1. Optimization and Characterization of Novel ALCAM-Targeting Antibody Fragments for Transepithelial Delivery.
- Author
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Bauer A, Klassa S, Herbst A, Maccioni C, Abhamon W, Segueni N, Kaluzhny Y, Hunter MC, and Halin C
- Abstract
Activated leukocyte cell adhesion molecule (ALCAM) is a cell adhesion molecule that supports T cell activation, leukocyte migration, and (lymph)angiogenesis and has been shown to contribute to the pathology of various immune-mediated disorders, including asthma and corneal graft rejection. In contrast to monoclonal antibodies (mAbs) targeting ALCAM's T cell expressed binding partner CD6, no ALCAM-targeting mAbs have thus far entered clinical development. This is likely linked with the broad expression of ALCAM on many different cell types, which increases the risk of eliciting unwanted treatment-induced side effects upon systemic mAb application. Targeting ALCAM in surface-exposed tissues, such as the lungs or the cornea, by a topical application could circumvent this issue. Here, we report the development of various stability- and affinity-improved anti-ALCAM mAb fragments with cross-species reactivity towards mouse, rat, monkey, and human ALCAM. Fragments generated in either mono- or bivalent formats potently blocked ALCAM-CD6 interactions in a competition ELISA, but only bivalent fragments efficiently inhibited ALCAM-ALCAM interactions in a leukocyte transmigration assay. The different fragments displayed a clear size-dependence in their ability to penetrate the human corneal epithelium. Furthermore, intranasal delivery of anti-ALCAM fragments reduced leukocyte infiltration in a mouse model of asthma, confirming ALCAM as a target for topical application in the lungs., Competing Interests: Noria Segueni is a study director at Artimmune (https://www.artimmune.com/, accessed on 20 June 2023), the contract research company that performed the mouse asthma study. Yulia Kaluzhny is a principal scientist at MatTek (https://www.mattek.com/, accessed on 20 June 2023), a company providing 3D corneal tissue models. The authors have no additional relevant affiliations or conflicting financial interests. All other co-authors declare no conflict of interests.
- Published
- 2023
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