The proteasome, a multicatalytic protease, is responsible for the degradation of intracellular proteins. Stimulation of cells with inflammatory cytokines, such as IFN-γ, leads to the replacement of the constitutive catalytic proteasome subunits by the inducible subunits low molecular mass polypeptide (LMP)2 (β1i), multicatalytic endopeptidase complex-like-1 (β2i), and LMP7 (β5i), which are required for the production of certain MHC class I-restricted T cell epitopes. In this study, we investigated the effect of immunoproteasomes on the development of dextran sulfate sodium-induced colitis. Colitis induction in LMP2-, LMP7-, and multicatalytic endopeptidase complex-like-1–deficient mice caused reduced weight loss compared with wild-type mice. Although colon lengths were shortened in wild-type mice, no reduction was observed in immunoproteasome-deficient mice. In accordance with this, proinflammatory cytokines, such as TNF-α and IL-1β, were not upregulated in these mice. Blockage of LMP7 by a novel LMP7-selective inhibitor (PR-957) strongly reduced pathological symptoms of dextran sulfate sodium-induced colitis. Production of numerous cytokines in PR-957–treated mice was suppressed, resulting in reduced inflammation and tissue destruction. Taken together, these results demonstrate that an immunoproteasome-specific inhibitor can be used to attenuate autoimmune diseases like colitis.

2009-11-15·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学

A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of the Novel Proteasome Inhibitor Carfilzomib (PR-171) in Patients with Hematologic Malignancies

1区 · 医学

Article

作者: Robert Z. Orlowski ; Lori A. Kunkel ; Owen A. O'Connor ; A. Keith Stewart ; Marcy Vallone ; John F. Gerecitano ; Christopher J. Molineaux

Abstract:

Purpose: Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib.Experimental Design: In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles.Results: Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patientsmostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses 11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenstrm's macroglobulinemia).Conclusion: This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing. (Clin Cancer Res 2009;15(22):708591)

2009-11-01·NATURE MEDICINE

Erratum: A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis

作者: Shields, Jamie ; Basler, Michael ; Ring, Eileen R. ; Sylvain, Catherine ; Lauer, Christoph ; Groettrup, Marcus ; Shwonek, Peter ; Parlati, Francesco ; Muchamuel, Tony ; Kalim, Khalid W. ; Aujay, Monette A. ; Bennett, Mark K. ; Kirk, Christopher J. ; Demo, Susan D. ; Suzuki, Erika ; Jiang, Jing

On page 782, in Figure 1a, the structure of PR-957 was incorrectly given; An-NH group was missing.The HTML and PDF versions have been corrected

