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|Ref Type||Journal Article|
|Authors||Yu S, Zhang J, Yan Y, Yao X, Fang L, Xiong H, Liu Y, Chu Q, Zhou P, Wu K|
|Title||A novel asymmetrical anti-HER2/CD3 bispecific antibody exhibits potent cytotoxicity for HER2-positive tumor cells.|
|Journal||Journal of experimental & clinical cancer research : CR|
|Date||2019 Aug 14|
|Abstract Text||Human epidermal growth factor receptor 2 (HER2) is overexpressed in multiple cancers, which is associated with poor prognosis. Herceptin and other agents targeting HER2 have potent antitumor efficacy in patients with HER2-positive cancers. However, the development of drug resistance adversely impacts the efficacy of these treatments. It is therefore urgent to develop new HER2-targeted therapies. Bispecific antibodies (BsAbs) could guide immune cells toward tumor cells, and produced remarkable effects in some cancers.A BsAb named M802 that targets HER2 and CD3 was produced by introducing a salt bridge and knobs-into-holes (KIHs) packing into the structure. Flow cytometry was performed to determine its binding activity and cytotoxicity. CCK-8, Annexin V/PI staining, western blotting, and ELISA were utilized to study its effect on cell proliferation, apoptosis, the signaling pathways of tumor cells, and the secretion of cytokines by immune cells. Subcutaneous tumor mouse models were used to analyze the in vivo antitumor effects of M802.We generated a new format of BsAb, M802, consisting of a monovalent unit against HER2 and a single chain unit against CD3. Our in vitro and in vivo experiments indicated that M802 recruited CD3-positive immune cells and was more cytotoxic than Herceptin in cells with high expression of HER2, low expression of HER2, and Herceptin resistance. Although M802 showed weaker effects than Herceptin on the PI3K/AKT and MAPK pathways, it was more cytotoxic due to its specific recognition of HER2 and its ability to recruit effector cells via its anti-CD3 moiety.Our results indicated that M802 exhibited potent antitumor efficacy in vitro and in vivo. M802 retained the function of Herceptin in antitumor signaling pathways, and also recruited CD3-positive immune cells to eliminate HER2-positive tumor cells. Therefore, M802 might be a promising HER2 targeted agent.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|M802||CD3 Antibody 26 HER2 (ERBB2) Antibody 47||M802 is a bi-specific antibody that targets ERBB2 (HER2) and CD3, potentially resulting in induction of immune response against ERBB2 (HER2)-expressing tumor cells (PMID: 31412896).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ERBB2 over exp||stomach cancer||sensitive||M802||Preclinical - Cell culture||Actionable||In a preclinical study, M802 inhibited growth of a gastric cancer cell line expressing high levels of ERBB2 (HER2) in culture, and inhibited tumor growth in xenograft models (PMID: 31412896).||31412896|
|ERBB2 over exp||breast cancer||sensitive||M802||Preclinical - Cell culture||Actionable||In a preclinical study, treatment with M802 increased apoptosis and inhibited growth of breast cancer cell lines expressing high levels of ERBB2 (HER2) in culture (PMID: 31412896).||31412896|