A Phase 3 Double-blind, Randomized, Placebo-controlled, Parallel-group Study To Assess The Efficacy, Safety And Tolerability Of Bococizumab (Pf-04950615) In Asian Subjects With Primary Hyperlipidemia Or Mixed Dyslipidemia At Risk Of Cardiovascular Events

This study is a Phase 3, double blind, placebo controlled, randomized, stratified, parallel group, multi-center clinical trial designed to compare the efficacy and safety of bococizumab 150 mg SC Q2wks to placebo for LDL-C lowering in subjects with primary hyperlipidemia or mixed dyslipidemia at high or very high risk for CV events. The study will enroll a total of approximately 750 subjects from 4 - 5 Asian countries/areas (including China mainland); of which approximately 600 subjects will be from sites in China. Subjects will be randomized into a bococizumab treatment arm and a placebo arm in a 1:1 ratio.

开始日期2016-10-31

申办/合作机构

Pfizer Inc.

NCT02524106 / Terminated临床3期

Bococizumab HIV Evaluation (B-HIVE) Study: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study to Assess the Efficacy and Safety of Bococizumab, a PCSK9 Inhibitor, in HIV-Infected Subjects

B-HIVE is a Phase 3, double blind, placebo-controlled, randomized, parallel group study, designed to compare the efficacy and safety of bococizumab 150 mg subcutaneously every 2 weeks to bococizumab placebo subcutaneously every 2 weeks for LDL-C lowering in HIV-infected subjects.

开始日期2016-08-01

申办/合作机构

The University of California, San Francisco

[+2]

CTR20160159 / Suspended临床3期

评估Bococizumab减少高危受试者主要心血管事件发生风险的疗效、安全性和耐受性的III期研究

本临床试验的主要目的是在接受背景降脂治疗但LDL-C≥70 mg/dL（1.81 mmol/L）或非HDL-C≥100 mg/dL（2.59 mmol/L）的主要心血管事件高危或极高危受试者中证明Bococizumab在降低主要心血管事件风险方面的疗效优于安慰剂。主要心血管事件是一个包括经裁定并证实的心血管死亡、非致死性心肌梗死、非致死性卒中及因需要紧急血运重建的不稳定型心绞痛住院的复合终点。

开始日期2016-07-09

申办/合作机构

Pfizer Inc.

[+2]

100 项与 Bococizumab 相关的临床结果

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100 项与 Bococizumab 相关的转化医学

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100 项与 Bococizumab 相关的专利（医药）

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项与 Bococizumab 相关的文献（医药）

2024-12-31·mAbs

Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG ₁ antibodies

Article

作者: Tran, Peter ; Peng, Kun ; Brumm, Jochen ; Carter, Paul J ; Wu, Patrick ; Li, Yinyin ; Phung, Qui ; Tsai, Wen-Ting K ; Cohen, Sivan ; Tam, Sien ; Ye, Zhengmao ; Spiess, Christoph ; Wong, Manda ; Qin, Dan ; Yin, Zhaojun ; Zhou, Zhenru

Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient in vivo assembly of bispecific IgG in single host cells. A panel of related monospecific and bispecific IgG₁ antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Assay methods used include dendritic cell internalization, T cell proliferation, and T cell epitope identification by in silico prediction and MHC-associated peptide proteomics. Data from each method were considered independently and then together for an overall integrated immunogenicity risk assessment. In toto, these data suggest that the KIH mutations and in vitro assembly of half antibodies do not represent a major risk for immunogenicity of bispecific IgG₁, nor do the Fab mutations used for efficient in vivo assembly of bispecifics in single host cells. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG₁ as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts.

2023-12-31·mAbs

Rapid in vitro assessment of the immunogenicity potential of engineered antibody therapeutics through detection of CD4 ⁺ T cell interleukin-2 secretion

Article

作者: Mishima, Masayuki ; Ikuno, Tatsuya ; Mizuno, Hideaki ; Takeiri, Akira ; Yano, Mariko ; Arata, Yoshiyuki ; Motoyama, Shigeki ; Nishito, Yukari ; Tabo, Mitsuyasu ; Yabuki, Nami ; Matsushita, Tomochika ; Kiyokawa, Jumpei ; Suzuki, Hiromi ; Ito, Shunsuke ; Chiba, Shuichi ; Kubo, Chiyomi ; Honda, Masaki ; Sampei, Zenjiro

Therapeutic antibodies sometimes elicit anti-drug antibodies (ADAs) that can affect efficacy and safety. Engineered antibodies that contain artificial amino acid sequences are potentially highly immunogenic, but this is currently difficult to predict. Therefore, it is important to efficiently assess immunogenicity during the development of complex antibody-based formats. Here, we present an in vitro peripheral blood mononuclear cell-based assay that can be used to assess immunogenicity potential within 3 days. This method involves examining the frequency and function of interleukin (IL)-2-secreting CD4⁺ T cells induced by therapeutic antibodies. IL-2-secreting CD4⁺ T cells seem to be functionally relevant to the immunogenic potential due to their proliferative activity and the expression of several cytokines. The rates of the donors responding to low and high immunogenic proteins, mAb1, and keyhole limpet hemocyanin were 1.3% and 93.5%, respectively. Seven antibodies with known rates of immunogenicity (etanercept, emicizumab, abciximab, romosozumab, blosozumab, humanized anti-human A33 antibody, and bococizumab) induced responses in 1.9%, 3.8%, 6.4%, 10.0%, 29.2%, 43.8%, and 89.5% of donors, respectively. These data are comparable with ADA incidences in clinical settings. Our results show that this assay can contribute to the swift assessment and mechanistic understanding of the immunogenicity of therapeutic antibodies.

