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2014年招商說明會技術簡介手冊

作用於血小板膠原受體的抗血栓小胜肽先導藥物之研發

研發特點(與目前世界技術比較)與成果

血小板凝集在血栓的產生上扮演重要的角色,而GPVI是血小板上已知的主要膠原蛋白(collagen)受體,針對GPVI為血栓疾病治療標的之研發甚為新穎且重要,目前在國外僅有兩項藥物進入臨床試驗。
血小板凝集為本實驗室篩選藥物技術的平台,對膠原蛋白所引發血小板凝集中,篩檢蛇毒蛋白和合成物抑制劑。目前已檢測多種合成胜肽(peptide), 並已完成hexapeptide及decapeptide抗血小板凝集及抗血栓之動物試驗。
Hexapeptide/Decapeptide及其衍生物是本實驗室利用特定蛇毒蛋白結構所設計合成最具發展潛力之胜肽。在試管實驗(in vitro)試驗中,證實它們會專一性作用在血小板膠原受體GPVI上,進而抑制collagen下游的活化路徑,包括thromboxane B2產生及P-selectin表現。於動物活體試驗中,投予Hexapeptide/Decapeptide可明顯抑制小鼠活體血栓的形成,但在出血副作用上則小於Aspirin或臨床使用之Tirofiban(一種醣蛋白IIb/IIIa拮抗劑)。
綜之,Hexapeptide/Decapeptide此先導胜肽目前雖處於Lead Optimization階段,但已顯現出其抗血栓潛力,具有繼續研發之價值。以下為本藥物之優勢簡述:
1. 目前國際上尚未有文獻發表蛇毒蛋白衍生之小分子血小板膠原受體的拮抗劑,本專利具有創新性。
2. 小分子胜肽合成方便。針對同樣機制作用之藥物,目前國際上僅有Revacept(一種可溶性Dimeric GPVI-Fc fusion protein)的製劑剛完成Phase I;另一為DZ-697b(一種C1q TNF-related protein-1)拮抗collagen與vWF的結合作用,亦處於臨床Phase I之完成階段。而Decapeptide為新穎之小分子胜肽(分子量約為1,000Da),少有抗體或大分子蛋白製劑之抗原性(antigenicity)問題
3. 安全性高:GPVI拮抗劑少有現今抗血栓藥物(包括Aspirin、Clopidogrel或Abciximab)過量使用出血問題
4. 廠商參與可能行動方案:
藥效最佳化或配方製劑之合作:利用結構-活性相關研發可得到更具藥效之藥物或改造成Non-peptide結構以利口服藥物之開發。
 
合作對象
尋求合作研發與技術授權廠商共同進行臨 床前及臨床試驗,尤以具備毒理、量產製程等臨床前開發經驗者為佳,以求本專利之適切商品化。
 
 
 
以周邊第一型大麻素受體(cannabinoid receptor 1) 為標靶之抗糖尿病小分子抑制劑: DBPR211
 
研發特點(與目前世界技術比較)與成果
 
糖尿病隨著全球營養、生活品質的改進、肥胖的普及以及年齡結構老化,對人類健康造成嚴重威脅;而肥胖所導致糖尿病患年齡層的下降,更是日益嚴重。糖尿病在台灣、中國、開發中或已開發國家皆相當普遍,而其伴隨之醫療花費相當驚人。因此,世界各國無不把糖尿病當成衛生政策上的重大議題。另外,從健康福祉與經濟效益兩方面來看,發展糖尿病治療用藥有其必要性及發展潛力。中樞神經及周邊組織的第一型大麻素受體(cannabinoid receptor 1, CB1)皆控制新陳代謝作用,但為避免抑制中樞神經CB1所產生的副作用,及發揮抑制周邊CB1改善新陳代謝的藥效,開發僅作用於周邊CB1之拮抗劑即為一新療法,而DBPR211即為此類化合物之代表。
本研發藥物主要用於治療第二型糖尿病,非酒精性脂肪肝症亦是可開發方向。同時,此藥物亦兼具減重效果。整體而言,對治療日趨嚴重之新陳代謝症候群有多面向的優勢,提供一治療新選擇。
本研發藥物與現有之技術相比較後,其優點簡述如下:
1. DBPR211 (binding affinity IC50 = 3.4 nM)是一可口服吸收之CB1受體拮抗劑,具良好藥物動力學特性。
2. DBPR211口服給予動物後,在腦中存量很低;且長期服用時,為一不累積且不影響中樞神經作用之化合物。
3. DBPR211在in vitro safety phamacology的研究上,展現良好選擇性,且在Patch Clamp功能測試上不具抑制hERG之活性(potassium channel inhibition IC50 > 30 μM)。
4. 在高油脂引發之肥胖鼠模型中,可改善胰島素阻抗性、降低脂肪肝及具減重效果。此外,在db/db糖尿病鼠模型中,DBPR211亦能改善胰島素阻抗性。
目前在國際上此新型態之CB1拮抗劑僅一家藥廠7TM Pharma發展至臨床一期,而Jenrin Discovery則進展至完成前臨床試驗,故此化合物極具競爭力。
 
