Platelet Aggregation Inhibitors - PROvendis

Platelet Aggregation Inhibitors Novel antagonists of the P2Y12-receptor with antithrombotic effect Invention Purinergic receptors have been in the focus of drug discovery for many years. Modulation of P2 receptors in platelets is of paramount importance in regulating platelet function, and, as a consequence, in controlling thrombotic diseases, which are the most common cause of morbidity and mortality in the Western world. The P2Y12-receptor on blood platelets is the target of known antithrombotic drugs (e.g. clopidogrel). The receptor is therefore validated for this therapeutic use. Furthermore, the P2Y12-receptor is expressed in certain parts of the brain, which opens new routes for the treatment of neuroinflammatory and neurodegenerative diseases.

Example of general formular of disclosed compounds - further specified in the patent application.

Competitive Advantages Innovative group of compounds for a validated target No bioactivation for faster onset of action Reversible binding to the receptor Small molecules for inexpensive production process.

This invention provides novel antagonists of the P2Y12-receptor. The disclosed novel compounds show reversible and selective binding to the P2Y12-receptor. The molecules do not require bioactivation. Further the patent application discloses synthesis of the compounds with optimised product yield.

Commercial Opportunities We offer a patent license as well as a research collaboration with licensing option to innovative companies. Current Status A patent application for the invention has been filed in Europe. An invention of Rheinische Friedrich-Wilhelms-Universität Bonn (UniBonn).

Contact: Ref. No. 1526 Dr. Andreas Wagener PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany

PROvendis GmbH is the patent licensing agency for the universities of North Rhine-Westphalia, Germany. PROvendis recommends: www.inventionstore.de - Free e-mail service to access the latest IP-protected top technologies.

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+49 (0) 208 94 105 38 +49 (0) 208 94 105 50 [email protected] www.provendis.info

ALXAN 8-Ethinylxanthines for the treatment of CNS diseases Invention Adenosine is a modulator of many physiological and pathophysiological processes in the central nervous system (CNS). Blockade of the adenosine receptors A1ARs and A2AARs has shown beneficial neuroprotective effects in animal models and in clinical studies of Parkinsons’s disease (PD) and Alzheimer’s disease (AD). Furthermore, selective inhibitors of the monoamine oxidase A (MAO-A) are applied as adjunctive therapeutics for PD, as they protect the brains of PD patients from oxidative stress.

8-Ethinylxanthines

Nevertheless, there is still no satisfactory multitarget drug approach which inhibits MAO-A and the two adenosine receptors A1ARs and A2AARs.

This invention provides newly designed tricyclic xanthine derivatives which allow overcoming this problem. A variety of 69 derivatives were prepared and evaluated in radioligand binding studies at adenosine receptors and for their ability to inhibit monoamine oxidases. Potent dual-target-directed A1/A2A adenosine receptor antagonists were identified. Several compounds even showed triple-target inhibition.

Competitive Advantages New potent dual- and tripletarget drugs for the treatment of PD and AD Multi-target drug with Improved compliance Less side effects Reduced toxicity

Significant advantages combination therapy

over

More predictable pharmacology Reduced drug-drug interactions Less complex pharmacokinetics

Together, these observations position tricyclic xanthine derivatives as ideal candidates for the treatment of neurodegenerative diseases such as PD and AD, but might also be suitable for the treatment of depression, addiction and restless legs syndrome. Commercial Opportunities On behalf of the University of Bonn, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. Current Status A European and a US patent have already been granted, other applications are pending. Relevant Publication Brunschweiger, A. et al. (2014) 8-Benzyltetrahydropyrazino[2,1-f]purinediones: WaterSoluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases. J Med Chem 9;1-22 Koch, P. et al. (2013) 1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4diones as multiple target drugs for the potential treatment of neurodegenerative diseases. Bioorg Med Chem 21, 7435-7452 Mertens, M. D. et al. (2014) Alkynyl-coumarinyl ethers as MAO-B inhibitors. Bioorg Med Chem 22; 1916-1928 An invention of Rheinische Friedrich-Wilhelms-Universität Bonn.


Contact: Ref. No.: 1613 Dr. Andreas Wagener PROvendis GmbH Schlossstrasse 11-15 D-45468 Muelheim an der Ruhr, Germany Phone:+49 (0)208 94 105 38 Fax: +49 (0)208 94 105 50 Email: [email protected] Web: www.provendis.info

Treating Alzheimer´s disease by targeting Amyloid β-nitration A novel therapeutic / diagnostic / prophylactic approach Invention Part of the inflammatory response in Alzheimer´s disease (AD) is the upregulation of the inducible nitric oxide synthase NOS2 resulting in increased NO production. NO contributes to cell signaling by inducing posttranslational protein modifications. Under pathological conditions there is a shift to the formation of protein tyrosine nitration by secondary products like peroxynitrite and nitrogen dioxide. The invention is based on the finding that amyloid β (Aβ) is nitrated at tyrosine 10 in AD-brains. Nitration accelerates its aggregation and is present in Aβ plaques. Injection of the nitrated protein into the brain of APP/PS1 transgenic mice leads to β-amyloidosis. An antibody specific to the nitrated form of Aβ has been developed. A therapeutic approach interfering with the Status of nitration (left) and aggregation (right) of Aβ 1-42 treated w/o peroxynitrite nitrated Aβ (rather than with the native Aβpeptide) may provide a very specific treatment with a reduced risk of sideeffects.

Competitive Advantages Specific early diagnosis of AD Novel and specific approach for treating AD Antibody specific to nitrated Aβ for further clinical development

Commercial Opportunities The invention offers a novel approach for an early diagnosis of AD. The invention also opens new avenues for developing either NCEs or biologicals interfering with the nitrated Aβ. Antibody-based therapeutic approaches (e.g. passive/active vaccination) are currently been developed. Prophylactic approaches are also conceivable. Aβ1-42 and nitrated Aβ 1-42 were intracerebrally injected into APP/PS1 mice. Analysis of mice 8 weeks later using α-Aβ -antibody (6E10) 10 and α-NTyr -Aβ-antibody showed strong immuno-reactivity in nitrated Aß-treated mice (right col.).

On behalf of the University of Bonn, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development.

Current Status Patent applications are pending in EP, US and Canada. Clinical trials with β-3NTyr10antibodies are currently in preparation. Relevant Publication Kummer et al. (2011) Neuron 71(5): 833-44. An invention of the University of Bonn (UniBonn).


Contact: Ref. No. 2311 Dr. Juergen Walkenhorst PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany Phone: Fax: E-Mail: Web:


ET-CORMs Enzyme-triggered CO releasing molecules for therapeutic use Invention Carbon monoxide (CO), which is endogenously produced mainly in the course of heme degradation, was recently recognized as a powerful cytoprotective and homeostatic agent. For instance, CO was shown to ameliorate experimental cardiac, lung and vascular injuries and protect against numerous inflammatory states. While the clinical use of CO gas is associated with severe safety problems, a controlled delivery of CO to specific target sites by means of CO-releasing molecules appears to be a most promising solution. In this context, the invention comprises a novel class of iron carbonyl complexes, which release their CO load only after enzymatic activation. The powerful CO-releasing properties and the structural variability form a promising basis for the development of safe and pharmacologically useful CO-releasing molecules (CORMs). Biological tests (using different cell lines) have proven the chemical concept and confirmed the intracellular CO-release. Moreover, structural variation revealed pronounced structure-activity relationships. The clear-cut chemical concept and the developed synthetic schemes (opening short and efficient entries both to compound libraries and to larger amounts of individual complexes) provide excellent pre-conditions for structural optimization. Some initial results have Figure 1: Enzymatically triggered CO release been published.

Competitive Advantages Acyl-oxydiene-Fe(CO)3 complex¬es are an innovative class of ET-CORMs allowing for the first time a controlled intracellular and potentially tissue-specific CO-release First water-soluble enzymetriggered CO-releasing molecules ET-CORMs open new perspectives for the prevention and cure of diseases involving inflammatory, infectious, thrombotic or proliferative processes

Commercial Opportunities CO-releasing molecules have the potential to become an important new class of drugs in the future. First generation CORMs reported in the literature do not meet the required pharmacological properties. However, the enzyme-triggered compounds (representing prodrugs) have a unique potential. The delivery of small amounts of CO to tissues can widen blood vessels, increase blood flow, prevent unwanted blood clotting, reduce inflammation and even suppress immune responses and the activity of cells and macrophages which attack transplanted organs. Current Status On behalf of the Universities of Cologne and Regensburg, PROvendis offers a patent license as well as a research collaboration with licensing option to innovative companies. In case of interest we will be pleased to inform you about the patent status. Relevant Publication Romanski, S.; et al.; Angew. Chem., Int. Ed. 2011, 50, 2392-96. Romanski, S.; et al.; Dalton Trans. 2012, 41, 13862-75. Romanski, S.; et al.; Organometallics 2012, 31, 5800-09. Botov, S.; et al.; Organometallics 2013, 32, 3587-94. Romanski, S.; et al.; Free Radical Bio. Med. 2013, 65, 78-88. Wegiel, B.; et al.; Trends in Molecular Medicine 2013 19, 3-11 An invention of the Universities of Regensburg and Cologne (UniKöln).

PROvendis GmbH offers IP services for universities, research facilities and technology-oriented companies. PROvendis recommends: www.inventionstore.de – free e-mail service to access the latest top technologies.

Contact: Ref. No. 2644 Dr. Andreas Wagener PROvendis GmbH Schlossstraße 11-15 45468 Muelheim an der Ruhr Germany Tel.: Fax: E-Mail: Web:


Mutation Detection (Platform Technology) Highly sensitive, fast and cost-effective detection of gene modifications and mutations in all kinds of DNA sources Invention Particularly in oncology, determination of gene mutation statuses serves as a biomarker to guide rational therapeutic decisions. Due to patient safety sequential biopsies or biopsies of multiple tumor lesions are not routinely performed. Scientists of the University of Duisburg-Essen developed a platform, which facilitates the detection of deletions and insertions as well as point mutations in target genes from any kind of DNA sources against a huge background of wild type alleles, making a clear “Yes” or “No” output possible and thereby simplifying therapeutic decisions. Neither expensive and complicated equipment nor specialized personnel is needed. The assay is robust and applicable in all laboratories equipped with an RT-PCR machine. It can easily be established for point of care (PoC) purposes.

Mutation detection Target gene mutation specific designed probes, labeled with fluorescent dyes allow fluorescence resonance energy transfer (FRET). Together with other automatable steps, a melting curve analysis indicates at the end of each PCR run the presence or absence of mutations in a particular sample.

This sensitive technology now enables clinicians to be independent of the scarce resource “tissue biopsy”. By using blood (ctDNA, cfDNA or CTC) it opens new non-invasive possibilities for monitoring the mutation status of patients before and during treatment as well as to detect disease relapse early. An adjustment of the treatment or a switch to another therapy could be done in time.

Competitive Advantages Platform technology with a unique sensitivity DNA sources e.g.: ctDNA (free DNA from plasma/ serum samples) CTC biopsies (e.g. EBUSTBNA) pleural effusion bronchial lavage A high background of wild type alleles is no problem Automatable A concentration of only one tumor cell per milliliter blood is sufficient "Online monitoring" of treatment response on a genomic level Fast and cost-effective

Commercial Opportunities This invention allows an easy and economical way for the stratification of patients (e.g. for treatment with tyrosine-kinaseinhibitors) with unique sensitivity. Based on RT-PCR and fully automatable (e.g. in a kit), the technical requirements are conventional and worldwide accessible. The non-invasive analysis of free DNA from plasma/serum samples is possible and facilitates continuous monitoring of treatment response. Current Status Platform technology established so far for common oncogenic mutations with similar impressive sensitivities - BRAF (V600E), EGFR (DelEx19, L858R, T790), KRAS (codon 12/13/61). Use for the development of a companion diagnostic certainly conceivable. On behalf of University of Duisburg-Essen, PROvendis offers access for commercial use in terms of a license as well as research collaborations. In case of interest, we are pleased to inform you about the current patent status. A European and a US patent have already been granted (EP2 486 146 B1; US 9,115,392 B2), further applications are pending (WO 2012/003950). Relevant Publication Breitenbuecher, F., et al. (2014) Development of a highly sensitive and specific method for detection of circulating tumor cells harboring somatic mutations in non-small-cell lung cancer patients. PLoS One 9(1): e85350 An invention of the University of Duisburg-Essen (UniDUE).


