News Column

"Compositions and Methods for Diagnosing and Treating an Inflammation" in Patent Application Approval Process

July 3, 2014



By a News Reporter-Staff News Editor at Politics & Government Week -- A patent application by the inventors KARIN, Nathan (Haifa, IL); Anunu, Rachel (Haifa, IL); Wildbaum, Gizi (Kiryat Yam, IL); Zohar, Yaniv (Kiryat-Haim, IL); Netzer, Nir (Mazkeret Batia, IL), filed on June 10, 2013, was made available online on June 19, 2014, according to news reporting originating from Washington, D.C., by VerticalNews correspondents.

This patent application is assigned to Rappaport Family Institute for Research in the Medical Sciences.

The following quote was obtained by the news editors from the background information supplied by the inventors: "The present invention relates to antibodies, compositions and methods for diagnosing and treating inflammation. More particularly, the present invention relates to the use of anti scavenger receptor antibodies in treatment of an inflammatory response.

"Inflammation is a physiological condition characterized in the acute form by the classical signs of pain, heat, redness, swelling and loss of function. Inflammation often accompanies diseases such as Multiple Sclerosis (MS), osteoarthritis, Inflammatory Bowl Disease (IBD) including Crohn's disease and ulcerative colitis, Rheumatoid Arthritis (RA), SLE, type I diabetes (IDDM), atherosclerosis, encephalomyelitis, Alzheimer's disease, stroke, traumatic brain injury, Parkinson's disease, septic shock and others. In most cases, there is no effective cure for inflammation associated with such disease and existing treatments are palliative and largely fail to control the underlying causes of tissue degradation.

"Scavenger receptors (SRs) are cell surface proteins, which are typically found on macrophages and bind various types of chemically modified lipoproteins (1-3), such as low-density lipoprotein (LDL). This family of trans-membrane receptors which are highly varied in structure are involved in receptor-mediated endocytosis, phagocytosis of apoptotic cells and bacteria, as well as in cell adhesion [Peiser L. et al., Curr. Opin. Immun. 14(1):123-128, 2002]. Since the massive receptor-mediated uptake of cholesterol from modified LDL can convert cultured macrophages into cholesteryl ester-filled foam cells, similar to those found in atherosclerotic plaques, it has been postulated that these receptors also function in deposition of LDL cholesterol of macrophages in artery walls during the initial stages of atherosclerotic plaque formation [1].

"Scavenger receptors (SRs) are termed as such since they mediate the binding of remarkably wide variety of polyanionic ligands [e.g., modified proteins, sulfated polysaccharides and certain polynucleotides [1, 3, 4]. This property led to the hypothesis that these receptors form a part of an in innate immune response by serving as pattern recognition receptors that bind a wide variety of pathogen components [2-5].

"SR-B 1 (also referred to as SR-BI or CLA-I) is a macrophage scavenger molecule and a receptor for high-density lipoprotein (HDL) [2, 3, 6, 7] that mediates cholesterol uptake from cells [Rigotti A. et al., Curr. Opin. Lipidol., 8:181-8, 1997; Rigotti A. et al., Proc. Natl. Acad. Sci., 94:12610-5, 1997]. SR-B1 can also serve as a receptor for non-HDL lipoproteins and appears to play an important role in reverse cholesterol transport. In vivo experiments showed that this receptor is important for HDL metabolism in mice, and for the metabolism of LDL and HDL cholesterol in humans [Stang H. et al., J. Biol. Chem. 274:32692-8., 1999; Swarnakar S. et al., J. Biol. Chem. 274:29733-9., 1999]. Studies involving the manipulation of SR-B1 gene expression in mice, indicate that its expression protects against atherosclerosis [Kozarsky K. F., and Krieger M., Curr. Opin. Lipidol. 10:491-7., 1999; Ueda Y. et al., J. Biol. Chem. 275:20368-73., 2000; Acton S. L. et al., Mol. Med. Today 5:518-24., 1999]. It was also suggested that HDL and particularly its protein fraction Apo-A1 affect the in vitro production of pro-inflammatory mediators by macrophages (8). Among mediators derived from macrophages that propagate inflammation are interleukin 12 (IL-12), TNF-.alpha. and possibly IL-6 whereas, TGF-.beta. and IL-10 have predominantly anti-inflammatory effects [Kiefer R. et al., Prog. Neurobiol. 64(2):109-27, 2001].

"PCT Publication No. WO 2004/041179 teaches targeting of scavenger receptor SR-B1 (Cla-I) for the treatment of infectious diseases associated with invasion of foreign antigens such as bacterial or viral antigens (e.g., infection, sepsis and associated inflammation). This is based on the discovery that peptides with an amphipathic helical motif block cellular uptake of LPS (lipopolysaccharide) and proinflammatory responses induced by LPS, LTA (lipoteichoic acid) and bacterial cpn60 (Chaperonin 60) and amyloid peptides in vitro. Thus the inventors of PCT Publication No. WO 2004/041179 conclude that agents with an amphipathic motif targeting SR-BI (scavenger receptor class B type I) could potentially be used to treat sepsis, bacterial and viral infections and inflammatory diseases where LPS, LTA, viral envelope proteins, and/or heat shock proteins contribute to pathogenesis.

