BG18

▎药明康德内容团队报道 根据华昊中天近期发布的公告，该公司将于今日（10月31日）正式在港交所IPO，联席保荐人为建银国际和中信建投国际。华昊中天成立于2002年，是一家合成生物学技术驱动的生物医药公司，致力于开发肿瘤创新药。根据华昊中天招股书介绍，截至最后实际可行日期，该公司拥有一种已商业化产品（优替德隆注射液）及19种其他管线候选产品。华昊中已持续开发优替德隆的其他制剂以及其他活性药物成分，例如BG22、BG18及BG44，这些产品均处于早期开发阶段。 截图来源：华昊中天招股书 华昊中天核心产品优替德隆注射液已经于2021年在中国获批上市，用于治疗既往接受过至少一种蒽环类或紫杉类药物化疗方案的复发或转移性乳腺癌患者。据华昊中天招股书介绍，优替德隆是一款创新的微管抑制剂类药物，其作用机制与紫杉类药物（微管稳定剂）相若，后者在过去三十多年已被广泛用于癌症治疗。 华昊中天研发管线（截图来源：华昊中天招股书） 针对复发或转移性乳腺癌适应症，优替德隆注射液已经获美国FDA开展国际多中心3期临床研究。华昊中天还在开展临床研究，探索优替德隆注射液用于HER2阴性乳腺癌新辅助治疗、晚期非小细胞肺癌治疗、联合PD-1抑制剂一线治疗晚期胃癌和食管癌，以及用于乳腺癌脑转移、肺癌脑转移等脑部肿瘤适应症。正在进行的两项优替德隆注射液联合疗法治疗HER2阴性乳腺癌脑转移2期临床试验显示，优替德隆具有透过血脑屏障的能力，使其在脑部依然能够达到较高的药物浓度。 此外，华昊中天还在开发优替德隆的多种剂型，包括： 口服剂型优替德隆胶囊，目前正在中国进行关键临床试验。华昊中天计划在2024年第四季度向中国国家药监局（NMPA）提交优替德隆胶囊联合卡培他滨治疗晚期乳腺癌的pre-NDA申请。 优替德隆纳米剂型，通过纳米制剂技术增加药物的溶解度，且可有效避免药物中的醇类溶剂及表面活性剂引起的过敏反应，降低用药复杂性。 优替德隆抗体偶联药物，兼具化疗药物的效果与抗体药物的肿瘤靶向性优势。华昊中天认为优替德隆有望成为ADC药物中的良好载荷。 华昊中天其他在研产品还包括： BG22，一种具有良好的抗肿瘤活性的非核糖体多肽类化合物，可通过抑制DNA的复制和转录、抑制缺氧诱导因子1α信号、抑制癌症干细胞而具有抗肿瘤活性。BG22可作为癌症干细胞抑制剂进行开发，适应症为实体瘤。 BG18，一款天然化合物的新型衍生物，为一种具有高度特异性抑制活性的蛋白磷酸酶抑制剂。研究显示，这种天然化合物在体外对白血病、肠癌、肺癌、乳腺癌、卵巢癌等人癌细胞株均有良好的抑制作用，在体内也具有较好的抗肿瘤效果。 BG44，一款通过基因工程菌生产的优替德隆衍生物。 根据华昊中天招股书介绍，未来该公司将不断加强研发活动，将产品推向全球，同时扩大销售团队建设，吸引和培养优秀人才，不断加快科技创新和产品商业化。 参考资料： [1] 02563-華昊中天醫藥-B-新上市. Retrieved Oct 29, 2024, from https://data.eastmoney.com/notices/detail/02563/AN202410291640557719.html [2]华昊中天招股书. From https://www1.hkexnews.hk/listedco/listconews/sehk/2024/1023/2024102300016_c.pdf 本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权及其他合作需求，请联系wuxi_media@wuxiapptec.com。 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

A major challenge in developing a vaccine for HIV is that the virus mutates fast -- very fast. Although a person initially becomes infected with one or a few HIV strains, the virus replicates and mutates quickly, resulting in a 'swarm' of viral strains existing in a single body. A major challenge in developing a vaccine for HIV is that the virus mutates fast -- very fast. Although a person initially becomes infected with one or a few HIV strains, the virus replicates and mutates quickly, resulting in a "swarm" of viral strains existing in a single body. But scientists at Scripps Research; IAVI; the Ragon Institute of Mass General, MIT, and Harvard; La Jolla Institute for Immunology; and additional institutions have conducted a series of preclinical trials indicating that they're potentially closer to an immunization regimen than ever before -- one that could produce rare antibodies that would be effective against a wide range of HIV strains. Published in Science, Science Immunology, and Science Translation Medicine on May 16, 2024, the findings are outlined in four individual papers and build on a 2022 phase I clinical trial conducted by the nonprofit scientific research organization IAVI. The findings represent a key step forward in an immunization strategy that could protect against the virus. "All in all, these studies show that we have a good chance at creating an effective HIV vaccine -- we just need to keep iterating and build on these findings in future clinical trials," says co-senior author of all four studies, William Schief, PhD, who is also a Scripps Research professor; vice president for antigen design and selection, Infectious Disease Research, at Moderna, Inc.; and executive director of vaccine design at IAVI's Neutralizing Antibody Center. The HIV vaccine strategy involves stimulating the body to produce mature broadly neutralizing antibodies (bnAbs). bnAbs are among the immune system's key players in fighting HIV, since they can block many variants of the virus. The problem is that bnAbs produced by the human body are rare. The IAVI trial, spearheaded in part by Schief, focused on inducing the immune cells that could eventually evolve into the right bnAbs -- ones that could protect host cells from multiple HIV strains. These precursor immune cells, known as B cells, were stimulated with the help of a priming immunogen -- a customized molecule to "prime" the immune system and elicit responses from the correct precursor cells. But the primer also requires additional "booster" immunogens to coax the immune system into producing not just precursor cells, but coveted VRC01-class bnAbs -- a rare and specific class of antibodies known to neutralize more than 90 percent of diverse HIV strains. Boosters are also needed for the production of BG18 -- another important bnAb class that binds to sugars on the HIV spike protein. That's where the new studies come in: Researchers developed immunization regimens that could prime either VRC01 or BG18 precursors, and subsequently boost those precursors further down the path toward becoming bnAbs. "The results contained in these papers are deeply exciting and further support the germline-targeting strategy to HIV vaccine development that IAVI and our partners are pursuing," says Mark Feinberg, MD, PhD, president and CEO of IAVI. "We look forward to continuing our collaboration with Scripps Research and partners to advance further research building on these promising findings." This groundbreaking science is enabled by collaboration between scientific institutions