Optimization and Characterization of Novel ALCAM-Targeting Antibody Fragments for Transepithelial Delivery
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Date
2023-06
Publication Type
Journal Article
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yes
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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.
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published
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Journal / series
Volume
15 (7)
Pages / Article No.
1841
Publisher
MDPI
Event
Edition / version
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Software
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Date collected
Date created
Subject
Antibody fragment; Monoclonal antibody fragment; ALCAM; Topical threatment; Asthma; Cornea; Drug delivery; Antibody
Organisational unit
03816 - Halin Winter, Cornelia / Halin Winter, Cornelia
Notes
Funding
207060 - Antibody-based topical treatment for corneal transplant rejection (SNF)
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