The success of therapeutic antibodies is largely attributed for their exquisite specificity, homogeneity, and functionality. There is, however, a need to engineer antibodies to extend and enhance their potency. One parameter is functional affinity augmentation, since antibodies matured in vivo have a natural affinity threshold. Generation of multivalent antibodies is one option capable of surpassing this affinity threshold through increased avidity. In this study, we present a novel platform consisting of an array of multivalent antibody formats, termed Quads, generated using the self-assembling tetramerization domain from p53. We demonstrate the versatility of this tetramerization domain by engineering anti-tumor necrosis factor (TNF) Quads that exhibit major increases in binding potency and in neutralizing TNF-mediated cytotoxicity compared to parental anti-TNF molecules. Further, Quads are amenable to fusion with different binding domains, allowing generation of novel multivalent monospecific and bispecific formats. Quads are thus a novel group of molecules that can be engineered to yield potential therapeutics with novel modalities and potencies.

中文翻译：

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使用新形式，具有更高化合价的多聚体抗体超过了功能亲和力和效价阈值。

治疗性抗体的成功很大程度上归因于其出色的特异性，同质性和功能性。但是，需要工程改造抗体以扩展和增强其效力。一个参数是功能亲和力增加，因为体内成熟的抗体具有天然亲和力阈值。多价抗体的产生是一种能够通过增加的亲和力超过该亲和力阈值的选择。在这项研究中，我们提出了一个新颖的平台，该平台由多价抗体形式的阵列（称为Quads）组成，使用来自p53的自组装四聚结构域生成。我们通过工程抗肿瘤坏死因子（TNF）Quads展示了这种四聚化结构域的多功能性，与亲本抗TNF分子相比，结合抗药性和中和TNF介导的细胞毒性都表现出极大的提高。此外，Quads适合与不同的结合域融合，从而允许产生新颖的多价单特异性和双特异性形式。因此，Quads是一组新的分子，可以进行工程改造，以产生具有新型功能和潜能的潜在疗法。