Dimethyl Sulfoxide

▲5月30-31日 第八届广州生物医药创新者峰会 扫码立即报名 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。任何文章转载需得到授权。全细胞生物催化剂（WCB）具有独特的优势，已广泛用于精细化学品和大宗化学品以及药物活性成分的高效生物合成。越来越多的研究者合理设计WCB，将异源酶或合成途径的基因引入到微生物宿主（例如大肠杆菌），利用廉价底物生成高价值的产品。在异源宿主中构建生物合成途径的技术在综述文章“New tools for reconstruction and heterologous expression of natural product biosynthetic gene clusters”中进行了广泛的讨论，包括快速多基因整合方法、基因编辑方法学以及组合酶表达技术等。目前，直接用于构建大于5个异源基因的代谢途径的策略暂未完全开发。因此，生物合成途径规划以及酶筛选和工程化至关重要。同时，需要通过代谢工程策略改进WCB生物合成途径降本增效，包括确定限速步骤，避开或者缓解限速步骤；平衡途径以消除有毒中间体或副产物的积累；缩短途径，减弱中间体的反馈抑制；最大化途径的产物通量：例如，阻断竞争途径、增强前体和辅助底物的供应以及改善辅因子的平衡等。近日，中科院微生物所/北京工商大学研究团队设计并优化了一种新的生物合成途径，以廉价的丁香酚为底物，高效生成香料成分香兰素。使用丁香酚的阿魏酸生物合成途径已报道，然而由于中间物质松柏醛抑制了香草酰辅酶A合成酶（Fcs）的活性，将其直接与使用阿魏酸作为底物的下游香兰素生物合成结合起来不可行。因此，作为概念验证，团队设计了香兰素生产的阿魏酰辅酶A生物合成途径，引入肉桂酰辅酶A还原酶（CCR），催化松柏醛转化为阿魏酰辅酶A，克服固有的抑制并简化合成过程（图1）。目前，这项研究成果已经以“Artificial Biosynthetic Pathway for Efficient Synthesis of Vanillin, a Feruloyl-CoA-Derived Natural Product from Eugenol”为题发表在Journal of Agricultural and Food Chemistry上。图1 阿魏酸生物合成途径（蓝色箭头）、香兰素生物合成途径（橙色箭头）以及新设计的以丁香酚为底物的香兰素生物合成途径（绿色背景所示）。该过程涉及绕过限速步骤、缩短生物合成路线、增强原子经济性、减少辅因子依赖性以及防止有毒中间体的积累。通过引入CCR酶来克服了松柏醛对Fcs的抑制，对CCR酶进行了定向进化，改变了辅因子特异性，使香兰素的产量得到了显著提高。同时，对宿主菌进行基因敲除：通过敲除宿主菌内源性醛还原酶，减少了香兰素还原为香草醇的损失，提高了香兰素产量。最后，通过优化以下条件进一步提高香兰素产量：（1）通过优化IPTG诱导剂浓度，提高了VaoA和Ech的表达水平，进而提高了香兰素产量。（2）底物溶解溶剂：通过比较不同溶剂，发现DMSO更适合溶解丁香酚，从而提高了香兰素产量。（3）底物投加方式：通过分批投加丁香酚，避免了高浓度丁香酚的毒性影响，提高了香兰素产量。（4）Ech表达优化：通过在Ech基因后插入稀有密码子，找到了最适合的Ech表达量，使香兰素产量最大化。总而言之，该研究为高效利用丁香酚生物合成香兰素提供了一种新的策略。此外，构建全细胞生物催化剂，反馈抑制是常见的问题。前日，中国海洋大学研究团队通过工程化且过表达反馈抑制耐受酶克服反馈抑制（图2），即对受到反馈抑制的酶进行改造以适应高浓度的底物、产物或者中间体。该研究通过逐步代谢工程改造毛霉菌株A1145,实现了环二苯丙氨酸（cFF）的高效生产。首先，从海洋真菌Penicillium janthinellum中异源表达了NRPS基因penP1，在A1145中获得初步的cFF生产能力。然后，通过敲除竞争途径关键基因、过表达反馈抑制耐受酶和引入途径增强前体供给等策略，系统地优化了A1145的苯丙氨酸途径和 shikimate 途径，最终实现了cFF产量的显著提升。图2 解除关键酶的反馈抑制来提高环二苯丙氨酸产量的策略。   总结通过设计并引入生物合成途径，构建全细胞生物催化剂，高效生产高附加值的化学品的生物催化备受关注并迅速发展着，为未来部分替代传统的化学催化合成化学品的生产方式奠定基础。论文链接：1、 https://doi.org/10.1021/acs.jafc.3c087232、https://doi.org/10.1016/j.ymben.2024.02.009版权声明：本文转自synbio深波，如不希望被转载的媒体或个人可与我们联系，我们将立即删除 活动推荐  8月 • NDC2024生物医药创新博览会  关键词：  抗体、多肽、核酸、核药，XDC、小分子、注册、临床、CMC（点击下方图片查看详情）▼【关于药融圈】药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。

Expanded access program (EAP) data for omidubicel are consistent with Phase 3 trial results on rates of hematopoietic recovery and infections following stem cell transplant with Omisirge® (omidubicel-onlv) Preliminary data presented on GDA-201, Gamida Cell’s natural killer (NK) cell therapy candidate in ongoing Phase 1 study for non-Hodgkin lymphoma, show promising early evidence of anti-tumor activity BOSTON, Feb. 23, 2024 (GLOBE NEWSWIRE) -- Gamida Cell Ltd. (Nasdaq: GMDA), a cell therapy pioneer working to turn cells into powerful therapeutics, today presented data highlighting its expanded access program (EAP) for FDA-approved allogeneic stem cell therapy Omisirge® (omidubicel-onlv) and Phase 1 data for its allogeneic cryopreserved natural killer (NK) cell therapy candidate GDA-201 at the 2024 Tandem Meetings, Transplantation & Cellular Therapy (TCT) Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood and Marrow Transplant Research (CIBMTR). The hybrid meetings take place February 21-24 virtually and in person in San Antonio, Texas. “The data presented at Tandem provide further evidence of the potential of Gamida Cell’s nicotinamide (NAM) technology to develop potentially curative therapies by expanding and enhancing cells,” said Ronit Simantov, MD, Chief Medical and Scientific Officer of Gamida Cell. “The EAP study provided the opportunity to treat patients after completion of enrollment of the Phase 3 trial and prior to the approval of Omisirge. It allowed for institutional variability in conditioning regimens