The group of companies around long-standing Haub business partner Stefan Heinig has held 15.2 percent of Kik so far. HHS Vulnerability Disclosure, Help In the MC38 model, female C57BL/6 mice were inoculated SC with 2×106 MC38 colon carcinoma cells (ATCC). Data are represented as mean±SEM for three donors for CD8+ T cells and NK cells and two donors for γδ T cells. Heinig und Alois Niederstätter, Heft 27: Die Urkunden und Briefe des Österreichischen Staatsarchivs in Wien, Abt. Co-Authors. Stefan Heinig in Schönberg, reviews by real people. To improve PK properties, the TransCon IL-2 β/γ prodrug was created by transiently conjugating a branched 40 kDa mPEG carrier to the receptor-selective IL-2 β/γ via the TransCon linker technology27 (figure 1B). KiK came under pressure by dumping salaries and abusing female workers in Bangladesh and other Third World countries. Pronunciation of Stefan Heinig with 1 audio pronunciation and more for Stefan Heinig. Unter den Gästen war auch Stefans Ex-Frau, die,. It is possible the name you are searching has less than five occurrences per year. We therefore reasoned that specific inhibition of IL-2Rα binding should be achieved by steric hindrance at the IL-2Rα binding interface. Für die Sängerin ein unüberwindbarer Verlust. Search or verify contact lists in minutes with bulk tasks. Accessibility . Get the latest business insights from Dun & Bradstreet. TransCon IL-2 β/γ is a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2. Aldesleukin is rapidly cleared requiring frequent dosing, resulting in high Cmax likely potentiating toxicity. Krieg C, Létourneau S, Pantaleo G, et al.. Stefan Heinig's colleagues are Eric Hayler, Joel Barnett, Herman Adams, Ricky Cash, Josef Kerscher. Although records vary from country to country, they are normally the most formal record of a person's relations. Devanshi ist die älteste Tochter einer der reichsten Familien Indiens, den . 4 l Vorwort von Stefan Heinig, Vorsitzender des Kuratoriums 5 l Vorwort von Sandra Heller, Vorstandsvorsitzende 6 l Unsere Ziele 7 l Unsere Botschafter 8 - 9 l Unser Jahr 2012 10 - 11 l Unsere . While several IL-2Rβ/γ-biased IL-2 molecules designed to more preferentially activate NK cells and CD8+ T cells have been described, most approaches still have limitations such as incomplete IL-2Rβ/γ selectivity,13 14 reduced IL-2Rβ/γ potency15 or high Cmax-mediated effects from delivery of fully bioactive agents.15–21 Here we describe the creation of TransCon IL-2 β/γ, a novel long-acting prodrug with sustained release of a novel receptor-selective IL-2 variant (IL-2 β/γ). DBR serves as the guarantor for this work. NK cytotoxicity assays used K562 target cells (ATCC) in a DELFIA dye release assay (PerkinElmer). Treatment with TransCon IL-2 β/γ alone reduced tumor volumes compared with control animals at Day 18 (1948 mm3 vs 2653 mm3, t-test p value: 0.011, figure 2A–C). Citations 18. Our Vision. Careers, This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. © Copyright 2023 Arounddeal Holdings Limited. Trending. Similarly, TransCon IL-2 β/γ induced robust and durable mechanistic signs of proliferative responses (measured as % Ki67+ cells) in CD8+ T cells, NK cells and γδ T cells at all dose levels. Initial experiments with CD8+ and γδ T cells utilized CD20+ Raji B cell target cells and a suboptimal dose of a CD3–CD20 targeting bispecific T cell engager (overnight assay), while experiments with NK cells used K562 target cells (4 hours assay). All TransCon IL-2 β/γ dose levels are expressed in IL-2 equivalents, and all dose levels of TransCon TLR7/8 Agonist correspond to the amount of resiquimod. Dienstag, 24.01.2023, 09:53. Non-compartmental analysis was applied to calculate Cmax, area under the curve (AUC) and terminal half-life (t1/2) for IL-2 β/γ or for aldesleukin. Similar to the CT26 model, a significant reduction in tumor growth was observed following treatment with TransCon IL-2 β/γ compared with control (Day 20: 1678 mm3 vs 2562 mm3, t-test p value: 0.0099, figure 2F, online supplemental figure S4). Nirschl CJ, Brodkin HR, Hicklin DJ, et al.. To improve pharmacokinetics, IL-2 β/γ was transiently attached to a 40 kDa mPEG carrier via a TransCon (transient conjugation) linker creating a prodrug, TransCon IL-2 β/γ, with sustained release of IL-2 β/γ. 1994년 4월 설립되었다. 