"WO 2004/041179 does not suggest the above-described agents for the favourable treatment of autoimmune diseases (which are not associated with foreign pathogenic agents such as LPS, nor with amyloid) such as IBD. Nor does the art teach the use of SR-B 1 specific antibody sequences having an anti-inflammatory activity activity for the treatment of inflammatory diseases in general and autoimmune diseases in particular, such as multiple sclerosis.

"There is thus, a widely recognized need for and it would be highly advantageous to have novel agents and methods using same for targeting SR-B 1 and treating autoimmune diseases."

In addition to the background information obtained for this patent application, VerticalNews journalists also obtained the inventors' summary information for this patent application: "According to one aspect of the present invention there is provided an isolated polypeptide comprising an antigen recognition domain capable of specifically binding a human scavenger receptor, wherein the antigen recognition domain comprises at least three CDR amino acid sequences selected from the group consisting of SEQ ID NO: 11, 15, 19, 23, 27 and 31.

"According to another aspect of the present invention there is provided an isolated polypeptide comprising an antigen recognition domain capable of specifically binding a human scavenger receptor, wherein the antigen recognition domain comprises CDR amino acid sequences as set forth in SEQ ID NO: NO: 11, 15, 19, 23, 27 and 31.

"According to yet another aspect of the present invention there is provided an isolated polynucleotide comprising a nucleic acid sequence encoding the polypeptide.

"According to still another aspect of the present invention there is provided a pharmaceutical composition comprising as an active ingredient the polypeptide.

"According to an additional aspect of the present invention there is provided a method of reducing inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the polypeptide, thereby reducing the inflammation in the subject.

"According to yet an additional aspect of the present invention there is provided use of the polypeptide for the manufacture of a medicament identified for treating IBD.

"According to still an additional aspect of the present invention there is provided use of the polypeptide for the manufacture of a medicament identified for treating multiple sclerosis.

"According to a further aspect of the present invention there is provided use of the polypeptide for the manufacture of a medicament identified for treating an autoimmune disease.

"The present invention successfully addresses the shortcomings of the presently known configurations by providing novel compositions and methods containing same for diagnosing and treating an inflammatory response.

"Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

"The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

"The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

"In the drawings:

"FIG. 1 is a photograph depicting cross-reactivity of monoclonal anti SR-B1 antibody, E12, with human and mouse orthologs. Recombinant proteins were resolved on SDS-PAGE and transferred to nitrocellulose membrane. The membrane was subjected to E12;

"FIG. 2 is a graph depicting dose-dependent induction of IL-10 secretion from cultured peritoneal macrophages treated with E12;

"FIG. 3 is a bar graph depicting dose-dependent suppression of NO levels in cultured peritoneal macrophages treated with E12;

"FIG. 4 is a graph depicting the effect of E12 (closed squares), control isotype matching antibody (circles) or no treatment on ongoing EAE in mice induced with such, as determined by reduction in EAE score;

"FIGS. 5a-c are bar graphs depicting the effect of E12 (pink) or control antibodies (grey) on cytokine secretion from spleen cells of 19 day EAE-induced mice. FIG. 5a--IL-4. FIG. 5b--IL-12. FIG. 5c--IL-10;

"FIGS. 6a-f are photographs showing IL-10 immunostaining of Lumbar spinal cord sections from EAE induced mice (19 days of disease onset) subjected to no treatment (FIG. 6a), or treated with E12 (FIG. 6b), or isotype matching control antibody (FIG. 6c). FIGS. 6a-c shows staining with biotinylated E12 for presence of scavenger receptor expressing cells. FIGS. 6d-f shows staining with anti IL-10 antibody. Anti-SR-BI therapy reduces the histological score of EAE;

"FIGS. 7a-e are photographs showing representative histological colon sections obtained at day 12 of disease onset from naive rats (FIG. 7a), positive control rats suffering form TNBS induced IBD (FIG. 7b), rats suffering from TNBS induced IBD that were subjected to repeated administration of isotype matched control IgG (FIG. 7c) in comparison to those treated with mAb E12 (FIGS. 7d-e); and

"FIGS. 8a-i show representative immuno-histological sections obtained at day 12 of disease onset from control rats suffering from TNBS induced IBD (FIGS. 8a-c), rats suffering form TNBS induced IBD that were subjected to repeated administration of isotype matched control IgG (FIGS. 8d-f) in comparison to diseased rats treated with mAb E12 (FIGS. 8g-i). FIGS. 8a, d and g are stained with mAb ED 1 (macrophages bio-marker); FIGS. 8b, e and h are stained with anti CD3 (T cell bio-marker) and FIGS. 8 c, f and I are stained with an anti IL-10 mAb."

URL and more information on this patent application, see: KARIN, Nathan; Anunu, Rachel; Wildbaum, Gizi; Zohar, Yaniv; Netzer, Nir. Compositions and Methods for Diagnosing and Treating an Inflammation. Filed June 10, 2013 and posted June 19, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=3428&p=69&f=G&l=50&d=PG01&S1=20140612.PD.&OS=PD/20140612&RS=PD/20140612

Keywords for this news article include: Antibodies, Viral, Virus, Lipids, Neurology, Metabolism, Cholesterol, Inflammation, Lipoproteins, LDL Receptors, Myeloid Cells, Blood Proteins, Immunoglobulins, Neuroimmunology, Membrane Proteins, Multiple Sclerosis, Scavenger Receptors, Autoimmune Disorders, Immunologic Receptors, Demyelinating Diseases.

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