作者: Zhou, Tongqing ; Roark, Ryan S. ; Doria‐Rose, Nicole A. ; Kwong, Peter D. ; Tourtellott‐Fogt, Emily ; Rawi, Reda ; Chan, Payton ; Shen, Chen‐Hsiang ; Tsybovsky, Yaroslav ; Einav, Tal ; Olia, Adam S. ; Wang, Shuishu ; Nazzari, Alexandra F. ; Pegu, Amarendra ; Stephens, Tyler ; Bender, Michael F. ; O'Dell, Sijy ; Zhang, Baoshan ; Shapiro, Lawrence ; Chaudhary, Ridhi ; Xu, Jianliang ; Lin, Bob C. ; Yang, Eun Sung ; Morano, Nicholas C. ; Chen, Xuejun ; Casellas, Rafael ; Louder, Mark K. ; Teng, I‐Ting ; Merriam, Jonah S. ; Liu, Cuiping ; Kwon, Young Do ; Changela, Anita ; Becker, Jordan E. ; McKee, Krisha

AbstractBroadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV‐1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion‐stabilized HIV‐1 envelope (Env) trimer, BG505 DS‐SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4‐binding site (CD4bs) of vulnerability. Two of the vaccine‐elicited CD4bs‐targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a‐hinge region and human IgG1‐constant region (G36×3‐IgG2a and R27×3‐IgG2a), neutralized 96% of a multiclade 208‐strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL−1, respectively. Cryo‐EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV‐1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2‐apex‐targeting broadly neutralizing antibody, CAP256V2LS. The resultant human‐llama bispecific antibody CAP256L‐R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV‐1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn‐Fc mice similar to the parent CAP256V2LS. Vaccine‐elicited llama nanobodies, when combined with V2‐apex broadly neutralizing antibodies, may therefore be able to fulfill anti‐HIV‐1 therapeutic and prophylactic clinical goals.

2022-01-01·Protein Expression and Purification4区 · 生物学

Effect of Clp protease from Corynebacterium glutamicum on heterologous protein expression

4区 · 生物学

Article

作者: Yang, Yankun ; Bai, Zhonghu ; Liu, Xiuxia ; Wang, Xinyue ; Meng, Lihong

The protease present in a host may reduce the yield and biological activity of heterologous proteins. In this study, we used protease overexpression and deletion strategies to examine the effect of the Clp protease system in Corynebacterium glutamicum on the recombinant protein and to produce a highly efficient heterologous protein expression host. In this study, we identified seven genes in the Clp protease family in Corynebacterium glutamicum ATCC 13032 through bioinformatics analysis, and studied their effects on the enhanced green fluorescent protein (EGFP) reporter protein. The fluorescence intensity of the knockout strain was significantly higher, and the effect of the clpS deletion strain was the most obvious. To verify the universal effect of the lack of clpS, the excellent industrial strain C. glutamicum 1.15647 was transformed to form recombinant 15647-ΔclpS. Based on the results, 15647-ΔclpS had a more significant effect on improving protein expression. Furthermore, recombinant human teriparatide (rhPTH) and variable domain of heavy chain of heavy-chain antibody (VHH) were selected to verify the universal applicability of the knockout strain for expressing heterologous proteins. Accordingly, we found that protease deficiency could increase the production of heterologous proteins. Finally, through a large-scale fermentation, the 15647-ΔclpS strain was used to produce VHH. Its yield was approximately 530 mg/L, which was 65% higher than that of WT-15647. In this study, a host that could effectively increase heterologous protein expression was successfully obtained.

2021-05-26·ACS Applied Materials & Interfaces2区 · 材料科学

Oral Delivery of Parathyroid Hormone Using a Triple-Padlock Nanocarrier for Osteoporosis via an Enterohepatic Circulation Pathway

2区 · 材料科学

Article

作者: Lee, Dong Yun ; Shahriar, S. M. Shatil ; An, Jeong Man ; Hwang, Yong Hwa ; Lee, Yong-kyu ; Cho, Sungpil ; Hwang, Seung Rim

Intermittent subcutaneous (S.C.) injection of teriparatide [PTH (1-34)] is one of the effective therapies to cure osteoporosis. However, a long-term repeated administration of teriparatide by S.C. to the patients is highly challenging. Herein, a triple padlock nanocarrier prepared by a taurocholic acid-conjugated chondroitin sulfate A (TCSA) is designed to develop an oral dosage form of recombinant human teriparatide (rhPTH). Oral administration of TCSA/rhPTH to the bilateral ovariectomized (OVX) rats resulted in the recovery of the bone marrow density and healthy serum bone parameters from the severe osteoporotic conditions. Also, it enhanced new bone formation in the osteoporotic tibias. This triple padlock oral delivery platform overcame the current barriers associated with teriparatide administration and exhibited a promising therapeutic effect against osteoporosis.