Contact: Ref. No. 2664/2702 Dr. Constanze Vogel PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany Phone: Fax: E-Mail: Web:


CorA as an effective therapeutic agent Natural product for the treatment of dirofilariasis Invention Dirofilariasis is caused by Dirofilaria immitis and D. repens, parasitic nematodes transmitted by mosquitoes. The heartworms harbour the bacterial endosymbionts Wolbachia, which are essential for worm development, fecundity and survival. Corallopyronin A (CorA) has efficacy against the intracellular Wolbachia of filarial nematodes. Experiments in mice and jirds show that all worms were depleted of their Wolbachia by more than 98%, resulting in blocked larval development and phenotypically altered worms. The results indicate the potential of CorA to effectively kill filarial nematodes in the larval stages as well as adult worms. Thus, this antibiotic is a good option for prophylactic as well as therapeutic treatment. No toxicity against eukaryotic cells or the treated rodents was detected. Resistance to ivermectin in heartworms has been Pharmacokinetic data show that the reported. However, development of resistance antibiotic is amenable to oral administration. against Corallopyronin A in Wolbachia is unlikely. Based on the present results CorA will be administered once a day for two to a maximum of four weeks. CorA is a non-competitive inhibitor of bacterial DNA-dependent RNA polymerase. Detrimental drug-drug interactions are not expected, since CorA does not induce expression or activation of CYP450.

Competitive Advantages Effective control of dirofilarial infections High efficacy against the bacteria Wolbachia – potential for killing larvae as well as adult worms Oral administration is probable Slow worm death prevents potential pulmonary thromboembolism

Is likely to be well tolerated and could be used in all dog races, e. g. Collies Will probably be suitable for the treatment of pregnant dogs

Commercial Opportunities Heartworm disease is endemic in all states of the USA, especially in the South. Prophylatically, the macrocyclic lactone (ML) ivermectin is given for prevention of infection. If pets are infected, Melarsomine is administered by injection, to clear the adult worms. In recent years loss-of-efficacy in infected dogs treated with ivermectin has been reported, indicating a resistance to ML. Melarsomine may cause severe side effects – one of the reasons why Melarsomine is not used for humans. One advantage of CorA is that formation of resistance is significantly reduced. As a therapeutic agent with adulticidal activity, CorA would prevent potential pulmonary thromboembolism after the death of the heartworm because the worms are killed slowly, thus avoiding a strong inflammatory reaction. On behalf of the University of Bonn, PROvendis offers an access to rights for commercial use of this invention and the opportunity for further co-development. Current Status US patent granted (US 9 168 244). An EP and a second US patent application are pending. Data of in vitro and in vivo experiments are available. Relevant Publications Schäberle, T.F., et al. (2013) Corallopyronin A – A promising antibiotic for treatment of filariasis. Int. J. Med. Microbiol. 304(1): 72-8. Schiefer, A., et al. (2012) Corallopyronin A specifically targets and depletes essential obligate wolbachia endobacteria from filarial nematodes in vivo. J. Inf. Diseases 206: 249-57. Hoerauf, A., et al. (2011) Filariasis in Africa—treatment challenges and prospects Clin. Microbiol. Inf.17: 977-85. An invention of the Rheinische-Friedrich-Wilhelms Universität Bonn (UniBonn).


Contact: Ref. No. 2838 Kordula Kruber PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany Phone: Fax: E-Mail: Web:


Exosomes Use of exosomes in prevention and therapy of acute inflammation associated diseases Invention Exosomes are nano-sized, secreted cell organelles that are released by a huge variety of different cell species, including mesenchymal stem cells (MSCs). Containing a combination of lipids and proteins as well as RNAs, exosomes participate in intercellular communication processes.

Effect of MSC exosome therapy on skin GvHD

Due to the wide range of molecules they enclose and their cell type specific assembly, these small membrane vesicles get more and more in the focus of diagnosis, drug delivery and clinical applications. Some preliminary preclinical and clinical application of MSC-derived exosomes of scientists at the University Duisburg-Essen revealed very promising results (see below). However, coupled with the fact that beneficial effects of MSC administration are controversially discussed, it appears very likely that not all MSC-derived exosome fractions will exert beneficial effects.

Competitive Advantages Selected MSC exosome preparations exert immune suppressive functions New treatment option in diseases associated with acute inflammatory processes Well tolerated

To select for MSC exosomes being able to efficiently suppress inflammation associated symptoms the scientists compared immune modulating activities of independent MSC-derived exosome preparations. Aiming to treat a 22-years female patient suffering from severe therapy-refractory cutaneous and intestinal Graft-versus-Host Disease (GvHD) grade IV with MSC-derived exosomes, the scientists administered exosomes which revealed the strongest immune-suppressive effects in vitro. The documentation of the impacts on the clinical symptoms and the immune response showed that the selected MSC exosome preparation helped to suppress GvHD symptoms in vivo. Since the in vivo administration appears to be safe, MSC exosome administration of selected preparations turned out to be a promising new treatment option in the prevention and therapy of diseases associated with acute inflammatory processes, such as GvHD, stroke, heart-attack and neonatal damages of the brain and lungs. Commercial Opportunities On behalf of the University Duisburg-Essen, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. Current Status In case of interest, we are pleased to inform you about the current status of the patent. Relevant Publications Kordelas, L., et al. (2014) MSC-derived exosomes: a novel tool to treat therapyrefractory graft-versus-host disease. Leukemia 28(4): 970-3. Ophelders, D.R., et al. (2016) Mesenchymal stromal cell-derived extracellular vesicles protect the fetal brain after hypoxia-ischemia. Stem Cells Transl. Med. 5(6): 754-63. An invention of the University Duisburg-Essen (UniDUE).

Contact: Ref. No. 3321 Dr. Constanze Vogel PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany




NHR2 inhibitors Treatment of AML by inhibitors of NHR2 and/or RUNX1/ETOtetramerization Invention The formation and onset of the prevalent form of acute myeloid leukemia (AML, FAB subtype M2) requires RUNX1/ETO, the product of the t(8;21) chromosomal translocation. Tetramerization through the nervy homology region 2 (NHR2) of ETO is essential for the RUNX1/ETO-mediated transformation. The inventors demonstrated that inhibition of NHR2 tetramerization by first-in-class small molecules is a viable entry point for the treatment of AML. Drug candidates have been identified by a small-molecule in silico screening and have been validated in cellular assays. Several compounds proved to be successful in inhibiting NHR2 tetramerization. Preferred compound 7.44 was able to slow tumor growth in a xenograft mouse model (SKNO 1 xenograft). The pending patent application covers claims directed to a variety of chemotypes Activity of 7.44 vs. control in biochemical and that proved activity against AML. cellular assay.

Competitive Advantages Compounds for treatment of AML Unique mode of action Medical use/compound protection achievable In vivo data from mouse model available Access to inventor know-how

Commercial Opportunities The Anillin fusion protein of the invention is located in the nucleus during G1-, S- and G2-phase, in the cytoplasm and cell cortex in early M-Phase, in the contractile ring during cytokinesis and in the midbody just before absission, making it possible to distinguish between different phases. At the end of mitosis the fusion protein gets degraded by the proteasome. Therefore, cells arrested in G0 do not show any fluorescence. The invention enables scientists to identify, isolate and characterize proliferating cells out of a composition of proliferating, differentiated and post-mitotic cells. Furthermore, it enables to distinguish between cell division and variations of the cell cycle such as acytokinetic mitosis and endoreplication that cause false positives in standard proliferation assays. Commercial Opportunities On behalf of University of Düsseldorf, PROvendis offers this opportunity for licensing or co-development. Current Status In case of interest we will be pleased to inform you about the patent status. Further Reading Wichmann et al.: Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity, Blood 2010, 116(4), 603-613. Metz et al.: From Determinants of RUNX1/ETO Tetramerization to Small-Molecule Protein-Protein Interaction Inhibitors Targeting Acute Myeloid Leukemia, J. Chem. Inf. Model. 2013, 53(9), 2197-202. Schanda et al.: Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of NHR2 tetramerization, manuscript available upon request.

Contact: Ref. No.: 3409 Dr. Andreas Wagener

An invention of University of Düsseldorf.


PROvendis GmbH Schlossstrasse 11-15 D-45468 Muelheim an der Ruhr, Germany Phone:+49 (0)208 94 105 46 Fax: +49 (0)208 94 105 50 Email: [email protected] Web: www.provendis.info

Biotechnological production of itaconic acid Efficient biotechnological production of itaconic acid in a controllable fungi expression system Invention Itaconic acid is one of the top bio-based chemical building blocks and thus a promising platform compound for the production of polymers, coatings, chemical compounds and biofuels. It is an important monomer for the synthesis of, e.g. polyacrylates, rubber, colours, additives, adhesives, emulsifying agents, lipids, pharmaceuticals, herbicides and biodegradable polymers for the packaging industry.

gene 1 gene 2 wildtype

Production of itaconic acid in relation to WT.

Currently, Itaconic acid is commercially produced by microbial fermentation using filamentous fungi of the genus Aspergillus, such as A. terreus. This itaconic acid producer is well characterized, but has several disadvantages. Filamentous fungi are particularly problematic as their morphology is difficult to be controlled in fermentation systems, thus the synthesis process and the quality of production is varying.

Competitive Advantages • Effective biotechnological production process of a basic chemical platform component • Easy to handle biosynthesis with unicellular fungi • Overexpression of Itaconic acid in recombinant host cells • Novel itaconate production genes and pathway allows freedom to operate • Expression cassette and vectors encoding itaconic acid synthesis pathway are available

The offered innovative production process of itaconic acid uses genes encoding for the biosynthesis pathway of unicellular fungi from the family of Ustilaginaceae, in particular Ustilago maydis. By modification of these genes the efficiency of itaconic acid production can be markedly improved and enables a more reliable process with less risk of batch failure. As another advantage over A. terreus, which is also classified as a toxin-producing animal pathogenic fungus in certain countries which is limiting its applicability at industrial scale, the species Ustilago maydis has a history of safe use. In addition, Ustilago maydis can be easily genetically engineered and grown in liquid culture up to high cell densities and good to handle temperatures of up to 34°C. Commercial Opportunities On behalf of the RWTH Aachen University, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. Current Status In case of interest we are pleased to inform you about the current patent status. Relevant Publication E. Geiser et al. (2014); “Prospecting the biodiversity of the fungal family Ustilaginaceae for the production of value-added chemicals.” Fungal Biology and Biotechnology, 1:2

Contact: Ref. No. 3419 Dr. Andreas Wagener

M. Bölker et al. (2015) WO 2015/140314 A1; “Means and methods for itaconic acid production.”

PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany

An invention of RWTH Aachen.




Vim3 Antibody Use of Vimentin3 for the diagnosis and differentiation of benign and malignant renal carcinoma Invention Kidney cancer is classified as malignant tumors originating from different renal cells with several subtypes. The cells of these subtypes can mimic a benign kidney tumor, called oncocytoma. The unequivocal differentiation is essential for planning the adequate operative procedure (tumor removal [oncocytoma] or complete kidney resection with lymph node preparation [malignant kidney cancer]) and potential follow up (not necessary in oncocytoma). Currently, immune histology with the protein Vimentin is used for differentiation whereas only the malignant renal carcinomas are expected to show a positivity for full length Vimentin. However, a Vimentin positivity has also been observed in a series of oncocytoma, making the accuracy and validity of this diagnostic approach questionable for differentiation. Surprisingly, the inventors found a splice isoform of Vimentin, namely Vimentin3 (Vim3), as an indicator of benign oncocytoma. In addition, the inventors found that renal cell carcinoma (RCCs) are negative for Vim3. Accordingly, Vim3 can be used for the diagnosis of a benign oncocyctoma and for the differentiation of benign oncocytoma from malignant renal cell carcinoma. The currently used antibodies detect not only the full length Vimentin, but also the spliced variant Vim3. This might lead to misdiagnosis of oncocytomas with the consequence of a not qRT-PCR analysis of Vim3-expression adequate therapy of the patients. Therefore, and staining of renal cell carcinoma and oncocytoma (positive for Vim3). the inventors designed an antibody detecting exclusively the Vim3 isoform.