合作對象
尋求合作研發或技術授權廠商共同進行臨床前及臨床試驗,尤以具備臨床前/臨床試驗開發經驗者為佳,以求本計畫之妥適商品化。
 
 
 

Recombinant coagulation Factor IX for the Treatment of Haemophilia B

Business Focus: Treatment of Haemophilia B
Application: Replacement therapy of Haemophilia B; Gene therapy of Haemophilia B
Inventors: Shu-Wha Lin et al
 
Invention Description:
Haemophilia B is caused by a deficiency of a blood plasma protein called factor IX that affects
the clotting property of blood. The disorder is caused by an inherited X-linked recessive trait, with
the defective gene located on the X chromosome. Thus, the disorder occurs primarily in males.
Haemophilia B occurs in about 1 out of 30,000 men.
The present invention provides a recombinant human factor IX protein with enhanced activity
which provides an alternative for replacement therapy and gene therapy for Haemophilia B. Using
recombinant techniques, factor IX having substitution of amino acid residue at amino acid position
selected from the group consisting of 86, 277, and 338 (exclude the circumstance of a single
substitution at amino acid position 338) exhibits better clotting activity than recombinant wild type
factor IX.
 
Competitive Advantages:
Recombinant factor IX products offer greatly reduced risk for HIV and hepatitis B and C
transmission. If recombinant factor IX with enhanced clotting activity can be generated through
genetic engineering of factor IX DNA, it will not only lower the cost for the clotting factor but also
reduce the dose of it in managing patients with Haemophilia. Moreover, this method will also
provide a more efficient tool for gene therapy trials in patients with Haemophilia.
Using recombinant techniques, the present invention with triple alanine replacement at
positions 86, 277, and 338(FIX-Triple) exhibits 13 times better clotting activity than wild type
recombinant factor IX. FIX-Triple also has enhanced 10-fold higher affinity for human factor VIIIa
than wild type. In vivo test, FIX-Triple presents 7-fold higher clotting activity than wild type in
transgenic Haemophilia mice.
Key Publication:
LIN, C. N., KAO, C. Y., MIAO, C. H., HAMAGUCHI, N., WU, H. L., SHI, G. Y., LIU, Y. L., HIGH, K. A.
and LIN, S. W. (2010), Generation of a novel factor IX with augmented clotting activities in vitro and in
vivo, Journal of Thrombosis and Haemostasis, 8: 1773–1783. doi: 10.1111/j.1538-7836.2010.03913.x
Wu, Yao-Ming; Kao, Chung-Yang; Huang, Yu-Jen; Yu, I-Shing; Lee, Hsuan-Shu; Lai, Hong-Shiee; Lee,
Po-Huang; Lin, Chia-Ni; Lin, Shu-Wha, Genetic Modification of Donor Hepatocytes Improves
Therapeutic Efficacy for Haemophilia B in Mice, Cell Transplantation, Volume 19, Number 9, 2010 , pp.
1169-1180(12)
Chung-Yang Kao; Chia-Ni Lin; I-Shing Yu; Mi-Hua Tao; Hua-Lin Wu; Guey-Yueh Shi; Yung-Li Yang;
Jau-Tsuen Kao; Shu-Wha Lin, FIX-Triple, a gain-of-function factor IX variant, improves haemostasis in
mouse models without increased risk of thrombosis, Thrombosis and Haemostasis, 2010
Aug;104(2):355-65
 
Intellectual Property: Two U.S. patents have been issued. A PCT application is pending.
Business Opportunity: License and/or Sponsored Research
Follow-up: Please contact Technology Transfer, citing docket number Factor IX.
 