and supportive care, more closely reflecting the real-world environment. Data were consistent with previous studies, showing that patients transplanted with omidubicel had rapid hematopoietic recovery and a low rate of serious infections post-transplant.” “The Phase 1 data on our natural killer (NK) cell candidate GDA-201 further support the anti-tumor activity of our NAM-enhanced cellular therapy, and today marked the first presentation of study results using our cryopreserved, readily available formulation,” Simantov added. Reporting on omidubicel’s EAP data, principal investigator Mitchell E. Horwitz, MD, Stem Cell Transplant Specialist and Professor of Medicine at Duke Cancer Institute, said, “I am highly encouraged by the results in the omidubicel expanded access program. The potential for rapid hematopoietic recovery post-transplant observed with omidubicel could make a meaningful impact on patient health. I am pleased to see that the EAP results are consistent with data from the Phase 3 study.” Additional details on the presentations are as follows: Title: Omidubicel-onlv for Allogeneic Transplantation (allo-HCT) in Patients with Hematologic Malignancies: Results of a Multicenter Open-Label Expanded Access Program (EAP)Abstract Number: 313Lead Author: Mitchell E. Horwitz, MD, Stem Cell Transplant Specialist and Professor of Medicine at Duke Cancer InstituteTime: February 22, 6:45-7:45 p.m. CT Presentation highlights: In this expanded access program (EAP) evaluating outcomes in 29 patients with hematologic malignancies following allogeneic hematopoietic stem cell transplant with omidubicel, outcomes were overall consistent with those from omidubicel’s Phase 3 study. Eligible patients ≥12 years of age received myeloablative conditioning, prophylactic medications and supportive care per individual institutional standards. Median time to neutrophil and platelet engraftment were 12 and 34 days, respectively. Results were also similar to the Phase 3 study for infection (first grade 2-3 bacterial / invasive fungal infections at 100 days posttransplant: 18%), graft-versus-host-disease (grades 3-4: 19%), disease-free survival (79%) and overall survival (87%). Demographics of transplanted patients were 55% White, 21% Asian, 17% Black, and 7% other, consistent with the Phase 3 trial, in which >40% of the study participants were racially or ethnically diverse. Omidubicel was approved under the brand name Omisirge® (omidubicel-onlv) by the U.S. FDA in April 2023 for allogeneic stem cell transplant. Title: A Phase I/II Study of GDA-201, Cryopreserved Nicotinamide-Enhanced Allogeneic Natural Killer Cells, in Patients with Relapsed/Refractory B-cell LymphomaAbstract Number: 255Lead Author: Brian C. Shaffer, Associate Professor of Medicine and Head of the Adult Mismatched Donor Sub-Program at Memorial Sloan Kettering Cancer Center in New YorkDate and Time: February 22, 6:45-7:45 p.m. CT Presentation highlights: In this ongoing multicenter Phase 1 study of allogeneic cryopreserved NK cell therapy candidate GDA-201 in patients with relapsed/refractory B-cell CD20 positive non-Hodgkin lymphoma, preliminary data for the first 12 patients were presented. Patients were heavily pretreated with a median of six prior lines of therapy including CAR-T cell therapy and hematopoietic stem cell transplant. Patients were treated with doses up to 2x108 cells/kg GDA-201 in combination with rituximab. There were no infusion reactions, dose-limiting toxicities or related serious adverse events. Seven patients exhibited a decrease in tumor burden. Efficacy evaluation using Lugano criteria showed three patients with complete response, two with partial response and