Claim 9 (depends on 2)

A method according to claim 2, wherein said agent is a combination of dopamine with a dopamine D2-R antagonist.

### Claim 10 (depends on 9)

The method according to claim 9, wherein said agent is a combination of dopamine with clozapine.

### Claim 11 (depends on 2)

A method according to claim 2, wherein said agent is a combination of a dopamine D1-R agonist with a dopamine D2-R antagonist.

### Claim 12 (depends on 11)

The method according to claim 11, wherein said agent is a combination of SKF-38393 and clozapine.

### Claim 13

A method for treatment of cancer,
said method comprising administering to a cancer patient an agent that down-regulates the suppressive activity of CD4+CD25+ regulatory T cells (Treg) on CD4+CD25− effector T cells (Teff), wherein said agent is selected from the group consisting of:
(i) dopamine or a pharmaceutically acceptable salt thereof;
(ii) a dopamine precursor or a pharmaceutically acceptable salt thereof;
(iii) an agonist of the dopamine receptor type 1 family (D1-R agonist) or a pharmaceutically acceptable salt thereof;
(iv) an antagonist of the dopamine receptor type 2 family (D2-R antagonist) or a pharmaceutically acceptable salt thereof;
(v) a combination of (i) and (ii); and
(vi) a combination of (i), (ii) or (iii) with (iv).

### Claim 14 (depends on 13)

A method according to claim 13 wherein said agent triggers tumor regression, stimulates the natural immunological defense against cancer, or inhibits cancer cell metastasis.

### Claim 15 (depends on 14)

The method according to claim 14 wherein said tumor is a solid tumor.

### Claim 16 (depends on 15)

The method according to claim 15 wherein said solid tumor is bladder, brain, breast, cervix, colon, esophagus, head and neck, larynx, liver, lung, melanoma, ovary, pancreas, prostate, renal, stomach, thyroid, uterus, vagina or vocal cord tumor.

### Claim 17 (depends on 15)

The method according to claim 15 wherein said tumor is a non-solid malignant neoplasm.

### Claim 18 (depends on 17)

The method according to claim 17 wherein said non-solid malignant neoplasma is a lymphoproliferative disorder selected from the group consisting of multiple myeloma, non-Hodgkin's lymphomas, and a lymphocytic leukemia, e.g., chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, large granular lymphocyte leukemia and Waldenstrom's macroglubulinemia.

### Claim 19 (depends on 13)

A method according to claim 13, wherein said agent is dopamine or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 13)

A method according to claim 13, wherein said agent is a combination of dopamine and the dopamine precursor levodopa, optionally in further combination with carbidopa.

### Claim 21 (depends on 13)

A method according to claim 13, wherein said agent is a dopamine D1-R agonist.

### Claim 22 (depends on 21)

The method according to claim 21, wherein said dopamine D1-R agonist is selected from the group consisting of A-77636, SKF-38393, SKF-77434, SKF-81297, SKF-82958, dihydrexidine and fenoldopam.

### Claim 23 (depends on 13)

A method according to claim 13, wherein said agent is a dopamine D2-R antagonist.

### Claim 24 (depends on 23)

The method according to claim 23, wherein said dopamine D2-R antagonist is selected from the group consisting of amisulpride, clozapine, domperidone, eticlopride, haloperidol, iloperidone, mazapertine, olanzapine, raclopride, remoxipride, risperidone, sertindole, spiperone, spiroperidol, sulpride, tropapride, zetidoline, CP-96345, LU111995, SDZ-HDC-912, and YM 09151-2.

### Claim 25 (depends on 13)

A method according to claim 13, wherein said agent is a combination of dopamine with a dopamine D2-R antagonist.

### Claim 26 (depends on 25)

The method according to claim 25, wherein said agent is a combination of dopamine with clozapine.

### Claim 27 (depends on 13)

A method according to claim 13, wherein said agent is a combination of a dopamine D1-R agonist with a dopamine D2-R antagonist.

### Claim 28 (depends on 27)

The method according to claim 27, wherein said agent is a combination of SKF-38393 and clozapine.

### Claim 29 (depends on 1)

A method according to claim 1 for up-regulating the suppressive effect of Treg on Teff, said method comprising administering to an individual in need an agent that up-regulates the suppressive activity of Treg on Teff, wherein said agent is selected from the group consisting of:
(i) an antagonist of the dopamine receptor type 1 family (D1-R antagonist) or a pharmaceutically acceptable salt thereof;
(ii) an agonist of the dopamine receptor type 2 family (D2-R agonist) or a pharmaceutically acceptable salt thereof; and
(iii) a combination of (i) and (ii).

### Claim 30 (depends on 29)

A method according to claim 29, wherein said agent is a dopamine D2-R agonist or a pharmaceutically acceptable salt thereof.

### Claim 31 (depends on 30)

A method according to claim 30, wherein said dopamine D2-R agonist is selected from the group consisting of bromocriptine, cabergoline, lisuride, pergolide, pramipexole, quinagolide, quinpirole, quinelorane, ropinirole, roxindole, talipexole, LY 171555, PPHT and TNPA.

### Claim 32 (depends on 29)

A method according to claim 29, wherein said agent is a dopamine D1-R antagonist or a pharmaceutically acceptable salt thereof.

### Claim 33 (depends on 32)

A method according to claim 32, wherein said dopamine D1-R antagonist is selected from the group consisting of SCH 23390, NNC 756, NNC 01-112 and CEE-03-310.

### Claim 34 (depends on 29)

A method according to claim 29, wherein said agent is a combination of a dopamine D2-R agonist and a dopamine D1-R antagonist.

### Claim 35

A method for treatment of an autoimmune disease, said method comprising administering to an individual suffering from an autoimmune disease an agent that up-regulates the suppressive activity of CD4+CD25++regulatory T cells (Treg) on CD4+CD25− effector T cells (Teff), wherein said agent is selected from the group consisting of (i) a dopamine D2-R agonist or a pharmaceutically acceptable salt thereof, a dopamine D1-R antagonist or a pharmaceutically acceptable salt thereof, and (iii) a combination of (i) and (ii).

### Claim 36 (depends on 35)

A method according to claim 35, wherein said agent is a dopamine D2-R agonist or a pharmaceutically acceptable salt thereof.

### Claim 37 (depends on 36)

A method according to claim 36, wherein said dopamine D2-R agonist is selected from the group consisting of bromocriptine, cabergoline, lisuride, pergolide, pramipexole, quinagolide, quinpirole, quinelorane, ropinirole, roxindole, talipexole, LY 171555, PPHT and TNPA.

### Claim 38 (depends on 35)

A method according to claim 35, wherein said agent is a dopamine D1-R antagonist or a pharmaceutically acceptable salt thereof.

### Claim 39 (depends on 38)

A method according to claim 38, wherein said dopamine D1-R antagonist is selected from the group consisting of SCH 23390, NNC 756, NNC 01-112 and CEE-03-310.

### Claim 40 (depends on 35)

A method according to claim 35, wherein said agent is a combination of a dopamine D2-R agonist and a dopamine D1-R antagonist.

### Claim 41 (depends on 35)

A method according to claim 35, wherein said autoimmune disease is Eaton-Lambert syndrome, Goodpasture's syndrome, Grave's disease, Guillain-Barré syndrome, autoimmune hemolytic anemia (AIHA), hepatitis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE), multiple sclerosis (MS), myasthenia gravis, plexus disorders, e.g., acute brachial neuritis, polyglandular deficiency syndrome, primary biliary cirrhosis, rheumatoid arthritis, scleroderma, thrombocytopenia, thyroiditis, e.g., Hashimoto's disease, Sjögren's syndrome, allergic purpura, psoriasis, mixed connective tissue disease, polymyositis, dermatomyositis, vasculitis, polyarteritis nodosa, polymyalgia rheumatica, Wegener's granulomatosis, Reiter's syndrome, Behçet's syndrome, ankylosing spondylitis, pemphigus, bullous pemphigoid, dermatitis herpetiformis, Crohn's disease or uveitis.

### Claim 42

A method for controlling graft rejection in an individual undergoing tissue or organ transplantation which comprises administering to said individual an agent that up-regulates the suppressive activity of CD4+CD25+ regulatory T cells (Treg) on CD4+CD25− effector T cells (Teff), wherein said agent is selected from the group consisting of (i) a dopamine D2-R agonist or a pharmaceutically acceptable salt thereof, a dopamine D1-R antagonist or a pharmaceutically acceptable salt thereof, and a combination of (i) and (ii).

### Claim 43 (depends on 42)

A method according to claim 42, wherein said agent is a dopamine D2-R agonist or a pharmaceutically acceptable salt thereof.

### Claim 44 (depends on 43)

A method according to claim 43, wherein said dopamine D2-R agonist is selected from the group consisting of bromocriptine, cabergoline, lisuride, pergolide, pramipexole, quinagolide, quinpirole, quinelorane, ropinirole, roxindole, talipexole, LY 171555, PPHT and TNPA.

### Claim 45 (depends on 42)

A method according to claim 42, wherein said agent is a dopamine D1-R antagonist or a pharmaceutically acceptable salt thereof.

### Claim 46 (depends on 45)

A method according to claim 45, wherein said dopamine D1-R antagonist is selected from the group consisting of SCH 23390, NNC 756, NNC 01-112 and CEE-03-310.

### Claim 47 (depends on 42)

A method according to claim 42, wherein said agent is a combination of a dopamine D2-R agonist and a dopamine D1-R antagonist.

### Claim at position 48

48-122. (canceled)