2023-12-01·CPT: pharmacometrics & systems pharmacology

Population PK/PD modeling of low‐density lipoprotein cholesterol response in hypercholesterolemic participants following administration of bococizumab, a potent anti‐PCSK9 monoclonal antibody

Article

作者: Sweeney, Kevin ; Yunis, Carla ; Gibiansky, Leonid ; Wang, Ellen Q ; Plowchalk, David ; Kaila, Nitin

Abstract:

We sought to characterize the population pharmacokinetic/pharmacodynamic (PK/PD) relationship of bococizumab (RN316/PF‐04950615), a humanized IgG2Δa monoclonal antibody that binds to secreted human proprotein convertase subtilisin kexin type 9 (PCSK9), using data derived from 16 phase I, II, and III clinical studies (36,066 bococizumab observations, 46,790 low‐density lipoprotein cholesterol [LDL‐C] measurements, 3499 participants). A two‐compartment disposition model with parallel linear and Michaelis–Menten elimination and an indirect response model was used to characterize the population PK and LDL‐C response of bococizumab. Potential model parameters and covariate relationships were explored, and visual predictive checks were used for model assessment and validation. Key covariates included the effect of anti‐drug antibodies (ADAs) on exposure through impact on clearance and bioavailability; impact of statins on bococizumab elimination (maximal rate of metabolism); and impact of statins, Asian race, and male sex on LDL‐C efficacy (maximum effect). ADAs and neutralizing ADAs did not have additional effects on LDL‐C beyond the influence on bococizumab exposure. In conclusion, the population PK/PD model adequately describes bococizumab concentration and LDL‐C efficacy. The covariate effects are consistent with the presumed mechanism of action of PCSK9 inhibitors. With increasing availability of antibody‐based therapeutics, improved understanding of the effect of ADAs and statins on bococizumab PK/PD adds to the literature and enhances our pharmacological understanding of how immunogenicity and concomitant medications may impact the PK/PD of biotherapeutics.

项与 Bococizumab 相关的新闻（医药）

2023-06-08

·美通社

药康生物推出全人源抗体转基因模型NeoMab（TM）及服务平台

南京 2023年6月8日 /美通社/ -- 经过4年的研发和验证，药康生物（股票代码：688046）自主研发的全人源抗体转基因小鼠模型 NeoMab ™ 正式走向市场，服务生物技术公司和制药企业的治疗性抗体研发。 Ne oMab ™ 小鼠是在BALB/c遗传背景下，保留了编码鼠源抗体基因的恒定区序列，但通过基因编辑将编码人类抗体可变区的基因序列原位替代鼠源序列（图1）。图1.NeoMab™模型人源化策略示意图经体外和体内实验验证， NeoMab ™ 小鼠有以下优势： NeoMab ™ 小鼠使用人类V(D)J基因编码抗体，且其使用频率与人类近似，序列多样性与人类接近。 NeoMab ™ 小鼠免疫系统健全，各免疫细胞亚群比例与BALB/c背景鼠接近。抗体类型转换及体细胞超突变正常发生，B细胞正常发育分化，血清中各种免疫球蛋白亚型含量与BALB/c背景鼠接近。人类重组蛋白抗原免疫后，NeoMab ™ 小鼠抗原特异性结合血清效价与同批免疫的BALB/c背景鼠接近，3次免疫之后效价达到10 5 -10 6 左右。获得的抗体亲和力（SPR检测）约10 -10 -10 -8 ，与FDA批准的临床治疗性抗体药物相当，甚至更高。抗体体外功能活性及体内药效与FDA批准的临床治疗性抗体药物近似。药康生物全人源抗体转基因模型NeoMab ™ 及技术平台，通过模型使用授权和高通量筛选平台，协助创新药企快速且低成本完成临床前发现和验证工作，优化药企资金投入，为创新药研发赋能。化零为整，合作共赢药康生物致力于为疾病机制研究、药物研发和转化医学研究提供模型和技术服务支持。目前，药康生物已经建成了斑点鼠、药筛鼠等模型资源库，可以为药物靶点验证和药理药效研究提供重要的模型支持。同时，药康生物还搭建了肿瘤、代谢、心血管、免疫、神经等领域的非临床研究服务平台。这些平台结合模型资源优势，可提供多领域的非临床研究服务。 NeoMab ™ 平台作为全新的成员，为抗体发现提供支持。通过与模型资源和各大专业技术服务平台整合，药康生物为药物研发企业提供全方位的支持，推动新药的发现与发展。关于全人源抗体转基因模型自1986年FDA批准第一个治疗性抗体OKT3(Ecker, Jones et al. 2015)以来，治疗性抗体迅速发展，抗体药已成为现代生物医药的重要组成部分，是近几年销量最高的一类药物。然而，研发成功率低、成本高、研发周期长等问题仍是抗体类药物研发面临的挑战。图2. 不同人源化程度的抗体结构示意图（来源：Luet al. Journal of Biomedical Science. 2020）作为大分子药物，免疫原性（ADA）是抗体药能否成功的决定性因素之一。为了降低免疫原性，治疗性抗体经历了鼠源抗体、嵌合抗体、改型抗体、人源化抗体及全人源抗体等不同发展阶段(Lu, Hwang et al. 2020)（图2）。研发实践证明，随着人类序列占比的提高，免疫原性风险下降(Safdari, Farajnia et al. 2013)。