Right before the New Year rockets are launched, we once again present and discuss some interesting life science patent disclosures. See you again in 2012!
PLEASE CITE AS : Mucke HAM. Patent Highlights for December 2011. Published online on the H.M. Pharma Consultancy Blog (URL:http://hmpharmacon.blogspot.com/2011/12/patent-highlights-for-december-2011.html) on December 30, 2011. Contact us at office@hmpharmacon.com .
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Screening for Calcification Modulators
In Greek mythology Klotho, the youngest of the three Moirae who guide the mortals’ fate, was responsible for spinning and maintaining the thread of human life which her sister Lachesis had measured out. Quite appropriately, a signalling protein associated with premature aging (see here), tumor suppression, and epigenetic modifications has been assigned this name. Klotho is a transmembrane protein that acts as a cofactor for fibroblast growth factor 23 ( FGF23), but it also exists as a soluble circulating form which appears to protect against renal disease, hyperphosphataemia, increased oxidative stress, endothelial dysfunction, and diffuse vascular calcification. It is also intimately associated with accretion processes in bone metabolism and with atherosclerosis. WO 2011/158655 (Hiroshima Univ. [JP]; Dec. 22, 2011) presents screening methods for compounds that modulate the formation of soluble Klotho-containing complexes with FGF-23 and the FGF receptor. See WO 2011/071783 and WO 2011/068893 for Amgen’s recent patenting on this subject.
Natural Compounds for MS and Pancreatic Cancer
Iridoids are bitter-tasting secondary plant metabolites, derived from isoprene and frequently glycosylated. They serve primarily as a defense against herbivores and insects, or against infection by microorganisms. There is also considerable medical value: iridoids from Valeriana species have recently been reported as having neuroprotective effects (see here); many others are known as anti-inflammatory constituents of plant extracts. WO 2011/153678 (Xuanwu Hospital [CN]; Dec. 15, 2011) combines these activities to suggest compositions containing morroniside and loganin (the actives in the traditional Chinese medicine Liu Wei Di Huang Wan, used i.a. for postmenopausal osteoporosis; paper here) for the treatment of multiple sclerosis. The neuroprotective potential of morroniside has been reported three years ago (see here).
In WO 2011/151831 (Carmel-Haifa Univ. Economic Coop. [IL]; Dec. 8, 2011) inventors have found cytotoxic components in new strains (CBS 126585 and HAI-1302) of Cyathus striatus , known as the bird’s nest fungus. While most bioactive substances isolated from mushrooms are high-molecular-weight polysaccharides, the inventors have shown that ethyl acetate extracts obtained from mycelium or its culture medium contains small molecules (not identified in the application) that are toxic to the human pancreatic cancer cell lines HPAF-II and PL45. Cell cycle analysis, DNA fragmentation assays, caspase activation, and TUNEL staining support the claims.
News on Noble Gases in Medicine
The time when noble gases were believed to be incapable of chemical reactions is long past. Although xenon, krypton and argon are chemically inert under most circumstances, all have anesthetic and neuroprotective properties (see this review). This applies especially to xenon, which has the best lipid solubility, and can exert anti-excitatory activity by blocking NMDA receptors (but not N-type voltage-gated calcium channels or GABA-A receptors) at normobaric conditions. Given this pharmacology it is not very surprising that it could prevent relapses in addicted patients, as WO 2011/151551 (L’Air Liquide [FR]; Dec. 8, 2011) claims. Xenon inhalation worked in a rat model of stimulus-induced relapse into alcohol consumption, a paradigm which is regarded as highly relevant in human alcoholism.
A companion application, WO 2011/154630 (L’Air Liquide [FR]; Dec. 15, 2011) claims inhaled krypton for peripheral organ failure. There are no animal data; instead, extensive in vitro experiments using the U2OS osteosarcoma cell line are presented, showing reduced apoptosis under conditions that promote ischemia-reperfusion injury. L’Air Liquide, the leading supplier of medical gases, has dominated this exquisite field of patenting for many years.