 
 
NOVEL TREATMENT FOR ISCHEMIC STROKE AND ARTERY STENOSIS
 
Inventors: Suh-Hang Hank Jou, et al
 
INVENTION DESCRIPTION:
The invention is a highly promising new treatment, with strong pre-clinical animal data, for
neurologic trauma such as ischemic stroke and balloon catheter or stent-associated artery
stenosis. Specifically, the inventor group has successfully administered a microRNA, miR-195,
in rat models of ischemic stroke and balloon injured carotid artery. This miR efficiently inhibits
inflammation and smooth muscle cell proliferation and can be targeted to oxygen-occluded sites
by a variety of delivery methods. Compared to histology from placebo-treated controls, miR-195
treatment strikingly reduces arterial thickening following induced balloon injury in rats. Similarly,
in a rat ischemic stroke model, miR-195 treatment improves neuronal cell viability and reduces
the expression of apoptotic markers. When administered soon after acute stroke in rats, mir-
195 treatment limits the infarct area in the brain. The inventor group is also assessing the
recovery of neurological function in miR-195 treated rats in the stroke model. The first human
clinical trials are in the planning stages.
 
COMPETITIVE ADVANTAGE:
Based on the compelling results from animal experiments, miR-195 is an excellent candidate
to treat acute stroke patients and also to prevent fibrotic stenosis in carotid arteries implanted
with balloons or stents. The promising and novel miR-195 treatment fills a significant need.
Tissue plasminogen activator (tPA) is currently the only FDA-approved treatment for ischemic
stroke, and potentially fatal hemorrhage presents a significant side effect risk of this therapeutic
approach. In contrast, miR-195 treatment has been demonstrated to be non-toxic in mouse
studies and has been extremely effective in the rat models of acute ischemic stroke and balloon
artery stenosis.
 
INTELLECTUAL PROPERTY: A PCT patent application is pending
 
KEY PUBLICATION:
Juo SH. Sacco RL. Chapter 41. Genetics of Stroke, Merritt’s Neurology. 11th edition. Lippincott
Williams & Wilkins, Baltimore 2005
BUSINESS OPPORTUNITY: License and/or Sponsored Research
 
FOLLOW-UP: Please contact Katherine Chou at techtransfercenter4aibp@gmail.com.
This marketing effort is a collaboration between the University of the Sciences in Philadelphia
(USciences) and the Taiwan-based Development Center for Biotechnology, through its Academic-
Industry Bridging Project (AIBP), to explore technology commercialization opportunities for the abovementioned
technology.

 

Compositions with Reduced Hepatotoxicity for TuberculosisTreatment
 
 Invention Description:
The invention is a pharmaceutical composition for the treatment of tuberculosis comprising isoniazid/rifampin/pyrazinamide and other ingredients that inhibit the P450 enzyme 2E1 (CYP2E1) and amidase. Ingredients that inhibit CYP2E1 and amidase include disulfuram (Antabuse), kaempherol, and many others, including some traditional Chinese medicinal herbs and common used pharmaceutical excipients. The inventors have shown in animal tests that inhibiting CYP2E1 and amidase results in substantially less liver toxicity as evidenced by decreases in serum aminotransferases (ALT and AST) whose presence in the blood is an indication of liver toxicity, as well as by the galactose single-point method for assessing liver function, and examination of liver tissues.
 
Background, Applications and Advantages:
The inventors have confirmed that the known hepatotoxicity of isoniazid/rifampin/pyrazinamide comes about because its metabolism results in the formation of excessive amounts of hepatotoxins. In particular they have shown that it is the Cytochrome 450 enzyme 2E1 (CYP2E1) and amidase that produces the excessive amount of hepatotoxins. They have further discovered that by inhibiting CYP2E1and/or amidase hepatic toxicity is much reduced.
Isoniazid, rifampin, and pyrazinamide are the most reliable and most commonly used medications for tuberculosis. Isoniazid, rifampin, and pyrazinamide therapy are often associated with minor, transient and asymptomatic elevations in serum aminotransferase levels, but more importantly, isoniazid or rifampin, or pyrazinamide is a well-known cause of acute clinically apparent liver injury (hepatitis) which can be severe and is sometimes fatal. About 3% of patients receiving isoniazid will go on to severe hepatitis. Some of these patients are in a terrible bind as isoniazid/rifampin/pyrazinamide is the only effective treatment for their tuberculosis.
 
Publications:
• The AAPS Journal, Vol. 15, No. 3, 753-762, July 2013
• Curr Drug Metab. 2013 Jul;14(6):720-8
• Antimicrob Agents Chemother. 2013 Apr;57(4):1685-90 .
 