然而，人源化改造需要花费额外的成本及时间，且即便经过人源化改造的抗体仍然不能消除免疫原性风险。以靶向PCSK9的抗体为例，Alirocumab和Evolocumab均为来源于转基因鼠的全人源抗体，顺利获批上市，而人源化抗体Bococizumab则因免疫原性高而折戟临床三期(Ridker, Tardif et al. 2017)。相对而言，完全由人类序列编码的全人源抗体更具研发优势。图3.截止2022年获批抗体分类及占比（左图来源：Lyu, Xiaochen, et al. Antib Ther. 2022;右图来源：根据各公司年报统计分析）截止2022年，已有超过160种抗体疗法获得监管机构批准上市，从趋势上看，全人源抗体所占比例越来越大(Lyu, Zhao et al. 2022)。2022年销量TOP50的抗体药中，全人源抗体占据45%，而这些获批的全人源抗体中，70%来自于转基因小鼠（图3）。可见，全人源抗体转基因小鼠平台用于全人源抗体研发的可行性及优势已经被充分验证过。第一代全人源化抗体转基因模型是采用"TG+KO"技术制作的，即通过转基因技术制备携带人类抗体编码基因片段的TG小鼠，并且将小鼠内源的抗体编码基因敲除（KO）。代表平台是于1994年研发成功的HuMab(Lonberg, Taylor et al. 1994, Taylor, Carmack et al. 1994)平台（BMS收购）及于1997年研发成功的XenoMouse(Jakobovits 1995)平台（Amgen收购）。虽然人类基因片段数量有限，且免疫响应与野生型小鼠有明显差距，但它们贡献了2/3已获批的来源于转基因小鼠的全人源抗体（19个）。第二代模型采用原位敲入的方式制作，即在小鼠内源抗体基因座插入人类抗体可变区基因库，保留小鼠恒定区基因片段，这也是NeoMab ™ 采用的策略。第二代模型克服了人类基因片段数量限制、保留内源表达调控及Fc端介导的信号传导(Murphy, Macdonald et al. 2014)，因此其免疫响应接近野生型小鼠。海外最知名的平台是Regeneron于2009年研发成功的VelocImmune(Macdonald, Karow et al. 2014, Murphy, Macdonald et al. 2014)，截止目前该平台已有7个抗体获批。如需了解更多全人源抗体转基因模型NeoMab™及服务平台，请点击这里参考文献: [1]Ecker, D. M., S. D. Jones and H. L. Levine (2015). "The therapeutic monoclonal antibody market." MAbs 7(1): 9-14. [2]Jakobovits, A. (1995). "Production of fully human antibodies by transgenic mice."Curr Opin Biotechnol 6(5): 561-566. [3]Lonberg, N., L. D. Taylor, F. A. Harding, M. Trounstine, K. M. Higgins, S. R. Schramm, C. C. Kuo, R. Mashayekh, K. Wymore, J. G. McCabe and et al. (1994). "Antigen-specific human antibodies from mice comprising four distinct genetic modifications." Nature 368(6474): 856-859. [4]Lu, R.-M., Y.-C. Hwang, I. J. Liu, C.-C. Lee, H.-Z. Tsai, H.-J. Li and H.-C. Wu (2020). "Development of therapeutic antibodies for the treatment of diseases." Journal of Biomedical Science 27(1): 1. [5]Lyu, X., Q. Zhao, J. Hui, T. Wang, M. Lin, K. Wang, J. Zhang, J. Shentu, P. A. Dalby, H. Zhang and B. Liu (2022). "The global landscape of approved antibody therapies." Antib Ther 5(4): 233-257. [6]Macdonald, L. E., M. Karow, S. Stevens, W. Auerbach, W. T. Poueymirou, J. Yasenchak, D. Frendewey, D. M. Valenzuela, C. C. Giallourakis, F. W. Alt, G. D. Yancopoulos and A. J. Murphy (2014). "Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes." Proc Natl Acad Sci U S A 111(14): 5147-5152. [7]Murphy, A. J., L. E. Macdonald, S. Stevens, M. Karow, A. T. Dore, K. Pobursky, T. T. Huang, W. T. Poueymirou, L. Esau, M. Meola, W. Mikulka, P. Krueger, J. Fairhurst, D. M. Valenzuela, N. Papadopoulos and G. D. Yancopoulos (2014). "Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice." Proc Natl Acad Sci U S A 111(14): 5153-5158. [8]Ridker, P. M., J. C. Tardif, P. Amarenco, W. Duggan, R. J. Glynn, J. W. Jukema, J. J. P. Kastelein, A. M. Kim, W. Koenig, S. Nissen, J. Revkin, L. M. Rose, R. D. Santos, P. F. Schwartz, C. L. Shear, C. Yunis and S. Investigators (2017). "Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab." N Engl J Med 376(16): 1517-1526. [9]Safdari, Y., S. Farajnia, M. Asgharzadeh and M. Khalili (2013). "Antibody humanization methods - a review and update." Biotechnol Genet Eng Rev29: 175-186. [10]Taylor, L. D., C. E. Carmack, D. Huszar, K. M. Higgins, R. Mashayekh, G. Sequar, S. R. Schramm, C. C. Kuo, S. L. O'Donnell, R. M. Kay and et al. (1994). "Human immunoglobulin transgenes undergo rearrangement, somatic mutation and class switching in mice that lack endogenous IgM." Int Immunol 6(4): 579-591.

