Fungal-specific metalloproteases and uses thereof

Patent metadata

Field	Value
Publication number	US-2017198060-A1
Application number	US-201615349928-A
Country	US
Kind code	A1
Filing date	Nov 11, 2016
Priority date	Sep 8, 2011
Publication date	Jul 13, 2017
Grant date	—

Abstract

The present invention relates to methods of reducing, delaying, preventing and/or inhibiting the progression of a Cryptococcus infection into the central nervous system (CNS) of a subject by inhibiting the activity of a M36 fungalysin metalloprotease (e.g., MPR1) secreted by the Cryptococcus . The invention further provides methods of increasing, promoting and/or enhancing delivery of a therapeutic agent across the blood-brain-barrier, comprising systemically administering the therapeutic agent in conjunction with a M36 fungalysin metalloprotease (e.g., MPR1), or an enzymatically active fragment thereof.

First claim

1 . A method of reducing, delaying, preventing and/or inhibiting the progression of a Cryptococcus infection into the central nervous system (CNS) of a subject in need thereof, comprising inhibiting the activity of a M36 fungalysin metalloprotease secreted by the Cryptococcus , wherein the M36 fungalysin metalloprotease has at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 1.

2 . A method of reducing, inhibiting and/or preventing the transmigration of Cryptococcus across the blood-brain-barrier in a subject in need thereof, comprising inhibiting the activity of a M36 fungalysin metalloprotease secreted by the Cryptococcus , wherein the M36 fungalysin metalloprotease has at least 80% sequence identity to an amino acid sequence of SEQ ID NO:1.

3 . The method of claim 1 , wherein the subject is suspected of being infected with Cryptococcus.

4 . The method of claim 1 , wherein the subject has pulmonary cryptococcosis.

5 . The method of claim 1 , wherein the subject has tested positive for Cryptococcus infection in the cryptococcal antigen lateral flow assay (CrAg LFA).

6 . The method of claim 1 , wherein the subject has no detectable Cryptococcus infection of the CNS.

7 . The method of claim 1 , wherein the subject is immunocompromised.

8 . The method of claim 1 , wherein the subject is human.

9 . The method of claim 1 , wherein the Cryptococcus is selected from the group consisting of Cryptococcus gattii, Cryptococcus neoformans, Cryptococcus neoformans var. grubii, Cryptococcus neoformans var grubii H99, Cryptococcus sp. Y13-1, Cryptococcus laurentii and Cryptococcus albidus.

10 . The method of claim 1 , wherein the M36 fungalysin metalloprotease is inhibited from binding to its substrate.

11 . The method of claim 1 , wherein the catalytic activity of the M36 fungalysin metalloprotease is inhibited.

12 . The method of claim 1 , wherein an antigen binding molecule that specifically binds to the M36 fungalysin metalloprotease is administered to the subject.

13 . The method of claim 12 , wherein the antigen binding molecule is an antibody or fragment thereof.

14 . The method of claim 1 , wherein expression levels of the M36 fungalysin metalloprotease are reduced and/or inhibited.

15 . The method of claim 14 , wherein an inhibitory nucleic acid that inhibits expression of the M36 fungalysin metalloprotease is administered to the subject.

16 . The method of claim 12 , wherein the antigen binding molecule specifically binds to the peptidase_M36 domain of the M36 fungalysin metalloprotease.

17 . The method of claim 12 , wherein the antigen binding molecule specifically binds to the M36 GluZincin superfamily domain of the M36 fungalysin metalloprotease.

18 . The method of claim 12 , wherein the antigen binding molecule specifically binds to the zinc binding site of the M36 fungalysin metalloprotease.

19 . The method of claim 12 , wherein the antigen binding molecule is administered intravenously.

20 - 35 . (canceled)

36 . An expression cassette comprising a nucleic acid encoding a M36 fungalysin metalloprotease having at least 80% sequence identity to an amino acid sequence of SEQ ID NO: 1, or a fragment thereof that retains protease activity, operably linked to a promoter that promotes expression in a mammalian cell.

37 - 46 . (canceled)

47 . A host cell comprising the expression cassette of claim 36 .

48 - 65 . (canceled)

Assignees

• Univ California

Inventors

• Gelli Angela C

Classifications

• A61K38/4886

  Metalloendopeptidases (3.4.24), e.g. collagenase · CPC title

• C12N9/1029

  transferring groups other than amino-acyl groups (2.3.1) · CPC title

• C12Y203/01

  transferring groups other than amino-acyl groups (2.3.1) · CPC title

• C07K16/40 Primary

  against enzymes · CPC title

• A61P31/12

  Antivirals · CPC title