项与 Proteolix, Inc. 相关的新闻（医药）

2024-09-10

·GlobeNewswire-Health Care

Passage Bio Welcomes Tom Kassberg to Board of Directors

PHILADELPHIA, Sept. 10, 2024 (GLOBE NEWSWIRE) -- Passage Bio, Inc. (Nasdaq: PASG), a clinical stage genetic medicines company focused on improving the lives of patients with neurodegenerative diseases, today announced the appointment of Tom Kassberg to the Board of Directors and his appointment to the Audit Committee. Mr. Kassberg is currently Chief Business Officer and Executive Vice President at Ultragenyx, a biopharmaceutical company committed to bringing novel therapies to patients for the treatment of serious rare and ultrarare genetic diseases. "We are pleased to welcome Tom Kassberg to the Passage Bio Board of Directors, where he will play an influential role in driving our mission forward during this critical time for the organization," said Will Chou, M.D., president and chief executive officer of Passage Bio. "Mr. Kassberg brings a wealth of experience from his time at Ultragenyx, where he leads business development and alliance management and has directly contributed to the company's success in advancing new treatments, including a number of gene therapies in late-stage development, for rare diseases. His deep understanding of strategic planning and corporate development make him exceptionally well-equipped to guide Passage Bio as we pursue PBFT02 across several neurodegenerative indications. We're thrilled to have him join our team." Mr. Kassberg is a seasoned biotech executive with deep expertise in corporate development and strategic planning. Prior to his role at Ultragenyx, Mr. Kassberg served as Executive Vice President of Corporate Development at Proteolix, Inc, leading business development and strategic initiatives. Before that, he was Senior Vice President of Corporate Development and Commercial Operations at InterMune, Inc. Mr. Kassberg co-founded Plexxikon, where he led business and corporate development, and earlier, was Senior Director of Business Development and Corporate Licensing at SUGEN, where he played a key role during its acquisition by Pharmacia. His career began at Bristol Myers Squibb in strategic planning, managed care sales and financial analysis. "I am excited to join the Passage Bio Board of Directors and contribute to the continued growth of the company,” said Mr. Kassberg. “The remarkable progress of the PBFT02 program and opportunity to expand into additional indications highlight Passage Bio’s dedication to making a critical impact in the field of neurodegenerative diseases. I look forward to collaborating with this exceptional team to drive forward our promising treatments and make a meaningful impact on the lives of patients and their families." Mr. Kassberg earned a B.A. in economics and management from Gustavus Adolphus College and an M.B.A. from Northwestern University’s Kellogg School of Management. About Passage Bio Passage Bio (Nasdaq: PASG) is a clinical stage genetic medicines company on a mission to improve the lives of patients with neurodegenerative diseases. Our primary focus is the development and advancement of cutting-edge, one-time therapies designed to target the underlying pathology of these conditions. Passage Bio’s lead product candidate, PBFT02, seeks to treat neurodegenerative conditions, including frontotemporal dementia, by elevating progranulin levels to restore lysosomal function and slow disease progression. To learn more about Passage Bio and our steadfast commitment to protecting patients and families against loss in neurodegenerative conditions, please visit: www.passagebio.com. For further information, please contact: Investors:Stuart HendersonPassage Bio267.866.0114shenderson@passagebio.com Media:Mike BeyerSam Brown Inc. Healthcare Communications312.961.2502MikeBeyer@sambrown.com

高管变更

2024-04-09

·GlobeNewswire-Health Care

Enliven Therapeutics Appoints Dr. Lori Kunkel to Board of Directors

BOULDER, Colo., April 09, 2024 (GLOBE NEWSWIRE) -- Enliven Therapeutics, Inc. (Enliven or the Company) (Nasdaq: ELVN), a clinical-stage precision oncology company focused on the discovery and development of next-generation small molecule kinase inhibitors, today announced the appointment of Lori Kunkel, MD, to its Board of Directors. Dr. Kunkel brings more than twenty-five years of experience in oncology and immunology drug development and commercialization to the Board. “Lori has served as scientific advisor to Enliven since its inception, and we are delighted to now welcome her to our Board,” said Sam Kintz, MBA, Enliven’s Co-founder and Chief Executive Officer. “She brings a wealth of experience as a clinician, academic and industry executive, and we look forward to her continued contributions and insights as we advance our two parallel lead product candidates, ELVN-001 and ELVN-002, through the next set of clinical milestones.” Dr. Kunkel is an accomplished industry executive and board member with a track record of success in corporate strategy, clinical development and commercialization, and business development. She currently serves on the Board of Directors of Nurix Therapeutics, Inc., ORIC Pharmaceuticals, Inc., and K36 Therapeutics, Inc. She is also a scientific advisor to several clinical-stage oncology and immunotherapy companies. Previously, Dr. Kunkel was the acting Chief Medical Officer (CMO) and board member of Loxo Oncology, Inc. (acquired by Eli Lilly and Company). She also served as the CMO at Pharmacyclics LLC (acquired by AbbVie) and Proteolix, Inc. (acquired by Onyx Pharmaceuticals). Prior to joining industry, Dr. Kunkel spent ten years in academic medicine and served as a faculty member at the Bone Marrow Transplant Unit in the Division of Hematology/Oncology at the University of California, Los Angeles. She received her medical degree from University of Southern California and her bachelor’s degree in biology from University of California, San Diego. She is board certified in internal medicine and held board certifications in hematology and oncology. “I am honored to transition from my role as a scientific advisor to a member of the Board of Directors,” said Dr. Kunkel. “I have been deeply engaged with the science at Enliven since the beginning, and I am thrilled to now play a more direct role in guiding its strategic direction. With the Company’s upcoming announcement of initial proof-of-concept data from the ongoing Phase 1a trial of ELVN-001, it is an exciting time for the Company.” About Enliven TherapeuticsEnliven Therapeutics is a clinical-stage biopharmaceutical company focused on the discovery and development of small molecule inhibitors to help people with cancer not only live longer, but live better. Enliven aims to address existing and emerging unmet needs with a precision oncology approach that improves survival and enhances overall well-being. Enliven’s discovery process combines deep insights in clinically validated biological targets and differentiated chemistry to design potentially first-in-class or best-in-class therapies. Enliven is based in Boulder, Colorado. Contact: Investorsir@enliventherapeutics.com Mediamedia@enliventherapeutics.com