Competitive Advantages Novel approach for the diagnosis of benign oncocytomas and their differentiation from malignant renal carcinomas Antibody already designed for use Optimized treatment of patients due to an accurate and valid diagnosis of benign oncocytomas

Commercial Opportunities As described above, the treatment of benign oncocytomas differs from that of malignant renal carcinoma. The newly identified protein Vim3 offers an attractive tool for the diagnosis of benign oncocytomas and their differentiation from malignant RCCs. On behalf of the University of Cologne, PROvendis offers a patent license as well as a research collaboration with licensing option. In addition the antibody is available for research. Current Status In case of interest we are pleased to inform you about the patent status. Relevant Publication Von Brandenstein, M., et al. (2015) Vimentin 3, the new hope, differentiating RCC versus oncocytoma Dis. Markers 368534 An invention of the University of Cologne (UniKöln).




SilenciO Advanced Protein Expression by Galectin-1-Silencing Invention Chinese Hamster ovary (CHO) cells are commonly used as a mammalian expression system for the production of recombinant proteins. They are one of the few cell types that can be grown at high cell density as the cells are resistant to metabolic stress. The SilenciO-technology is a powerful tool for the expression of non-antibody proteins and antibodies suffering from an initially only poor expression rate SilenciO-technology is based on a Galectin-1-knock down (>90%) by RNAi. This knock down reduces the metabolic load of the CHO expression system. The expression level of the protein of interest is increased by more than 1.5-fold. Galectin-1 (Lgals-1) mRNA obtained from Lgals1 knockdown (Lgals-kd) cells compared to control cells

Competitive Advantages Enabling expression of sophisticated proteins (e.g. complex non-antibody proteins) Reduction of host cell proteins Increased yield of viable cells Increased growth rate Improved process robustness Application in existing cell lines and bioprocesses

Additional experiments revealed that using this method the yield of viable cells during fed-batch culture experiments is twice as high compared to control cells. The level of host cell protein production is reduced by SilenciO-technology.

Significant increase of antibody production at early development stage (in small scale laboratory shaker flask)

SilenciO-technology can be applied afterwards in all existing cell lines currently producing the protein with low and very low expression rates. Thus it enables the universal use for all protein drug candidates which are difficult to express and where the currently used manufacturing process leads to high costof-goods.

Commercial Opportunities On behalf of the University Bielefeld, PROvendis offers non-exclusive licenses for commercial use (rights to this technology have already been granted to Boehringer Ingelheim). Current Status EP and US patent applications are pending. Further Reading Krämer, O. (2014) RNAi-vermittelter knockdown zur Identifikation von Zielgenen für die Verbesserung von Produktionszelllinien. Dissertation, University of Bielefeld. Bielefeld 2014. WO 2015/011172 „Method for recombinant protein production in mammalian cells“ An invention of the University Bielefeld.


Contact: Ref. No. 3533 Dr. Jürgen Walkenhorst PROvendis GmbH Schlossstr. 11-15 45468 Mülheim an der Ruhr Germany Phone: Fax: E-Mail: Web:


Multifunctional Aptamers Aptamers for treatment and diagnosis of cancer Invention Targeted therapy has become a promising therapeutic approach within the last decade due to its reduced toxicity. However, further development of targeted approaches for the specific delivery of therapeutically active substances is required. Especially the targeted delivery of macromolecular charged drug-like molecules, for example antagomirs and siRNA, is limited since these candidates do not cross cell membranes but rather have to be actively provided to the intracellular milieu. The present invention provides novel aptamers capable of recognizing tumour cells and delivering macromolecular molecules into tumour cells. Aptamers are short single-stranded nucleic acids that recognize specific target structures with high affinity and specificity. Additionally, since aptamers have been shown to possess almost no toxicity and immunogenicity they are promising candidates for biomedical applications.

Aptamers for treatment and diagnosis of cancer

Competitive Advantages Aptamers as novel broadspectrum therapeutics and diagnostics for the treatment of cancer Aptamers specifically recognize tumour cells without affecting healthy cells Suitable for the specific delivery macromolecular molecules

Surprisingly, the identified aptamers recognize various cancer cells particularly those derived from solid tumours, while non-tumourgenic and primary healthy cells are not recognized.

Thus, these findings render the aptamers applicable as broad-spectrum diagnostics and therapeutics. Commercial Opportunities The described technology enables diagnosis and treatment of several tumour types with one formulation, thereby reducing the developing costs for pharmaceuticals. On behalf of the University Bonn, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. Current Status In case of interest we are pleased to inform you about the current patent status. Relevant Publication Pofahl, M., et al. (2014) Multifunctional nucleic acids for tumor cell treatment. Nucleic Acid Ther. 24(2): 171-7. An invention of the Rheinische Friedrich-Wilhelms-University Bonn (UniBonn).





FimH Expression of recombinant proteins on the cell surface of bacteria Invention The expression and production of recombinant proteins in bacteria, such as E. coli is a long standing and well known procedure. However, expression in bacterial systems is limited due to cytoplasmic accumulation of the protein of interest (POI). Even though, various attempts have been made to prevent the accumulation of the desired protein in inclusion bodies, there is still no satisfactory solution available to overcome this problem.

Immunogold Staining: FimH-Gaussia construct in E. coli

The present invention enables the expression of POI on the cell surface of bacteria, thereby preventing the cytoplasmic and periplasmic accumulation. This is achieved by using an expression vector comprising the bacterial cell-surface protein FimH and the POI. Bacterial expression of this fusion protein leads to the localization of the protein on the cell surface. Thus, the fusion protein may be isolated from the surface of the bacterial cells or, alternatively, be isolated from the bacterial cell medium subsequent to secretion.

Competitive Advantages Recombinant protein with Natural folding structure Natural biological activity Recombinant protein expression on the bacterial cell surface No cytoplasmic or periplasmic protein accumulation

Thus, this novel strategy allows the production of recombinant proteins having a natural folding structure and the same biological activity as a natural protein. Commercial Opportunities This invention offers a novel approach for the production of recombinant proteins, which can be used for the production of reagents suitable for diagnostics and therapy. Current Status On behalf of the University Hospital Cologne, PROvendis offers access for commercial use in terms of a license as well as research collaboration to innovative companies. In case of interest we will be pleased to inform you about the patent status. An invention of the University Medical Center of Cologne (UKKöln)..





Druggable oncogenic fusions NRG1 Gene Fusions as Markers & Targets for Various Cancers Invention Cancer patients frequently bear therapeutically relevant genome alteration. For instance, lung adenocarcinomas of patients that have never smoked carry genome alterations affecting kinases, such as EGFR mutations and translocations affecting ALK, ROS1, and RET genes. These patients can be effectively treated with an evergrowing number of kinase inhibitors. However, despite substantive cancer genome sequencing efforts a majority of tumors still lacks therapeutically tractable alterations.

Competitive Advantages CD74-NRG1 is a novel fusion gene which - by itself or its products – can be used both for diagnosis and as a target for medical intervention e.g. in invasive mucinous adenocarcinomas MTSS1-NRG1 as another druggable oncogenic NRG1 fusion gene Known Signalling Pathways Enables stratification of patients for ERBB2 and/or ERBB3 inhibitor treatment

Figure 1: Genomic intron/exon structure of the CD74 (green) and the NRG1 Locus (orange) with the genomic breakpoints marked in red Cancer Discovery (2014)

Scientists of the University of Cologne identified NRG1 gene fusions as ideal diagnostic and prognostic markers and targets for various tumours. The MTSS1NRG1 fusion event has e.g. been detected in patients with small cell lung cancer and the gene fusion CD74-NRG1 has been shown to occur frequently in never smokers with invasive mucinous lung adenocarcinoma lacking KRAS mutation. The latter has been verified by several other groups. CD74-NRG1 was found to signal through induction of ERBB2-ERBB3 heterodimers. In light of the multitude of available drugs or drugs in clinical trials targeting ERBB2, ERBB3 and their downstream pathways, the detection of CD74-NRG1 fusions may aid making a decision on the appropriate medical treatment e.g. for invasive mucinous lung adenocarcinomas. Furthermore, the fusion itself represents a promising target for the development of medical interventions. Thus, these findings position MTSS1-NRG1 and CD74-NRG1 as druggable oncogenic fusions.. Commercial Opportunities On behalf of the University of Cologne, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. Current Status In case of interest we will be pleased to inform you about the patent status. Further Reading Fernandez-Cuesta, L. et al. (2014) CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 4(4):415-22 Nakaoku, T. et al. (2014) Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res 20(12):3087-93 Duruisseaux, M. and Wislez, M. (2014) CD74-NRG1: a new fusion gene in lung adenocarcinomas characterizing mucinous adenocarcinomas. Bull Cancer 101(6):529-30 Gow, Ch. et al. (2014) Multidriver mutation analysis in pulmonary mucinous adenocarcinoma in Taiwan: identification of a rare CD74-NRG1 translocation case. Med Oncol. 31(7):34 Fernandez-Cuesta, L. and Thomas, RK (2015) Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer. Clin. Cancer Research 21 (9): 1989-1994 An invention of University of Düsseldorf.


Contact: Ref. No. 3769 Dr. Constanze Vogel PROvendis GmbH Schlossstrasse 11-15 45468 Muelheim an der Ruhr Germany Phone: Fax: Email: Web:

+49 (0)208 94 105 41 +49 (0)208 94 105 50 [email protected] www.provendis.info

EMULSION BUSTER 2.0 Easy Emulsion Separation in Bioprocesses Invention A process for an efficient phase separation of emulsions resulting from biphasic whole cell-biotransformations has been developed at the TU Dortmund. The phase separation of unavoidable emulsions typically present due the presence of microorganisms and bio-surfactants, which has previously been seen as problematic, has been greatly simplified to permit further processing of the reaction mixture. In contrast to other approaches such as the use of de-emulsifiers or centrifuges a phase separation can be achieved with a minimal effort in both energy and equipment. Using a physical effect the new methods enables a high potential for an industrial application due to its scalability, low costs and easy process control.

Competitive Advantages Easy to use technique Applicable on an industrial scale Easy scale-up Low equipment costs Easy process control No additives needed Low energy consumption Independent on product concentration or concentration differences due to biotransformation step

Commercial Opportunities The new method enables the separation of stable emulsion by an easy and tricky process based on the so called “catastrophic phase inversion”. The method was designed as a continuous process suitable for application on an industrial scale. In contrast to conventional processes such as e.g. centrifuging or membrane filtration, a complete phase separation can be achieved without a dilution of the product containing (mostly organic) phase. After separation of the phases, these can be further processed using conventional methods. The invention is distinguished in particular by its simplicity and universal applicability to any biphasic whole-cell biotransformation where stable emulsions occur as a result of the reaction step.

Current Status Patent applications have been filed in Europe and the USA. PROvendis is offering licenses for the invention to interested companies on behalf of the TU Dortmund. There is also the possibility of collaboration with the inventors. An invention of the Technical University of Dortmund (TU Dortmund).


Contact: Ref. No. 3841 Dr. Andreas Wagener PROvendis GmbH Schlossstraße 11-15 45468 Muelheim an der Ruhr Germany Tel.: Fax: E-Mail: Web:


Enzymatic Bio-Coating Specific coating of surfaces by enzymes

Fig. 1: Concept of enzymatic deposition

Fig. 2: Casein coated surface (SEM-image)

Invention Biological coatings have a high potential for manifold applications, especially for medical applications or biodegradable coatings. Up to now, the formation of biological coatings is accompanied either by a low control over film formation or connected to high costs. Current challenges that need to be overcome are a high control over the film thickness, an even and continuous coating of objects with a complex geometry, or the sitespecific coating of single areas on one object. The new concept Enzymatic Bio-Coating is able to solve these problems and at the same time exhibits low costs. In this new process, film-forming particles are deposited from a dispersion in direct proximity to a support surface by destabilization of the dispersion. To this, the presented concept uses immobilized enzymes to „trigger“ the deposition reaction. Enzyme is immobilized onto the support surface and destabilizes film-forming particles closely to the support. The destabilized particles subsequently deposit only there, where immobilized enzyme is present (Fig.1). This is practically realized by a simple dipping process. Depending on the applied immobilization method, various structures are obtained, which range from the deposition of single micelles to the formation of monolayers to the deposition of hybrid structures (Fig. 2).

