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    抗体-寡核苷酸缀合物 (AOC) 开发服务

Antibody-Oligonucleotide Conjugates (AOC) Development Services
抗体-寡核苷酸缀合物 (AOC) 开发服务

Antibody-oligonucleotide conjugates (AOCs) are a novel class of synthetic chimeric biomolecules that has been continually gaining traction in different fields of modern biotechnology. Creative Biolabs focuses on developing this new class of oligonucleotide conjugates to overcome the current limitations of oligonucleotide (ON) therapies for a wide range of serious diseases. Base on our perfect AOC platform, AOCs can be designed, engineered, and developed to combine the tissue and disease selectivity of monoclonal antibodies (mAbs) and the precision of oligonucleotide-based therapies to access previously undruggable tissue and cell types, and more effectively target underlying genetic drivers of diseases. Creative Biolabs provides comprehensive AOC development services for our honor clients and the AOCs candidates derived from our platform will have the potential to offer distinct advantages over ON itself.
抗体-寡核苷酸缀合物(AOC)是一类新型的合成嵌合生物分子,在现代生物技术的不同领域不断受到关注。 Creative Biolabs专注于开发此类新型寡核苷酸缀合物,以克服当前寡核苷酸 (ON) 疗法对多种严重疾病的限制。基于我们完善的 AOC 平台,AOC 可以经过设计、工程和开发,将单克隆抗体 (mAb) 的组织和疾病选择性与基于寡核苷酸的疗法的精确性结合起来,以访问以前不可成药的组织和细胞类型,并更有效地靶向疾病的潜在遗传驱动因素。 Creative Biolabs 为我们的荣誉客户提供全面的 AOC 开发服务,从我们的平台衍生的 AOC 候选者将有可能比 ON 本身提供明显的优势。

Background Our Service Highlights FAQ Published Data
背景我们的服务亮点常见问题已发布数据

Background  背景

AOC Introduction  AOC简介

Combining different functionalities in one entity by generating chimeric constructs has always been an attractive strategy in various fields such as biology, chemistry, and medicine. Two important families of biomolecules have gained a lot of attention and have already revolutionized the field of diagnostics and therapeutics, they are mAbs and Oligonucleotide Synthesis (ONs). Combining the distinct functionalities of mAb and ON in one chimeric construct (namely AOC) has been explored. The AOC constructs can trigger complex biological mechanisms ranging from immune responses to cell differentiation, apoptosis, and protein expression, thus AOC attracted a lot of interest in both academic and industrial fields.
通过生成嵌合结构将不同的功能组合在一个实体中一直是生物学、化学和医学等各个领域中一种有吸引力的策略。两个重要的生物分子家族引起了广泛关注,并且已经彻底改变了诊断和治疗领域,它们是单克隆抗体和寡核苷酸合成(ON)。人们已经探索了将 mAb 和 ON 的不同功能结合在一个嵌合构建体(即 AOC)中。 AOC构建体可以触发从免疫反应到细胞分化、凋亡和蛋白质表达等复杂的生物机制,因此AOC引起了学术界和工业领域的广泛兴趣。

Conjugation Strategies of AOC Development
AOC发展的结合策略

Similar to antibody-drug conjugation, ONs can be attached to different sites of an antibody using diverse conjugation chemistry. Multiple endogenous amino acids can serve as potential conjugation sites. Antibody and ON could be conjugated via different covalent and noncovalent conjugation strategies. Among them, amine conjugation, sulfhydryl conjugation, and carbohydrate conjugation are the most known three methods.
与抗体-药物缀合类似,可以使用不同的缀合化学将ON连接到抗体的不同位点。多个内源氨基酸可以作为潜在的缀合位点。抗体和 ON 可以通过不同的共价非共价缀合策略进行缀合。其中,胺缀合、巯基缀合和碳水化合物缀合是最知名的三种方法。