6. Yelp is a fun and easy way to find, recommend and talk about what's great and not so great in Schönberg and beyond. $52.92. In agreement with other IL-2Rβ/γ agonists,42 higher expansion was observed in effector memory compared with total CD8+ T cells (53-fold vs 19-fold increases at 0.3 mg/kg TransCon IL-2 β/γ, respectively), which aligns with their reported higher IL-2Rβ expression levels.43 44 Lastly, while effects on monkey γδ T cells, a cell type whose proliferative and cytolytic functions are known to be augmented by IL-2Rβ/γ engagement,45 have not been reported for other IL-2 variants, ≥0.3 mg/kg of TransCon IL-2 β/γ increased γδ T cells by on average 403-fold. In July 2010 Heinig together with Karl-Erivan Haub, co-owner of Tengelmann, bought the German branch of Woolworth's, insolvent . van Haelst Pisani C, Kovach JS, Kita H, et al.. Administration of interleukin-2 (IL-2) results in increased plasma concentrations of IL-5 and eosinophilia in patients with cancer. Stefan Heinig founded the clothing discount chain Kik 15 years ago. $52.92. As both cycles gave similar PK/PD results, only data from the first cycle are presented. Dem „Stern“ sagte sie jetzt: „Ich will nicht über den Tod meiner Tochter hinwegkommen, ich will keine Hilfe, es je hinter mir zu lassen“. To generate an optimally biased IL-2 compound, selective for IL-2Rβ/γ, several strategies were pursued. As no control group was included, all data were compared with predose levels for each animal. In agreement, increased levels of TNF-α, Fas ligand (FasL), granzyme A, granzyme B and perforin were observed in supernatants from the same CD8+ T cell, NK cell and γδ T cell cytotoxicity conditions described above (figure 7B, online supplemental figures S12A-C). Heinig는 도르트문트 피르마 H. H. H. 홀딩 GmbH에서 Co-Author. Nun sprach sie über den Tod ihrer . Jost-Stefan Heinig is Chief Executive Officer of the major German company KiK Textilien und Non-Food GmbH from Bönen. 5. IL-2 containing an engineered cysteine within the IL-2Rα binding region and a C125S stabilizing mutation was expressed and purified from Escherichia coli or Chinese hamster ovary cells. Wenn ich etwas über Liebe gelernt habe, dann nicht das Richtige. Ship This Item — Qualifies for Free Shipping Pick up in Store Check Availability at Nearby Stores. Regesten Kaiser Friedrichs III. (B) Proliferative responses compared as the fold change of the ratios of proliferating (Ki67+) CD8+ T cells, NK cells and γδ T cells to Tregs. Doch nicht etwa die groß angekündigte zweite Hochzeit von Claudia und Stefan steht an. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al.. Pharmacokinetics and pharmacodynamic effects of Nemvaleukin alfa, a selective agonist of the Intermediate-Affinity IL-2 receptor, in cynomolgus monkeys, Xencor Q3 2021 Investor summary (Xmab306), Abstract LB041: THOR-707 (SAR444245), a novel not-alpha IL-2 as monotherapy and in combination with pembrolizumab in advanced/metastatic solid tumors: interim results from hammer, an open-label, multicenter phase 1/2 study. Provenance and peer review: Not commissioned; externally peer reviewed. Jost-Stefan Heinig (born 1962 in Dortmund) is CEO of the major German company KiK Textilien und Non-Food GmbH from Bönen. Proliferation of CD8+ T cells, NK cells, γδ T cells and Tregs was determined by flow cytometry based on Ki67 expression as total cell count and as frequency (% of each cell type expressing Ki67). Moreover, levels of IL-5, IL-6, IFN-γ and TNF-α remained low in animals administered with up to 0.9 mg/kg of TransCon IL-2 β/γ, whereas a dose-dependent induction of MCP-1 and sCD25 was seen (online supplemental figure S8B). Vielleicht stimmt das, vielleicht war ich zu selbstsüchtig, zu sehr auf mich fokussiert. In a second study, 0.1 to 0.9 mg/kg TransCon IL-2 β/γ was administered IV (slow bolus) to male and female monkeys (n=1 animal/sex/group) on Days 1 and 15. Ihr Kommentar wurde abgeschickt. Further analyses demonstrated that effector memory CD8+ T cells were more sensitive to TransCon IL-2 β/γ for Ki67 induction and expansion responses than total CD8+ T cells with, for example, average 53-fold versus 19-fold expansion at 0.3 mg/kg (online supplemental figure S10). We