小柯机器人

英国南安普顿大学Mark S. Cragg小组发现，降低亲和度可作为增强免疫调节抗体激动作用的策略。相关论文于2023年2月1日在线发表在《自然》杂志上。

研究人员研究了横跨两个受体超家族的三个独立的免疫重要受体：CD40、4-1BB和PD-1。结果表明，低亲和度而不是高亲和度通过增加的聚集产生更大的活性。在体内T细胞扩张和抗肿瘤活性在CD40的情况下，这种方法提供了更高的免疫细胞活化。此外，惰性抗4-1BB单克隆抗体转化为激动剂。临床重要的拮抗PD-1单克隆抗体nivolumab的低亲和变异也介导了更有效的信号转导，并影响T细胞活化。这些发现揭示了在不同受体家族中增强激动作用的新范式，并阐明了抗体介导的受体信号转导机制。这种亲和工程提供了一个合理、高效和高度可变的解决方案，以提供抗体介导的受体活性，并适用于转化到人类疾病的治疗。

据了解，感染和接种期间的抗体反应通常经历亲和成熟，以实现高亲和结合，有效中和病原体。同样，高亲和力通常是治疗性抗体生成的目标。然而，与天然存在的或直接靶向的治疗性抗体相比，免疫调节抗体，其设计用于调节受体信号，尚未被广泛研究其亲和-功能关系。

附：英文原文

Title: Reducing affinity as a strategy to boost immunomodulatory antibody agonism

Author: Yu, Xiaojie, Orr, Christian M., Chan, H. T. Claude, James, Sonya, Penfold, Christine A., Kim, Jinny, Inzhelevskaya, Tatyana, Mockridge, C. Ian, Cox, Kerry L., Essex, Jonathan W., Tews, Ivo, Glennie, Martin J., Cragg, Mark S.

Issue&Volume: 2023-02-01

Abstract: Antibody responses during infection and vaccination typically undergo affinity maturation to achieve high-affinity binding for efficient neutralization of pathogens1,2. Similarly, high affinity is routinely the goal for therapeutic antibody generation. However, in contrast to naturally occurring or direct-targeting therapeutic antibodies, immunomodulatory antibodies, which are designed to modulate receptor signalling, have not been widely examined for their affinity–function relationship. Here we examine three separate immunologically important receptors spanning two receptor superfamilies: CD40, 4-1BB and PD-1. We show that low rather than high affinity delivers greater activity through increased clustering. This approach delivered higher immune cell activation, in vivo Tcell expansion and antitumour activity in the case of CD40. Moreover, an inert anti-4-1BB monoclonal antibody was transformed into an agonist. Low-affinity variants of the clinically important antagonistic anti-PD-1 monoclonal antibody nivolumab also mediated more potent signalling and affected Tcell activation. These findings reveal a new paradigm for augmenting agonism across diverse receptor families and shed light on the mechanism of antibody-mediated receptor signalling. Such affinity engineering offers a rational, efficient and highly tuneable solution to deliver antibody-mediated receptor activity across a range of potencies suitable for translation to the treatment of human disease.

DOI: 10.1038/s41586-022-05673-2

Source: https://www.nature.com/articles/s41586-022-05673-2

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