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Engineering single-domain antibodies targeting Gasdermin E activation by the chemotherapeutic agent
Jinyi Ma1, Jintao Xu1, Qiuyun Gao1
1Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Abstract:
As mediators of pyroptosis, gasdermins (GSDMs) are closely associated with systemic cytotoxicity or so-called side effects and are also involved in the inflammatory response during chemotherapy. Using in situ proximity ligation assay followed by sequencing (isPLA-seq), which we recently developed, we screened a single-domain antibody (sdAb) library and identified several sdAbs against Gasdermin E (GSDME) that specifically recognize the N-terminal domain (1-270 aa) of GSDME (GSDME-NT). One of them mitigated the release of inflammatory damage-associated molecular patterns (DAMPs) and cytokines, including high mobility group protein b1 (Hmgb1) and interleukin-1β (Il-1β), in isolated mouse alveolar epithelial cells (AECs) upon chemotherapeutic agent cis-diaminodichloroplatinum (CDDP) treatment. Further investigation showed that this anti-GSDME sdAb also alleviated CDDP-induced pyroptotic cell death and lung tissue injury and decreased systemic Hmgb1 release in C57/BL6 mice, due to GSDME inactivation. Collectively, our data define an inhibitory role of the specific sdAb against GSDME, providing a potential strategy for systemically alleviating chemotherapeutic toxicities in vivo.
Insights
This study identifies a novel single-domain antibody (sdAb) that inhibits Gasdermin E (GSDME). This antibody effectively reduces chemotherapy side effects, offering a potential strategy to alleviate systemic toxicity.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Gasdermins (GSDMs) mediate pyroptosis, contributing to chemotherapy side effects and inflammation.
- Gasdermin E (GSDME) is implicated in chemo-induced cytotoxicity and inflammatory responses.
Purpose of the Study:
- To identify and characterize single-domain antibodies (sdAbs) targeting Gasdermin E (GSDME).
- To evaluate the therapeutic potential of an anti-GSDME sdAb in mitigating chemotherapy-induced toxicity.
Main Methods:
- Development and application of in situ proximity ligation assay followed by sequencing (isPLA-seq).
- Screening of an sdAb library against GSDME N-terminal domain (GSDME-NT).
- In vitro assessment in mouse alveolar epithelial cells (AECs) and in vivo studies in C57/BL6 mice.
Main Results:
- Identified specific sdAbs targeting GSDME-NT.
- One sdAb mitigated release of damage-associated molecular patterns (DAMPs) like Hmgb1 and cytokines (Il-1β) in vitro.
- The anti-GSDME sdAb alleviated pyroptosis, lung injury, and systemic Hmgb1 release in mice treated with cis-diaminodichloroplatinum (CDDP).
Conclusions:
- The developed sdAb demonstrates an inhibitory function against GSDME.
- This anti-GSDME sdAb presents a promising strategy for alleviating systemic chemotherapy toxicities in vivo.
