2020 年生物制药领域的顶尖时刻

事实证明了 2020 年对于生物制药行业来说是真正的前所未有的一年。从世界各地研究人员的令人难以置信的动员和合作，开发针对 COVID-19 的抗体疗法，到 mRNA 疫苗的突破性和概念验证的里程碑，以及治疗转移性三阴性乳腺癌（mTNBC）和其他癌症的疗法。今年促使业界跳出条条框框进行思考，解决一些世界上最紧迫的挑战。这里是一些亮点：

前所未有的针对 COVID-19 的国际间合作
 

While it seems like COVID-19 has dominated our lives, it has also prompted researchers to collaborate in extraordinary ways. After the SARS-CoV-2 virus was sequenced in January, the National Institutes of Health (NIH) in collaboration with Moderna designed an mRNA vaccine. Two months later, Moderna started Phase I/II trials and in July published their results in The New England Journal of Medicine. Along with Moderna, Pfizer and BioNTech began Phase 3 trials in late July and have since reported over 90% efficacy and vaccines are now available to the public on a rolling basis. This is the fastest vaccine development in history.

这些并非是正在开发的唯一治疗方法。以 SARS-CoV-2 刺突蛋白为靶标的快速抗体发现可以确定病毒中的弱点，并证明了 Twist Biopharma 部门等抗体发现平台的速度和稳定性。Vanderbilt 疫苗中心的研究小组将单细胞测序和功能检测结合起来使用（类似于他们以前对 Zika 病毒所做的工作），根据与刺突蛋白亚结构域的反应性以及与 SARS-CoV 的交叉反应性，将发现的单克隆抗体分为五类。许多抵消抗体识别刺突蛋白的受体结合结构域。

mRNA 疫苗取得了重大突破，并取得了概念验证的里程碑
 

In 1990, a proof-of-concept study showed that cells injected with DNA or RNA could successfully produce the encoded protein, giving credence to gene-based therapeutics. However, subsequent studies revealed problems with introducing foreign mRNA. First, it has low protein production efficiency. Second, it can trigger an immune response independent of the response to the encoded protein. Third, it is unstable. However, two key technological advances have paved the way for mRNA-based vaccines: 合成核苷和脂质纳米颗粒。这些有助于稳定 mRNA，减少以 mRNA 为基础的免疫反应，并增加蛋白质的制造。最终，这些因素为针对 COVID-19 的 mRNA疫苗 的成功做出了贡献，并为未来的 mRNA 疫苗开发打开了大门。

The two most promising and recently approved mRNA vaccines for COVID-19 are the mRNA-1273 vaccine by Moderna and the BNT162b2 vaccine from Pfizer and BioNTech. Both vaccines have a roughly 95% efficacy and require a second dose four weeks after the first injection. Moderna predicts that they can produce 20 million doses by the end of the year for the US, and 500 million to 1 billion doses to be distributed globally in 2021. Pfizer-BioNTech predicts that they can produce 50 million doses by the end of the year and 1.3 billion doses in 2021. Combined, 35 million people can start receiving doses at the end of 2020.

抗体治疗对 COVID-19 的作用
 

Eli Lilly and AbCellera obtained Emergency Use Authorization (EUA) for the neutralizing monoclonal antibody, bamlanivimab (LY-CoV555), for mild-to-moderate COVID-19 treatment in adults and some pediatric patients who are at high risk for progressing to severe status and/or hospitalization. Bamlanivimab came from one of the first recovered COVID-19 patients in the US. It targets the SARS-CoV-2 spike protein and blocks viral entry into human cells. In a Phase II clinical trial, patients receiving bamlanivimab early had reduced viral load, symptoms, and hospitalizations. Eli Lilly predicts that they will have 1 million doses by the end of 2020 and will increase production throughout 2021.

Similarly, Regeneron obtained EUA for a non-competing monoclonal antibody cocktail (REGN-COV2) consisting of casirivimab and imdevimab for patients older than 12 years old who exhibit mild-to-moderate COVID-19 and are at high risk for progressing to severe symptoms and/or hospitalization and are not hospitalized or require oxygen therapy. REGN-COV2 is designed to mimic a well-functioning immune system by neutralizing the virus with potent antibodies that targets the receptor-binding domain of the spike protein, decreasing the ability of viruses to avoid treatment and protecting against spike variants that have evolved in humans. REGN-COV2 is most useful in patients who have recently been diagnosed but have not yet mounted an immune response or have high viral load. Phase II/III clinical trial results demonstrate that REGN-COV2 reduces viral load and hospital visits. Regeneron has partnered with Roche and predicts that they will have enough doses for 200,000 patients by the beginning of 2021.

Gilead Sciences 收购了 Immunomedics
 

Gilead 以 210 亿美元的价格收购了Immunomedics，并将 TrodelvyTM（sacituzumab govitecan-hziy）（一种用于治疗 mTNBC 的一流的 Trop-2 定向抗体-药物偶联物（ADC）添加到其癌症药物组合中。TrodelvyTM 于 4 月获得了美国食品和药物管理局（FDA）的加速批准，用于治疗 HR+/HER2- 乳腺癌和膀胱癌，并且也处于 II/III 期临床试验中。目前正在研究其用于治疗非小细胞肺癌和其他实体瘤类型。由于TrodelvyTM 可以改善 mTNBC 患者的无进展生存期和总体生存期，所以一致投票已提前中止了 III 期的临床试验。

Roche 为癌症免疫疗法提供的新型抗-TIGIT 数据
 

在《美国临床肿瘤学会》，Roche 展示了其第一个 II 期 CITYSCAPE 临床数据，该数据涉及新型抗-TIGIT（具有免疫球蛋白和以酪氨酸为基础的抑制基序域的 T 细胞免疫受体）和 tiragolumab，用于癌症免疫治疗。与用于尿路上皮癌的单克隆抗体治疗 Tecentriq® 联合使用时，tiragolumab 对 PD-L1 阳性转移性非小细胞肺癌（NSCLC）患者具有良好的耐受性。Tiragolumab 通过与 TIGIT（一种同时在免疫细胞上表达的免疫检查点蛋白）以及 PD-L1 通路同时结合而起作用。Roche 数据表明，含有 Tecentriq® 的 tiragolumab 可提高客观反应率，并降低疾病恶化或死亡的风险。副作用类似于仅使用 Tecentriq® 观察到的副作用。

Twist Bioscience 纳米抗体可预防 COVID-19 严重性的关键指标

在 Twist Bioscience，我们从包含超过 100 亿个单域序列的大型合成文库中开发了两个单域抗体（“纳米抗体”） ——、 TB202-63 和 TB202-3。这些纳米抗体可防止已感染 SARS-CoV-2 的仓鼠的体重下降，这是疾病严重程度的关键指标。这些纳米抗体天然存在于美洲驼和其他骆驼科动物中，与传统抗体相比具有三个优势。首先，它们较小，可以挤入较小的抗原结合区域。第二，更容易扩大制造规模。第三，它们可以通过鼻内进行给药，或作为更常规治疗方案的一部分，TB202-63TB202-3并通过结合到刺突蛋白受体结合结构域来抵消 SARS-CoV-2。该设想是鼻内给药，TB202-63并TB202-3防止病毒的雾化颗粒进入鼻腔中的细胞，从而防止感染。此外，我们还与 Vanderbilt 大学医学中心合作，展示了该TB181-36抗体可保护仓鼠的体重下降。

生物制药行业的 2020 年是不可小觑一年，我们期待着乘势而上，迈入更好的 2021 年！