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Psmp antagonists for use in treatment of fibrotic disease of the lung, kidney or liver

A technology of liver fibrosis and kidney fibrosis, applied in allergic diseases, urinary system diseases, antibodies, etc.

Pending Publication Date: 2021-09-03
MAPLE BIOTECH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Clearly, alternative therapeutic avenues are needed

Method used

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  • Psmp antagonists for use in treatment of fibrotic disease of the lung, kidney or liver
  • Psmp antagonists for use in treatment of fibrotic disease of the lung, kidney or liver
  • Psmp antagonists for use in treatment of fibrotic disease of the lung, kidney or liver

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0195] Example 1: PSMP expression is upregulated in human and murine liver fibrosis

[0196] To evaluate whether the expression of PSMP is associated with liver disease, PSMP levels were detected by immunohistochemistry in tissue microarrays containing different liver disease tissues. PSMP was significantly upregulated in cirrhosis and adjacent non-neoplastic liver tissues ( Figure 1A and 1B ). This finding was confirmed in human liver fibrosis tissues of different causes, including hepatitis B virus (HBV)-induced cirrhosis (n = 14), hepatitis C virus (HCV)-induced cirrhosis (n =1), primary biliary cirrhosis (n=5) and alcohol-induced cirrhosis (n=2). Immunohistochemical analysis showed that the expression of PSMP in the liver of patients with cirrhosis was significantly increased compared with normal human liver tissues ( Figure 2A and 2B ). Similar to the human data, compared with livers from control mice, in CCl 4 PSMP expression was also significantly increased i...

Embodiment 2

[0197] Example 2: PSMP deficiency protects against liver fibrosis in mice

[0198] To further examine the role of PSMP signaling in liver fibrosis, fibrogenesis was then studied in PSMP knockout mice subjected to CCl 4 A mouse model of treatment-induced toxic fibrosis. Repeated exposure of mice to CCl 4 4 weeks (2 times / week), compared with oil control, Psmp - / - Mice show significantly attenuated liver injury and fibrosis assessed by hematoxylin and eosin (H&E), Sirius red staining, and hepatic hydroxyproline content, in contrast to Ccr2 - / - Mice can be compared ( Figures 5A-5D ). Consistently, as by immunohistochemistry and immunoblotting with Ccr2 - / - Mice consistently assessed that upregulation of α-SMA, a marker of HSC activation, was - / - Significantly decreased in mice ( Figure 5A and 5F ). Serum levels of alanine aminotransferase (ALT) are shown in Psmp - / - A clear decreasing trend in mice, indicating improvement of liver damage ( Figure 5E ). with Ccr2...

Embodiment 3

[0201] Example 3: Neutralization of PSMP signaling attenuates liver fibrosis in mice

[0202]Based on the fact that PSMP deficiency significantly attenuates the development of liver fibrosis in mice, the specific PSMP neutralizing antibody 3D5 was tested against CCl 4 Induced hepatic fibrosis. First, in order to study 3D5 pairs with 4 weeks of CCl 4 Protective effect of induced liver fibrosis in mice each time CCl 4 Mice were treated with 3D5 after injection ( Figure 7A ). H&E and Sirius red staining assays showed decreased liver damage and fibrosis after 3D5 treatment compared to control and mIgG-treated groups ( Figures 7B-7D ). Thus, 3D5 significantly reduced α-SMA expression in fibrotic liver ( Figure 7B and 7G ). In addition, the hepatic hydroxyproline content in the 3D5-treated group was significantly lower than that in the control and mIgG-treated groups ( Figure 7E ). The serum level of ALT in the 3D5-treated group was significantly lower than that in t...

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Abstract

Disclosed are antagonists of PC3-secreted microprotein (PSMP) and use of the antagonists for treatment of liver, lung, or kidney fibrosis, including various diseases or disorders associated with liver, lung, or kidney fibrosis such as, e.g., non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), drug-induced lung injury, acute kidney injury (AKI), chronic kidney disease (CKD), lupus nephritis, IgA nephropathy, and membranous glomerulonephritis. Also disclosed are PSMP antagonists and their use for treatment of graft-versus-host disease (GVHD) and systemic lupus erythematosus (SLE). Suitable PSMP antagonists for use in disease treatment include PSMP-binding proteins such as, for example, neutralizing anti-PSMP antibodies.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 797,440, filed January 28, 2019, U.S. Provisional Application No. 62 / 911,511, filed October 7, 2019, and U.S. Provisional Application No. 62 / 911,511, filed October 11, 2019. 62 / 913,937 entitlement. Each of the foregoing applications is incorporated herein by reference in its entirety. [0003] Sequence Listing Reference [0004] This application contains a Sequence Listing, which has been submitted in ASCII format via EFS-Web, and is incorporated by reference in its entirety. Said ASCII copy, created on December 26, 2019, is named "MAB_0110PC_20191226_Seq_Listing_ST25" and is 11,153 bytes in size. Background technique [0005] Liver Fibrosis and Nonalcoholic Fatty Liver Disease (NAFLD) [0006] Fibrosis is the excessive accumulation of extracellular matrix that often occurs as a wound-healing response to repeated or chronic tissue injury and can lead to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/24A61P37/06A61P1/16
CPCC07K16/24C07K2317/76A61P37/06A61P1/16A61K2039/505A61P13/12C07K2317/21C07K2317/24
Inventor 王应佘少平裴晓磊李青青刘中天宋占明狄春辉C·刘
Owner MAPLE BIOTECH LLC
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