Competitive Advantages Deposition of single particles Deposition of mono- and multilayers Control over film thickness Uniform coating Site-specific deposition Coating of objects with complex geometry Antimicrobial properties High adhesion of films Coating is renewable Easy dipping process Low-cost process

Commercial Opportunities High biocompatibility and biodegradability of proteins allows for versatile medical applications (Stents, implants, catheters). Specific deposition of single particles has a high potential for micro- and nanotechnology. Immersion of two enzyme-functionalized supports in a casein dispersion enables a pressureless gluing of both supports, exactly only there, where immobilized enzyme is present. Suitable supports are: Glass, wood, and miscellaneous plastics and metals. Casein layers are antibacterial, edible, and renewable. Current Status The process was investigated with casein which forms micelles in aqueous environments, and with the protease chymosin, but is not restricted to this system. PROvendis offers licenses for Enzymatic Bio-Coating on behalf of the University of Paderborn to companies and seeks partners for exploration of specific applications. In case of interest we are pleased to inform you about the current patent status.


An invention of the University of Paderborn.




Immunological tolerance Induction of immunological tolerance in autoimmune diseases Invention Autoimmune diseases affect millions of people worldwide. They can have serious effects on life span and quality of life. Despite intensive research, the exact reasons for the onset of autoimmune diseases are still poorly understood. At present, therapies of autoimmune disorders mainly focus on the relief of symptoms rather than on the prevention of the underlying biological mechanism. Therefore, current therapeutic strategies are mostly restricted to immunomodulators or immunesuppressants.

The safe fodder yeast Candida utilis (Torula yeast) expressing Myelin oligodendrocyte glycoprotein (MOG) on the cell surface.

Competitive Advantages Novel preventive and therapeutic approach for autoimmune disorders The treatment with antigenexpressing Candida utilis is safe simple effective

The present invention provides a novel preventive and therapeutic approach based on the induction of tolerance, which is a key mechanism for the prevention of autoimmunity. The induction of tolerance is achieved through the oral administration of antigen-expressing microorganisms.

In an animal model of multiple sclerosis, the severity and occurrence of the disease symptoms could be significantly reduced by feeding the mice with the safe fodder yeast Candida utilis (Torula yeast) expressing Myelin oligodendrocyte glycoprotein (MOG). Thus, the oral administration of antigen-expressing Candida utilis suppresses the cellular and humoral immune responses taking place in the gut-associated lymphoid tissue. Furthermore, the described treatment is considered to be safe, effective and simple. Commercial Opportunities On behalf of the Heinrich-Heine University Duesseldorf, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. Current Status In case of interest we are pleased to inform you about the current patent status. An invention of the Heinrich-Heine University Duesseldorf (HHU).





Cure for CLL Derivates of para-NO-ASA for the treatment of CLL Invention Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. The disease is very heterogeneous with some patients showing extremely slow progression while others proceed rapidly into advanced disease stages and require immediate treatment. Despite considerable improvement of therapeutic strategies in the last decade, CLL remains incurable by conventional chemo¬immunotherapies. The development of new treatment options remains an important goal. The present invention provides compounds acting as an effective and selective medicament for the treatment of neoplastic diseases or proliferative disorders, in particular compounds which induce selectively apoptosis of degenerated cells providing reduced side effects in living organisms. The compounds of the present invention are characterized by a high selectivity towards neoplastic cells. CLL cells show a higher sensitivity towards the compounds than PBMCs opening a therapeutic window. The EC50 for CLL cells is in the lower micromolar range.

Competitive Advantages Compound claims towards novel derivatives of para-NOASA High selectivity High activity Tested on different CLL cell populations Proven in a xenograft model of CLL Development team comprising chemists and clinicians Compounds may be suitable for the treatment of other neoplasias

Furthermore, compounds have proven activity on different CLL populations. The activity against CLL cells has been shown in a xenograft model of CLL. It has been shown that compounds may be suitable for the treatment of other neoplasias. Commercial Opportunities On behalf of the University of Cologne, we are offering this opportunity for licensing. Current Status In case of interest we will be pleased to inform you about the patent status. Relevant Publication Gehrke, I. et al. (2011) The antineoplastic effect of nitric oxide-donating acetylsalicylic acid (NO-ASA) in chronic lymphocytic leukemia (CLL) cells is highly dependent on its positional isomerism. Ther Adv Hematol 2(5):279-89 Razavi, R. et al. (2011) Nitric Oxide-Donating Acetylsalicylic acid induces Apoptosis in chronic Lymphocytic Leukemia cells and shows strong antitumor efficacy In Vivo. Clin Cancer Res 17(2):286-93 An invention of University of Cologne.

Contact: Ref. No.: 4045 Dr. Andreas Wagener


PROvendis GmbH Schlossstrasse 11-15 D-45468 Muelheim an der Ruhr, Germany Phone: +49 (0)208 94 105 38 Fax: +49 (0)208 94 105 50 Email: [email protected] Web: www.provendis.info

Separation of Itaconic and other Dicarboxylic Acids New adsorption process for the purification of dicarboxylic acids

Adsorbed amount / mmol gads-1

Invention The annual production of dicarboxylic acids such as itaconic acid, a promising platform chemical derived from biomass, is about 80,000 t. A significant growth is expected in 2020 to a market volume of about more than 400,000 t with an estimated overall price of $ 567 million. Currently, the state of the art production 5 of itaconic acid is a biotechnological process using bacterial strains like 4 Aspergillus terreus with carbohydrates like glucose or starch as C6-source. 3 Itaconic Acid The most energy-consuming and 2 therefore most expensive step is the recovery of the pure product from Glucose 1 fermentation broth. 0 0.0

0.1 0.2 0.3 0.4 0.5 Concentration / mmol gsol-1

Exceptionally high selectivities can be obtained for the adsorption of itaconic acid from a mixed aqueous solution with glucose using highly hydrophobic adsorbents.

Competitive Advantages Effective purification process of itaconic and related dicarboxylic acids Separation from biological or chemical processes Almost full recovery Adsorption technology possible at different pH-values and / or temperatures

Process optimization result so far in itaconic acid concentrations of about 86 g/L which is not yet cost-covering in view of poor recovery of the desired product in the range of approximately 30% from typically used resins.

The present invention provides a novel procedure for a selective and quantitative purification of itaconic and similar dicarboxylic acids especially from mixtures thereof from aqueous solutions via adsorption techniques. Several conventional and new adsorbent materials and different conditions (temperature and pH-values) have been tested to identify an optimized purification process for numerous dicarboxylic acids with almost full recovery. Commercial Opportunities The described technology enables the separation of dicarboxylic acids (e.g. itaconic, succinic, malic, maleic, fumaric acid) or of fractions thereof from biological and/or chemical processes via adsorption technology. On behalf of RWTH Aachen University, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. Current Status In case of interest we are pleased to inform you about the current patent status. Relevant Publications Wilke, D. & Vorlop, K.-D. (2001) Biotechnological production of itaconic acid. Appl. Microbiol. Biotechnol. 56: 289-95. Okabe, M., et al. (2009) Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84: 597-606. Klement, T. & Büchs, J. (2013) Itaconic acid – a biotechnological process in change. Biores. Technol. 135: 422-31. Detoni, C., et al. (2014) Selective liquid phase adsorption of 5-Hydroxymethylfurfural on nanoporous hyper-cross-linked polymers. ACS Sustainable Chem. Eng. 2: 240715.

Contact: Ref. No. 4242 + 4649 Dr. Andreas Wagener PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany

An invention of the University of Aachen (RWTH Aachen).




Extracellular production of designer HAAs Production process for the preparation of designer HAAs Invention One important biosynthetic precursor of fatty alcohols is hydroxyalkanoyloxy alkanoic acid (HAA). HAA can be produced by microbes using sugars as substrate. Currently, no commercial production of HAA is established in the art and only few literature exist that relates to HAA production. Due to their amphiphilic nature, HAA can be used as biosurfactant on one hand and as a precursor for the synthesis of alkanes, which can be used as fuel especially aviation fuel on the other hand.

Competitive Advantages Effective production process of HAAs Extracellular product accumulation is equivalent to easy separation from biological processes Different short and / or long side chains (C8, C10, C12, C14, C16) can be provided Very fast production times within one day

Possible designer structure of HAA produced with P. putida.

P. putida KT2440 generally regarded as safe

With the goal of diminishing dependency from oil and turning towards a sustainable chemical industry based on renewable resources, a demand for catalysts, which are able to provide basic chemicals for the chemical industry out of plant resources (e.g. oils or sugars) arises. One important class of said basic chemicals are fatty alcohols. The annual production of plant oils is located in the range of 140 million tons and market increases are difficult to achieve and will be accompanied by severely negative impact on environment. In contrast, the potential of using sugars is tremendous, as about 790 million tons are easily available and further 800 million tons can be obtained from the timber industry. Short chain fatty alcohols are rarely derived from renewable resources because the primarily used oil plants produce oils with longer fatty acids, thus hindering the production of such short chain fatty alcohols. In addition, nearly all oil plants produce a broad product spectrum with the result that a specific production of a narrowly defined fat alcohol composition or even a single fatty alcohol is hampered and is thus connected with high costs. Furthermore, these products derived from plants or yeast cells are accumulated intracellular, with consequently extensive down-stream processes. The present invention provides a novel procedure for a selective and quantitative (> 1g/L) production of HAAs from biotechnological process engineering. Industrial relevant strains like P. putida and E. coli have been tested and specific chain lengths of HAAs (short or long) can be obtained via direct product secretion into the media. Within one day, already 40% of theoretical product (in view of glucose as C-source) can be achieved. Commercial Opportunities The described technology enables the fast and competitive production of specific HAAs via biotechnological process technology. On behalf of the University of Aachen, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development.

Contact: Ref. No. 4249 Dr. Andreas Wagener

Current Status In case of interest we are pleased to inform you about the current patent status.

PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany

An invention of the University of Aachen (RWTHAachen).




CADA to 5AVA Bacterial production of 5-aminovalerate from cadaverine Invention Limitation of natural sources, especially of fossil resources, for base material that is currently used to produce polyamides and related composites together with the increasing demand of these products, promotes the search for renewable sources of the base material.

Competitive Advantages Renewable source for base material of polyamide production New biosynthetic route

Fermentation by genetically engineered bacteria gains increasing interest as one of these possible sources. Cadaverine is a biogenic amine that can be produced by Corynebacterium glutamicum from the amino acid lysine by heterologous expression of a lysine decarboxylase from Escherichia coli. Overexpression of the patA and patD genes from Escherichia coli in Corynebacterium glutamicum enables the latter to further metabolize cadaverine to 5-aminovalerate (5AVA), which is a potential base material for the production of nylon 5 and a C5 platform for the synthesis of base materials for other polyamides. Commercial Opportunities Chemical industry is facing an increasing demand on polyamides and related composites, whereas in contrast the accessibility of base material from fossil sources for their production alleviates. Therefore, in seek for alternative and renewable sources, bacterial fermentation has become into focus in several chemical production areas. The offered invention provides such a source for nylon production and related composites. Current Status The production of 5AVA has been tested in a laboratory scale. Up-scaling for industrial usage in terms of fermentation conditions needs to be established. On behalf of the University of Bielefeld, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. In case of interest we will be pleased to inform you about the patent status. Relevant Publications Park, S.J., et al. (2013) Metabolic engineering of Escherichia coli for the production of 5-aminovalerate and glutarate as C5 platfrom chemicals. Metab. Eng. 16: 42-7. Schneider, J. & Wendisch, V.F. (2011) Biotechnological production of polyamines by bacteria: recent achievements and future perspectives. Appl. Microbiol. Biotechnol. 91: 17-30. An invention of the University of Bielefeld.


