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Anti-αLβ2 antibodies reveal novel endocytotic cross-modulatory functionality

Mancuso, Riccardo V. and Casper, Jens and Schmidt, Albrecht G. and Krähenbühl, Stephan and Weitz-Schmidt, Gabriele. (2020) Anti-αLβ2 antibodies reveal novel endocytotic cross-modulatory functionality. British Journal of Pharmacology, 177 (12). pp. 2696-2711.

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Official URL: https://edoc.unibas.ch/78300/

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Abstract

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.
Faculties and Departments:05 Faculty of Science
05 Faculty of Science > Departement Pharmazeutische Wissenschaften
UniBasel Contributors:Mancuso, Riccardo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley
ISSN:0007-1188
e-ISSN:1476-5381
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:15 Sep 2020 12:48
Deposited On:15 Sep 2020 12:48

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