Monovalency Unleashes the Full Therapeutic Potential of the DN-30 Anti-Met Antibody

Pacchiana, Giovanni; Chiriaco, Cristina; Stella, Maria Cristina; Petronzelli, Fiorella; Santis, Rita De; Galluzzo, Maria; Carminati, Paolo; Comoglio, Paolo M.; Michieli, Paolo; Vigna, Elisa

doi:10.1074/jbc.m110.134031

Cited by 74 publications

(112 citation statements)

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“…Moreover, they can lead to stabilization of their target receptor on the cell surface, which implies the risk of prolonged signal transduction (8). Biologics (bivalent or one armed Abs) are limited by their inability to impact on ligand-independent activation of the receptor and/or residual agonistic activity (2,(24)(25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

“…Although these antibodies may have ligand-independent activity, they have the potential to act as partial agonists through receptor clustering thereby creating a potential safety risk. A monovalent form of DN-30 mAb was engineered to eliminate agonist activity and although it does not directly inhibit HGF binding it causes receptor cleavage and shedding in preclinical models (25). The one-armed Ab, MetMab, was also developed in an effort to counteract this agonism (26).…”

Section: Introductionmentioning

confidence: 99%

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A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

Olwill

Joffroy

Gille

et al. 2013

Molecular Cancer Therapeutics

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Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients. Mol Cancer Ther; 12(11); 2459-71. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

Olwill

Joffroy

Gille

et al. 2013

Molecular Cancer Therapeutics

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“…However, the DN-30 Fab fragment was capable of high-affinity MET binding, efficient receptor shedding, and down-regulation and yet did not enhance kinase activation. The monovalent DN-30 Fab displayed potent in vitro and in vivo inhibitory efficacy in MET-dependent tumor cell lines, supporting it as a promising anti-MET targeted antibody therapy (11). AMG 102 (Amgen) is a fully human IgG2 monoclonal antibody against HGF that inhibits MET binding.…”

Section: Viewsmentioning

confidence: 98%

Anti-MET Targeted Therapy Has Come of Age: The First Durable Complete Response with MetMAb in Metastatic Gastric Cancer

Yan

Patrick

2011

Cancer Discovery

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The MET/hepatocyte growth factor (HGF) signaling pathway plays important roles in oncogenesis and tumor progression in a variety of human cancers. MET/HGF drives an invasive signaling program that can be dysregulated in human cancers through a number of activating mechanisms, including mutations, overexpression, amplification, alternative splicing, and HGF ligand–induced autocrine/paracrine loop signaling. As a testimony of MET-targeting therapeutics is beginning to come to clinical fruition, Catenacci and colleagues report the first case of durable complete response under an anti-MET receptor monoclonal antibody, MetMAb, in a patient with chemotherapy-refractory, advanced gastric cancer metastatic to the liver, found to have high MET gene polysomy and remarkably high serum HGF level. Serum and tissue studies also revealed predictive biomarkers for therapeutic response to MET inhibition. Cancer Discovery; 1(7); 550–4. ©2011 AACR. Commentary on Catenacci et al., p. 573.

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“…Unlike CBL-mediated endosomal degradation, regulated proteolysis of MET is ligand-and ubiquitin-independent and does not require the kinase activity of the receptor: the mechanism occurs basally and affords MET signalling with chronic, low-grade attenuation under steady-state conditions. The shedding of MET that is catalysed by ADAM metalloproteases can be acutely enhanced by various agents such as phorbol esters, suramin, lysophosphatidic acid and monoclonal antibodies (mAbs) against the MET ectodomain 94,95,96,97,98,99,100,101,102 . Importantly, the extracellular shedding of MET not only decreases the number of receptor molecules on the cell surface but also generates a decoy moiety that interacts with both HGF (by sequestering the ligand) and full-length MET (by impairing dimerization and transactivation of the native receptor) to further inhibit MET signalling 103,104 .…”

Section: Regulation Of Met Signallingmentioning

confidence: 99%

MET signalling: principles and functions in development, organ regeneration and cancer

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

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The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.Throughout embryogenesis, cells bud off from developing tissues and move outwards to shape and pattern the complex architecture of prospective organs 1 . A similar process occurs in adult life during wound healing and tissue repair, when lingering cells migrate into injury sites to recreate the pre-existing structures 2 . The acquisition of cell motility is necessary, but not sufficient, for this event. Cells that detach from their neighbours must elude anoikis, a form of apoptotic cell death that occurs when cells lose adhesion with the extracellular matrix 3 . Moreover, migratory cells undergo extensive mitotic divisions to produce 'founder populations', which settle in newly forming organs during development or colonize worn tissues during repair 4,5 . The normal phases of embryogenesis and organ regeneration strongly resemble the pathological process of tumour invasiveness: similarly to cells at the wound edge, cells at the tumour's leading front disrupt intercellular contacts and infiltrate the adjacent surroundings, where they resist anoikis and grow before lodging in the blood vessels for systemic dissemination 6 . This resemblance is not simply a biological correlate, it has a common mechanistic basis: cancer cells resurrect the latent schemes of cellular reorganization, which are usually confined to embryonic development and damaged adult organs, and leverage them to become competent for metastasization 7 . The activities -motility, survival and proliferation -that occur in developing, injured and neoplastic tissues embody a biological programme that is defined as 'invasive growth' 8 . This is triggered by extracellular stimuli that regulate the activity of several transcription factors that, in turn, modulate the expression of a number of proteins, ranging from cytoskeletal and cell-cell junctional components to cell cycle regulators and anti-apoptotic effectors 9, 10 . One major environmental inducer of invasive growth is hepatocyte growth factor (HGF, also known as scatter factor), the ligand for the MET tyrosine kinase receptor (also known as the HGF receptor) 11,12,13,14,15,16,17,18,19,20 (Box 1). ...

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Monovalency Unleashes the Full Therapeutic Potential of the DN-30 Anti-Met Antibody

Abstract: Met, the high affinity receptor for hepatocyte growth factor, is one of the most frequently activated tyrosine kinases in human cancer and a validated target for cancer therapy. We previously developed a mouse monoclonal antibody directed against the extracellular portion of Met (

Cited by 74 publications

References 31 publications

A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

Anti-MET Targeted Therapy Has Come of Age: The First Durable Complete Response with MetMAb in Metastatic Gastric Cancer

MET signalling: principles and functions in development, organ regeneration and cancer

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