two with stable disease. Cytokine release syndrome was reported in two patients (grade 1 and grade 2, respectively). There were no cases of immune effector cell associated neurotoxicity syndrome or graft versus host disease reported. Treatment and evaluation of patients in the fourth cohort of the study at the highest dose level of 2x108 cells/kg is ongoing. Full results are expected in Q1 2024. Posters are available at: https://www.gamida-cell.com/our-rd/ About Gamida CellGamida Cell is a cell therapy pioneer working to turn cells into powerful therapeutics. The company’s proprietary nicotinamide (NAM) technology leverages the properties of NAM to enhance and expand cells, creating allogeneic cell therapy products and candidates that are potentially curative for patients with hematologic malignancies. These include Omisirge® (omidubicel-onlv), an FDA-approved nicotinamide modified allogeneic hematopoietic progenitor cell therapy, and GDA-201, an intrinsic NK cell therapy candidate being investigated for the treatment of hematologic malignancies. For additional information, please visit www.gamida-cell.com or follow Gamida Cell on LinkedIn, X, Facebook or Instagram. About GDA-201GDA-201 is an intrinsic NK cell therapy candidate being investigated for the treatment of hematologic malignancies. NAM-modified NK cells have previously been shown to have enhanced metabolic fitness, resistance to oxidative stress and potent cytotoxicity. A multicenter Phase 1 study of GDA-201 for the treatment of non-Hodgkin lymphoma is ongoing (NCT05296525). Results are expected in Q1 2024. GDA-201 is an investigational cell therapy candidate, and its safety and efficacy have not been established by the FDA or any other health authority. Omisirge® (omidubicel-onlv) IndicationOmisirge is a nicotinamide modified allogeneic hematopoietic progenitor cell therapy derived from cord blood indicated for use in adults and pediatric patients 12 years and older with hematologic malignancies who are planned for umbilical cord blood transplantation following myeloablative conditioning to reduce the time to neutrophil recovery and the incidence of infection. Important Safety Information for Omisirge BOXED WARNING: INFUSION REACTIONS, GRAFT VERSUS HOST DISEASE, ENGRAFTMENT SYNDROME, AND GRAFT FAILURE Infusion reactions may be fatal. Monitor patients during infusion and discontinue for severe reactions. Use is contraindicated in patients with known allergy to dimethyl sulfoxide (DMSO), Dextran 40, gentamicin, human serum albumin or bovine material.Graft-versus-Host Disease may be fatal. Administration of immunosuppressive therapy may decrease the risk of GvHD.Engraftment syndrome may be fatal. Treat engraftment syndrome promptly with corticosteroids.Graft failure may be fatal. Monitor patients for laboratory evidence of hematopoietic recovery. ContraindicationsOMISIRGE is contraindicated in patients with known hypersensitivity to dimethyl sulfoxide (DMSO), Dextran 40, gentamicin, human serum albumin, or bovine products. Warnings and PrecautionsHypersensitivity ReactionsAllergic reactions may occur with the infusion of OMISIRGE. Reactions include bronchospasm, wheezing, angioedema, pruritis and hives. Serious hypersensitivity reactions, including anaphylaxis, may be due to DMSO, residual gentamicin, Dextran 40, human serum albumin (HSA) and bovine material in OMISIRGE. OMISIRGE may contain residual antibiotics if the cord blood donor was exposed to antibiotics in utero. Patients with a history of allergic reactions to antibiotics should be monitored for allergic reactions following OMISIRGE administration. Infusion ReactionsInfusion reactions occurred following OMISIRGE