# US 11,305,014 B2 · Modulating permeability of the blood cerebrospinal fluid barrier

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- Number: US 11,305,014 B2
- Document ID: US11305014B2
- Status: Granted
- Kind: B2
- Application number: 15/984,087
- Filed: 2018-05-18
- Published: 2018-11-22
- Granted: 2022-04-19
- Earliest claimed: 2015-11-20
- Assignees: Memorial Sloan Kettering Cancer Center
- Applicants: Memorial Sloan-Kettering Cancer Center
- Inventors: Adrienne Boire; Joan Massague
- Web page: https://patentgrep.com/patent/US11305014B2

## CPC

- A61K 45/00: Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K 31/166: having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61P 35/04: specific for metastasis
- G01N 33/57557: {of other specific parts of the body, e.g. brain}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates to methods and compositions for modulating the blood CSF barrier and for diagnosing, preventing and/or treating leptomeningeal metastasis. In particular embodiments of the invention, the permeability of the blood CSF barrier is modulated by agonists or antagonists of Complement Component 3 (C3) or its receptor.

## Claims

### Claim 1

A method of treating leptomeningeal metastasis in a subject with cancer, comprising diagnosing leptomeningeal metastasis in the subject and administering an effective inhibitory amount of an antagonist of C3 or C3aR to the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the cancer is breast cancer, lung cancer, or melanoma.

### Claim 3 (depends on 1)

The method of claim 1, wherein the antagonist is an antagonist of C3.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antagonist is an antagonist of C3aR.

### Claim 5 (depends on 1)

The method of claim 1, comprising further treating the subject with a second therapeutic agent.

### Claim 6 (depends on 5)

The method of claim 5, wherein the second therapeutic agent is a chemotherapeutic agent.

### Claim 7 (depends on 1)

The method of claim 1, further comprising alternately treating the subject with (i) a C3 or C3aR antagonist and (ii) a C3 or C3aR agonist together with a therapeutic agent.

### Claim 8 (depends on 1)

The method of claim 1, wherein diagnosing comprises determining that the level of C3 in the CSF of the subject is elevated relative to the level in the CSF of a healthy control subject.

### Claim 9 (depends on 1)

The method of claim 1, wherein the antagonist of C3aR is:
wherein the R is aryl, heteroaryl, phenyl, diphenyl, diphenyl lower (C1-C4) alkyl, lower alkyl diphenyl, naphthyl, naphthyl lower alkyl, lower alkyl naphthyl, quinoline, quinoline lower alkyl, lower alkyl quinoline, purine, lower alkyl purine, purine lower alkyl, lower alkyl, halogen, hydroxy, or lower alkoxy.

### Claim 10 (depends on 9)

The method of claim 9, wherein the antagonist of C3aR is:

### Claim 11 (depends on 9)

The method of claim 9, wherein the antagonist of C3aR is:

### Claim 12 (depends on 1)

The method of claim 1, wherein the antagonist of C3 or C3aR is a Phe-Leu-Thr-Cha-Ala-Arg peptide.