Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Syk is a key mediator of signaling events downstream of a wide array of receptors important for immune functions, including the B cell receptor, immunoglobulin receptors bearing the Fcg or Fce chain. Therefore, modulation of Syk could provide a novel therapeutic approach for autoimmune diseases and cancers. HM-0523, a highly potent and selective, orally available Syk inhibitor, is currently in Phase I clinical trials. The aim of this study is to evaluate the efficacy of HM-0523 in a systemic lupus erythematous (SLE) model in lupus-prone (MRL/lpr) mice.
Methods:
HM-0523 was orally administered to MRL/lpr mice before the disease onset. Key lupus features, including skin lesions, proteinuria and blood urea nitrogen levels were examined periodically. Overall survival and renal pathologic parameters were also assessed during the study (8–25 weeks).
Results:
Lupus-prone (MRL/lpr) mice, commonly used as a SLE model, spontaneously develop autoimmune disorders that reflect pathologies of human SLE, including enlargement of lymph nodes, elevation of IgG levels, anti-nuclear antibody production, proteinuria, and kidney failure caused by inflammation of the glomeruli.
In this study, in vivo efficacy of the orally active HM-0523 was evaluated in the lupus-prone (MRL/lpr) mice. The mice, at the age of 8 weeks, were prophylactically administrated with HM-0523 at 0, 5 and 20 mg/kg (QD), respectively. HM-0523, at 20 mg/kg, significantly blocked skin lesions [skin lesion score: 1.0 ± 0.3 (vehicle control) vs. 0.0 ± 0.0 (HM-0523); p< 0.05], delayed the onset of proteinuria and reduced the immune organs to body weight ratios [for example, spleen: 1.744 ± 0.158 (vehicle control) vs. 0.426 ± 0.034 (HM-0523) p< 0.05]. HM-0523, at 20 mg/kg, also significantly suppressed production of anti-dsDNA antibodies [408.6 ± 172.6 KU/ML (vehicle control) vs. 156.3 ± 25.8 KU/ML (HM-0523) p< 0.05]. Histopathological investigation demonstrated that HM-0523, at 20 mg/kg, greatly alleviated the pathological changes in renal, including glomerulonephritis, interstitial nephritis, and perivascular infiltration. HM-0523, at 20 mg/kg, also significantly inhibited increase of serum BUN and creatinine. Overall survival rate at week 25 in the HM-0523 treated mice was 100% (at 20 mg/kg and 5 mg/kg) compared to 70.0% in controls (p< 0.01). These comprehensive data indicate that HM-0523 has significant activity against the development of lupus and could be developed as a novel therapeutic agent for the treatment of SLE.
Conclusion:
Our data demonstrated that HM-0523, acting through selective inhibition of Syk activation, exhibited significant beneficial effects in a murine lupus model. HM-0523 is currently in Phase I clinical trials. These new data provided support that HM-0523 could potentially become a novel therapeutic agent for systemic lupus erythematous.
Disclosure:
Y. Cai,
Hutchison Medipharma Limited,
3;
Z. Wu,
Hutchison Medipharma Limited,
3;
P. Ren,
Hutchison Medipharma Limited,
3;
X. Dai,
Hutchison Medipharma Limited,
3;
J. He,
Hutchison Medipharma Limited,
3;
F. Yin,
Hutchison Medipharma Limited,
3;
W. Deng,
Hutchison Medipharma Limited,
3;
G. Dai,
Hutchison Medipharma Limited,
3;
W. Su,
Hutchison Medipharma Limited,
3;
X. Li,
Hutchison Medipharma Limited,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hm-0523-a-novel-syk-inhibitor-blocks-glomerulonephritis-and-extends-life-spans-in-lupus-prone-mrllpr-mice/