HuM195 and its single-chain variable fragment increase Aβ phagocytosis in microglia via elimination of CD33 inhibitory signaling Journal Article
| Authors: | Wong, E.; Malviya, M.; Jain, T.; Liao, G. P.; Kehs, Z.; Chang, J. C.; Studer, L.; Scheinberg, D. A.; Li, Y. M. |
| Article Title: | HuM195 and its single-chain variable fragment increase Aβ phagocytosis in microglia via elimination of CD33 inhibitory signaling |
| Abstract: | CD33 is a transmembrane receptor expressed on cells of myeloid lineage and regulates innate immunity. CD33 is a risk factor for Alzheimer’s disease (AD) and targeting CD33 has been a promising strategy drug development. However, the mechanism of CD33’s action is poorly understood. Here we investigate the mechanism of anti-CD33 antibody HuM195 (Lintuzumab) and its single-chain variable fragment (scFv) and examine their therapeutic potential. Treatment with HuM195 full-length antibody or its scFv increased phagocytosis of β-amyloid 42 (Aβ42) in human microglia and monocytes. This activation of phagocytosis was driven by internalization and degradation of CD33, thereby downregulating its inhibitory signal. HumM195 transiently induced CD33 phosphorylation and its signaling via receptor dimerization. However, this signaling decayed with degradation of CD33. scFv binding to CD33 leads to a degradation of CD33 without detection of the CD33 dimerization and signaling. Moreover, we found that treatments with either HuM195 or scFv promotes the secretion of IL33, a cytokine implicated in microglia reprogramming. Importantly, recombinant IL33 potentiates the uptake of Aβ42 in monocytes. Collectively, our findings provide unanticipated mechanistic insight into the role of CD33 signaling in both monocytes and microglia and define a molecular basis for the development of CD33-based therapy of AD. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | signal transduction; controlled study; protein expression; protein phosphorylation; human cell; flow cytometry; metabolism; computer assisted tomography; drug effect; phosphorylation; enzyme linked immunosorbent assay; physiology; monoclonal antibody; alkaline phosphatase; immune response; genetic transfection; peptide fragments; peptide fragment; western blotting; fluorescence resonance energy transfer; innate immunity; down regulation; monocyte; monocytes; phagocytosis; cxcl2 chemokine; alzheimer disease; single chain fragment variable antibody; peripheral blood mononuclear cell; cd33 antigen; tumor necrosis factor; amyloid beta protein; microglia; binding assay; atomic force microscopy; lintuzumab; antibodies, monoclonal, humanized; amyloid beta-peptides; humans; human; article; interferometry; polyvinylidene fluoride; single-chain antibodies; amyloid beta-protein (1-42); thp-1 cell line; sialic acid binding ig-like lectin 3; cd33 protein, human |
| Journal Title: | Molecular Psychiatry |
| Volume: | 29 |
| Issue: | 7 |
| ISSN: | 1359-4184 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-07-01 |
| Start Page: | 2084 |
| End Page: | 2094 |
| Language: | English |
| DOI: | 10.1038/s41380-024-02474-z |
| PUBMED: | 38383769 |
| PROVIDER: | scopus |
| PMCID: | PMC11336028 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding authors are David Scheinberg and Yue-Ming Li -- Source: Scopus |
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