O’Sullivan JA, Youngblood BA, Schleimer RP, Bochner BS (2024) Siglecs as potential targets of therapy in human mast cell- and/or eosinophil-associated diseases. Semin Immunol 69:101799. doi: 10.1016/j.smim.2023.101799 PMID: 37413923

Objective: To review a subset of Siglecs and their various endogenous or synthetic sialoside ligands that regulate eosinophil and mast cell function and survival.

Summary: Sialic acid-binding immunoglobulin-like lectins (Siglecs) are vertebrate glycan-binding cell-surface proteins. Many Siglecs mediate cellular inhibitory activity and are of interest as part of a strategy to therapeutically lessen unwanted cellular responses. Human eosinophils and mast cells express overlapping but distinct patterns of Siglecs, and certain Siglecs have become the focus of novel therapies for allergic and other eosinophil and mast cell-related diseases.

Usage: Saporin in conjunction with CD22 glycomimetic ligand BPCNeuAc leads to cells death induction in a ligand-dependent manner on B-lymphoma cells (Collins et al.). Incubation with anti-Siglec-8 monoclonal antibody conjugated to saporin led to the death of malignant mast cells and eosinophils (O’Sullivan et al.)

Related Products: Saporin (Cat. #PR-01)

See Also:

• Collins BE, Blixt O, Han S, Duong B, Li H, Nathan JK, Bovin N, Paulson JC (2006) High-affinity ligand probes of CD22 overcome the threshold set by cis ligands to allow for binding, endocytosis, and killing of B cells. J Immunol 177(5):2994-3003. doi: 10.4049/jimmunol.177.5.2994 PMID: 16920935
• O’Sullivan J et al. Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells. J Allergy Clin Immunol 141:1774-1785.e1777, 2018.

Su Y, Xu J, Zhu Z, Chin J, Xu L, Yu H, Nudell V, Dash B, Moya EA, Ye L, Nimmerjahn A, Sun X (2024) Brainstem Dbh+ neurons control allergen-induced airway hyperreactivity. Nature 631(8021):601-609. doi: 10.1038/s41586-024-07608-5 PMID: 38987587

Objective: To map a full allergen circuit from the lung to the brainstem and back to the lung. Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner.

Summary: Ablation or chemogenetic inactivation of Dbh+nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh+nTS neurons project to the nucleus ambiguous (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh+nTS and NA.

Usage: To determine whether Dbh+nTS neurons are essential for hyperreactivity chemical ablation, anti-dopamine beta-hydroxylase antibody conjugated to saporin (Anti-DBH-SAP, IT-03), shown to be specific for DBH+neurons, was injected into the nTS.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Metz M, Kolkhir P, Altrichter S, Siebenhaar F, Levi-Schaffer F, Youngblood BA, Church MK, Maurer M (2023) Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases. Allergy doi: 10.1111/all.15850 PMID: 37605867

Objective: Authors review the role of mast cells (MC) in the pathogenesis of chronic urticaria (CU), explore current therapeutic strategies, and introduce the concept of MC silencing as a strategy to block activation of MCs without eliciting immunosuppressive adverse effects.

Summary: CU is a MC-dependent disease with limited therapeutic options. Current strategies are directed at inhibiting IgE-mediated activation of MCs. MC depletion or silencing strategies are being developed to overcome limitations of singularly targeted agents. MC silencers, such as monoclonal antibodies that engage inhibitory receptor like sialic acid-binding immunoglobulin-like lectin8 (Siglec-8) have reached preclinical stages of development. Siglecs have been shown to be internalized upon antibody engagement, such as Siglec-8, and is being used to deplete MCs via conjugating saporin to the internalizing Siglec-8 antibody to cause cell death in human mast cells.

Usage: Usage: Anti-Siglec-8 (2C4)-SAP was used at 2.5 µg/ml to eliminate eosinophils and at 1.25 µg/ml to eliminate the HMC-1.2 human mast cell line.

Related Products: Saporin (Cat. #PR-01)

See Also:

• O’Sullivan J et al. Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells. J Allergy Clin Immunol 141:1774-1785.e1777, 2018.

Plum T (2019) Identification of lineage-specific markers for therapeutic targeting of mast cells. Ruperto-Carola University of Heidelberg, Germany Thesis. doi: 10.11588/heidok.00023555

Usage: Mice were injected i.v. with either 100 µg of 1:1 molar mixture of biotinylated CD63 antibody and Streptavidin-ZAP (60 µg mAb + 40 µg SAP) or with 40 µg SAP alone. All injections were performed in 200 µl PBS.

Related Products: Streptavidin-ZAP (Cat. #IT-27), Saporin (Cat. #PR-01), Anti-CD63-SAP (Cat. #IT-99)

O’Sullivan J, Carroll D, Cao Y, Salicru A, Bochner B (2018) Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells. J Allergy Clin Immunol 141:1774-1785.e1777. doi: 10.1016/j.jaci.2017.06.028

Summary: Therapeutic payloads can be targeted selectively to eosinophils and malignant mast cells by exploiting this Siglec-8 endocytic pathway.

Usage: Eosinophil cell death was assessed with 2C4 mAb or isotype control (both at 2.5 μg/mL).

Related Products: Custom Conjugates