Contact: Ref. No. 4270 Dr. Andreas Wagener PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany Phone: Fax: E-Mail: Web:


Advanced ATR-antagonists Novel compounds targeting ATR protein kinase for cancer treatment Invention The ATR (ATM and Rad3 related) kinase plays a crucial role in maintaining genome integrity during DNA replication and is involved in the coordination of the DNA damage response (“DDR”) and repair signaling pathways. Activation of ATR is directly triggered by DNA lesions facilitating DNA repair and thus promotes tumor cell survival. Therapeutic inhibition of ATR can reverse this mechanism and thereby increase tumor cell killing. Preventing ATR signaling from stalled replication forks enhances the formation of DNA damage, especially under conditions of increased replication stress as typically observed in cancer cells. Therefore, ATR inhibitors can potentiate the effect of chemotherapy or radiation, which makes ATR an attractive target for cancer therapy. At present, two ATR inhibitors (VX-970 and AZD6738; for ref. see “Relevant publication”) have already entered clinical studies. However, with the developmental risks associated with these compounds, there is a Schematic illustration of the ATR-kinase and huge interest in advanced ATR inhibitors its role in DNA damage response displaying an improved safety-/efficacy-profile. The present invention thus relates to advanced ATR antagonists, which have been shown to be effective in various cellular assays (both on its own in Burkitt Lymphoma and in combination with cisplatin). Furthermore, they show a promising ADME-profile as deducted from predictive ADME modeling in relation to the aforementioned ATR inhibitors.

Competitive Advantages Novel compounds targeting a key player in cancer cells Promising eADME-profile

Commercial Opportunities On behalf of RWTH Aachen University, PROvendis offers licenses for commercial use as well a research collaboration with licensing option. Current Status A priority patent application has been filed. Relevant Publications Llona-Minguez et al. (2014) Chemical strategies for development of ATR inhibitors. Exp. Rev. Mol. Med. 16: e10 Fokas, E. et al. (2014) Targeting ATR in DNA damage response and cancer therapeutics. Cancer Treat Rev. 40(1): 109-17 International Patent Application WO 2011/154737 International Patent Application WO 2010/071837 An invention of RWTH Aachen University.

Contact: Ref. No. 4306 Dr. Juergen Walkenhorst PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany




Parthenolide supports PNS repair Parthenolide and its derivatives for use in the treatment of axonal damage Invention Peripheral nerve damage is a common cause of considerable functional morbidity, and healthcare expenditure. Surgery can be done in case of a peripheral nerve cut or rupture but a large section of injuries however is unsuitable for primary repair, and standard clinical management results in inadequate sensory and motor restoration in the majority of cases, despite the rigorous application of complex microsurgical techniques. In general, injured peripheral nervous tissue possesses the capacity to regenerate severed axons and therefore the ability for repair. Mechanisms of so-called neuroregeneration may include generation of new glia, extension of axons, remyelination or restoration of functional synapses. However, the ability for neuroregeneration differs strongly between the peripheral nervous system (PNS) and the central nervous system (CNS). However, although injured axons of the peripheral Quantification of functional motor recovery nervous system show generally greater determined in adult wild type mice treated with potential for intrinsic axonal regrowth, either parthenolide (par, n=11) or vehicle (veh, functional regeneration is often limited, n=11) by the static sciatic index (SSI) at 1, 4, 7, 9, 12, 14 and 21 days after sciatic nerve mainly due to a decline in neurotrophic crush (dpc). support from Schwann cells over time and axonal misguidance. These aspects become particularly evident in cases of long distance regeneration, for example after sciatic nerve injury in legs or median nerve damage in arms. Therefore, the development of novel therapeutic measures aiming to accelerate axon regeneration and thereby improving functional recovery is highly desirable.

Competitive Advantages Use of a natural product for the treatment of injured peripheral nerves Unique mode of action Medical use/compound protection achievable. Functional in vivo data from mouse model available Access to inventor know-how

It was found by the inventors of the present invention that the natural product parthenolide and its derivatives facilitate the axonal growth and guidance of injured peripheral nerves in cell culture and most significantly also in vivo. The inventors demonstrate that the intraneural injection of parthenolide at the regenerating nerve results in an improved functional motor recovery as well as in an improved sensory functional recovery. Commercial Opportunities On behalf of University Düsseldorf, PROvendis offers this opportunity for licensing or co-development. Current Status A PCT application is pending. An invention of University Düsseldorf.





Food Quality Control Culture medium for yeasts with high osmotic tolerance Invention Food with high sugar content is prone to contamination with yeasts that have a high osmotic tolerance. This contamination leads to a shortened storage life and a loss of quality. Therefore, potential contamination of each food production charge needs to be carefully monitored before delivery. The problem is that these contaminating yeasts are slowly growing and difficult to detect. Therefore, the analysis process is time consuming and the food production charge ages in the meantime accompanied by a loss of quality. Consequently, there is a strong market need to expedite the quality control analysis. The herewith presented invention contributes to troubleshooting by a Food with high sugar content is especially susceptible to contamination with osmo-tolerant yeast culture medium that strongly enhances growth activity of the yeasts. This reduces the time needed for quality analysis and allows an earlier delivery of the respective food production charge with higher freshness and quality.

Competitive Advantages Expedite food quality control Enhanced quality of sugar containing food

Commercial Opportunities Food industry is seeking for strategies to enhance production throughput in order to reduce costs. One bottleneck is not the production process itself, but the subsequent quality control analysis of each production charge. The herein described invention expedites this process and is therefore of interest for contract analytic labs as well as for food production companies with an own quality analysis laboratory. Current Status The culture medium has been optimized for osmo-tolerant yeast growth and has been tested and validated in comparison to conventional culture media. The invention is ready for industrial use. On behalf of the University of Applied Sciences Ostwestfalen-Lippe, PROvendis offers access to rights for commercial use as well as the opportunity for further codevelopment. In case of interest we will be pleased to inform you about the patent status. Relevant Publication Colombie S, Latrille E, Sablayrolles JM. Online estimation of assimilable nitrogen by electrical conductivity measurement during alcoholic fermentation in enological conditions. J. Biosci. Bioeng. 2007; 103(3): 229–35. Schnierda T, Bauer FF, Divol B, van Rensburg E, Görgens JF. Optimization of carbon and nitrogen medium components for biomass production using non-Saccharomyces wine yeasts. Letters Applied Microbiol. 2014; 58(5), 478–85. An invention of the University of Applied Sciences Ostwestfalen-Lippe.





CPAP-tubulin inhibitors Inhibition of CPAP-tubulin interaction in cancer therapy Invention Centrosomes are major microtubule organizing centers in mammalian cells, which play a pivotal role in mitosis. Centrosome amplification is a hallmark of human cancers that can trigger cancer cell invasion. To survive, cancer cells cluster extra centrosomes to achieve pseudo-bipolar division. The invention aims to prevent clustering of extra centrosomes by prematurely activating centrosomes to induce microtubule nucleation before mitotic onset. Tubulin, by interacting with the centrosomal protein CPAP, negatively regulates CPAP-dependent pericentriolar material recruitment and concurrently microtubule nucleation. Screening for compounds that perturb CPAP-tubulin interaction led to the identification of novel compounds, which selectively bind at the CPAP binding site of tubulin. These compounds prematurely activate extra centrosomes to nucleate microtubules causing cancer cells to undergo centrosome declustering, multipolar mitosis, prolonged mitotic arrest and cell death. 3D-organotypic invasive assays reveal those compounds to have broad antiSchematic overview of centrosome activation strategy invasive activity against various cancers including tyrosine-kinase inhibitor (TKI)-resistant EGFR- and KRAS-mutant non-small cell lung cancers. Moreover, those compounds have been shown to impair in vivo growth of xenograft tumors in nude mice. Therefore, cancer cells are vulnerable to extra centrosomal activation, which may serve as a novel general approach to target various cancers including drug resistant cancers.

Competitive Advantages Novel target in cancer therapy First-in-class compounds Therapy option of drug resistant cancers

Commercial Opportunities Novel compounds are offered for licensing. Current Status A PCT-application is pending. Relevant Publications Mariappan, A., et al. (2017) Premature activation of extra centrosomes by a CPAPtubulin inhibitor selectively prevents cancer cellular proliferation (under review in Nature Chemical Biology) Zheng, X., et al. (2016) Molecular basis for CPAP-tubulin interaction in controlling centriolar and ciliary length. Nat Commun.7: 11874. Gabriel, E., et al. (2016) CPAP promotes timely cilium disassembly to maintain neural progenitor pool. EMBO J. 35: 803-19

Contact: Ref. No. 4392 Prof. Dr. Frank Entschladen PROvendis GmbH Schlossstraße 11-15 45468 Muelheim an der Ruhr Germany

An invention of the University of Cologne and the Helmholtz Center Munich.


Tel.: Fax: E-Mail: Web:


CAAI - Covalent-allosteric AKT inhibitors Inhibitors of the AKT pathway with a new mode of binding Invention The development of new drugs in oncology has shifted from unspecific cytotoxic drugs to highly specific substances with known targets and modes of action. A prominent group of these target specific cancer drugs are the kinase inhibitors. The invented substances are inhibitors of the kinase AKT which is involved in several pathways regulating cell functions in cancer, e.g. survival and proliferation. The particular novelty of the invented compounds is based on their combined covalent-allosteric binding mode. These are first-in-class modulators of AKT with a novel mode of inhibition. Covalent-allosteric inhibitors show extended drug-target residence times.

Competitive Advantages AKT inhibitors with a new mode of action The inhibitors bind AKT irreversibly and specifically with highest affinity

Covalent-allosteric inhibitors (green) binding to the interface of the pleckstrin homology (PH) and the kinase domain, thereby keeping AKT in its enzymatically inactive conformation (taken from Weisner et al., DOI: 10.1002/anie.201502142R1).

Commercial Opportunities AKT is a serine/threonine kinase and oncogene that has already been identified and addressed as a target in cancer therapy by several pharma companies. The invented substances are of high interest for any pharma company with an oncology pipeline and are of special advantage for those who seek to improve, broaden or supplement their kinase inhibitor portfolio. Current Status Binding specificity as well as an IC50 of 0.2 nM for the most promising compound have been determined by in vitro experiments so far. On behalf of the Technical University (TU) of Dortmund, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. In case of interest we will be pleased to inform you about the patent status. Relevant Publications Weisner, J., et al. (2015) Covalent-allosteric kinase inhibitors. Angewandte Chemie 54(35): 10313-6 Vivanco, I., et al. (2014) A kinase-independent function of AKT promotes cancer cell survival. eLife 31: 3. Barf, T. & Kaptein, A. (2012) Irreversible protein kinase inhibitors: balancing the benefits and risks. J. Med. Chem. 55: 6243-62. Hers, I., et al. (2011) Akt signaling in health and disease. Cell. Signal. 23: 1515-27. Garcia-Echeverria, C. & Sellers, W.R. (2008) Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27: 5511-26. An invention of the Technical University of Dortmund.

Contact: Ref. No. 4410 Prof. Dr. Frank Entschladen PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany




Anti-TOSO CAR T Cells Highly selective immunotherapeutic approach to CLL treatment Background Cancer-immunotherapy is currently gaining interest thanks to novel genetic engineering technologies. The most promising approach is the chimeric antigen receptor (CAR) technique for redirecting hereby modified T cells against cancer-associated antigens. TOSO (also known as Faim 3) is a type I transmembrane protein that is involved in Fasinduced apoptosis. It is overexpressed on chronic lymphatic leukemia (CLL) cells, whereas the level of expression is correlated with the aggressiveness of the disease. In contrast, TOSO is only weakly expressed on normal lymphocytes. This expression profile qualifies TOSO as target antigen for immunotherapeutic anti-leukemia approaches by means of CAR T cells. Invention The herein presented CAR constitutes of a B cell-derived single chain antibody fragment (scFv) directed against TOSO. This ectodomain is fused with a costimulatory CD28 T cell activation domain, finally followed by a CD3ζ domain. The receptor is introduced into allogenic or autologous peripheral blood T cells by retroviral gene transfer.

Competitive Advantages Novel immunotherapeutic approach of the CAR T cell technology High selectivity for CLL cells with low adverse effects on normal cells Improved alternative approach for B-CLL treatment in comparison to anti-CD19 CAR T cells

Cell-based assays show high killing specificity of the anti-TOSO CAR T cells against CLL cells, whereas normal B cells remain intact. The discrimination is strongly improved in comparison to previously engineered anti-CD19 CAR T cells that are currently used in clinical studies. Commercial Opportunities The described anti-TOSO CAR T cells have a strongly improved selectivity of target cell killing. The reduction of adverse effects on normal cells provides a competitive advantage against all other CAR T cell approaches that are currently on the market. Current Status Functional data have been generated in cell-based assays with allogenic and autologous CAR T cells showing selectivity and efficiency of target cell killing activity (original data available on a confidential basis). A European patent application and a US patent application are pending. On behalf of the University of Cologne, PROvendis offers a patent license as well as a research collaboration with licensing option. Relevant Publications Faitschuk, E., et al. (2016) Chimeric antigen receptor T cells targeting Fc µ receptor selectively eliminate CLL cells while sparing healthy B cells. Blood 128: 1711-1722. Chmielewski, M., et al. (2013) Antigen-Specific T-Cell Activation Independently of the MHC: Chimeric Antigen Receptor-Redirected T Cells. Front. Immunol. 4: 371. Cheadle, E.J., et al. (2012) Chimeric antigen receptors for T-cell based therapy. Methods Mol. Biol. 907: 645-66. An invention of University of Cologne.




