Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland.
Department of Biomedicine, University of Basel, Basel, Switzerland.
Br J Pharmacol. 2020 Jun;177(12):2696-2711. doi: 10.1111/bph.14996. Epub 2020 Mar 9.
Antibodies targeting cell surface receptors are considered to enable highly selective therapeutic interventions for immune disorders and cancer. Their biological profiles are found, generally, to represent the net effects of antibody-target interactions. The former therapeutic anti-integrin αLβ2 antibody efalizumab seems to defeat this paradigm by eliciting, via mechanisms currently unknown, much broader effects than would be predicted based on its target specificity.
To elucidate the mechanisms behind these broad effects, we investigated in primary human lymphocytes in vitro the effects of anti-αLβ2 antibodies on the expression of αLβ2 as well as unrelated α4 integrins, in comparison to Fab fragments and small-molecule inhibitors.
We demonstrate that anti-αLβ2 mAbs directly induce the internalization of α4 integrins. The endocytotic phenomenon is a direct consequence of their antibody nature. It is inhibited when monovalent Fab fragments or small-molecule inhibitors are used. It is independent of crosslinking via anti-Fc mAbs and of αLβ2 activation. The cross-modulatory effect is unidirectional and not observed in a similar fashion with the α4 integrin antibody natalizumab.
The present study identifies endocytotic cross-modulation as a hitherto unknown non-canonical functionality of anti-αLβ2 antibodies. This cross-modulation has the potential to fundamentally alter an antibody's benefit risk profile, as evident with efalizumab. The newly described phenomenon may be of relevance to other therapeutic antibodies targeting cluster-forming receptors. Thus, pharmacologists should be cognizant of this action when investigating such antibodies.
靶向细胞表面受体的抗体被认为能够针对免疫紊乱和癌症进行高度选择性的治疗干预。通常情况下，它们的生物学特性代表了抗体-靶标相互作用的净效应。之前用于治疗的抗整合素αLβ2 抗体 efalizumab 似乎通过目前尚不清楚的机制产生了比基于其靶标特异性预测的更广泛的作用，从而打破了这一模式。
为了阐明这些广泛作用的机制，我们在体外原代人淋巴细胞中研究了抗-αLβ2 抗体对 αLβ2 以及不相关的 α4 整合素表达的影响，与 Fab 片段和小分子抑制剂进行了比较。
我们证明抗-αLβ2 mAbs 直接诱导 α4 整合素内化。内吞现象是其抗体性质的直接结果。当使用单价 Fab 片段或小分子抑制剂时，该现象被抑制。它独立于通过抗-Fc mAbs 的交联和 αLβ2 的激活。这种交叉调节作用是单向的，在类似的情况下，α4 整合素抗体 natalizumab 没有观察到这种作用。
本研究确定了内吞交叉调节作为抗-αLβ2 抗体的一种迄今未知的非典型功能。这种交叉调节有可能从根本上改变抗体的获益风险状况，正如 efalizumab 所证明的那样。新描述的现象可能与其他针对形成簇的受体的治疗性抗体有关。因此，药理学家在研究此类抗体时应意识到这种作用。