  • Amine Conjugation  胺结合

Antibodies contain several amino groups (NH2), which can be distributed throughout as lysine side chain epsilon-amine and N-terminal alpha-amino groups. These residues are most often targeted for conjugation as they can easily be modified owing to their steric accessibility. Besides amino groups, glutamic acid, aspartic acid residues, and carboxylic acid can also be conjugated.
抗体含有多个氨基 (NH2),它们可以作为赖氨酸侧链ε-胺和 N 末端 α-氨基分布。这些残基通常是缀合的目标,因为它们的空间可及性很容易被修饰。除了氨基之外,谷氨酸、天冬氨酸残基和羧酸也可以缀合。

  • Sulfhydryl Conjugation  巯基缀合

Antibody-ON conjugation is also possible via a reactive thiol (sulfhydryl) group. Antibodies contain oxidized sulfhydryl (-SH) groups present as disulfide (S-S) bridges and these disulfide bridges must be reduced first to expose their reactive groups by a reducing agent
抗体-ON 缀合也可以通过反应性硫醇(硫氢基)基团实现。抗体含有以二硫键 (SS) 桥形式存在的氧化硫氢基 (-SH),这些二硫键必须首先被还原剂还原以暴露其反应基团

  • Carbohydrate Conjugation  碳水化合物结合

An alternative method of site-directed conjugation can occur at carbohydrate residues, which occurs mainly in the Fc region because they are less susceptible to steric hindrance due to their remoteness from antigen-binding sites. For conjugation via this complex method, the carbohydrate group must be oxidized to an aldehyde (-CHO) using periodic acid. An advantage is that AOCs produced via site-specific conjugation techniques have distinct advantages for in vivo applications.
另一种定点缀合方法可以发生在碳水化合物残基上,这主要发生在 Fc 区,因为它们远离抗原结合位点,不易受到空间位阻的影响。为了通过这种复杂的方法进行缀合,必须使用高碘酸将碳水化合物基团氧化为醛(-CHO)。一个优点是,通过位点特异性缀合技术产生的 AOC 对于体内应用具有明显的优势。

A schematic illustration of the antibody-ON conjugation process.Fig.1 A schematic diagram of the antibody-ON conjugation process.1
图1 抗体-ON缀合过程示意图。 1

Application of AOCs AOC 的应用

In AOC complex, the antibody is usually employed as a target recognition unit or delivery vehicle and the ON serves in a variety of functional roles such as scaffold for spatial arrangement or therapeutic drug (small interfering RNA, siRNA). AOCs have been used in numerous applications ranging from diagnostics to therapeutics and were developed through an unmet need for precise and efficient detection of low-abundance proteins. AOCs have since played a significant role in immuno-polymerase chain reaction (iPCR), proximity extension assay (PEA), electrochemical proximity assay (ECPA), DNA-PAINT imaging, and protein arrays. Based on the exceptional ability of PCR to amplify the number of DNA labels and the transformation of readily accessible ON-arrays into otherwise difficult to access antibody arrays, AOCs can largely improve the detection limits.
在AOC复合物中,抗体通常用作靶标识别单元或递送载体,ON发挥多种功能作用,例如空间排列或治疗药物的支架(小干扰RNA,siRNA)。 AOC 已被用于从诊断到治疗的众多应用中,并且是为了满足对低丰度蛋白质的精确和有效检测的未满足的需求而开发的。此后,AOC 在免疫聚合酶链式反应 (iPCR)、邻近延伸测定 (PEA)、电化学邻近测定 (ECPA)、DNA-PAINT 成像和蛋白质阵列中发挥了重要作用。基于 PCR 放大 DNA 标记数量的卓越能力以及将易于访问的 ON 阵列转化为难以访问的抗体阵列,AOC 可以大大提高检测限。

