胰腺癌是一種高度轉移性且惡性的癌症，超過80％的患者在確診時已是癌症末期，因此而錯過了黃金治療時間。此外胰腺癌經常在化療時產生抗藥性反應，以致大多數治療最終無效。因此目前極迫切需要開發新的胰腺腫瘤靶向治療藥物。先前透過IL-17B / IL-17RB訊息傳遞的研究，我們證實了IL-17RB在接受IL-17B的信號下不僅促進胰腺腫瘤生長，更透過下游化學因子訊息活化並聚集巨噬細胞，致使胰臟腫瘤細胞因此有機會滲透與轉移至肺臟。在本論文中，我們發展出了專一識別IL-17RB的小鼠單株抗體D9能辨識蛋白質3D結構並在異種移植小鼠模型中延緩胰腺癌細胞生長速度且顯著延長存活天數。除此之外，我們更解出IL-17RB與D9抗體的複合蛋白質晶體Ｘ光繞射結構，從此結構中了解到D9透過與IL-17RB A’-A loop 的結合，使loop產生構造型太改變而阻抗其配體 (ligand) IL-17B的結合，有效使腫瘤生長變遲緩。我們在CDR移植的人類化抗體D9上，透過此複合體結構的資訊設計之噬菌體表現單鏈抗體庫來篩選出應用於人體治療用途的人類化單株抗體1B12，並證實此人類化抗體也在異種移植小鼠模型中延緩胰腺癌細胞生長速度。

Pancreatic cancer is a highly metastatic cancer with over 80% of the patients are diagnosed in advanced disease stages and are beyond the treatment window for curative resection. Most treatments are ineffective. There is an urgent need to develop targeting therapies for pancreatic cancer. Using both gain- and loss- of-function studies, we previously demonstrated that IL-17B/IL-17RB signaling plays an essential role in supporting pancreatic tumor growth, invasion and metastasis, and mediates downstream cytokine activation and macrophage recruitment. In this thesis, a mouse monoclonal antibody (D9) recognizing IL-17RB on its conformational epitope successfully delays the malignancy of pancreatic cancer cells and significantly extends survival in an orthotropic xenograft mice model. Moreover, clinical data suggests that high-level expression of IL-17RB is associated with shortened progression-free survival in pancreatic cancer patients. Thus, targeting IL-17B/IL-17RB pathway is potentially a new approach for pancreatic cancer treatment. Here, we solved the X-ray crystal structure of the IL-17RB ectodomain in complex with its neutralizing antibody D9. The structure shows that D9 binds to a predicted ligand-binding interface and engages with the A’-A loop of IL-17RB fibronectin III domain 1 in a unique conformational state that was observed for the first time among IL-17 receptors. Moreover, this structure also provides important paratope information to guide the design of antibody humanization and affinity maturation of D9, resulting in a humanized 1B12 antibody with marginal affinity loss and effective neutralization of IL-17B/IL-17RB signaling to impede tumorigenesis in a mouse xenograft model.

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