引进/卖出临床1期

2023-02-06

·生物制药小编

药明生物巨作：单抗、BsAb以及ADC药物的可开发性评估

与抗体相关的生物药物，包括单抗、双特异性抗体（BsAb）和ADC，已成为一类重要的创新药物。在此类药物的研究和开发的发现阶段，最初的重点通常是在候选药物的作用机理和生物学功能，但这些候选药物的可开发性评估后期将变得至关重要。近日，来自药明生物的团队在Antibody Therapeutics期刊上发表了题为“Developability assessment at early-stage discovery to enable development of antibody-derived therapeutics”的综述，系统的介绍了单抗、BsAb和ADC的物理化学性质对其可开发性的重要贡献(图1)。本文就一些重要内容做一个介绍。图1. 影响可开发性评估的关键因素抗体药物发现与发展的一般过程抗体的发现和开发过程包括几个步骤(图2)。一旦确定了靶标或与疾病相关的信号通路，就可以使用体内免疫、体外展示技术、B细胞分选或其组合技术来产生抗体。数百到数千个与靶标结合的抗体，可以使用几个筛选步骤来缩小范围，以获得具有适当亲和力、特异性和功能性的抗体。这些抗体可以通过亲和力成熟、人源化、Fc工程等过程进一步优化。这些抗体的物理化学性质也可以在这个过程中发生改变。图2. 从靶标评估到IND的不同阶段考虑与可开发性相关的衡量标准一般，如果抗体在结合到细胞上的靶点时能够内化，抗体可与有效载荷结合以产生ADC。BsAb可以从单抗对的原始筛选中产生，或者可以在鉴定出一对单抗之后进行工程化设计(图3)。图3.IgG单抗的结构和双抗或多抗的基本构建块一旦抗体被确定为临床前候选抗体，将建立抗体稳定表达的细胞系，并将开发一系列纯化步骤。在临床前开发期间，抗体可能会在猴子或其他相关物种身上进行测试，以进行毒理学研究。ICH指南(S6R1)建议“应选择剂量水平，以提供关于dose-response关系的信息，包括毒性剂量和未观察到的不良反应水平(NOAEL)”。在毒理学研究中选择高剂量水平以指导临床使用是常见的，有时也是必要的。可开发性评估在发现和发展阶段是不同的如图4所示，发现阶段的可开发性评估与不同于CMC阶段的可开发性研究。在发现阶段，重要的是确定具有靶标产品特征的治疗分子。在CMC阶段将进一步评估lead分子的关键质量属性(CQA)，以建立质量目标产品概况。在发现阶段进行可发性评估，可使用快速和高通量方法识别潜在的可开发性风险。图4. 发现和开发阶段的不同目的和测试指标即使在发现阶段只确定了一种功能最优的抗体，它的可开发性仍然需要评估和可能的优化。在发现阶段设计抗体的成本显著低于在开发阶段优化工艺和配方的成本。此外，抗体的不良物理化学性质可能会影响其在体外和体内的生物学功能。例如， CDR的翻译后修饰(PTM)会显著降低其效力。如果在发现阶段发现抗体存在可开发性问题，可以通过蛋白质工程来解决。例如，抗体CDR结构域中疏水残基改造可降低其沉淀倾向。相反，在发展阶段进行可开发性研究，以获得足够的材料和合理的工艺和配方，用于临床前和临床用途。这项研究通常是复杂和耗时的，需要大量(数百毫克到几克)的测试材料，这些材料通常来自稳定的细胞系或pool。通过聚乙二醇沉淀法在不同的pH值下筛选不同的缓冲液(如醋酸盐、柠檬酸盐和磷酸盐缓冲液)，以确定具有最高溶解度的缓冲液，进行溶解性研究。可以通过筛选含有适当辅料(例如蔗糖和聚山梨酸酯80)的缓冲液来进一步评估溶解度。在每个配方中，抗体被溶解到可能的最高浓度，并储存在2◦C-8◦C中。以不同的时间间隔采集样本，测定其外观、浓度和SEC色谱图，并将结果与T0时的结果进行比较。该研究的这一部分可作为配方前筛选。然后，可以使用所选择的缓冲液中的样品，在stress条件下使用目标浓度的赋形剂进行展开性研究。一组测试通常用来评估候选药物的可开发性 (图5)，包括测试方法和在stress条件下的稳定性研究，例如，暴露在高温、低或高pH、光、氧化剂和冻融中。图5. 在发现和CMC阶段进行可开发性评估的测试项生物候选药物的可开发性极大地影响了这些候选药物从发现到临床开发和商业化的速度、成本和成功率。随着现代生物技术的进步和经验的积累，应在早期发现阶段进行可开发性评估，以降低此类药物开发的风险。在发现阶段可开发性相关的考量和评估对已批准的抗体药物的分析可以对发现阶段的可开发性评估提供重要参考。图6汇总了美国、欧洲、日本和中国机构批准的129种抗体药物的浓度和给药途径。在54种批准用于癌症治疗的抗体中，中位浓度为11.25 mg/mL，远低于自身免疫性疾病皮下注射抗体的中位浓度(100 mg/mL)。用于眼科治疗的玻璃体内注射抗体是以小体积和高浓度配制的。例如，抗VEGF抗体brolucizumab的体积为0.05 mL，浓度为120 mg/mL。图6. 根据疾病适应症(A)和给药途径(B)批准的抗体浓度在几个已获批准的BsAb中，有三个是T细胞结合分子：抗CD3和CD19的blinatumomab制剂为冻干粉，剂量为009-0.028 mg/day；抗CD3和gp100的tebentafusp以0.2 mg/mL的浓度储存在溶液中，剂量为0.02-0.068 mg/day；抗CD3和CD20的mosunetuzumab以1 mg/mL的浓度在溶液中制备。另外4种BsAb分别为amivantamab, cadonilimab, emicizumab 和faricimab，其浓度分别为静脉注射50 mg/mL、静脉注射12.5 mg/mL、皮下注射150 mg/mL和玻璃体内注射120 mg/mL。经批准的13个ADC中有12个是冻干粉，这可能是由于连接子和有效载荷在液体状态下不稳定所致。