TiDEC (OligoThymidine-initiated-DNA-Encoded) Enabling chemistry for DNA-encoded screening libraries Chemistry Invention The need of new drugs is high in many medical indications, for instance in oncology, and infectious diseases. However, the success rate of drug research and development has declined to unsustainable levels. As conventional high throughput screening of large compound libraries often fails to deliver compounds, the de novo identification of bioactive small molecules represents a significant hurdle in drug research. DNAencoded small molecule libraries (DELs) have emerged as a cost-efficient, validated screening method of very large chemical space. These libraries consist of DNA-tagged small molecules. They can be pooled and screened on drug targets by affinity-based selection. Bioactive compounds are efficiently identified by DNA sequencing. Current library synthesis strategies, though, can make use of only a very limited set of chemical reactions, thus delivering large numbers but low diversity. Notably, access to encoded libraries of drug-like heterocycles is currently lacking. TiDEC addresses this severe limitation. TiDEC exploits the stability of oligopyrimidine adapter sequences to a large variety of reaction conditions, and reagents such as transition metal catalysts and acidic organocatalysts. Thus, TiDEC enables efficient access to diverse heterocyclic structures conjugated to oligopyrimidine sequences from simple and readily available starting TiDEC enables access to encoded screening libraries materials by a large variety of based on natural product- and drug-derived core These oligonucleotidestructures. These are efficiently screened on disease catalysts. relevant proteins of interest (POI) by selection. Protein heterocycle conjugates are readily binders are identified by DNA sequencing. ligated to coding DNA sequences. Combinatorial mix-and-split synthesis yielded a proof-of-concept screening library counting 15,000 molecules: tiDEL, oligothymidine-initiated DNA-Encoded Library. The tiDEL is based on biologically relevant heterocyclic core structures that are found in natural products, drug candidates and approved drugs. It is currently expanded to diverse classes of drug-like structures comprising heterocycles and macrocycles.

Competitive Advantages Handling of large encoded compound screening libraries: tiDELs Access to biologically relevant chemical space that is inaccessible by conventional DNA-encoded libraries: encoded natural product- and drug-derived compound classes Efficient and rapid screening on target proteins by selection Extremely reduced costs in comparison to conventional high-throughput screening Accelerated identification of starting points for drug development programs

Commercial Opportunities The TIDEC platform technology and the tiDEL screening library are offered to pharmacompanies, biotech companies, and non-profit organizations for drug identification and development programs. On behalf of the Technical University of Dortmund, PROvendis offers a patent license as well as a research collaboration with licensing option. Current Status TiDEC is currently used to synthesize DNA-encoded screening libraries (tiDELs), and these are provided for target-based screening on disease-relevant proteins. In case of interest we are pleased to inform you about the patent status. An invention of the Technical University of Dortmund (TUDo).

PROvendis GmbH offers IP services for universities, research facilities and technology-oriented companies. PROvendis recommends: www.inventionstore.de - Free e-mail service to access the latest IP-protected top technologies.

Contact: Ref. No. 4452 Prof. Dr. Frank Entschladen PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany Phone: Fax: E-Mail: Web:


Peripherally acting NMDAR Antagonists as new Antidiabetic Medication Novel anti-diabetic compounds optimized for exhibiting a high safety profile Invention According to the International Diabetes Federation (IDF), diabetes affects close to 400 million people worldwide and caused 500 billion Euros in health expenditure in 2013. Most of the costs are associated with the treatment of subsequent disorders that, to a large extent, are caused by chronic hyperglycaemia. Diabetes is progressive with worsening hyperglycaemia likely caused by progressive decline of pancreatic beta cells, which cannot be stopped by current medication.

Competitive Advantages Novel approach for reduction of blood sugar levels without risk of Hypoglycaemia Preclinical evidence of protection of insulin-secreting beta cells Possible prevention or delay of diabetes progression Good results with starting substance in two clinical studies on human type 2 diabetics (Phase IIa) Possible enhanced safety and reduced adverse effects compared to the OTC drug dextromethorphan

Reduced blood brain barrier (BBB) permeability of a dextrorphan (DXO)-derived compound compared to DXO (left side). Significant reduction of postprandial blood glucose concentrations upon application of this DXO-derived compound to mice during a glucose tolerance test (right side).

In preclinical and clinical trials, the NMDA receptor antagonist dextrorphan (DXO) and its prodrug dextromethorphan have been shown to harbor antidiabetic properties (Marquard et al., Nat Med 2015). In addition, DXO was shown to protect mouse and human pancreatic beta cells from cell death during a diabetogenic setting. DXO is well tolerated and sold as over-the-counter (OTC) medication for more than 50 years. However, adverse events are observed, which are likely caused by the action of DXO on the central nervous system (CNS). Here, the scientists developed DXOderivatives that do not efficiently pass the blood brain barrier (BBB), and thus should cause fewer adverse effects on the CNS, but maintain their antidiabetic properties. Therefore, the derivatives might maintain the good safety profile and antidiabetic properties of its starting substance dextrorphan, but with fewer adverse effects. The inventors now aim to demonstrate the expected novel clinical benefit in clinical studies. As suggested by recent phase 2a clinical trials using DXO, also the novel compounds may be combined with existing antidiabetic drugs exerting a synergistic effect (Marquard et al., Diabetes Obes Metab 2015). Commercial Opportunities On behalf of the Heinrich-Heine-University of Duesseldorf, PROvendis is offering access for commercial use in terms of a license as well as research collaboration to innovative companies. Current Status A priority patent application has been filed for the novel compounds and their use in treating diabetes (patent applications covering the use of DXO for treating diabetes as shown by the inventors laboratory are also pending). An invention of the Heinrich-Heine-University of Duesseldorf (Uni Düsseldorf).


Contact: Ref. No. 4501 Dr. Juergen Walkenhorst PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany Phone: Fax: E-Mail: Web:


Optical Clearing Non-harmful optical clearing of biological samples Invention The latest developments in microscopy and imaging techniques (e.g. light-sheet microscopy, two-photon microscopy, optical projection tomography) facilitate the display of large three-dimensional tissue samples. Refractive index matching of the biological sample with the surrounding medium is an established method for optical clearing of entire organs, whereas the key challenge is the preservation of fluorescence staining that has been performed beforehand. However, all of the currently established protocols are based on the use of harmful chemicals (ref. Richardson & Lichtman).

Competitive Advantages First and only protocol for optical clearing that completely dispenses with harmful chemicals Clearing process fully preserves fluorescence-staining for high quality imaging Cheap and easy to use method

The herewith presented invention substitutes these harmful chemicals by a Mouse kidney after optical clearing, CD31-AL647 non-harmful substance with comparable staining in red results of fluorescence preservation. By means of this substance, an easy to use protocol has been established that allows a safe optical clearing of biological samples for microscopy even by unpracticed laboratory personnel. Commercial Opportunities There is currently a strongly growing need for methods and chemicals for the preparation of large biological samples for three-dimensional imaging. The invented substance and protocol are of high interest for any supplier or company in the field of microscopy and imaging techniques. The unique selling proposition is that the herewith offered invention constitutes the sole methodology optical clearing of biological samples without use of harmful chemicals combined with high quality fluorescence preservation. Current Status The invented substance and protocol is routinely used by the inventors and has thus been shown to be robust for general laboratory usage. On behalf of the University of Duisburg and Essen, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development, e.g. of a kit. In case of interest we will be pleased to inform you about the patent status. Relevant Publications Richardson, D.S. & Lichtman, J.W. (2015) Clarifying tissue clearing. Cell 162(2): 24657. Ertürk, A., et al. (2012) Three-dimensional imaging of solvent-cleared organs using 3DISCO. Nat. Protoc. 7(11): 1983-95. Hama, H., et al. (2011) Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain. Nat. Neurosci. 14(11): 1481-8. An invention of the University Duisburg Essen.




A Novel Marker for Brown Fat Activity Exosomal microRNA-92 in serum reflects brown fat activity Invention Brown adipose tissue (BAT) is a special type of fat, which regulates the body temperature by fatty acid oxidation. High BAT activity is involved in leanness, whereas obesity comes along with a reduced activity of BAT. Therefore, the measurement of BAT activity is an important diagnostic parameter for various weight-related pathological conditions including diabetes, but was so far a complicated matter to measure. The current procedure utilizes glucose-based, radioactive tracer, positron-emission-tomographie combined with computertomography and requires pretreatment of the patients by cold exposure. The present invention is a technology that significantly simplifies the measurement of BAT by PCR-based quantification of exosomal microRNA-92a in serum. Exosomal miR-92a levels inversely correlate with BAT activity. This novel method is as the first of its PET-CT of a subject with BAT activity and low miR-92a kind qualified to routinely measure levels (left), compared to a subject with low BAT activity the BAT activity in large cohorts of and high miR-92a levels (right) patients.

Competitive Advantages Novel and simple method for the measurement of brown adipose tissue activity First of its kind method for the routine clinical use in large patient cohorts Functional screening tool for the development of drugs for weight-related and metabolic diseases

Commercial Opportunities The measurement of BAT activity is not only important in the diagnosis and treatment of weight-related diseases, but is also a screening tool for the development of drugs that regulate the BAT activity. Such drugs are of use in pathological leanness (e.g. cachexia), obesity and other metabolic diseases. Current Status The invention has been validated by studies in mice and man. On behalf of the University of Bonn, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. In case of interest we will be pleased to inform you about the patent status. Relevant Publication Chen J, Buyel JJ, Hanssen MJW, Siegel F, Pan R, Naumann J, Schell M, van der Lans A, Schlein C, Froehlich H, Heeren J, Virtanen KA, van Marken Lichtenbelt W, Pfeifer A. Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nature Communications; DOI: 10.1038/ncomms11420 An invention of the University of Bonn.

Contact: Ref. No. 4527 Prof. Dr. Frank Entschladen PROvendis GmbH Schlossstr. 11-15 45468 Muelheim an der Ruhr Germany




AstaLys Bacterial production of Lysin, Astaxanthin and other Carotenoids Invention L-glutamate and L-lysine already produced with the GRAS organism C. glutamicum in the million-ton scale every year for the food and feed markets with a market value expected to reach US$ 15.5 billion for glutamate and US$ 5.9 billion for lysine. Carotenoids, the colourful representatives of tetraterpenoids act as antioxidants and are therefore attractive components for pharmaceutical and cosmetic applications. Especially the annual demand of the feed additive astaxanthin is estimated to be 130 tons e.g. for aquaculture and poultry breeding with an expected value of US$ 423 million in 2019. The present invention provides a fermentative method of producing astaxanthin in conjunction with lysine via recombinant gram-positive bacteria.

The orange ring surrounding Grand Prismatic Spring is due to carotenoid molecules, produced by mats of algae and bacteria.

Competitive Advantages Renewable source for high value carotenoids New biosynthetic route Besides lysine also different carotenoids, astaxanthin or decaprenoxanthin reachable Simultaneous production of amino acids, carotenoids and astaxanthin Only one fermentation step for multiple target compounds Simple extraction of products from C. glutamicum cells

For industrial fermentations usage of different carbon sources which are available in high quantities at low prices are possible, while competition with the food and feed resources can be avoided.