infusion, including hypertension, mucosal inflammation, dysphagia, dyspnea, vomiting, and gastrointestinal toxicity. Premedication with antipyretics, histamine antagonists, and corticosteroids may reduce the incidence and intensity of infusion reactions. In patients transplanted with OMISIRGE in clinical trials, 47% (55/117) patients had an infusion reaction of any severity. Grade 3-4 infusion reactions were reported in 15% (18/117) patients. Infusion reactions may begin within minutes of the start of infusion of OMISIRGE, although symptoms may continue to intensify and not peak for several hours after the completion of the infusion. Monitor patients for signs and symptoms of infusion reactions during and after OMISIRGE administration. When a reaction occurs, pause the infusion and institute supportive care as needed. Graft-versus-Host DiseaseAcute and chronic GvHD, including life-threatening and fatal cases, occurred following treatment with OMISIRGE. In patients transplanted with OMISIRGE Grade II-IV acute GvHD was reported in 58% (68/117). Grade III- IV acute GvHD was reported in 17% (20/117). Chronic GvHD occurred in 35% (41/117) of patients. Acute GvHD manifests as maculopapular rash, gastrointestinal symptoms, and elevated bilirubin. Patients treated with OMISIRGE should receive immunosuppressive drugs to decrease the risk of GvHD, be monitored for signs and symptoms of GvHD, and treated if GvHD develops. Engraftment SyndromeEngraftment syndrome may occur because OMISIRGE is derived from umbilical cord blood. Monitor patients for unexplained fever, rash, hypoxemia, weight gain, and pulmonary infiltrates in the peri-engraftment period. Treat with corticosteroids as soon as engraftment syndrome is recognized to ameliorate symptoms. If untreated, engraftment syndrome may progress to multiorgan failure and death. Graft FailurePrimary graft failure occurred in 3% (4/117) of patients in OMISIRGE clinical trials. Primary graft failure, which may be fatal, is defined as failure to achieve an absolute neutrophil count greater than 500 per microliter blood by Day 42 after transplantation. Immunologic rejection is the primary cause of graft failure. Monitor patients for laboratory evidence of hematopoietic recovery. Malignancies of Donor OriginTwo patients treated with OMISIRGE developed post-transplant lymphoproliferative disorder (PTLD) in the second-year post-transplant. PTLD manifests as a lymphoma-like disease favoring non-nodal sites. PTLD is usually fatal if not treated. The etiology is thought to be donor lymphoid cells transformed by Epstein-Barr virus (EBV). Serial monitoring of blood for EBV DNA may be warranted in patients with persistent cytopenias. One patient treated with OMISIRGE developed a donor-cell derived myelodysplastic syndrome (MDS) during the fourth-year post-transplant. The natural history is presumed to be the same as that for de novo MDS. Monitor life-long for secondary malignancies. If a secondary malignancy occurs, contact Gamida Cell at (844) 477-7478. Transmission of Serious InfectionsTransmission of infectious disease may occur because OMISIRGE is derived from umbilical cord blood. Disease may be caused by known or unknown infectious agents. Donors are screened for increased risk of infection, clinical evidence of sepsis, and communicable disease risks associated with xenotransplantation. Maternal and infant donor blood is tested for evidence of donor infection. See full Prescribing Information, Warnings and Precautions, Transmission of Serious Infections for list of testing performed. OMISIRGE is tested for sterility, endotoxin, and mycoplasma. There may be an effect on the reliability of the sterility test results