Intellectual Property: A US issued patent #8,304,394 B2 and PCT patents application (PCT/CN2011/000688). The technology also has patent protection in China, India, and Taiwan.
.
Follow-up: Please contact Katherine Chou at techtransfercenter4aibp2013@gmail.com
This marketing effort is a collaboration between the University of the Sciences in Philadelphia (USciences) and the Taiwan-based Development Center for Biotechnology, through its Academic-Industry Bridging Project (AIBP), to explore technology commercialization opportunities for the above-mentioned technology.
 
 
 
 
Novel Peptides that Inhibit Collagen Activated Platelet Aggregation for the Treatment and Prevention of Cardiovascular Conditions

Disease Area: thrombosis, atherosclerosis, stroke, myocardial infarction

Applications: coronary intervention
Invention Description:
The invention is a series of novel peptides that inhibit collagen activation of platelets. Collagen activation of platelets is the first step in the formation of thrombuses or clots. A number of disease conditions are the result of the platelet aggregation process going awry – such as thrombosis, stroke, myocardial infarction, and others. The peptides of the invention can potentially treat or prevent such conditions. The peptides are derived from the snake venom C-type lectin trowaglerix. Trowaglerix is known to induce platelet aggregation by specific binding to the collagen receptor glycoprotein IV (GPIV) expressed on platelets. The inventors have located within the larger protein those peptides that bind to GPIV. An active hexapeptide and decapeptide were discovered and many variations of these wild-type sequences were made by conservative amino acid substitutions. The hexapeptide inhibits collagen activation of platelets by 50% and the decapeptide by almost 100%. Despite this strong antiplatelet activity the peptides result in only a mildly prolonged bleeding time, as shown by the bleeding-tail test in mice. The peptides and pharmaceutical compositions comprising the peptides are potential antiplatelet drugs for the treatment and prevention of cardiovascular conditions.
 
Applications:
The most promising application of the peptides is as an IV infusion for prevention of thrombosis and restenosis during percutaneous coronary intervention, placement of coronary stents and coronary angioplasty. Restenosis occurs 25 – 50% of the time after a balloon angioplasty or in the placement of an arterial stent. Over two million angioplasties are performed per year worldwide. Currently administration of Plavix and aspirin is used to prevent thrombosis during coronary intervention. However these drugs have an infrequent but serious side effect of hemorrhage. The inventive peptides are free of this side effect and thus are potential replacements for aspirin and Plavix, as well as other drugs now in development which all have a bleeding side effect.
Current and new antiplatelet agents, such as clopidogrel (Plavix) and ticagrelor (Brilinta), cannot be used in all patients without increased risk of bleeding. The danger of bleeding with anti-platelet medicines is a serious problem that may be solved with the inventive peptides. The inventive peptides may represent the “Holy Grail” of antithrombotic medicines – ones that prevent clotting without causing unwanted bleeding.
 
Intellectual Property: A patent application has been filed; please see PCT/IB2012/0001345 http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012172427&recN...
 
Follow-up: Please contact Katherine Chou at techtransfercenter4aibp2013@gmail.com
This marketing effort is a collaboration between the University of the Sciences in Philadelphia (USciences) and the Taiwan-based Development Center for Biotechnology, through its Academic-Industry Bridging Project (AIBP), to explore technology commercialization opportunities for the above-mentioned technology.
 
 
 
 
 
RAPID, SENSITIVE QUANTIFICATION OF PEGYLATED SMALL MOLECULES IN BIOLOGICAL SAMPLES
 
Inventors: Tian-Lu Cheng et al.
 
Invention Description:
The invention is an anti-PEG cell-based ELISA for rapid, highly sensitive quantitative detection
of PEGylated samples. An anchoring fibroblast cell line expresses PEG-specific antibody fragment
as a cell surface receptor for PEG-capture. The anti-PEG cell can pair with a biotin-conjugated
anti-PEG antibody for a sandwich ELISA or a competition ELISA using biotinylated PEG to
compete with PEG or PEGylated small molecules for the cell surface-expressed, anti-PEG receptor
binding sites. Compared to conventional antibody-directly ELISA, the anti-PEG cell-based ELISA
components provide a stable, high surface area scaffold of optimally-oriented antibody molecules
for enhanced antigen capture.
Polyethylene glycol (PEG) is commonly employed as a protein, drug, and probe- modifying
agent for biomedical applications. PEG-detection, however, relies on decades-old methods such
as colorimetric assays or high performance liquid chromatography (HPLC), which are laborious
and insensitive (5-100 mg/ml range). The inventor team, therefore, developed many PEG-specific
antibodies recognizing different PEG/PEG-derivative sizes and their functional groups, for rapid,
highly sensitive and accurate quantification of PEG and PEGylated small molecules by conventional
ELISA.
 