Our Service  我们的服务

AOC Development Services  AOC 开发服务

Creative Biolabs takes full advantage of our featured platform to develop a portfolio of AOCs that combine the selectivity of mAbs and the precision of oligonucleotide therapy and diagnosis. Our deep experience with modulation of RNA processes, oligonucleotide therapeutics, mAb engineering and conjugation, and various drug delivery techniques provide the foundation for our efforts to promote your novel AOC development. The know-how and advanced technology born out of this experience, and their systematic application in the design and development of our product candidates, form the basis of our AOC development platform. Based on our platform, our scientists have also established a framework for screening potential cell surface protein-mAb pairs to determine which pairs we believe are well suited to deliver active ONs to specific cell types.
Creative Biolabs 充分利用我们的特色平台开发 AOC 产品组合,将 mAb 的选择性与寡核苷酸治疗和诊断的精确性结合起来。我们在 RNA 过程调节、寡核苷酸治疗、mAb 工程和缀合以及各种药物递送技术方面的丰富经验为我们努力促进您的新型 AOC 开发奠定了基础。源自这一经验的专业知识和先进技术,以及它们在我们候选产品的设计和开发中的系统应用,构成了我们 AOC 开发平台的基础。基于我们的平台,我们的科学家还建立了一个框架,用于筛选潜在的细胞表面蛋白-mAb 对,以确定我们认为哪些对非常适合将活性 ON 传递到特定细胞类型。

Our goal is to help clients discover, develop and commercialize novel AOCs that overcome current barriers to the delivery of ONs and unlock their potential to treat or diagnose diseases currently lacking adequate treatment or detection options. Based on the data-driven hypothesis that the delivery of ONs can be greatly enhanced by using antibodies as conjugates, Creative Biolabs offers high-quality AOCs development services for our global clients. If you are interested in our AOC development services, please feel free to contact us for more information.
我们的目标是帮助客户发现、开发和商业化新型 AOC,克服目前 ON 输送的障碍,并释放其治疗或诊断目前缺乏足够治疗或检测方案的疾病的潜力。基于数据驱动的假设,即使用抗体作为缀合物可以大大增强 ON 的递送, Creative Biolabs为我们的全球客户提供高质量的 AOC 开发服务。如果您对我们的 AOC 开发服务感兴趣,请随时与我们联系以获取更多信息。

Highlights  亮点

  • Versatile AOC Platform: Supports diverse applications from drug delivery to diagnostics, leveraging robust antibody and oligonucleotide synthesis capabilities.
    多功能 AOC 平台:利用强大的抗体和寡核苷酸合成功能,支持从药物输送到诊断的多种应用。
  • Streamlined Client Support: Offers integrated AOC development services from conceptualization through to market, enhancing speed to clinical trials.
    简化的客户支持:提供从概念化到上市的综合 AOC 开发服务,提高临床试验的速度。
  • Data-Driven Development: Employs a data-centric approach for AOC development, ensuring optimal pairing of antibodies with oligonucleotides for targeted therapeutic action.
    数据驱动的开发:采用以数据为中心的方法进行 AOC 开发,确保抗体与寡核苷酸的最佳配对,以实现靶向治疗作用。
  • Advanced Conjugation Methods: Utilizes amine, sulfhydryl, and carbohydrate conjugation techniques to enhance AOC stability and efficacy for therapeutic and diagnostic uses.
    先进的缀合方法:利用胺、巯基和碳水化合物缀合技术来增强 AOC 的稳定性和治疗和诊断用途的功效。
  • Comprehensive Development Services: Offers full lifecycle support from AOC design to commercialization, backed by extensive expertise in antibody and oligonucleotide technologies.
    综合开发服务:以抗体和寡核苷酸技术方面丰富的专业知识为后盾,提供从 AOC 设计到商业化的完整生命周期支持。

FAQ  常问问题

  1. Q: What are the primary conjugation strategies used in AOC development at Creative Biolabs?
    问:Creative Biolabs 在 AOC 开发中使用的主要缀合策略是什么?

