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Dual Constant Domain-Fab: A novel strategy to improve half-life and potency of a Met therapeutic antibody.

Abstract：

:The kinase receptor encoded by the Met oncogene is a sensible target for cancer therapy. The chimeric monovalent Fab fragment of the DN30 monoclonal antibody (MvDN30) has an odd mechanism of action, based on cell surface removal of Met via activation of specific plasma membrane proteases. However, the short half-life of the Fab, due to its low molecular weight, is a severe limitation for the deployment in therapy. This issue was addressed by increasing the Fab molecular weight above the glomerular filtration threshold through the duplication of the constant domains, in tandem (DCD-1) or reciprocally swapped (DCD-2). The two newly engineered molecules showed biochemical properties comparable to the original MvDN30 in vitro, acting as full Met antagonists, impairing Met phosphorylation and activation of downstream signaling pathways. As a consequence, Met-mediated biological responses were inhibited, including anchorage-dependent and -independent cell growth. In vivo DCD-1 and DCD-2 showed a pharmacokinetic profile significantly improved over the original MvDN30, doubling the circulating half-life and reducing the clearance. In pre-clinical models of cancer, generated by injection of tumor cells or implant of patient-derived samples, systemic administration of the engineered molecules inhibited the growth of Met-addicted tumors.

journal_name

Mol Oncol

journal_title

Molecular oncology

authors

Cignetto S,Modica C,Chiriaco C,Fontani L,Milla P,Michieli P,Comoglio PM,Vigna E

doi

10.1016/j.molonc.2016.03.004

subject

Has Abstract

pub_date

2016-06-01 00:00:00

pages

938-48

issue

6

eissn

1574-7891

issn

1878-0261

pii

S1574-7891(16)30011-4

journal_volume

10

pub_type

杂志文章

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