Moreover also high value compounds including the sesquiterpenoid valencene, the C40 carotenoids β-carotene and astaxanthin can be synthesised with this microorganism. Commercial Opportunities Chemical industry is facing an increasing demand on food and feed composites. Therefore, in seek for alternative and renewable sources, bacterial fermentation has become into focus in several chemical production areas. The offered invention provides such a source for astaxanthin, lysin and other carotenoid production. Current Status Simultaneous production of lysine, astaxanthin and other carotenoids has been tested in a laboratory scale. This production of C40/C50 carotenoids and the amino acid lysine in one cultivation is possible with the strains used and constructed in this invention. Upscaling for industrial usage in terms of fermentation conditions needs to be established. On behalf of the University of Bielefeld, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. In case of interest we will be pleased to inform you about the patent status. Relevant Publications Henke, N.A., et al. (2017) Carotenoid production by Corynebacterium: The workhorse of industrial amino acid production as host for production of a broad spectrum of C40 and C50 carotenoids. In: Carotenoids. Cvetković D (Ed); 1st ed. Rijeka, Croatia: Chapter 10: 159-173. Henke, N.A., et al. (2016) Production of the marine carotenoid astaxanthin by metabolically engineered Corynebacterium glutamicum. Marine Drugs. 14(7): 124 An invention of the University of Bielefeld.




Liquid biopsy based early breast cancer detection SPAG6, NKX2-6, PER1 promoter methylation biomarker panel Invention Early breast cancer detection, most favorably in a pre-cancerous (in situ) state is critical for the course of the disease and its outcome. Currently, mammography screening is the standard method of medical prevention. However, the compliance among women invited for mammography is low ranging from merely 20 to 89 percent depending on country and age group. Similar to colorectal cancer prevention by coloscopy, a much easier and less stressful examination method might find stronger compliance.

Competitive Advantages Blood-based easy to perform pre-screen to current standard mammography Likelihood of much higher compliance of eligible women and consequently increasing screening participation

Researchers of the University Medical Center of Aachen have identified biomarkers, which are suitable for detection of early breast cancer and its precancerous stages in blood, Analysis of 3-gene biomarker performance in patients (blood based on the measurement of both samples) with ductal carcinoma in situ (DCIS) as compared to grade and intensity of CpG normal donors (controls). Sensitivity reaches 70% at 80% promoter methylation of i.e. the specificity. genes SPAG6, NKX2-6 and PER1. A combination of two genes or the inclusion of other genes (e.g. DKK3 or ITIH5) may also apply. It is very likely that a blood-based test would increase compliance of women to medical prevention programs of breast cancer. In addition, this concept may allow to broaden prevention to elderly women (>70 years) who currently are not invited to mammography screening. Commercial Opportunities In April 2016, a blood-based early detection system for colon cancer has been approved by the FDA. The inventive biomarkers could be applied in an analogous way for breast cancer detection. Both tests have similar sensitivity and specificity, suggesting a good chance of the present test also to be approved in a similar setting. Notably, a key argument for the approval by the FDA has been the likelihood of increased acceptance by the relevant population thus reinforcing screening participation. On behalf of the University of Aachen (RWTH Aachen), PROvendis offers a patent license as well as a research collaboration with licensing option. Current Status The initial study included blood samples of 130 age-matched donors that comprised early breast cancer stages (T1N0M0), non-invasive DCIS (ductal carcinoma in situ) and healthy controls. The methylation intensity was measured by means of pyrosequencing. Currently, an additional 400 blood samples are being analyzed. In parallel, the inventors are establishing a NGS based protocol for methylation detection to improve the technical sensitivity. In case of interest we are pleased to inform you about the patent status. An invention of the University Medical Center of Aachen (UKA).




Multiphase Loop Reactor New architecture forLoop a bioreactor Multiphase Reactor Invention Bioreactors and fermenters are often used in a multiphase design. The mixture of the phases leads to the development of foams and emulsions that cannot be separated afterwards. Consequently, the in-situ product extraction is a major challenge of such multiphase systems. The herein presented new architecture of a bioreactor basically consists of an inner and outer cylinder, whereas the disperse phases are added in either one of the cylinders. The two key elements of the design are baffles on the upper end of the inner cylinder, which prevent a mixture of the disperse phases, in combination with a collection device placed on top of the inner cylinder. This design allows continuous product extraction by means of biocompatible solvents and a simultaneous oxygen supply. Moreover, the addition of both disperse phases and the regulation of the loop flow can be adapted continuously and anytime through steering of the Left: Outline of the water flow Right: Sketch of the reactor with the rate averaged two disperse phases volume flow rates. With this over time invention three or four phases can be brought together intensively with only small transport hindrances while the two additional disperse phases are spatially separated.

Competitive Advantages No emulsification due to the spatial separation of the disperse phases Continuous product extraction by means of biocompatible solvents In-situ product extraction or substrate provision with a disperse phase is operable in co-current or reverse flow

In summary, this new architecture of a multiphase loop reactor overcomes several hurdles of current designs of loop reactors and other approaches such as membranebased systems. Commercial Opportunities On behalf of the University of Aachen (RWTH Aachen), PROvendis offers access to rights for commercial use as well as the opportunity for further co-development and evaluation. The design of the reactor and the requested fluid dynamics can be assisted by the inventors. Current Status A functional prototype has been built, and a European priority patent application has been filed so far.


An invention of the University of Aachen (RWTH Aachen).




Vim3-based Fertility Diagnosis Vimentin 3 as a new marker for proof of sperm quality Invention Infertility affects an estimated 15 percent of couples globally, amounting to 48.5 million couples. Forty percent of cases are linked to men. An important factor of male infertility is an insufficient quality of sperms due to abnormal shape and/or motility. Currently, the quality of the sperm cells is assessed in a spermiogram, analyzing their morphology, concentration and motility. However, the results may vary due to manual analysis, so that the test must be repeated at least twice. In addition, spermiograms need to be performed by certified laboratories and accordingly educated persons. Therefore, there is a strong need for more reliable and standardized diagnostic methods for the assessment of sperm quality.

Competitive Advantages Vim3 staining of sperm cells works as an easy and reliable initial test for sperm quality Vim3 staining overcomes variations of manually assessed sperm morphology and motility in spermiograms May be offered as test to be performed at home and may thus find higher compliance than current lab-based sperm analysis

Researchers of the University Hospital of Cologne have identified Vimentin 3 (Vim3) as a novel marker for the diagnosis of sperm quality: the expression of Immunofluorescence-staining of sperms with an anti-Vim3 Vim3 is significantly higher in antibody and a secondary FITC-conjugated antibody (left). ejaculates from persons with Counterstaining with DAPI (middle) and merged staining normozoospermia, whereas in (right). Normal sperms (upper panel) were compared with ejaculates from patients with patients suffering from azoospermia (middle panel), and OAT oligo-astheno-teratozoo-spermia syndrome (lower panel). (OAT) syndrome and azoospermia the expression of Vim3 is significantly decreased (please see figure). Furthermore, in OAT syndrome cells, staining is less intensive but is also found in the head and tail region, as compared to a predominant staining of neck region in normal sperm cells. In additional advantage of the invention is the fact that conventional spermiograms can only be performed with ejaculates not older than one hour, which requires the patients to show up in the laboratory and thus increases psychological pressure. Vim3 staining may offer access to sperm quality analysis of ejaculates won at home or maybe even home-based test systems. In addition, assessment of fertility and sperm quality is not only important in humans, but also applies to veterinary medicine in terms of horse and other animal breeding. Commercial Opportunities The technology is offered for licensing and further development as diagonstic test. Current Status The researcher plan to conduct a large cohort study for verification of usability. In case of interest we are pleased to inform you about the patent status. An invention of the University Hospital of Cologne


Contact: Ref. No. 4631 Dipl.-Biol. Kordula Kruber PROvendis GmbH Schlossstraße 11-15 45468 Mülheim an der Ruhr Germany Tel.: Fax: E-Mail: Web:


Enantiomerically pure chiral N-Acyl-α-aminonitriles Method for chemical production of enantiomerically pure chiral N-Acyl-α-aminonitriles or N-Sulfonyl-α-aminonitriles Invention Enantiomerically pure N-acyl-α-aminonitriles gained these days interest in the pharmaceutical industry since a range of recently developed pharmaceuticals are based on this product class. Prominent examples are Vildagliptin®, Saxagliptin® or NVP-DPP-728, which are active pharmaceutical ingredients against diabetes type II and at least two of them are successful already on the market. α Important precursors of these so-called “gliptins” are synthesized via multiple phase reactions as state of the art and typical strategies towards such types of molecules are based on toxic reagents such as cyanides or Vilsmeier reagents. Furthermore, the production of the latter one includes toxic precursors like oxalylchloride and phosphorylchloride. Currently, e.g. the synthesis of Vildagliptin® starts from an enantiomerically pure amino acid (here L-proline), which is transformed first into an amide derivative and then via Vilsmeier reagent into the nitrile product (process by Novartis).

Competitive Advantages Effective chemical production process of N-acyl-αaminonitriles or N-sulfonyl-αaminonitrilesFirst-in-class compounds Enantiomerically pure Gliptin derivatives New optimized chemocatalytic route New approach for important precursors, e.g., of Vildagliptin® or Saxagliptin® Starting material easy accessible and avoiding cyanide or Vilsmeier reagents as toxic reagents

The present invention focuses on a production process which avoids the need of such toxic reagents. In addition, it has the advantage that the reaction can be conducted under mild conditions. The innovative reaction is also using amino acids as precursors but they are then transformed via an aldehyde intermediate into its corresponding aldoxime, which subsequently is transformed via a chemocatalytic dehydration to the nitrile target molecule. A selected product is a proline derived nitrile as shown below:

Commercial Opportunities The described technology enables a safe, fast and competitive chemical production of specific N-acyl-α-aminonitriles or N-sulfonyl-α-aminonitriles, serving as intermediates for the synthesis of, e.g., Vildagliptin®. On behalf of the Bielefeld University, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. Current Status In case of interest we are pleased to inform you about the current patent status. Relevant Publication In preparation An invention of Bielefeld University.




Treatment of MRSA infections Bis-indol-alcaloids for the treatment of MRSA infections Invention Infection with methicillin-resistant Staphylococcus aureus (MRSA) is a major health problem in hospitals, long-term care facilities, and community medicine settings worldwide. There are new compounds in development for the treatment of MRSA. Unfortunately, there is a significant risk that new antibiotics targeting pathogen-specific proteins will exert the sort of selective pressure on the pathogen that ultimately leads to antibiotic resistance. Consequently, there is still a medical need for new antibiotics targeting MRSA.

Staphylococcus aureus

Competitive Advantages High potency Ease of synthetical access

The inventors of the present invention identified derivatives of the bis-indol-compounds hyrtinadine A and allocasine A as being active against MRSA. The minimum inhibitory concentration of compounds is in the submicromolar range. The strong bactericidal effect seems to suppress the formation of any resistances.

Next to its potency, easy synthetical access is a key feature of the compounds of the present invention. The compounds are accessible by a one-pot synthesis. The molecular scaffold may easily be modified in order to develop further derivatives. Commercial Opportunities On behalf of University of Düsseldorf, PROvendis offers the invention for licensing. Current Status A European priority application has been filed. Relevant Publication Tasch, B.O. et al. (2013) Masuda borylation-Suzuki coupling (MBSC) sequence of vinylhalides and its application in a one-pot synthesis of 3,4-biarylpyrazoles. Org.Biomol. Chem. 11(36): 6113-8 An invention of University of Düsseldorf

Contact: Ref. No. 4686 16 Dr. Jürgen Walkenhorst PROvendis GmbH Schlossstraße 11-15 45468 Muelheim an der Ruhr Germany




CEACAM1 antibodies for anti-viral therapy Anti-CEACAM1 antibodies promote the anti-viral T cell response Invention Cytotoxic CD8-positive T cells constitute the crucial leukocyte subpopulation for a cellular response against viral infection. Since only very few direct anti-viral therapeutics are available, the stimulation of an efficient and specific immune response against a viral infection is a valid alternative or additional therapeutic approach. The first of such strategies has been established by use of high doses of interferon, which however has a high risk of adverse reactions of the immune system, and low response rates. Therefore, it is mandatory to search for further immune stimulatory strategies that more specifically induce an anti-viral T cell repsonse.

Tetramer+ CD8+ T cells (per l of Blood)

1500

Isotype-muIgG1

*

-huCeacam1-muIgG1

1000 P = 0.059 500

0 GP33

NP396

Competitive Advantages  Complementary anti-viral therapy option  Applies to a broad range of viruses  Specific immune response against specific viruses

The herein described approach is based on a antibody-mediated stimulation of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which activates early parts of both the B cell and T cell receptor-induced signal transduction.