通过对这些批准的抗体药物分析，可以得出，根据抗体药物治疗的疾病适应症以及抗体药物可能的剂量和给药途径，不同项目的开发标准可以不同。在靶标评估阶段，应考虑治疗性抗体的可能临床用途。例如，眼科适应症的治疗性抗体是通常玻璃体内注射，体积很小，因此候选抗体需要具有高溶解度和低粘度。在抗体产生阶段，通常通过抗原结合活性和生物学功能来筛选候选抗体。在这一阶段表达和纯化的抗体数量很少(通常小于1mg)。应检查抗体的外观、表达水平、产率、纯度和与靶标同源物的结合情况。在抗体的整个制造和使用过程中，应观察抗体的外观，包括细胞培养、培养上清液的采集、纯化、浓缩、储存、冻融和稀释到分析缓冲液中。有可见颗粒或沉淀物的抗体应引起注意，并可能需要优化。表达水平可以通过protein A层析测定。通常，100 mg/L的Expi293瞬时表达的单抗被认为是可以接受的。通常，大于90%的纯度对于大多数体外检测是可以接受的。发现颗粒、聚集体、低表达、低纯度或与同源物结合是可开发性的警告信号。当抗体序列可用时，应进行计算机分析，以标记PTM热点、特定位置的异常残基、序列的缺失或添加等。单抗通常被进一步工程化以满足项目的要求，如人源化、亲和力成熟、Fc工程等。在这一阶段，除了监测外观、表达水平和纯度外，还应去除高危的PTM热点并进行热稳定性检查。应去除高危基序，包括NG/NS/DG基序、额外半胱氨酸残基和可变区上的N糖基化基序，以减少对疗效和安全性的潜在风险。一旦一些候选抗体被确定用于临床前研究，建议测试与溶解性相关的特征和广泛的非特异性结合。当单抗通过连接子与有效载荷结合以形成ADC时，有效载荷、连接子可能改变单抗的构象。有效载荷的疏水性和电荷分布的不均匀可能会引发ADC的聚集。因此，在偶联后，ADC的纯度、产率和药物抗体比(DAR)需要测量，特别注意高分子量的百分比。还应测量ADC在多次冷冻和解冻后的稳定性。可检测ADC的血清稳定性，以测量从ADC中分离出的有效载荷的百分比。一个BsAb通常由一对针对不同靶点的亲本抗体组装而成。由于亲本抗体可变区的物理化学性质将携带到BsAb上，建议在构建和优化BsAb之前评估并在必要时优化亲本抗体。还应检查BsAb的外观、表达、纯度、热稳定性等。在进行BsAb工程化改造时，还应进行计算机分析，以避免增加PTM热点。对于具有潜在可开发性风险的候选抗体，可以采用几种策略。带有轻微可见颗粒或沉淀物的抗体分子可以在不同的配方缓冲液中进行测试。对于具有严重可开发性风险的抗体，如具有连续聚集、稳定性差、低溶解度或显著的非特异性结合的分子，有必要对抗体序列进行工程化改造。序列优化后，应重新评估所有可开发性属性，如果发现风险信号，则需要进一步优化。最后，如果在不改变抗原结合的情况下不能去除PTM热点，应进行stress应激研究以评估潜在的风险。抗体的内在特性决定其可开发性为了分析和优化与可开发性相关的属性，如均质性、稳定性和溶解性，有必要了解影响其可展性的抗体的内在属性，包括其多肽折叠、电荷分布和疏水性。抗体聚集是一个常见的发展问题，抗体结构域的部分展开可以触发抗体聚集，导致单体-单体结合，随后成核和聚集。CDR环的表面电荷分布也会影响抗体聚集/胶体稳定性。当表面电荷分布不对称或变化时，局部的表面电荷斑块可能通过静电相互作用产生蛋白质-蛋白质的相互作用，最终导致胶体不稳定。蛋白的静电表面电荷分布在控制分子间相互作用以及随后的自结合和粘度行为中起主导作用，特别是在抗体浓度较高的情况下。疏水性和亲水性由20个氨基酸及其翻译后或共翻译修饰的衍生物的侧链决定。疏水表面斑块的强度可以通过邻近的带电残基来调节。CDR中疏水斑块的展开或错误折叠可以赋予抗体高度的疏水性，并可能导致分子间的吸引、低溶解度、高粘度甚至聚集。BsAb或多特异性抗体通常是由几个构建块组装而成的，如VHH(单域抗体)、可变区(Fv)、单链可变区(ScFv)、Fab和单链Fab(ScFab)，靶向不同的抗原或表位。这些抗体片段的折叠稳定性可能比全长抗体低。另外，不同的域可能具有极性电荷，一个分子上的多个域可能会增加其聚集或不稳定性的趋势。影响化学稳定性的风险，如脱胺和异构化，与单抗相似。然而，BsAb的化学不稳定性的累积效应可能比单抗更为严重。匀质性因为抗体是由活细胞产生的，所以抗体衍生的药物不可能像化学合成的小分子药物那样同质。ICH指南(Q6B)建议，与制造过程相关的杂质和一些与产品相关的杂质应减少到可接受的水平。与制造过程相关的杂质包括细胞底物(例如宿主细胞蛋白质、宿主细胞DNA)、细胞培养成分(例如诱导剂、抗生素或培养基成分)和下游加工基质。与产品相关的杂质(如前体、某些降解产物)是在制造或储存过程中产生的分子变体，在活性、有效性和安全性方面无法与预期产品的特性相媲美。在发现阶段，与产品相关的杂质是评估和优化可开发性的主要关注点。未配对、丢失或不匹配的链未配对或缺失的LC是单抗和BsAb制剂中常见的异质性。一般来说，缺少LC的抗体的大小、电荷或疏水性/亲水性与完整抗体的大小、电荷或疏水性/亲水性不同。这种差异可用于纯化完整抗体产品。在BsAb产品中防止错配是一个特别的挑战，因此为了获得均一的BsAb产品，已经开发了不同的BsAb格式。下游净化工艺，如亲和、电荷、尺寸、疏水性和基于混合模式的纯化方法，已经被用来去除不需要的BsAb副产物。裂解抗体的裂解也会出现，其可发生在N末端、铰链区、恒定区或C末端。与抗体的其他部分相比，铰链区具有高度的灵活性。多肽键的断裂，酶或化学断裂，主要发生在铰链区和CH2-CH3界面上，导致不同大小的片段。切割敏感性与铰链区的长度和灵活性有关。研究发现，IgG1抗体比IgG2和IgG4抗体更容易受到切割过程的影响。铰链切割可能会对二价结合、Fc效应功能和FcRn功能产生负面影响，导致疗效降低和清除速度加快。因此，应根据抗体的作用机制来评价铰链切割对抗体效力的影响。