International immunopharmacology · 2025
Preclinical evaluation of STSA-1002, a novel human and rhesus monkeys cross-reactive monoclonal antibody targeting C5a, in acute respiratory distress syndrome models.
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Fang Yingying, Wang Xiaoqian, Xu Chang, Zhu Qing, Zang Xin, Liu Ju, Zhang Jingyi, Wang Xinghe
Аннотация
BACKGROUND: The complement-activated product (C5a) is a key mediator in the pathogenesis of acute respiratory distress syndrome (ARDS). While blocking C5a represents a promising therapeutic strategy, novel anti-C5a therapies require further development.
PURPOSE: This study aimed to develop a novel, human anti-C5a monoclonal antibody (STSA-1002) and evaluate its efficacy in treating ARDS through in vitro and vivo studies.
RESULTS: In vitro, STSA-1002 exhibited high binding affinity to human and rhesus monkey C5a (EC50: 29.41 ± 10.74 ng/mL and 32.29 ± 10.96 ng/mL, respectively) and effectively inhibited C5a-induced neutrophil degranulation, chemotaxis, and CD11b expression. In vivo, single intravenous administration of STSA-1002 (1, 3 and 10 mg/kg) significantly reduced the levels of interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), granulocyte-macrophage colony stimulating factor (GM-CSF), monocyte chemotactic protein-1 (MCP-1) and mortality in a COVID-19-related LPS-induced ARDS mouse model (Model 1). In a second LPS-induced ARDS model (Model 2), STSA-1002 (1, 5 and 25 mg/kg) significantly reduced IL-6, TNF-α concentrations and leukocyte counts in serum and diminished IL-6 in bronchoalveolar lavage fluid (BALF), alongside improvements in lung weight index. In addition, pharmacokinetic (PK) studies in rhesus monkeys demonstrated linear exposure (5-50 mg/kg) and a favorable safety profile in a 4-week repeat-dose toxicity study.
CONCLUSION: These results furnish comprehensive preclinical evidence for STSA-1002 as an innovative anti-C5a therapeutic agent and provide a preliminary rationale for developing immunomodulatory therapy in ARDS.
PURPOSE: This study aimed to develop a novel, human anti-C5a monoclonal antibody (STSA-1002) and evaluate its efficacy in treating ARDS through in vitro and vivo studies.
RESULTS: In vitro, STSA-1002 exhibited high binding affinity to human and rhesus monkey C5a (EC50: 29.41 ± 10.74 ng/mL and 32.29 ± 10.96 ng/mL, respectively) and effectively inhibited C5a-induced neutrophil degranulation, chemotaxis, and CD11b expression. In vivo, single intravenous administration of STSA-1002 (1, 3 and 10 mg/kg) significantly reduced the levels of interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), granulocyte-macrophage colony stimulating factor (GM-CSF), monocyte chemotactic protein-1 (MCP-1) and mortality in a COVID-19-related LPS-induced ARDS mouse model (Model 1). In a second LPS-induced ARDS model (Model 2), STSA-1002 (1, 5 and 25 mg/kg) significantly reduced IL-6, TNF-α concentrations and leukocyte counts in serum and diminished IL-6 in bronchoalveolar lavage fluid (BALF), alongside improvements in lung weight index. In addition, pharmacokinetic (PK) studies in rhesus monkeys demonstrated linear exposure (5-50 mg/kg) and a favorable safety profile in a 4-week repeat-dose toxicity study.
CONCLUSION: These results furnish comprehensive preclinical evidence for STSA-1002 as an innovative anti-C5a therapeutic agent and provide a preliminary rationale for developing immunomodulatory therapy in ARDS.