    A: Creative Biolabs employs various conjugation strategies to attach oligonucleotides to antibodies, enhancing the specificity and stability of AOCs. The three main methods include amine conjugation targeting amino groups on antibodies, sulfhydryl conjugation via reactive thiol groups, and carbohydrate conjugation at carbohydrate residues typically found in the Fc region. These techniques ensure that AOCs are optimally designed for their specific in vivo applications.
    答:Creative Biolabs 采用各种缀合策略将寡核苷酸附着到抗体上,从而增强 AOC 的特异性和稳定性。三种主要方法包括针对抗体上氨基的胺缀合、通过反应性硫醇基团的巯基缀合以及通常在 Fc 区中发现的碳水化合物残基处的碳水化合物缀合。这些技术确保 AOC 针对其特定的体内应用进行优化设计。

  2. Q: What makes AOCs unique in targeting diseases?
    问:AOC 在针对疾病方面有何独特之处?

    A: AOCs uniquely combine monoclonal antibodies with oligonucleotides, targeting diseases with unmatched precision and selectivity, enabling access to previously undruggable cells.

  3. Q: What are Creative Biolabs' capabilities in AOC engineering?
    问:Creative Biolabs 在 AOC 工程方面的能力是什么?

    A: We specialize in custom AOC design, leveraging cutting-edge conjugation methods and extensive mAb and ON therapy expertise to craft effective solutions.

  4. Q: How do AOCs enhance diagnostic capabilities?
    问:AOC 如何增强诊断能力?

    A: AOCs improve diagnostics by significantly lowering detection thresholds for proteins, utilizing advanced PCR techniques to amplify diagnostic signals in challenging samples.

  5. Q: What therapeutic roles do AOCs play?
    问:AOC 发挥什么治疗作用?

    A: AOCs deliver therapeutic oligonucleotides directly to target cells, offering innovative treatment options for genetic and autoimmune diseases by modulating gene expression or silencing pathological genes.

  6. Q: How can clients engage with Creative Biolabs for AOC development?
    问:客户如何与 Creative Biolabs 合作开发 AOC?

    A: Clients can initiate AOC development projects with Creative Biolabs by contacting our expert

Published Data  公布数据

In the experiment, Antibody-Oligonucleotide Conjugates (AOCs) played a crucial role in delivering antisense oligonucleotides (ASOs) to the central nervous system (CNS) for the treatment of spinal muscular atrophy (SMA). Specifically, ASOs were conjugated to an antibody targeting the murine transferrin receptor (8D3130). This conjugation facilitated the crossing of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), enhancing the bioavailability of ASOs in the brain and spinal cord. The results demonstrated that systemic administration of 8D3130-ASO conjugates increased SMN2 splicing, which led to elevated levels of functional SMN protein in CNS and peripheral tissues, extending the survival of a severely affected SMA mouse model. This approach offers significant potential for treating neuromuscular and neurodegenerative diseases.
在实验中,抗体-寡核苷酸缀合物(AOC)在将反义寡核苷酸(ASO)输送到中枢神经系统(CNS)以治疗脊髓性肌萎缩症(SMA)方面发挥了至关重要的作用。具体来说,ASO 与针对鼠转铁蛋白受体 (8D3130) 的抗体缀合。这种结合促进了血脑屏障 (BBB) 和血脊髓屏障 (BSCB) 的穿过,增强了 ASO 在大脑和脊髓中的生物利用度。结果表明,全身施用 8D3130-ASO 缀合物可增加 SMN2 剪接,从而导致中枢神经系统和外周组织中功能性 SMN 蛋白水平升高,从而延长严重受影响的 SMA 小鼠模型的存活时间。这种方法为治疗神经肌肉和神经退行性疾病提供了巨大的潜力。

PK comparison results of antibody and antibody-PMO conjugates in mice.Fig.2 PK of antibody and antibody-PMO conjugates in mice.2
图2 抗体和抗体-PMO缀合物在小鼠体内的PK。 2

References 参考

  1. Soler Aznar, Maria. Nanoplasmonic biosensors for clinical diagnosis at the point of care. Universitat Autònoma de Barcelona,, 2015.
    索莱尔·阿斯纳尔,玛丽亚。用于护理点临床诊断的纳米等离子体生物传感器。巴塞罗那自治大学,2015。
  2. Hammond, Suzan M., et al. "Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy." JCI insight 7.24 (2022).
    哈蒙德,苏珊·M.,等人。 “抗体-寡核苷酸缀合物在脊髓性肌萎缩动物模型中实现了中枢神经系统递送。” JCI 见解7.24 (2022)。

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