修饰抗体的修饰会导致异质性，其可以发生在抗体药物制造过程的任何阶段，甚至在给药之后。通常需要研究的修饰包括半胱氨酸相关的修饰、脱氨基、异构化、氧化和糖基化。这些修饰可能导致抗体大小或电荷的异质性，也可能影响抗体的稳定性、安全性和有效性。这里不再一一细述。聚集聚集是治疗性抗体的CQA之一。蛋白质聚集的主要机制包括天然单体的缔合、构象改变单体的聚集、化学修饰单体的聚集、成核控制聚集和表面诱导聚集。抗体的聚集可能导致候选抗体的免疫原性增强和生物学功能降低。抗体的聚集倾向主要与折叠稳定性和表面的疏水性有关。一些外在因素可诱导或减少抗体聚集。候选抗体在低pH值、超滤/浓缩步骤、物理应力、冻融循环后、通过与容器相互作用或在长期储存后可加速聚集。对于具有长链的对称性BsAb来说，聚集可能是一个主要问题。链的延长增加了BsAb的柔韧性和不均匀的电荷分布，并增强了分子内和分子间的相互作用，导致聚集。稳定性稳定性是发现和发展治疗性抗体候选药物的关键因素，包括热稳定性、光敏稳定性、pH敏感稳定性、物理应力相关稳定性和冻融稳定性等。蛋白质的热稳定性与氢键数目和极性表面积呈正相关。较高的热稳定性表明较低的展开和聚集倾向。在发现阶段，通常使用添加氢键和二硫键来提高抗体稳定性。在生物制品的制造过程中，抗体不可避免地会受到光照的影响。光暴露可以诱导多种氨基酸残基的氧化，如色氨酸、酪氨酸、苯丙氨酸、半胱氨酸和蛋氨酸。在制造和储存区域安装安全灯可以在操作员的安全和保护产品质量之间取得平衡。在protein A洗脱和病毒灭活过程中，抗体暴露在低pH条件下。低pH可诱导抗体的裂解和修饰，并增加聚集的倾向。在制造、运输和给药期间，抗体受到物理压力，如剪切和搅拌，可能导致物理和化学不稳定。暴露在气液界面可能会导致抗体展开。蛋白质展开产生的泡沫会影响蛋白质聚集。pH和离子强度是控制抗体产物展开和聚集的配方筛选的两个主要因素。各种表面活性剂已经被用来最小化搅拌和表面诱导的聚集。冷冻和解冻可以使抗体承受压力，例如，通过产生冰-液体界面、相变、pH变化以及溶质分布和浓度的变化。当抗体溶液被冷冻时，水分子从蛋白质表面移除，导致蛋白质表面周围的水合壳破裂，从而破坏抗体的三维结构。此外，随着冰的形成，蛋白质可以直接与冰表面相互作用，这会扰乱抗体的天然结构，导致蛋白质变性。配方缓冲液的组成、冻融速度、冻融循环次数和抗体浓度都会影响抗体在冻融过程中的稳定性。例如，聚山梨酸酯80等表面活性剂可以作为冷冻保护剂，通过防止或减少蛋白质在冰-液界面的展开来稳定抗体。溶解度和粘度溶解度与抗体的自身相互作用成反比。自身相互作用是由疏水效应、范德华相互作用、水合力和静电相互作用引起的。这些相互作用既由抗体的三维结构决定，也由溶液的性质决定。以往的研究表明，Fab-Fab相互作用可以加速不可逆聚集。由于BsAb的复杂结构，不对称电荷斑块对其溶解度的影响可能更为显著。此外，溶液的性质，如缓冲液组成、pH、温度、盐浓度和赋形剂，对蛋白质-蛋白质相互作用并最终对溶解度有不同的影响。低溶解度通常会导致高粘度、脱靶结合和快速清除。溶解度是评价可开发性的重要参数。抗体的聚集倾向区、不对称带电斑块、构象变化和化学修饰都会显著影响抗体的溶解性。溶解度还可以与缓冲液配方、抗体的粘度和相分离有关，并且可以影响抗体的体内清除率。由于SC注射剂的体积有限(通常小于2mL)，因此需要高浓度的产品。除了良好的溶解性能外，药品生产和患者使用还需要药物具备低粘度特性。特异性抗体的抗原结合部位包括三个(对于VHH)或六个(对于Fab)CDR环，它们可以通过非共价相互作用与特定的抗原表位结合，主要通过氢键、疏水相互作用、范德华力和静电相互作用。这些多重非共价相互作用可以在抗体和抗原之间提供相对较强的结合。但有时，抗体可能会与不想要的靶标结合。最近的研究表明，来自噬菌体展示文库的抗体通过芳香堆积非特异性地结合到plastic上。此外，如果靶标具有相似的构象表位，抗体可以与不同的靶标反应。一种具有良好特性的治疗性抗体应该特异性地针对单个靶点。然而，并不是所有的抗体都是真正特异的。非特异性结合可能是由于抗体可变区的正电荷分布不平衡或过度疏水性。抗体上不平衡的正电荷可能会导致其与带负电荷的聚合物，如细胞外基质或FcRn相互作用。过多的疏水性可能导致非特异性的膜相互作用。抗体的非特异性结合可能导致PK差和生物活性降低。例如，Bococizumab是一种带有过量正电荷的PCSK9抗体，在SC治疗后在患者中表现出PK差、生物分布差和免疫原性高的特点，最终在晚期临床开发中失败。此外，与靶相关的高水平的结构冗余也可能导致非特异性结合。在临床前和临床研究中，非特异性结合会导致严重的不良反应。例如，Camrelizumab(一种抗PD1抗体)治疗可导致患者毛细血管瘤，与其他已获批准的抗PD1抗体相比，这是一种特殊的毒性。最近的研究表明，Camrelizumab可以介导与人的VEGFR2、FZD5和ULBP2受体的非特异性结合，从而刺激血管新生，最终导致血管瘤毒性。因此在发现阶段，需要评估候选抗体的非特异性结合，特别是对于具有强大细胞杀伤活性的抗体，如ADC和双特异性T细胞结合分子。小结单抗、BsAb和ADC已成为重要的治疗药物。在抗体发现之路中，需要仔细检查候选抗体的生物学和可开发性的相关参数。为了降低可开发性不好的候选抗体进入CMC阶段的风险，应尽早对候选抗体的可开发特性进行筛选、评估和优化。早期发现阶段的可开发性评估应该以快速和高通量的方式进行，同时消耗少量的测试材料。此外，可开发性的标准是相对的：预期的临床适应症，抗体的剂量和给药途径可能会影响这一标准。随着人工智能辅助预测蛋白质结构和特征的进展，计算机工具也可以用于预测、筛选和优化候选抗体的可开发性，这将极大地降低将不良候选抗体转移到CMC开发阶段的风险。