strive to be the partner of choice for retailers and consumer in the categories we serve. [1] Jost-Stefan Heinig ist ein deutscher Einzelhändler, dem Anteile an TEDi und Woolworth Deutschland gehören. Author pages are created from data sourced from our academic publisher partnerships and public sources. At later time points the combination with TransCon IL-2 β/γ demonstrated superior efficacy compared with TransCon TLR7/8 Agonist alone (Day 25: 2226 mm3 vs 1032 mm3, t-test p value: 0.003). (A) Individual animal tumor volumes. nig projection (hiґnig) [C.F. Supplemental material: This content has been supplied by the author(s). Data are shown as fold change compared with untreated cells at an E:T ratio of 1.25 for CD8+ T cells and NK cells and 1.0 for γδ T cells. TransCon IL-2 β/γ was designed to optimize these features by two independent and complementary approaches. In contrast, some other IL-2 prodrug approaches are designed to be activated by tumor specific proteases and still utilize wild type IL-2Rα interactions to achieve increased potency for intratumoral IL-2Rα+ activated lymphocytes, however this approach could also have increased potency for intratumoral Tregs.35, In mice, TransCon IL-2 β/γ demonstrated antitumor efficacy and potentiated the induction of long-term immunological memory in combination with TransCon TLR7/8 Agonist. 1Ascendis Pharma Inc, Redwood City, California, USA, 3Ascendis Pharma GmbH, Heidelberg, Germany, 4Ascendis Pharma Inc, Palo Alto, California, USA. (A) Cell count of different lymphocyte subsets as fold change over predose (mean±SEM). IL, interleukin. TransCon IL-2 β/γ was evaluated in vivo in tumor-bearing mice alone and in combination with TransCon TLR7/8 Agonist, an investigational prodrug for sustained intratumoral (IT) release of the toll-like receptor (TLR)7/8 agonist resiquimod,22 currently in Phase 1/2 testing ({"type":"clinical-trial","attrs":{"text":"NCT04799054","term_id":"NCT04799054"}}NCT04799054). Van Gool F, Molofsky AB, Morar MM, et al.. Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy. The antitumor effect of TransCon IL-2 β/γ was also assessed in C57BL/6 mice with established MC38 tumors. All TransCon IL-2 β/γ dose levels are expressed in IL-2 equivalents. As TransCon IL-2 β/γ induced a robust expansion of CD8+ T cells, NK cells and γδ T cells in monkeys, the effects of IL-2 β/γ on proliferation and cytotoxicity of human primary cells were explored. She was last seen in Richmond, although a witness has said someone matching her description was seen walking away from an SUV . von Sonja Dünnebeil und Daniel Luger, Wien/Köln/Weimar 2012. Bild: rtl / stefan gregorowius. (C) Mice were administered 60 µg (approximately 3 mg/kg) of TransCon IL-2 β/γ intravenously on Days 0 and 6. Im Interesse unserer User behalten wir uns vor, jeden Beitrag vor der Veröffentlichung zu prüfen. sharing sensitive information, make sure you’re on a federal Active IL-2 β/γ was tested in vitro for IL-2R binding, IL-2 pathway signaling and in functional assays to assess proliferation and cytotoxic activity using primary human cells. TransCon IL-2 β/γ robustly activates CD8+ T and NK cells in CT26 bearing BALB/C mice. In agreement with IL-2Rβ binding data, increasing mPEG size beyond 5 kDa resulted in decreasing potency for induction of pSTAT5 (online supplemental figure S2) and cytotoxicity (online supplemental figure S3) in human IL-2Rβ/γ+ NK cells and CD8+ T cells. Birth, Death and Marriage records are often the best method of making the links to the Heinig Genealogy that will form part of your family tree. So lief das damals ab. Jost-Stefan Heinig (born 1962Tageszeitung Die Welt:, Interview with Stefan Heinig (14 September 2007) in Dortmund) is CEO of the major German company KiK Textilien und Non-Food GmbH from Bönen (Germany). Accordingly, at tolerable doses of TransCon IL-2 β/γ in monkeys, active IL-2 β/γ was slowly released from the mPEG carrier, leading to a low Cmax with prolonged levels of IL-2 β/γ (effective t1/2>30 hours) capable of inducing robust PD effects. Recombinant interleukin-2 (IL-2, aldesleukin) therapy is approved for treatment of metastatic melanoma and renal cell carcinoma and elicits durable clinical responses in a subset of patients.1 However, major