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Optimizing Siglec-8-Directed Immunotherapy for Eosinophilic and Mast Cell Disorders
Sheryl Y T Lim1, Jenny Huo1, George S Laszlo1
1Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Cancers
|October 26, 2024
Summary
New immunotherapies targeting Siglec-8 show potent activity against eosinophilic and mast cell disorders. These novel treatments, including bispecific antibodies and CAR-NK cells, offer improved efficacy for difficult-to-treat conditions.
Area of Science:
- Immunology
- Eosinophil and Mast Cell Biology
- Therapeutic Antibody Development
Background:
- Current treatments for eosinophilic and mast cell disorders have limited effectiveness.
- Sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) is a promising therapeutic target.
- Existing Siglec-8 monoclonal antibodies (mAbs) and unconjugated therapies show inadequacy, particularly against mast cells.
Purpose of the Study:
- To develop novel Siglec-8-targeting immunotherapies.
- To evaluate the efficacy of different Siglec-8 antibody formats and targeting strategies.
- To assess the potential of Siglec-8-directed therapies for eosinophilic and mast cell disorders.
Main Methods:
- Generated a panel of fully human Siglec-8 monoclonal antibodies (mAbs) targeting different domains (V-set, C2-set) using transgenic mice.
- Developed T cell-engaging bispecific antibodies (BiAbs) and chimeric antigen receptor (CAR)-modified natural killer (NK) cells utilizing Siglec-8 mAb fragments.
- Assessed the cytolytic activity of these novel therapeutics against Siglec-8-expressing cells, including human cell lines and primary patient eosinophils.
Main Results:
- All generated Siglec-8 mAbs demonstrated efficient internalization into target cells, indicating potential for payload delivery.
- Siglec-8-directed BiAbs and CAR-NK cells exhibited potent, antigen-specific cytotoxicity against Siglec-8-positive cells, even at low target expression levels.
- Targeting membrane-proximal Siglec-8 epitopes (V-set domain) enhanced cytotoxicity compared to targeting full-length Siglec-8; C2-set targeting also showed high efficacy.
Conclusions:
- Siglec-8-directed immunotherapies, including BiAbs and CAR-NK cells, are highly potent and effective.
- These novel therapeutic strategies demonstrate significant potential for treating eosinophilic and mast cell disorders.
- Further development of Siglec-8-based immunotherapies is warranted for improved patient outcomes.