Competitive Advantages:
Although HPLC/tandem mass spectrometry (MS/MS) significantly improves detection of PEG,
the requirement for expensive instruments and specially trained operators may limit its routine use.
The innovative anti-PEG cell based sandwich or competition ELISA reproducibly detects low (3-50
ng/ml) concentrations of a wide range of small (2KDa to 20KDa) PEGylated molecules. The rapid,
affordable and user-friendly anti-PEG cell-based ELISA does not require sophisticated instruments
or methods. Importantly, the presence of serum does not interfere with the assay, which is key for
the quantification of PEG in blood and/or other biological samples.
 
Key Publication:
Chuang, K-H, S-C Tzou, T-C Cheng, C-H Kao, W-L Tseng, J Shiea, K-W Liao, Y-M Wang, Y-C
Chang, B-J Huang, C-J Wu, P-Y Chu, SR Roffler, T-L Cheng (2010), Measurement of poly(ethylene
glycol) by cell-based anti-poly(ethylene glycol) ELISA, Analytical Chem, 82, 2355-2362.
 
Intellectual Property: A U.S. patent application is pending.
Business Opportunity: License and/or Sponsored Research
Follow-up: Please contact Katherine Chou at techtransfercenter4aibp@gmail.com, citing docket
number CaPE.
This marketing effort is a collaboration between the University of the Sciences in Philadelphia (USciences)
and the Taiwan-based Development Center for Biotechnology, through its Academic-Industry Bridging Project
(AIBP), to explore technology commercialization opportunities for the above-mentioned technology.
 
 
POWERFUL SYSTEM FOR TYPING KLEBSIELLA PNEUMONIAE
 
Inventors: Tzu-Lung Lin, Yi-Jiun Pan, Pei-Fang Hsieh, Meng-Chuan Wu, Chun-Ru Hsu and Jin-Town Wang
 
Invention Description:
The invention is a comprehensive panel of bacteriophage/recombinant glycosidase pairs,
each of which specifically targets one of 78 known capsule types of virulent Klebsiella pneumoniae.
The inventor group identified the bacteriophages and capsule-specific glycosidases from more than
200 novel isolates. The individual bacteriophage/glycosidase combinations rapidly and accurately
detect K. pneumoniae capsule types in simple, 6-8 hour agar spot assays, which can be ramped up
for high volume testing. An upcoming clinical trial and research project will exploit the technology
to identify the dominant capsular types of K. pneumoniae strains of different countries and will
build the epidemiological database for all K. pneumoniae, generating a global prevalence rate of K.
pneumoniae capsular types. This valuable resource will reveal the regional geographic pathology of
K. pneumoniae, which is critical for developing a rational vaccine and treatment strategy.
 
Competitive Advantage:
In side-by-side comparisons, the novel bacteriophage/glycosidase panel outperforms the
current serotyping standard in K. pneumoniae typing. The bacteriophage/glycosidase combinations
accurately detected 97% of K. pneumoniae strains, while serotyping accuracy was only 57%. The
new reagents target a broader range of K. pneumoniae capsule types and address an important
unmet need. Hospital-acquired K. pneumoniae infections are highly contagious and can lead
to potentially life-threatening pneumonia and bloodstream infections as well as urinary tract and
intra-abdominal infections. Moreover, community-acquired pyogenic liver abscess is linked to K.
pneumoniae infection. The invention provides a very promising solution for effective diagnosis, and
potential treatment and prevention of K. pneumoniae infections.
 
Key Publication:
Lin TL, YJ Pan, PF Hsieh, MC Wu, CR Hsu, JT Wang. 2012. Development of a bacteriophage/
glycosidase system for capsular typing of Klebsiella pneumoniae. (Manuscript submitted)
 
Intellectual Property: A PCT application is pending.
Business Opportunity: License and/or Collaboration and Sponsored Research
Follow-Up: Please contact Katherine Chou at techtransfercenter4aibp@gmail.com
This marketing effort is a collaboration between the University of the Sciences in Philadelphia (USciences)
and the Taiwan-based Development Center for Biotechnology, through its Academic-Industry Bridging Project
(AIBP), to explore technology commercialization opportunities for the above-mentioned technology.