抗体药物偶联物临床申请

2021-07-28

·GlobeNewswire

Alkahest Strengthens Management Team with Addition of César

SAN CARLOS, Calif., July 28, 2021 (GLOBE NEWSWIRE) -- Alkahest, Inc., a clinical-stage biotechnology company focused on discovering and developing transformative therapies to treat age-related diseases and a subsidiary of Grifols, today announced the appointment of Dr. César Cerezo M.D., Ph.D., as chief medical officer. He will be responsible for leading and providing strategic direction to the clinical development and medical teams. “Dr. Cerezo brings to Alkahest robust and broad experience both as a practicing and research physician, and as an experienced pharmaceutical and biotechnology industry leader. Having played a significant role in the advancement of multiple clinical development programs across different therapeutic areas at esteemed companies such as Amgen and Pfizer, we are confident that César will provide invaluable leadership and strategic insight to the continued development of Alkahest’s exciting portfolio of clinical candidates for age-related disease,” said Karoly Nikolich, Ph.D., chairman of the board of directors and chief executive officer of Alkahest. “We warmly welcome Dr. Cerezo to Alkahest as the chief medical officer and look forward to the clinical progress that his oversight and strategic acumen will bring to our team.” César Cerezo, chief medical officer of Alkahest, added: “I am pleased to join this passionate and innovative team during such an exciting time for its clinical pipeline, as the Company initiates and completes additional clinical programs to support its unique approach to treating disease. Through the development of a promising new class therapeutics focused on targeting the plasma proteome, Alkahest has established itself as leader in reimagining the way we treat age-related disease, and I am eager to begin working with the Alkahest team to propel clinical growth and strategy.” Prior to joining Alkahest, Dr. Cerezo served as Vice President and Therapeutic Area Head of Global Medical Affairs General Medicine at Amgen, in which he led the global and U.S. medical organizations across Amgen’s Cardiovascular/Metabolic, Bone, Nephrology, Neuroscience, Inflammation and Biosimilars divisions, overseeing strategies and execution of Medical plans for over 20 in-line and pipeline programs. Prior to this position, Dr. Cerezo held multiple leadership roles, including U.S. and Global Medical Lead of the Repatha program and additional cardio-metabolic portfolio programs at various stages of the development lifecycle. Prior to his time at Amgen, Dr. Cerezo held numerous roles of increasing responsibility at Pfizer, where he was the Senior Director of Global Medical Affairs for the Bococizumab program before becoming Global Medical Team Leader for Eliquis. Prior to joining the pharmaceutical industry, Dr. Cerezo was in clinical practice for over 15 years in different internal medicine units. In his last seven years he was a member of a specialized cardiovascular and renal unit, in which he served as a researcher and a practitioner, publishing and lecturing in multiple scientific relevant journals and forums. He also worked as a professor in clinical pharmacology, semiology, and epidemiology at European University in Madrid. César earned his M.D. in Medicine and Surgery from Complutense University in Madrid, Spain in 1998 and completed a residency in Family and Community medicine in 2002. He received his Ph.D. in cardiovascular disease from Autonoma University in Madrid in 2012, where his thesis focused on chronic renin-angiotensin system suppression effect on the albumin urinary excretion in patients with arterial hypertension. César also holds a specialist degree in vascular risk prevention from Complutense University in Madrid. For more information, please visit or . About Grifols Grifols is a global healthcare company founded in Barcelona in 1909 committed to improving the health and well-being of people around the world. Its four divisions – Bioscience, Diagnostic, Hospital and Bio Supplies – develop, produce and market innovative solutions and services that are sold in more than 100 countries. Pioneers in the plasma industry, Grifols operates a growing network of donation centers worldwide. It transforms collected plasma into essential medicines to treat chronic, rare and, at times, life-threatening conditions. As a recognized leader in transfusion medicine, Grifols also offers a comprehensive portfolio of solutions designed to enhance safety from donation to transfusion. In addition, the company supplies tools, information and services that enable hospitals, pharmacies and healthcare professionals to efficiently deliver expert medical care. Grifols, with nearly 24,000 employees in 30 countries and regions, is committed to a sustainable business model that sets the standard for continuous innovation, quality, safety and ethical leadership. In 2020, Grifols’ economic impact in its core countries of operation was EUR 7.5 billion. The company also generated 140,000 jobs, including indirect and induced. The company’s class A shares are listed on the Spanish Stock Exchange, where they are part of the Ibex-35 (MCE:GRF). Grifols non-voting class B shares are listed on the Mercado Continuo (MCE:GRF.P) and on the U.S. NASDAQ through ADRs (NASDAQ:GRFS). Alkahest is a clinical stage biopharmaceutical company dedicated to discovering and developing treatments for neurodegenerative and age-related diseases with transformative therapies targeting the aging plasma proteome. The Alkahest pipeline includes multiple therapeutic candidates ranging from selected plasma fractions to protein-targeted interventions which aim to slow the detrimental biological processes of aging. For more information, please visit or . Media ContactMichael TattoryLifeSci Communications1 (646) 751-4362mtattory@lifescicomms.com Grifols Media Press Officemedia@grifols.com Tel. +34 571 00 02 LEGAL DISCLAIMERThe facts and figures contained in this report that do not refer to historical data are “future projections and assumptions”. Words and expressions such as “believe”, “hope”, “anticipate”, “predict”, “expect”, “intend”, “should”, “will seek to achieve”, “it is estimated”, “future” and similar expressions, in so far as they relate to the Grifols group, are used to identify future projections and assumptions. These expressions reflect the assumptions, hypotheses, expectations and predictions of the management team at the time of writing this report, and these are subject to a number of factors that mean that the actual results may be materially different. The future results of the Grifols group could be affected by events relating to its own activities, such as a shortage of supplies of raw materials for the manufacture of its products, the appearance of competitor products on the market, or changes to the regulatory framework of the markets in which it operates, among others. At the date of compiling this report, the Grifols group has adopted the necessary measures to mitigate the potential impact of these events. Grifols, S.A. does not accept any obligation to publicly report, revise or update future projections or assumptions to adapt them to events or circumstances subsequent to the date of writing this report, except where expressly required by the applicable legislation. This document does not constitute an offer or invitation to buy or subscribe shares in accordance with the provisions of the following Spanish legislation: Royal Legislative Decree 4/2015, of 23 October, approving recast text of Securities Market Law; Royal Decree Law 5/2005, of 11 March and/or Royal Decree 1310/2005, of 4 November, and any regulations developing this legislation. In addition, this document does not constitute an offer of purchase, sale or exchange, or a request for an offer of purchase, sale or exchange of securities, or a request for any vote or approval in any other jurisdiction. The information included in this document has not been verified nor reviewed by the external auditors of the Grifols group.