Four Pieces of News on Vaccines
Active immunotherapies can be relied on to make their mark in international patenting each and every month. WO 2011/149389 (individual inventors [RU]; Dec. 1 2011) deals with autologous dendritic cell vaccines for hepatitis C virus; the patient’s antigen-presenting cells are isolated, loaded with fragments of recombinant HCV core or NS3 protein (e.g., by electroporation), and re-infused. In a case study, a patient was treated with 1.5 ml of composition comprising 106 autologous dendritic cells 10 μg of a 192 amino acid NS3 protein fragment) and 107 activated lymphocytes. After the first course of therapy consisted of 5 rounds, the virus titre was decreased to from 10 6-107 virus particles/ml 400 ME/ml.
WO 2011/150249 (Selecta Biosciences [US]; Dec. 1, 2011) deals with multivalent vaccines where the individual immunization antigens are immobilized on distinct sets of synthetic nanocarriers. This can enable vaccine properties previously thought impossible. As an example, vaccines for Streptococcus pneumonia ( US 6,132,723 to Alberta Research Council and WO 2008/143709 to Wyeth) contain multiple polysaccharide-coupled antigens. Since the attachment chemistry conditions are not the same for all of them, coupling methods that would attach all of the surface antigens to a single population of nanocarriers in a single coupling environment would be undesirable. Another example of multivalent vaccines that could benefit from this embodiment of the invention comprise vaccines against Neisseria meningitides which is polysaccharide-based and multivalent, being directed at serogroups A and C (bivalent) or groups A, C, W135 and Y (tetravalent). Agonists for toll-like receptors 7 and 8, such as those disclosed in US 6,696,076, can also be attached to the carriers to act as adiuvants. Preferred adjuvants comprise imiquimod and resiquimod.
The leading cause of bacterial gastrointestinal disease worldwide is Campylobacter jenuni. Such infections are more frequent than those caused by Salmonella sp. or E. coli 0157:H7, which receive much more publicity. WO 2011/156619 (Univ. Arkansas [US]; Dec. 15, 2011) presents DNA vaccines that that include immunostimulatory polypeptide such as CD154 (CD40 ligand) or HMGB1 (high mobility group box 1) and are claimed to elicit mucosal, humoral, and cell-mediated immune responses against multiple serovars. Efficacy studies in broiler chicken and turkey poults are presented.
Reverse vaccinology, where a synthetic antigen is designed which structurally mimics an epitope of the target to be neutralized, must build on a good knowledge of the carbohydrate moieties that define this epitope and are a necessary component for antibody binding. WO 2011/156690 (Brandeis Univ. [US; Dec. 15, 2011) presents a method of directed evolution of carbohydrate-oligonucleotide conjugates by attaching carbohydrates to a library of DNA backbones and performing iterative aptamer selection with a monoclonal antibody that binds to the target. The mAb 2G12, which recognizes an epitope of the HIV envelope protein gp120, is used as an example.
NAGLU For Sanflippo
The type-III mucopolysaccharidoses (MPS-III; sometimes called the Sanflippo syndromes) are autosomal recessive deficiencies in brain enzymes that degrade gylcosaminoglycans. In MPS-IIIB the deficiency is in alpha-N-acetylglucosaminidase, expressed from the NAGLU gene. The most severe symptom is the progressive loss of cognitive ability, which results not only to the accumulation of heparan sulfate in neurons, but also the subsequent elevation of gangliosides. WO 2011/163652 (Shire Human Genetic Therapies [US]; Dec. 29, 2011) presents an enzyme replacement therapy consisting of an intrathecally delivered fusion protein consisting of the Naglu protein and a terminal lysosomal targeting moiety, such as insulin-like growth factor II (IGF-II) or Kif. Injection of Naglu-IGFII into Sanfilippo B mutant mice demonstrated extensive distribution well beyond the meninges, and reversal of lysosomal storage was achieved in the cerebral cortex as well as in the subcortical regions. For a recent paper on AAV vector-mediated gene therapy for MPS-IIIB see here.