Tris DBA醫藥組合物及其用於自體免疫疾病之用途

專利類型

發明

專利國別 (專利申請國家)

中華民國

專利申請案號

108147439

專利證號

I 738156

專利獲證名稱

Tris DBA醫藥組合物及其用於自體免疫疾病之用途

專利所屬機關 (申請機關)

國防醫學院

獲證日期

2021/09/01

技術說明

Tris (dibenzylideneacetone) dipalladium (Tris-DBA)是一種小分子鈀絡化合物，目前文獻指出在胰腺癌、血液淋巴癌及多發性骨髓瘤能有效抑制細胞生長及增生，鑑於該化合物對B細胞惡性腫瘤（慢性淋巴細胞白血病和多發性骨髓瘤）具有療效。本發明驗證了Tris DBA能有效抑制狼瘡腎炎中腎絲球的細胞增生、腎臟發炎以及免疫細胞的浸潤，利用惡化型狼瘡腎炎(ASLN)小鼠模式經由Tris DBA治療後能顯著改善腎功能、蛋白尿及腎臟組織型態學的變化，其中包含測量腎絲球細胞增生、腎絲球的新月結構產生、嗜中性浸潤、纖維化及細胞壞死、腎間質發炎並評估及計算腎絲球腎炎嚴重度。同時也能觀察到Tris DBA顯著降低腎絲球補體C3及IgG免疫球蛋白的沉澱。此外，我們也證實了Tris DBA能[1]抑制T細胞的功能經由骨髓分化的樹突狀細胞所誘導以及抑制惡化型狼瘡腎炎小鼠模式中anti-dsDNA自體抗體的產生；[2]能促進自噬作用並進一步抑制NLRP3發炎體(NLRP3 inflammasome)的活化和[3]抑制JNK、ERK和 p38 MAPK訊息路徑的磷酸化。Tris DBA的生效機制是透過抑制MAPK(JNK、ERK)的磷酸化來調控NLRP3發炎路徑的第一訊息傳遞路徑以及促進自噬作用並抑制NLRP3發炎體的活化。這些結果顯示，Tris DBA具有高度開發成為治療狼瘡腎炎，特別是疾病惡化之預防，候選藥物。 Tris (Dibenzylideneacetone) dipalladium (Tris DBA), a small molecule palladium complex, has been shown to inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukemia and multiple myeloma. Given that this compound is particularly active against B cell malignancies (Chronic lymphocytic leukemia and multiple myeloma), we wished to evaluate its efficacy in an autoimmune disease with prominent B cell involvement, lupus nephritis. In the present study, we examined the therapeutic effects of Tris DBA on glomerular cell proliferation, renal inflammation and immune cells. Treatment of accelerated and severe lupus nephritis (ASLN) mice with Tris DBA resulted in improved renal function, albuminuria and pathology, including measurements of glomerular cell proliferation, cellular crescents, neutrophils, fibrinoid necrosis and tubulointerstitial inflammation in the kidneys as well as scoring for glomerulonephritis activity. The treated ASLN mice also showed significantly decreased glomerular IgG and C3 deposits. Furthermore, the compound was able to [1] inhibit BMDC-mediated T-cell functions and reduce serum anti-dsDNA autoantibody levels; [2] differentially regulate autophagy and both the priming and activation signals of the NLRP3 inflammasome; and [3] suppress the phosphorylation of JNK, ERK, and p38 MAPK signaling pathways. Tris DBA improved ASLN in mice through immunoregulation, by blunting the MAPK (ERK, JNK)-mediated priming signal of the NLRP3 inflammasome and by regulating the autophagy/NLRP3 inflammasome axis. These results suggest that the pure compound may be a drug candidate for treating the accelerated and deteriorated type of LN.

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