if the cord blood donor was exposed to antibiotics in utero. Product manufacturing includes bovine-derived reagents. All animal-derived reagents are tested for animal viruses, bacteria, fungi, and mycoplasma before use. These measures do not eliminate the risk of transmitting these or other transmissible infectious diseases and disease agents. Test results may be found on the container label and/or in accompanying records. If final sterility results are not available at the time of use, Quality Assurance will communicate any positive results from sterility testing to the physician. Report the occurrence of transmitted infection to Gamida Cell at (844) 477-7478. Transmission of Rare Genetic DiseasesOMISIRGE may transmit rare genetic diseases involving the hematopoietic system because it is derived from umbilical cord blood. Cord blood donors have been screened to exclude donors with sickle cell anemia, and anemias due to abnormalities in hemoglobins C, D, and E. Because of the age of the donor at the time cord blood collection takes place, the ability to exclude rare genetic diseases is severely limited. ADVERSE REACTIONSThe most common adverse reactions (incidence > 20%) are infections, GvHD, and infusion reaction. Please see full Prescribing Information, including Boxed Warning. About Gamida CellGamida Cell is a cell therapy pioneer working to turn cells into powerful therapeutics. The company’s proprietary nicotinamide (NAM) technology leverages the properties of NAM to enhance and expand cells, creating allogeneic cell therapy products and candidates that are potentially curative for patients with hematologic malignancies. These include Omisirge® (omidubicel-onlv), an FDA-approved nicotinamide modified allogeneic hematopoietic progenitor cell therapy, and GDA-201, an intrinsic NK cell therapy candidate being investigated for the treatment of hematologic malignancies. For additional information, please visit www.gamida-cell.com or follow Gamida Cell on LinkedIn, Facebook, X and Instagram. Cautionary Note Regarding Forward-Looking StatementsThis press release may contain forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, including with respect to the potentially life-saving or curative therapeutic and commercial potential of Omisirge® (omidubicel-onlv), and the Company’s cell therapy candidate, GDA-201. Any statement describing Gamida Cell’s goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to a number of risks, uncertainties and assumptions including those related to clinical, scientific, regulatory and technical developments and those inherent in the process of developing and commercializing product candidates that are safe and effective for use as human therapeutics. In light of these risks and uncertainties, and other risks and uncertainties that are described in the Risk Factors section and other sections of Gamida Cell’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 14, 2023, and other filings that Gamida Cell makes with the SEC from time to time (which are available at www.sec.gov), the events and circumstances discussed in such forward-looking statements may not occur, and Gamida Cell’s actual results could differ materially and adversely from those anticipated or implied thereby. Although Gamida Cell’s forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Gamida Cell. As a result, you are cautioned not to rely on these forward-looking statements. Omisirge® is a registered mark of Gamida Cell Inc. © 2024 Gamida Cell Inc. All Rights Reserved. Media Contact:  Dan Boyle  Orangefiery  media@orangefiery.com1-818-209-1692  Investor Contact:  Chuck Padala  LifeSci Advisors  Chuck@lifesciadvisors.com1-646-627-8390