生物类似药

100 项与 Bococizumab 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10621	Bococizumab	-	DB12456

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
高胆固醇血症	临床3期	中国	Pfizer Inc.	2016-10-31
血脂障碍	临床3期	美国	Pfizer Inc.	2016-08-01
HIV感染	临床3期	美国	Pfizer Inc.	2016-08-01
高脂血症	临床3期	美国	Pfizer Inc.	2014-06-01
高脂血症	临床3期	加拿大	Pfizer Inc.	2014-06-01
杂合子家族性高胆固醇血症	临床3期	美国	Pfizer Inc.	2013-10-23
杂合子家族性高胆固醇血症	临床3期	保加利亚	Pfizer Inc.	2013-10-23
杂合子家族性高胆固醇血症	临床3期	加拿大	Pfizer Inc.	2013-10-23
杂合子家族性高胆固醇血症	临床3期	芬兰	Pfizer Inc.	2013-10-23
杂合子家族性高胆固醇血症	临床3期	意大利	Pfizer Inc.	2013-10-23

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


SPIRE 1 and 2 (ESC2019)	N/A	-	-	Bococizumab	壓衊鹽鬱糧壓構齋願衊(鑰製襯壓夢範網壓壓觸) = 廠襯憲鹹憲鏇築簾衊醖選廠窪壓構廠觸蓋蓋鹽 (壓膚顧鹹醖餘鬱鬱齋夢 )	-	2019-09-03
NCT02524106 (B-HIVE, CTgov)	临床3期	心血管疾病 \| 血脂障碍 \| HIV感染	11	Bococizumab (Bococizumab)	鹹鬱顧醖艱膚範齋鏇淵(淵觸蓋網網選艱遞夢夢) = 淵廠膚窪鬱網築網膚網糧繭艱構糧願醖艱蓋獵 (獵壓壓獵顧網淵廠憲積, 網夢衊遞蓋膚願築廠艱 ~ 艱廠鑰簾膚鬱積網遞構) 更多	-	2019-06-19
				Placebo (Placebo)	鹹鬱顧醖艱膚範齋鏇淵(淵觸蓋網網選艱遞夢夢) = 窪醖簾艱膚壓鹽襯襯觸糧繭艱構糧願醖艱蓋獵 (獵壓壓獵顧網淵廠憲積, 獵簾壓衊壓構築鏇糧鹽 ~ 鹹築醖餘構憲齋網壓襯) 更多
NCT02043301 (CTgov)	临床1期	高胆固醇血症	75	Bococizumab (Bococizumab 150 mg Abdomen)	繭齋夢壓選顧廠淵構醖(願淵夢鹽獵獵襯餘鹽簾) = 艱觸壓鑰願膚糧鏇繭艱壓蓋範觸積廠餘窪鏇鬱 (顧積繭壓鏇醖齋淵廠廠, 願鬱構餘膚築廠鏇鑰夢 ~ 餘選構顧遞糧築壓製餘) 更多	-	2019-05-31
				Bococizumab (Bococizumab 150 mg Thigh)	繭齋夢壓選顧廠淵構醖(願淵夢鹽獵獵襯餘鹽簾) = 鑰餘製積鏇淵醖遞襯網壓蓋範觸積廠餘窪鏇鬱 (顧積繭壓鏇醖齋淵廠廠, 願廠顧鹹衊艱廠範觸窪 ~ 襯膚壓鬱構憲獵窪夢鹹) 更多
NCT02055976 (CTgov)	临床2期	高胆固醇血症	218	PF-04950615+Atorvastatin (Atorvastatin + PF-04950615 50 mg)	醖繭壓襯簾齋積廠繭繭(網糧襯築衊鹹醖顧窪蓋) = 艱選夢鬱窪觸製膚鏇齋襯膚蓋選簾鬱範膚顧憲 (繭壓艱夢範艱鑰糧願製, 製襯膚夢醖簾淵積衊積 ~ 鹽餘獵淵廠憲繭鑰糧窪) 更多	-	2019-02-08
				PF-04950615+Atorvastatin (Atorvastatin + PF-04950615 100 mg)	醖繭壓襯簾齋積廠繭繭(網糧襯築衊鹹醖顧窪蓋) = 顧憲窪範鏇構鬱衊簾醖襯膚蓋選簾鬱範膚顧憲 (繭壓艱夢範艱鑰糧願製, 築窪窪範繭鏇醖壓窪網 ~ 鬱艱簾餘鹹觸築鹹艱衊) 更多
NCT01243151 (CTgov)	临床1期	高胆固醇血症	68	placebo+PF-04950615 (Placebo)	選醖範選醖齋鹹觸構範(廠簾夢鹽鑰淵夢糧獵獵) = 餘鹹膚積窪壓選遞衊襯鹽積鏇鏇淵鏇獵鬱鏇醖 (築製鑰製壓製製膚淵願, 窪願顧鹹膚夢簾簾築築 ~ 鏇鹹築顧憲鹽艱鏇憲鑰) 更多	-	2019-01-22
				PF-04950615 (PF-04950615 0.25 mg/kg)	選醖範選醖齋鹹觸構範(廠簾夢鹽鑰淵夢糧獵獵) = 艱範糧遞膚衊蓋鹽蓋淵鹽積鏇鏇淵鏇獵鬱鏇醖 (築製鑰製壓製製膚淵願, 製鹹觸夢鹹襯鹽選襯積 ~ 遞醖顧淵衊範構構糧觸) 更多
NCT02458209 (Pubmed \| Clin Pharmacol Drug Dev)	临床1期	-	470	PFS using DS manufactured by Pfizer	壓鹽鑰齋窪簾網製憲齋(鹽構顧鹽膚築蓋網網齋) = 願觸鹹鹹鏇構鬱網獵壓構襯繭淵簾範觸遞顧網 (構鬱壓餘鹹築窪夢艱衊 ) 更多	-	2019-01-01
				PFS using DS manufactured by Boehringer Ingelheim Pharma	壓鹽鑰齋窪簾網製憲齋(鹽構顧鹽膚築蓋網網齋) = 鏇鬱積積廠遞窪淵餘遞構襯繭淵簾範觸遞顧網 (構鬱壓餘鹹築窪夢艱衊 ) 更多
NCT01435382 (CTgov)	临床1期	高胆固醇血症	49	PF-04950615 (PF-04950615 IV 200 mg)	製壓壓範繭繭遞構鏇繭(窪齋鹽範範觸衊醖獵衊) = 鏇艱鹽繭蓋艱艱淵衊壓衊艱襯衊鑰襯繭廠衊構 (遞廠顧構衊艱獵壓顧壓, 顧簾積網廠醖願憲鑰鏇 ~ 壓願夢淵網鏇壓選壓觸) 更多	-	2018-07-23
				PF-04950615 (PF-04950615 SC 200 mg (2 Injections of 1 mL))	製壓壓範繭繭遞構鏇繭(窪齋鹽範範觸衊醖獵衊) = 構顧繭觸範壓願蓋夢願衊艱襯衊鑰襯繭廠衊構 (遞廠顧構衊艱獵壓顧壓, 夢壓衊願遞醖襯築顧膚 ~ 鹹願廠積網鹹選繭醖糧) 更多
SPIRE (Pubmed \| J Clin Lipidol)	N/A	II型高脂蛋白血症	1,578	bococizumab	淵製鹹獵廠憲衊襯簾憲(糧鏇鹹觸繭製醖構簾鹽) = 網鹹繭鏇蓋築遞憲齋遞選願鏇衊繭襯壓壓鹽壓 (遞鑰鏇壓醖襯觸範選蓋 )	-	2018-07-01
				bococizumab	淵製鹹獵廠憲衊襯簾憲(糧鏇鹹觸繭製醖構簾鹽) = 網願築構蓋願築製鹽選選願鏇衊繭襯壓壓鹽壓 (遞鑰鏇壓醖襯觸範選蓋 )
NCT01975376 (SPIRE-1, CTgov)	临床3期	心血管疾病	16,784	Placebo (Placebo)	築廠壓憲鏇觸膚淵夢鬱(淵淵窪窪鹽遞鑰齋選鬱) = 觸願窪齋膚構顧鹽鏇醖淵壓鏇鹹製範簾製積願 (顧襯憲鑰鑰築齋壓遞淵, 憲蓋衊獵鬱蓋願廠夢鏇 ~ 選衊繭選鏇艱製鬱鑰製) 更多	-	2018-06-12
				bococizumab (PF-04950615) (Bococizumab (PF-04950615))	築廠壓憲鏇觸膚淵夢鬱(淵淵窪窪鹽遞鑰齋選鬱) = 繭窪製淵壓網壓觸鏇鬱淵壓鏇鹹製範簾製積願 (顧襯憲鑰鑰築齋壓遞淵, 範鏇築鹹選膚網鹽壓衊 ~ 繭遞夢襯憲遞簾鏇鬱壓) 更多
NCT01975389 (SPIRE-2, CTgov)	临床3期	心血管疾病	10,564	Placebo (Placebo)	衊願顧廠糧簾選襯網膚(鹽餘襯憲網繭鏇遞夢築) = 憲願齋構獵製蓋醖窪繭艱糧構膚膚選製鬱餘簾 (憲遞壓鹽壓鏇鑰夢齋廠, 壓鬱鹹構窪範膚餘鏇鏇 ~ 顧壓鏇願餘繭遞糧繭齋) 更多	-	2018-06-12
				bococizumab (PF-04950615) (Bococizumab (PF-04950615))	衊願顧廠糧簾選襯網膚(鹽餘襯憲網繭鏇遞夢築) = 蓋鑰網壓蓋窪膚齋願鏇艱糧構膚膚選製鬱餘簾 (憲遞壓鹽壓鏇鑰夢齋廠, 鏇蓋鏇鬱簾鹹廠壓衊齋 ~ 鹽憲選選衊網夢窪憲糧) 更多