公开(公告)号：US11007266B2

公开(公告)日：2021-05-18

申请号：US16032482

申请日：2018-07-11

Applicant: UNIVERSITY OF MACAU

Inventor： Hang Fai Kwok

IPC: A61K39/395 ,  A61K45/06 ,  A61P9/12 ,  C07K16/40 ,  C07K16/28 ,  A61K39/00

Abstract: Angiotensin II (AngII) has been strongly implicated in hypertension and its complications. Evidence suggests the mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances cardiovascular remodeling and damage may be distinct. In vascular smooth muscle cells, a metaloproteinase ADAM17 mediates epidermal growth factor receptor (EGER) transactivation, which may be responsible for cardiovascular remodeling but not hypertension induced by AngII. Treatment with a human cross-reactive ADAM17 inhibitory antibody (A9B8) also prevented cardiovascular, remodeling and ER stress but not hypertension in C57Bl/6 mice infused with AngII. In vitro data further supported these findings. In conclusion, vascular ADAM17 mediates AngII-induced cardiovascular remodeling via EGFR activation independent of blood pressure regulation. ADAM17 presents a unique therapeutic target for antibodies such as A9B8 for the prevention of hypertensive complications.

公开(公告)号：US10858441B2

公开(公告)日：2020-12-08

申请号：US16033654

申请日：2018-07-12

Applicant: UNIVERSITY OF MACAU

Inventor： Hang Fai Kwok ,  Ruiyu Xie

IPC: C07K16/28 ,  A61K31/7068 ,  A61K31/519 ,  A61K31/517 ,  A61K39/395 ,  A61K31/437 ,  A61P35/00 ,  A61K31/513 ,  A61K39/00 ,  A61K31/282

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumor amongst all human cancers due to late diagnosis and resistant to treatment with chemotherapy and radiation. Preclinical and clinical studies have revealed that ErbB family for example epidermal growth factor receptor (EGFR) is a validated molecular target for pancreatic cancer prevention and therapy. The ErbB signaling cascade is regulated by a member of the ADAM (a disintegrin and metalloprotease) family, namely ADAM17, by enzymatic cleavage of precursor ligands into soluble cytokines and growth factors. Mouse genetic studies have demonstrated that ADAM17 is required for PDAC development. In this study, we evaluated the anti-tumor effects of A9(B8) IgG—the first specific ‘human and mouse cross-reactive’ ADAM17 inhibitory antibody on pancreatic malignant transformation. We found that inhibition of ADAM17 with A9(B8) IgG efficiently suppressed the shedding of ADAM17 substrates both in vivo and in vitro. Furthermore, we demonstrated that administration of A9(B8) IgG significantly suppressed motility in human pancreatic cancer cells and also significantly delayed tumorigenesis in the Pdx1Cre;KrasG12D;Trp53fl/+ PDAC mouse model. Inhibition of ADAM17 with A9(B8) IgG particularly affected the progression of pre-invasive pancreatic lesions to advanced PDAC in mice. Taken together, the preclinical data presented here will provide a starting point for clinical applications of ADAM17 targeted therapy.