高管变更临床1期

2024-01-16

·药通社

全球超13亿重磅品种，国内竟无企业获批？

注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需要得到授权。近日，据CDE官网显示，海南普利制药递交的4类仿制化药注射用卡非佐米的上市申请今日获受理。据药融云数据统计，目前该品种尚无本土药企获批生产销售。截图来源：CDE官网卡非佐米（carfilzomib）最初由Proteolix公司研发，2009年奥尼克斯（Onyx）收购Proteolix获得该品种，2013年8月，安进收购奥尼克斯制药公司，并获得卡非佐米的专利权。最早于2012年7月在美国获批上市，用于至少接受过两种（硼替佐米和免疫调节剂）先前的多发性骨髓瘤患者，是继硼替佐米后第二个被 FDA 批准的蛋白酶体抑制剂。全球超13亿重磅品种，首仿竞争进入白热化阶段目前卡非佐米已在全球多个国家上市。早在2020年，卡非佐米全球销售额已超10亿美元。据药融云数据统计，近三年（2020-2022年）卡非佐米全球销售额分别11.2、11.8和13.2亿美元。注射用卡非佐米在2022年院内市场上线以来，销售额直线上升，销售额超2956万元，同比增长达231.35%。截图来源：药融云全国医院销售数据库据药融云数据统计，卡非佐米注射品种国内尚无药企获批，豪森药业是最早进行卡非佐米仿制申报的企业，申报类别是3类仿制药。继豪森药业之后，上海创诺制药、齐鲁制药、四川汇宇制药、以及扬子江药业也相继报产，此次海南普利制药，是最新报产的企业，预计不久后将进入注射用卡非佐米首仿竞争的白热化阶段。纳入医保目录，多发性骨髓瘤患者又添有力武器2023年3月1日起，2022版医保目录正式实施，众多创新性强、临床价值高、疗效显著的药物被纳入新版目录，让更多中国患者能够及时获得有效治疗。对于多发性骨髓瘤（MM）患者来说，一个特别值得关注的好消息是，创新药物注射用卡非佐米首次被纳入医保，用于治疗复发或难治性多发性骨髓瘤成人患者。这一消息将大大提高新药的可及性，真正减轻患者的经济负担，为多发性骨髓瘤患者又添了一款有力武器。注射用卡非佐米作为年销10亿美元的重磅药物，在中国化合物专利即将于25年8月到期，仿制药企闻风而动，除11家国内仿制药企的争先布局，同时还有安进生物技术、杭州泰格医药科技等药企开展了临床试验，目前处于3期阶段。截图来源：药融云中国上市药品专利卡非佐米作为新一代的高度选择性不可逆蛋白酶体阻断药，属于环氧甲酮四肽蛋白酶体抑制剂类似物，主要抑制20S蛋白酶体的糜蛋白酶。它的结构和作用机理不同于二肽硼酸类似物硼替佐米，硼替佐米与蛋白酶体的催化β5亚组可逆性结合，而卡非佐米不可逆共价结合蛋白酶体的催化β5亚组和免疫蛋白酶体β5i(LMP7)亚组，相比于硼替佐米具有更好的效力和耐药性，业界预计其可能会取代硼替佐米，市场前景看好。除此次提交的注射用卡非佐米，目前海南普利制药还提交了钆特酸葡胺注射液、左亚叶酸钙注射液、硝普钠氯化钠注射液等26个品种的仿制申请，均在审评审批中。END本文为原创文章，转载请留言获取授权点击阅读原文，申请药融云企业版免费试用！

并购专利到期上市批准免疫疗法

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100 项与 Proteolix, Inc. 相关的转化医学

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