The researchers have shown on the example of the lymphocytic choriomeningitis virus (LCMV) that these antibodies stimulate the activation and expansion of virus specific cytotoxic T cells, which comes along with a reduced virus load in serum and organs of mice. In vitro studies confirmed efficacy also against influenza virus and cytomegalovirus. Mice expressing human Ceacam1 instead of murine Ceacam1 (huCeacam1+/+ × muCeacam1–/–) were treated with αhuCeacam1-mIgG1 or Isotype-mIgG1 on days -1 and day 3. Mice were infected with 2x104 PFU LCMV-Docile. Virus specific Tet-GP33+ and Tet-NP396+ CD8+ T cell numbers were analyzed in the blood on day 8.

Commercial Opportunities The monoclonal, humanized anti-CEACAM1 antibodies are offered for licensing and further therapeutic development. Current Status The researcher have conducted experiments with a LMCV-specific immune response mouse model. Further proof of principle with the humanized variant of the antibody has been provided by means of humanized CEACAM1 mice. The antibody activates human virus-specific CD8+ T cells in vitro. In case of interest we are pleased to inform you about the patent status. Relevant Publications Khairnar, V., et al. (2015) CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production. Nature Communications 6: 6217. An invention of the University of Duisburg and Essen.


Contact: Ref. No. 4782 Kordula Kruber PROvendis GmbH Schlossstraße 11-15 45468 Muelheim an der Ruhr Germany Tel.: Fax: E-Mail: Web:


Optimal Biogas Generation from Algae Fermentation Method for a biotechnological production of biogas via bacterial fermentation of low-protein microalgae biomass Invention The production of biogas from algae biomass has been of interest for quite a long time. Microalgae is an interesting biosystem as it is really fast growing and has a high biomass productivity which is about ten times higher than conventional agriculture crops.

Competitive Advantages Effective production process of biogas through continuous fermentation of microalgae

But until today, several obstacles like inefficient degradation and low C/N ratio limit the applicability of algae biomass for a large scale biogas production process. The present invention overcomes most of the technical and biological difficulties and establishes now an improved cultivation and fermentation process for microalgae biomass.

New optimized cultivation procedure (low-N) for fertilizer cost reduction

Fig. 1 Overview of microalgae cultivation and fermentation procedure

The present invention provides a simple and effective microalgae cultivation method (under nitrogen limiting conditions) for subsequent use of this biomass as mono-substrate for a highly efficient and stable anaerobic fermentation in continuous long-term mode (Fig.1).

Efficient energy source

No pretreatment of biomass needed Methane content (61%) in biogas, higher than plant material Highly efficient fermentation to biogas / methane without inhibition risks

The continuous fermentation of algae biomass, generated under replete-N and low-N culture conditions, was performed under constant hydraulic retention time (HRT 20 days) and increasing organic loading rate. In contrast to conventional biomass (replete-N BM), the biogas as well as methane productivity of the low-N biomass (low-N BM) reactor was constantly high (see Fig. 2), with biomass to methane energy conversion efficiency of 84%, which is close to the theoretical maximum without any pretreatment.

Fig. 2 Biogas and methane productivity via anaerobic fermentation of algal biomass in continuous mode.

Commercial Opportunities The described technology enables the fast and competitive production of biogas in a continuous biotechnological process in industrial scale. On behalf of the University of Bielefeld, PROvendis offers access to rights for commercial use as well as the opportunity for further co-development. Current Status In case of interest we are pleased to inform you about the current patent status. Relevant Publication Klassen V. et al. Efficiency and biotechnological aspects of biogas production from microalgal substrates. J. Biotechnol. 2016; Sep 20; 234:7-26. doi: 10.1016/j.jbiotec.2016.07.015 An invention of University of Bielefeld.




Ultrastiff Hydrogels Ultrastiff and tough hydrogels for membranes and bone replacement Invention Today Hydrogels are widely used in membranes e.g. in seawater desalination plants. Conventional hydrogels, however, have very low stiffness and therefore have to be embedded in supporting structures. This is a complicated process and prevents the membranes from being cleaned when they are clogged with microorganisms. By means of a special production process, it has now been possible for the first time to produce ultrastiff (up to 400 MPa) and very tough hydrogels, which do not require a supporting structure. The mechanical and optical properties are specifically adjustable. The production process is based on a biomineralization in which enzymes, so-called phosphatases, are extremely finely distributed in the material and homogeneously catalyze the structure formation process. The mineralization occurs directly in the material a) Hydrogel before mineralisation itself. This results in a solid and well-ordered calcium phosphate nanostructure, which forms a stable network and is responsible for the special properties.

Competitive Advantages Ultrastiff Hydrogel (up to 400 MPa) Very tough Mechanical properties adjustable Optical properties adjustable (from white to transparent) No need for supporting structures

Commercial Opportunities Possible applications are semipermeable membranes for water treatment and desalination plants as well as for nanofiltration and for proton exchangers in fuel cells, batteries and electrodes. It is also possible to use the hydrogels as an replacement material for skin, cartilage or bones, whereby the properties and the structure of the new b) Hydrogel after mineralisation hydrogels can be adjust very similar to those of the natural substances. The materials are biocompatible and show good cell adhesion. Finally, the hydrogels can also be used as drug delivery systems. Current Status An European patent application for this invention has been filed at the end of 2016. Extensive experimental data on the invention are available. On behalf of the TU Dortmund, PROvendis is seeking a licensee for the new technology. Relevant Publication N. Rauner et al.: “Enzymatic mineralization generates ultrastiff and tough hydrogels with tunable mechanics”, Nature 2017, doi:10.1038/nature21392. An invention of the Technical University of Dortmund.


Contact: Ref. Nr. 4864 Dr. Andreas Wagener PROvendis GmbH Schloßstraße 11-15 45468 Muelheim an der Ruhr Germany Tel.: Fax: E-Mail: Web:

+49 (0) 208-94105-38 +49 (0) 208 94 105 50 [email protected] www.provendis.info

Novel Anti-Tuberculosis Compounds Novel Mycobacterium tuberculosis thioredoxin reductase inhibitors with antimycobacterial activity in infected macrophages Invention The resurgence of tuberculosis, caused primarily by Mycobacterium tuberculosis (Mtb), and the appearance of multi‐drug and extensively drug resistant Mtb strains strengthen the need for new drugs with alternative modes of action. The interaction between the mycobacterial thioredoxin reductase (TrxR) and its substrate thioredoxin (Trx) is a promising new drug target for the treatment of tuberculosis, since Mtb lacks the common glutathione system and the mycobacterial TrxR shows a substantial difference in sequence, mechanism and structure to human TrxRs. It was shown that TrxR is essential for thiol redox homeostasis and genetic inactivation in vivo eradicates Mtb during acute and chronic mouse infections (Lin et al., PLoS Pathog. 2016).

Competitive Advantages Novel class of compounds that inhibit a novel target with potential to overcome resistance problems of M. tuberculosis to other drugs Viability of infected macrophages is not affected Increased bioactivity by optimized permeability through the cell wall of M. tuberculosis

In order to further improve the bioactivity of promising compounds, researchers of the TU Dortmund University have focused on optimizing the physico-chemical properties that are important for permeability, since M. tuberculosis shows an unusual thick and impermeable cell wall. Compounds with improved physicochemical properties with regard to increased permeability and bioactivity were designed. The most promising compound (BE‐068) was also tested on infected human macrophages and showed a clear dose‐dependent activity on mycobacterial growth (upper graph), without affecting macrophage viability (lower graph).

Commercial Opportunities The technology is offered for licensing and further therapeutic development.

Current Status The researcher are preparing the further development towards mice studies to confirm in vivo efficacy, as well as ADME-Tox studies. In case of interest we are pleased to inform you about the patent status. Relevant Publications Koch, O., et al. (2013) Identification of M. tuberculosis thioredoxin reductase inhibitors based on high-throughput docking using constraints J. Med. Chem. 56(12): 4849-59. An invention of the Technical University of Dortmund

Contact: Ref. No. 4941 Prof. Dr. Frank Entschladen PROvendis GmbH Schlossstraße 11-15 45468 Mülheim an der Ruhr Germany




Inhibition of IKK complex Dual inhibition of IκB kinase 1/2 for cancer therapy Invention The NF-κB signaling pathway plays a pivotal role in a broad range of cellular processes including cell proliferation and survival and is tightly linked to diseases such as cancer. The invention provides com-positions comprising IKK1 and IKK2 antagonists for use in medical treatments of proliferative disorders, in particular for the treatment of cancer. Most preferred in context of the invention is a gene editing approach for a targeted simultaneous knockout of the genes of IKK1 and IKK2 in a cell associated with the proliferative disorder. Simultaneous CRISPR/Cas9mediated knockout of IKBKA (IKK1) and IKBKB (IKK2) resulted in cells highly sensitized for programmed cell death (apoptotic/necroptotic) after exposure to tumor necrosis factor (TNF)α. This effect was not observable in single knockouts for either IKK1 or IKK2. Targeting of IKK1 and IKK2 simultaneously, preferably on the genome level, therefore opens up new therapeutic avenues to tackle proliferative disorders such as cancer. Hence, the present methods and compositions provide a means for the selective induction of apoptosis in cells associated with a proliferative disorder, such as tumor cells.

Competitive Advantages Novel gene therapy for cancer Novel screening strategy Therapy option for drugresistant cancers

Commercial Opportunities Novel gene therapy and a novel drug screening concept are offered for licensing. Current Status In case of interest we are pleased to inform you about the patent status. Relevant Publications Slotta, C., et al. CRISPR/Cas9-mediated deficiency of human IKBK1/IKBK2 leads to TNFα-induced programmed cell death. In preparation Slotta, C., et al. (2017) CRISPR/Cas9-mediated knockout of c-REL in HeLa cells results in profound defects of the cell cycle. PLoS ONE 12(8): e0182373 Karin, M., et al. (2002) NF-kappaB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer 2(4): 301-10

Contact: Ref. No. 5028 Prof. Dr. Frank Entschladen PROvendis GmbH Schlossstraße 11-15 45468 Mülheim an der Ruhr Germany

An invention of the University of Bielefeld




BMP-Mimetics A test system to morphogenic mimetics

identify bone protein (BMP)-

Invention Small molecule activators of the Bone Morphogenetic Protein (BMP)-signaling pathway hold promise for many applications in stem cell research such as (cost-)efficient and robust mesodermal differentiation from pluripotent stem cells (e.g., ESCs, iPSCs) or as therapeutics for degenerative bone (and cartilage) diseases (please see relevant publications). In this context, a phenotypic assay in murine embryonic stem cells, designed to combine assets of a high-throughput format with physiological (morphogenetic) relevance was developed to identify BMP-mimetics. A chemical biology approach employing known cardiogenic compounds enabled the characterization of BMP signaling selectivity compared to other develop-mental pathways for the first time in this assay system. Mechanistic as well as technical assay parameters were optimized and allowed pilot-screening of a 1,408 compounds-comprising library. Ten small molecule BMP mimetics were identified and validated via IC50 determination and a set of orthogonal assays. Their utility as chemical tools for stem cell technologies and as regenerative therapeutics will have to be explored in future studies.

Competitive Advantages  Unique, innovative, stem cellbased assay for the identification of BMP-mimetic agents  Ligand-independent BMPmimetic compounds with novel mode-of-action

Commercial Opportunities The test system as well as novel BMP-mimetic compounds are offered for licensing and further biotechnological and/or therapeutic development. Current Status Ready-to-screen assay format for up to 50,000 compounds comprising libraries. In addition, several functionally validated BMP mimetic compounds have been identified, including first profiling of structure-activity relationships by means of medicinal chemistry. A European priority application is pending. Relevant Publications Feng, L., et al. (2016) Discovery of a small-molecule BMP sensitizer for human embryonic stem cell differentiation. Cell Reports 15: 2063-75. Ali, I.H. & Brazil, D.P. (2014) Bone morphogenetic proteins and their antagonists: current and emerging clinical uses. British Journal of Pharmacology 171: 3620-32. An invention of the Technical University of Dortmund and the Ernst-Moritz-Arndt University of Greifswald


Contact: Ref. No. 5063 Prof. Dr. Frank Entschladen PROvendis GmbH Schlossstraße 11-15 45468 Mülheim an der Ruhr Germany Tel.: Fax: E-Mail: Web:
