# US 12,006,343 B2 · C4BP-based compounds for treating immunological diseases

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- Number: US 12,006,343 B2
- Document ID: US12006343B2
- Status: Granted
- Kind: B2
- Application number: 16/603,427
- Filed: 2018-04-05
- Published: 2020-05-14
- Granted: 2024-06-11
- Earliest claimed: 2017-04-06
- Assignees: Fundacio Institut D'Investigacio Biomedica De Bellvitge (Idibell)
- Applicants: Fundacio Institut D'Investigacio Biomedica De Bellvitge (Idibell)
- Inventors: Josep M. Aran Perramon; Luis Antonio Ruiz Avila; Jordi Ortiz Sagrista; Nuria Lluch Lafuente
- Web page: https://patentgrep.com/patent/US12006343B2

## CPC

- C07K 14/472: {Complement proteins, e.g. anaphylatoxin, C3a, C5a}
- A61K 38/13: Cyclosporins
- A61K 38/1725: {Complement proteins, e.g. anaphylatoxin, C3a or C5a}
- A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)}
- A61K 38/1793: {for cytokines; for lymphokines; for interferons}
- A61K 38/2278: {Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)}
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- 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 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/57: {characterised by the type of response, e.g. Th1, Th2}
- 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

## Abstract

Compounds for use in the prevention and/or treatment of immunological diseases, particularly rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis, are described, characterized by the subcutaneous administration of isoforms of C4BP lacking the beta chain or polypeptides comprising the CCP6 region of the alpha chain of C4BP no more than once a week or at a dose ranging from 0.24 mg/m2 to 9.99 mg/m2. Pharmaceutical compositions comprising from 0.45 mg to 18.90 mg of these compounds for the prevention and/or treatment of these diseases are also described.

## Claims

### Claim 1

A method for the treatment of an immunological disease caused by an undesired activation of the immune system by increasing tolerogenic dendritic cell and/or regulatory T cell populations in a subject in need thereof comprising administering to said subject:
a C4BP isoform lacking the beta chain wherein if at least one of the alpha-chains forming said isoform is a deletion mutant which lacks at least one of the complement control protein (CCP) domains, a complement control protein 6 (CCP6) domain is preserved in said alpha-chain; and
wherein said C4BP isoform is:
(i) administered subcutaneously in a regimen comprising a plurality of administrations and wherein the C4BP isoform is administered no more than once a week; or
(ii) administered subcutaneously at a dose of from 0.24 mg/m2 to 9.99 mg/m2.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the dose of each administration in the regimen ranges from 0.24 mg/m2 to 9.99 mg/m2.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the C4BP isoform is administered once every two weeks.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the C4BP isoform is administered once a week.

### Claim 5 (depends on 1)

The method according to claim 1, further comprising a previous step of subcutaneous administration of the C4BP isoform separated by less than seven days from the subsequent administration.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the immunological disease is an autoimmune disease selected from the group consisting of systemic lupus erythematosus, lupus nephritis, and rheumatoid arthritis.

### Claim 7 (depends on 6)

The method according to claim 6, wherein the autoimmune disease is rheumatoid arthritis.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the C4BP isoform lacking the beta chain is selected from the group consisting of α7β0, α6β0 and combinations thereof.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the C4BP isoform lacking the beta chain comprises at least one C4BP alpha-chain which is a deletion mutant lacking domains CCP1, CCP2, CCP3 and CCP4.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the C4BP isoform comprises the C4BP alpha-chain, wherein the C4BP alpha-chain is a variant in which:
the C4BP alpha-chain comprises the CCP6 domain and a modified complement control protein 8 (CCP8) domain;
wherein the modified CCP8 domain is obtained by modifying an original CCP8 domain having Lys residues; and
wherein the original CCP8 is modified by replacing at least one of the Lys residues in the original CCP8 domain by a residue selected from the group consisting of Pro, Asp, Glu, His, Ile, Ala, Ser, Thr, Val, Gln and Asn.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the dose ranges from 4 mg/m2 to 6 mg/m2.

### Claim 12 (depends on 1)

The method according to claim 1, wherein the C4BP isoform is administered in combination with one or more therapeutic agents useful in the treatment of an immunological disease caused by an undesired activation of the immune system, wherein said therapeutic agent is selected from the group consisting of cyclosporine A, tacrolimus, methotrexate, thiopurines, anti-TNF agents, infliximab, adalimumab, certolizumab, golimumab, etanercept, rituximab, epratuzumab, belimumab, rapamycin, anti-interferon antibodies, tocilizumab, laquinimod, tabalumab, ofatumumab, ixekizumab, brodalumab, briakinumab, sarilumab, rilonacept, anifrolumab, cyclophosphamide, mycophenolate mofetil, azathioprine, anticalcineurinics, prednisolone, methylprednisolone, vitamin D, vasoactive intestinal peptide, hydroxychloroquine, chloroquine, ocrelizumab, atacicept, abatacept, alemtuzumab, sirukumab, eculizumab and T cell vaccine.

### Claim 13 (depends on 2)

The method according to claim 2, wherein the dose of each administration is 4.26 mg/m2.

### Claim 14

A method for the treatment of an immunological disease caused by an undesired activation of the immune system by increasing tolerogenic dendritic cell and/or regulatory T cell populations in a subject in need thereof comprising administering to said subject of a pharmaceutical composition comprising from 0.45 mg to 18.90 mg of:
a C4BP isoform lacking the beta chain wherein if at least one of the alpha-chains forming said isoform is a deletion mutant which lacks at least one of the complement control protein (CCP) domains, the complement control protein 6 (CCP6) domain is preserved in said alpha-chain; and
wherein the pharmaceutical composition is administered subcutaneously.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the pharmaceutical composition comprises 8.05 mg of the C4BP isoform.