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.
| Original language | English |
|---|---|
| Pages (from-to) | 938-948 |
| Number of pages | 11 |
| Journal | Molecular Oncology |
| Volume | 10 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 1 2016 |
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Keywords
- Antibody
- Cancer targeted therapy
- Fab
- Half-life
- Met
- Protein engineering
ASJC Scopus subject areas
- Cancer Research
- Genetics
- Molecular Medicine
Cite this
Dual Constant Domain-Fab : A novel strategy to improve half-life and potency of a Met therapeutic antibody. / Cignetto, Simona; Modica, Chiara; Chiriaco, Cristina; Fontani, Lara; Milla, Paola; Michieli, Paolo; Comoglio, Paolo M.; Vigna, Elisa.
In: Molecular Oncology, Vol. 10, No. 6, 01.06.2016, p. 938-948.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dual Constant Domain-Fab
T2 - A novel strategy to improve half-life and potency of a Met therapeutic antibody
AU - Cignetto, Simona
AU - Modica, Chiara
AU - Chiriaco, Cristina
AU - Fontani, Lara
AU - Milla, