# Optimization of Siglec-8-Directed Immunotherapy for Eosinophilic and Mast Cell Disorders

> **NIH NIH R21** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $106,142

## Abstract

ABSTRACT
In a wide variety of human diseases, eosinophils and/or mast cells are thought to play an important pathogenetic
role. Several drugs are available to treat affected patients, but they are often ineffective. Thus, the need for novel
therapeutics to improve outcomes for these disorders is unquestioned. One promising drug target for this
purpose is sialic acid immunoglobulin (Ig)-like lectin 8 (Siglec-8; also known as SAF2). Siglec-8 is uniquely
expressed on eosinophils, mast cells and (weakly) basophils late during the maturation process and is not
displayed on hematopoietic stem cells and other blood and non-blood cells. This very restricted expression
pattern – together with the observation that unconjugated Siglec-8 antibodies (mAbs) cause apoptosis of
eosinophils in vitro – provides the impetus to develop Siglec-8-directed immunotherapy for patient application.
While early clinical trials with a humanized Siglec-8 mAb have been initiated, it is unknown how Siglec-8 is best
targeted therapeutically. In vitro data showing Siglec-8 mAbs inhibit mast cell function but do not induce mast
cell apoptosis suggest that unconjugated mAbs may have insufficient activity in some Siglec-8-positive disorders.
This is reminiscent of the experience with Siglec-3 (CD33) – the currently most widely targeted Siglec family
member – where unconjugated mAbs have been largely ineffective in the clinic. More potent treatment
modalities, e.g. CD3-directed bispecific antibodies (BiAbs), may be required for successful Siglec-8 therapy.
Besides treatment modality, our data suggest that the efficacy of Siglec-directed immunotherapy is also affected
by the location of the domain it targets. Specifically, in our studies with Siglec-3, we found membrane-proximal
binding substantially enhances effector functions of CD3-directed BiAbs. As a first step toward our long-term
goal of developing and optimizing Siglec-8-directed immunotherapy for eosinophilic and mast cell disorders, we
here propose to use humanized (“Trianni”) mice to generate a panel of diverse, fully human Siglec-8 mAbs and
then to carefully compare the efficacy of different treatment modalities (mAbs vs. BiAbs) and to determine the
role of membrane-proximal targeting as means to enhance the cytotoxicity of Siglec-8-targeted therapeutics. Our
studies are expected to provide critical insight into the principles of how Siglec-8 should be targeted for maximal
therapeutic benefit while, at the same time, they generate candidate molecules for further clinical development.
Our work may lead to a new treatment option for patients with eosinophilic or mast cell disorders for whom
outcomes continue to be unsatisfactory.

## Key facts

- **NIH application ID:** 10112172
- **Project number:** 5R21AI150566-02
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Roland Bruno Walter
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $106,142
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112172

## Citation

> US National Institutes of Health, RePORTER application 10112172, Optimization of Siglec-8-Directed Immunotherapy for Eosinophilic and Mast Cell Disorders (5R21AI150566-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112172. Licensed CC0.

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