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云南快乐十分中奖明细:MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM
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Although MET is an established oncogene that drives tumorigenesis, metastasis, and resistance to therapy, antibody therapeutics targeting Met have thus far eluded successful clinical development. Met is a particularly challenging target because bivalent antibodies typically agonize Met, whereas monovalent antibodies lack potency and the capacity to downregulate it. We report the design and preclinical development of a purely antagonistic anti-Met antibody that potently blocks both ligand-dependent and ligand-independent signaling by exploiting the concept of avidity. MM-131 is a bispecific antibody that is monovalent for Met, but exhibits high avidity by concurrently binding to the tumor-specific antigen epithelial cell adhesion molecule. Preclinically, MM-131 inhibits proliferation in Met-driven cancer cells, inhibits hepatocyte growth factor (HGF)-mediated cell migration, and inhibits tumor growth in HGF-dependent and -independent mouse xenograft models.
Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challenging, however, as bivalent antibodies exhibit agonistic properties, whereas monovalent antibodies lack potency and the capacity to down-regulate Met. Through computational modeling, we found that the potency of a monovalent antibody targeting Met could be dramatically improved by introducing a second binding site that recognizes an unrelated, highly expressed antigen on the tumor cell surface. Guided by this prediction, we engineered MM-131, a bispecific antibody that is monovalent for both Met and epithelial cell adhesion molecule (EpCAM). MM-131 is a purely antagonistic antibody that blocks ligand-dependent and ligand-independent Met signaling by inhibiting HGF binding to Met and inducing receptor down-regulation. Together, these mechanisms lead to inhibition of proliferation in Met-driven cancer cells, inhibition of HGF-mediated cancer cell migration, and inhibition of tumor growth in HGF-dependent and -independent mouse xenograft models. Consistent with its design, MM-131 is more potent in EpCAM-high cells than in EpCAM-low cells, and its potency decreases when EpCAM levels are reduced by RNAi. Evaluation of Met, EpCAM, and HGF levels in human tumor samples reveals that EpCAM is expressed at high levels in a wide range of Met-positive tumor types, suggesting a broad opportunity for clinical development of MM-131.
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Author contributions: J.B.C., M.L.G., A.O.A.-Y., K.M., A.R., B.D.H., U.B.N., B.S., A.A.L., and G.M. designed research; J.B.C., M.L.G., A.O.A.-Y., K.M., A.F., A.B., T.M., J.D.K., N.K., S.S., M.R., A.K., M.H., D.T.L., and M.W. performed research; J.B.C., M.L.G., A.O.A.-Y., K.M., A.F., A.B., T.M., J.D.K., N.K., S.S., M.R., A.K., M.H., D.T.L., M.W., S.C., and B.D.H. analyzed data; and J.B.C., M.L.G., T.M., J.D.K., A.R., M.H., and G.M. wrote the paper.
Conflict of interest statement: Several authors are or were employees of Merrimack Pharmaceuticals, Inc. at the time of contributing to the manuscript.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID codes 6HYG, for the Fc domain; 6I07, for the scFV::EpCAM complex; and 6I04, for the Fab::Met complex). Data and code for the computational model are available at //www.data2dynamics.org/.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1819085116/-/DCSupplemental.
Published under the PNAS license.