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MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM
Authors:
Jessica B.
Casaletto
(Merrimack Pharmaceuticals, Inc)
,
Melissa L.
Geddie
(Merrimack Pharmaceuticals, Inc)
,
Adnan O.
Abu-Yousif
(Merrimack Pharmaceuticals, Inc)
,
Kristina
Masson
(Merrimack Pharmaceuticals, Inc)
,
Aaron
Fulgham
(Merrimack Pharmaceuticals, Inc)
,
Antoine
Boudot
(Merrimack Pharmaceuticals, Inc)
,
Tim
Maiwald
(Merrimack Pharmaceuticals, Inc)
,
Jeffrey D.
Kearns
(Merrimack Pharmaceuticals, Inc)
,
Neeraj
Kohli
(Merrimack Pharmaceuticals, Inc)
,
Stephen
Su
(Merrimack Pharmaceuticals, Inc)
,
Maja
Razlog
(Merrimack Pharmaceuticals, Inc)
,
Andreas
Raue
(Merrimack Pharmaceuticals, Inc)
,
Ashish
Kalra
(Merrimack Pharmaceuticals, Inc)
,
Maria
HÃ¥kansson
(SARomics Biostructures AB)
,
Derek T.
Logan
(SARomics Biostructures AB)
,
Martin
Welin
(SARomics Biostructures AB)
,
Shrikanta
Chattopadhyay
(Merrimack Pharmaceuticals, Inc)
,
Brian D.
Harms
(Merrimack Pharmaceuticals, Inc)
,
Ulrik B.
Nielsen
(Merrimack Pharmaceuticals, Inc)
,
Birgit
Schoeberl
(Merrimack Pharmaceuticals, Inc)
,
Alexey A.
Lugovskoy
(Merrimack Pharmaceuticals, Inc)
,
Gavin
Macbeath
(Merrimack Pharmaceuticals, Inc)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Proceedings Of The National Academy Of Sciences
, VOL 10
State:
Published (Approved)
Published:
March 2019
Diamond Proposal Number(s):
12427
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. 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.
Journal Keywords: bispecific antibody; Met; HGF; EpCAM; cancer
Diamond Keywords: Immunotherapy
Subject Areas:
Biology and Bio-materials,
Medicine
Instruments:
I02-Macromolecular Crystallography
Added On:
09/04/2019 12:11
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)