0000000000460626
AUTHOR
Paolo M. Comoglio
showing 17 related works from this author
Targeting the MET oncogene by concomitant inhibition of receptor and ligand via an antibody-"decoy" strategy
2018
MET, a master gene sustaining "invasive growth," is a relevant target for cancer precision therapy. In the vast majority of tumors, wild-type MET behaves as a "stress-response" gene and relies on the ligand (HGF) to sustain cell "scattering," invasive growth and apoptosis protection (oncogene "expedience"). In this context, concomitant targeting of MET and HGF could be crucial to reach effective inhibition. To test this hypothesis, we combined an anti-MET antibody (MvDN30) inducing "shedding" (i.e., removal of MET from the cell surface), with a "decoy" (i.e., the soluble extracellular domain of the MET receptor) endowed with HGF-sequestering ability. To avoid antibody/decoy interaction-and …
Additional file 7 of A receptor-antibody hybrid hampering MET-driven metastatic spread
2021
Additional file 7: Supplementary Fig. 7. Serum concentration of AbDec-L1 after single i.v. administration to Sprague Dawley rats at different time points.
Additional file 3 of A receptor-antibody hybrid hampering MET-driven metastatic spread
2021
Additional file 3: Supplementary Fig. 3. IVIS images of lungs excised from hHGF-ki mice that received intra-pancreatic injection of HPAF-II cells.
Additional file 2 of hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers
2022
Additional file 2.
Additional file 6 of A receptor-antibody hybrid hampering MET-driven metastatic spread
2021
Additional file 6: Supplementary Fig. 6. Analysis of CL-901 primary tumors treated with AbDec-L1.
Additional file 2 of A receptor-antibody hybrid hampering MET-driven metastatic spread
2021
Additional file 2: Supplementary Fig. 2. IVIS images of livers excised from hHGF-ki mice that received intra-pancreatic injection of Capan-1 cells.
MET/HGF Co-Targeting in Pancreatic Cancer: A Tool to Provide Insight into the Tumor/Stroma Crosstalk
2018
The ‘onco-receptor’ MET (Hepatocyte Growth Factor Receptor) is involved in the activation of the invasive growth program that is essential during embryonic development and critical for wound healing and organ regeneration during adult life. When aberrantly activated, MET and its stroma-secreted ligand HGF (Hepatocyte Growth Factor) concur to tumor onset, progression, and metastasis in solid tumors, thus representing a relevant target for cancer precision medicine. In the vast majority of tumors, wild-type MET behaves as a ‘stress-response’ gene, and relies on ligand stimulation to sustain cancer cell ‘scattering’, invasion, and protection form apoptosis. …
Additional file 1 of hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers
2022
Additional file 1.
Additional file 3 of hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers
2022
Additional file 3.
Additional file 5 of A receptor-antibody hybrid hampering MET-driven metastatic spread
2021
Additional file 5: Supplementary Fig. 5. IVIS images of organs excised from hHGF-ki mice that received sub-cuteaneous injection of CL-901 cells.
Dual Constant Domain-Fab: A novel strategy to improve half-life and potency of a Met therapeutic antibody
2016
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…
Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody
2020
The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) inducing the physical removal of the receptor from the cell surface and resulting in suppression of the biological responses to MET. In its bivalent form, the antibody displayed a residual agonist activity, due to dimerization of the lingering receptors, and partial activation of the downstream signaling cascade. The balance between the two opposing activities is variable in different…
Additional file 4 of A receptor-antibody hybrid hampering MET-driven metastatic spread
2021
Additional file 4: Supplementary Fig. 4. Immunohistochemical analysis of MET phosphorylation in pancreatic primary tumors treated with AbDec-L1.
Met inhibition revokes IFNγ-induction of PD-1 ligands in MET-amplified tumours
2019
BACKGROUND: Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immuneevasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-gamma modulation of PD-L1/PD-L2 in MET-amplified tumours.METHODS: PD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-gamma were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-gamma stimulation, and after anti-MET therapy.RESULTS: PD-L1 and PD-L2 were upregulated in MET-amplified tumour cells up…
Additional file 1 of A receptor-antibody hybrid hampering MET-driven metastatic spread
2021
Additional file 1: Supplementary Fig. 1. IVIS analysis of primary tumors excised from mice that received intra-pancreatic injections of Capan-1 or HPAF-II pancreatic cancer cells.
A receptor-antibody hybrid hampering MET-driven metastatic spread
2021
AbstractBackgroundThe receptor encoded by the MET oncogene and its ligand Hepatocyte Growth Factor (HGF) are at the core of the invasive-metastatic behavior. In a number of instances genetic alterations result in ligand-independent onset of malignancy (METaddiction). More frequently, ligand stimulation of wild-type MET contributes to progression toward metastasis (METexpedience). Thus, while MET inhibitors alone are effective in the first case, combination therapy with ligand inhibitors is required in the second condition.MethodsIn this paper, we generated hybrid molecules gathering HGF and MET inhibitory properties. This has been achieved by ‘head-to-tail’ or ‘tail-to-head’ fusion of a sin…
hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers
2022
Abstract Background The tyrosine kinase receptor encoded by the MET oncogene is a major player in cancer. When MET is responsible for the onset and progression of the transformed phenotype (MET-addicted cancers), an efficient block of its oncogenic activation results in potent tumor growth inhibition. Methods Here we describe a molecular engineered MET antibody (hOA-DN30) and validate its pharmacological activity in MET-addicted cancer models in vitro and in vivo. Pharmacokinetics and safety profile in non-human primates have also been assessed. Results hOA-DN30 efficiently impaired MET activation and the intracellular signalling cascade by dose and time dependent removal of the receptor fr…