Novel CD33 antibodies unravel localization, biology and therapeutic implications of CD33 isoforms.

Future Oncol

Department of Pharmacotherapy & Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.

Published: January 2021

The aim of this study was to establish the therapeutic relevance of the CD33 isoform by developing novel antibodies targeting the IgC domain of CD33. Two novel IgC-targeting antibodies, HL2541 and 5C11-2, were developed, and CD33 isoforms were assessed using multiple assays in cells overexpressing either CD33 or CD33 isoforms, unmodified acute myeloid leukemia (AML) cell lines and primary AML specimens representing different genotypes for the CD33 splicing single nucleotide polymorphism. CD33 was recognized on cells overexpressing CD33 and unmodified AML cell lines; however, minimal/no cell surface detection of CD33 was observed in primary AML specimens. Both isoforms were detected intracellularly using novel antibodies. Minimal cell surface expression of CD33 on primary AML/progenitor cells warrants further studies on anti-CD33 immunotherapeutics.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10621775PMC
http://dx.doi.org/10.2217/fon-2020-0746DOI Listing

Publication Analysis

Top Keywords

cd33 isoforms
12
cd33
9
novel antibodies
8
cells overexpressing
8
aml cell
8
cell lines
8
primary aml
8
aml specimens
8
cell surface
8
novel
4

Similar Publications

Targeting splicing for hematological malignancies therapy.

BMC Genomics

November 2024

Department of Experimental Hematooncology, Medical University of Lublin, Chodzki 1, Lublin, 20-093, Poland.

Alterations in splicing patterns of leukemic cells have a functional impact and influence most cellular processes since aberrantly spliced isoforms can provide a proliferative advantage, enable to evade apoptosis, induce metabolic reprogramming, change cell signaling and antitumor immune response, or develop drug resistance. In this Review, we first characterize the general mechanism of mRNA processing regulation with a focus on the role of splicing factors, which are commonly mutated in blood neoplasms. Next, we provide a comprehensive summary on the current understanding of alternative splicing events, which confer resistance to targeted treatment strategies and immunotherapy.

View Article and Find Full Text PDF

Large-scale genetic studies have identified numerous genetic risk factors that suggest a central role for innate immune cells in susceptibility to Alzheimer's disease (AD). CD33, an immunomodulatory transmembrane sialic acid binding protein expressed on myeloid cells, was identified as one such genetic risk factor associated with Alzheimer's disease. Several studies explored the molecular outcomes of genetic variation at the locus.

View Article and Find Full Text PDF

Increasing evidence suggests that alternative splicing plays an important role in Alzheimer's disease (AD) pathology. We used long-read sequencing in combination with a novel bioinformatics tool (FICLE) to profile transcript diversity in the entorhinal cortex of female transgenic (TG) mice harboring a mutant form of human tau. Our analyses revealed hundreds of novel isoforms and identified differentially expressed transcripts - including specific isoforms of Apoe, App, Cd33, Clu, Fyn and Trem2 - associated with the development of tau pathology in TG mice.

View Article and Find Full Text PDF

The single-nucleotide polymorphism (SNP) rs12459419 is located at the intron/exon junction of CD33 exon2. When exon2 is skipped by this CD33 SNP, the full-length CD33 (CD33FL) is converted to a short CD33 isoform (CD33D2). Since gemtuzumab ozogamicin (GO) only recognizes CD33FL, the CD33 SNP may affect the clinical efficacy of GO.

View Article and Find Full Text PDF

Microglia play diverse pathophysiological roles in Alzheimer's disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!