and funding partners. Without the ongoing, critical support of the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), the Collaboration for AIDS Vaccine Discovery (CAVD), the Bill & Melinda Gates Foundation, and Moderna (the manufacturer of the mRNA used in these studies), this research would not have been possible. Priming rare antibodies In the first study, which focused on BG18, Scripps Research scientists collaborated with co-senior authors Shane Crotty, PhD, chief scientific officer at La Jolla Institute for Immunology, and Devin Sok, PhD, former vice president, discovery and innovation at IAVI. Using a priming immunogen, they consistently primed exceptionally rare BG18 precursors in a wild-type animal model. To confirm they were able to prime the correct precursors, the researchers then teamed up with Andrew Ward, PhD, Scripps Research integrative structural and computational biology professor and co-senior author of the study. Using cryo-EM structural analysis, they validated that the antibodies were indeed part of the BG18 class. "The fact that priming worked well in macaques suggests that it has a good chance of succeeding in humans," says co-first author, Jon Steichen, PhD, an institute investigator in the Department of Immunology and Microbiology at Scripps Research. Steichen was also co-first author on a second study, in which mice were modified to produce a low frequency of BG18 precursors. Scripps Research and IAVI scientists, along with the team of co-senior author Facundo Batista, PhD, associate director and scientific director of the Ragon Institute of MGH, MIT, and Harvard, used priming methods similar to the ones used in the first paper. However, a key difference was that this time, they also administered one of two boost immunogens using RNA technology. This resulted in boosting the primed B cells to adapt to recognize more native-like versions of HIV. "This study showed that we can start to walk the B cells along toward bnAb development," Steichen explains. Supercharging the immune system into action For the third study, Schief and his team worked with IAVI scientists, wherein they primed a mouse model with the same immunogen used in the 2022 IAVI clinical trial. This resulted in mice that produced VRC01-class precursor B cells similar to those found in people. But the researchers also designed a new booster immunogen to drive the antibody response toward becoming matured bnAbs -- the next vital step in a sequential immunization series that could effectively fight HIV. The results: a "prime-boost" regimen that can drive VRC01-class B cells toward bnAb development. "The findings demonstrate that we are able to make the antibody responses go in the right direction using this heterologous booster, which administers a different version of the vaccine than was given previously," says Christopher Cottrell, PhD, a senior staff scientist at Scripps Research who was the first co-author on this study. Understanding the immunology In the fourth and final study, on which Cottrell was also a co-first author, the team worked again with Batista's team at the Ragon Institute and used the same immunogens -- but in a different mouse model where his team could control the frequency of bnAb precursors that were modified to be similar to those found in humans. This allowed the researchers to take a deeper dive into the immunology associated with HIV vaccination by examining the germinal centers -- specialized microstructures in the body that protect against viral reinfection. Germinal centers provide B cells with a space to rapidly increase and mutate their antibody genes, ultimately helping the immune system fight off viral strains. In addition, the researchers examined how germinal centers accumulate HIV mutations over time. They found that a prime-boost regimen increased precursor B-cell activity in germinal centers across different lineages, which could eventually lead to an increase in matured VRC01-class bnAbs. What's next Overall, all four papers confirm that the priming step to turn on the right bnAb precursors is possible when it comes to developing an HIV vaccine. Three of those papers specifically demonstrate that it's also possible to guide antibody precursors toward becoming bnAbs that can fight HIV. "Taken together, the findings give us more confidence that we're able to prime precursors from multiple bnAb targets, and they also show that we're starting to learn the rules for how to advance precursor maturation through heterologous boosting," Schief added. Following these results, the researchers are advancing phase 1, experimental medicine trials for both the VRC01 and BG18 projects. Vaccines aiming to prime and boost VRC01-class antibodies are being further evaluated in two clinical trials run by IAVI, IAVI G002 and IAVI G003, and a vaccine to prime BG18-class responses is being evaluated in HVTN144. These studies use both adjuvanted protein immunizations (IAVI G001 and HVTN144) and mRNA delivery (IAVI G002 and G003). The results of these studies will guide the critical next steps on the discovery path to an HIV vaccine.