toxicities with life-threatening complications, including vascular leak syndrome (VLS), eosinophilic infiltration of cardiac and pulmonary tissues and cytokine release syndrome (CRS), have limited its scope of treatment.2 VLS is characterized by vascular damage, increased vascular permeability, leakage of fluids, proteins and electrolytes into interstitial spaces, tissue edema, hypotension and ultimately multiorgan failure that can be fatal.3–5 IL-2 activates not only cells with antitumor function, including natural killer (NK) cells, gamma delta (γδ) T cells and CD4+ and CD8+ effector T cells, but also IL-2Rα+ immunosuppressive regulatory T cells (Tregs) that likely limit efficacy.1 6 IL-2 can signal with picomolar affinity to trimeric IL-2 receptor IL-2Rα/β/γ or with nanomolar affinity through dimeric IL-2Rβ/γ.1 T cells and NK cells can upregulate IL-2Rα on activation, while Tregs constitutively express high IL-2Rα levels.7 Therefore, IL-2 potently activates Tregs compared with IL-2Rβ/γ+ CD8+ T cells, γδ T cells and NK cells that possess antitumor function. Competing interests: All authors are or were employees and/or stockholders of Ascendis Pharma and declare competing financial interests. Additionally, these changes corresponded with increases in the CD8/CD4 and CD8/Treg ratios (online supplemental figure S5A). Stefan Raabs legitimer Nachfolger Sebastian Pufpaff hat „TV total“ zur kleinen Kalauer-Kollektion der Woche umgestaltet – weniger anarchisch, aber ähnlich lustig wie die Ur-Sendung. KiK is a joint project of the Tengelmann Group holding and the entrepreneur Jost-Stefan Heinig. In mouse tumor models, TransCon IL-2 β/γ promoted CD8+ T cell and NK cell activation and antitumor activity. (F) Female C57BL/6 mice with established MC38 tumors were treated with buffer control or 60 µg TransCon IL-2 β/γ on Days 0, 7 and 14 (n=20 mice/group). Out of 6,215,834 records in the U.S. Social Security Administration public data, the first name Heinig was not present. Additionally, multiple doses of TransCon IL-2 β/γ and higher dose levels were required in mice compared with monkeys to induce robust proliferative responses and increases in CD8+ T cell numbers. Mean tumor volume ±SEM are shown. IL, interleukin; TLR, toll-like receptor. CD8+ and γδ T cell assays were using CD20+ Raji B cell lymphoma cells as target cells in the presence of 1 nM CD3-CD20 bispecific engager, while NK cell cytotoxicity assays used K562 erythroleukemia cells as target cells. Pretreatment with IL-2 β/γ clearly enhanced the cytotoxic potential of these cells (figure 7A). Also, IL-2 potently activates IL-2Rα+ eosinophils, type 2 innate lymphoid cells and endothelial cells, which may promote VLS and limit the therapeutic window.8–11 In addition to IL-2Rα engagement, another major drawback of aldesleukin therapy for cancer is its suboptimal pharmacokinetic (PK) properties with a short (85 min) elimination half-life requiring frequent, high dose administrations resulting in high Cmax values that likely potentiate toxicity.12. In vitro, cynomolgus monkey lymphocytes demonstrated almost identical IL-2Rβ/γ selectivity and pSTAT5 potency results as seen with human cells (online supplemental figure S6). Stefan Heinig. TransCon IL-2 β/γ promotes robust lymphocyte expansion in cynomolgus monkeys, without inducing eosinophils, systemic endothelial cell injury or inflammatory cytokines. While treatment with both TransCon IL-2 β/γ and aldesleukin increased absolute lymphocyte counts (ALC), treatment with aldesleukin, but not TransCon IL-2 β/γ, increased eosinophil counts (figure 4A). All statistical analyses were performed using GraphPad Prism or Microsoft Excel. Find many great new & used options and get the best deals for Integrierte Stadtentwicklungsplanung ~ Stefan Heinig ~ 9783837658392 at the best online prices at eBay! Highly Influential Citations 0. Jost-Stefan Heinig is CEO of the major German company KiK Textilien und Non-Food GmbH from Bönen. The authors acknowledge Mads Kjelgaard-Hansen and Christian Krapp for critical review of the manuscript and Melany Musso, Francois J Villinger, and Jason Goetzmann from the University of Louisiana for contributions to cynomolgus monkey studies and immunophenotyping development.
Löwenzahn Samen,