项与重组特立帕肽 (上海联合赛尔) 相关的新闻（医药）

2023-07-16

·药融圈

走出集采低谷！心血管专科龙头，1类新药持续发力！

▲8月03-04日 CMC-China大会 · 限时免费扫码报名中注：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。据CDE官网公示，深圳信立泰药业的1类新药SAL0120片再度递交临床申请并获受理。此前，该药物获批开展用于轻、中度原发性高血压的临床试验。作为心血管代谢专科龙头，信立泰已有多个新药取得成果，在创新转型的路上已进入加速期。截图来源：CDE官网内皮素（endothelin，ET）是由21个氨基酸肽组成的家族，目前发现有ET-1、ET-2、ET-3等，其中ET-1是至今发现的最强效的缩血管物质，因此ET-1及其受体ETA作为病原因素和诱发因子在心血管疾病中被广泛研究。SAL0120片是信立泰自主研发的小分子ETA受体拮抗剂。通过选择性拮抗ETA受体，在现有用药基础上达到进一步降低血压的目的。目前，国内外尚无以原发性高血压为适应症的ETA受体拮抗剂上市销售，若能研发成功并获批上市，将有望为原发性高血压患者提供全新机制的降压药物。创新转型加速，走出集采低谷国家心血管病中心2021年7月发布的《中国心血管健康与疾病报告2020》推算认为，国内心血管疾病患病人数约为3.3亿人，其中高血压2.45亿，脑卒中1300万，冠心病1139万，心力衰竭890万。作为中国传统心血管用药龙头企业，2000年信立泰药业抗血小板聚集药物硫酸氢氯吡格雷片（泰嘉）抢先在原研赛诺菲上市前获批，享有八年保护期，院内销售额一度接近30亿元。后随着国家集采的中标和执行，包括氢氯吡格雷片在内，多个用于高血压、抗血栓、降血脂等心血管疾病的药物销售额接连下滑。信立泰国家集采中标情况截图来源：药融云药品集中采购数据库截图来源：药融云全国医院销售数据库而在2022年，信立泰实现营业收入34.82亿元，同比增长13.85%；净利润6.37亿元，同比增长19.34%。可见，信立泰业绩已逐渐走出集采低谷期，由仿到创的转型也迎来成果验证期。在高血压领域，2012年，信立泰从艾力斯引进高血压1.1类新药药品阿利沙坦酯，2013年，阿利沙坦酯获批上市（商品名：信立坦），近年来院内销售额峰值为7.2亿元。随后信立泰围绕信立坦，布局ARNI类1类药物沙库巴曲阿利沙坦钙片（S086）、首个国产ARB/CCB类2类复方制剂阿利沙坦酯氨氯地平片（SAL0107）、ARB/利尿剂类2类复方制剂阿利沙坦酯吲达帕胺缓释片（SAL0108）等药物。其中，阿利沙坦酯氨氯地平片和沙库巴曲阿利沙坦钙片均已提交上市申请，在审评审批中；阿利沙坦酯吲达帕胺缓释片也已步入III期临床，预计2023年提交NDA申请。此外，沙库巴曲阿利沙坦钙片在慢性心衰适应症上，也已推进至临床3期。在高血压领域以外，信立泰还向抗心衰、肾科、代谢、骨科、自身免疫等领域拓展延伸，建立起了系列产品梯队：在抗心衰领域，除了上述提及的沙库巴曲阿利沙坦钙，还同时在中美布局有重组人神经调节蛋白1-抗HER3抗体融合蛋白注射液（SAL007），均已进行至I期临床阶段；在肾病领域，恩那度司他片已于今年6月获批上市，成为继罗沙司他后第2个国内上市的HIF-PHI；在骨科领域，重组特立帕肽（欣复泰Pro®）水针已经上市，长效剂型有望进一步满足潜在临床需求，骨质疏松蓝海市场抢占新发优势。在代谢领域，1类创新药苯甲酸复格列汀片的NDA申请已获得承办，拟用于治疗2型糖尿病。版权声明：本文转自药融云，如不希望被转载的媒体或个人可与我们联系，我们将立即删除关于CMC-China 博览会融合产业力量，重构行业未来！本次CMC-China博览会汇聚300+医药及上下游全产业链的企业积极报名参展，数千名专业观众报名参观，展会现场将举办15场专业论坛。充分体现了“医药人办医药展，专业人办专业展”的理念。了解更多：数据看展会丨一文看懂第五届CMC-China制药博览会观众亮点点分享点点赞点在看

财报上市批准申请上市带量采购医药出海

100 项与重组特立帕肽 (上海联合赛尔) 相关的药物交易

登录后查看更多信息