Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM

Casaletto, Jessica B. ; Geddie, Melissa L. ; Abu-Yousif, Adnan O. ; Masson, Kristina LU ; Fulgham, Aaron ; Boudot, Antoine ; Maiwald, Tim ; Kearns, Jeffrey D. ; Kohli, Neeraj and Su, Stephen , et al. (2019) In Proceedings of the National Academy of Sciences of the United States of America 116(15). p.7533-7542
Abstract

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.... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Bispecific antibody, Cancer, EpCAM, HGF, Met
in
Proceedings of the National Academy of Sciences of the United States of America
volume
116
issue
15
pages
10 pages
publisher
National Academy of Sciences
external identifiers
  • scopus:85064140079
  • pmid:30898885
ISSN
0027-8424
DOI
10.1073/pnas.1819085116
language
English
LU publication?
no
additional info
Publisher Copyright: © 2019 National Academy of Sciences. All Rights Reserved.
id
ef1aa6e4-8b9f-4b11-8414-f92a92154fd6
date added to LUP
2022-04-08 08:53:54
date last changed
2024-05-11 23:40:52
@article{ef1aa6e4-8b9f-4b11-8414-f92a92154fd6,
  abstract     = {{<p>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.</p>}},
  author       = {{Casaletto, Jessica B. and Geddie, Melissa L. and Abu-Yousif, Adnan O. and Masson, Kristina and Fulgham, Aaron and Boudot, Antoine and Maiwald, Tim and Kearns, Jeffrey D. and Kohli, Neeraj and Su, Stephen and Razlog, Maja and Raue, Andreas and Kalra, Ashish and Håkansson, Maria and Logan, Derek T. and Welin, Martin and Chattopadhyay, Shrikanta and Harms, Brian D. and Nielsen, Ulrik B. and Schoeberl, Birgit and Lugovskoy, Alexey A. and MacBeath, Gavin}},
  issn         = {{0027-8424}},
  keywords     = {{Bispecific antibody; Cancer; EpCAM; HGF; Met}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{15}},
  pages        = {{7533--7542}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM}},
  url          = {{http://dx.doi.org/10.1073/pnas.1819085116}},
  doi          = {{10.1073/pnas.1819085116}},
  volume       = {{116}},
  year         = {{2019}},
}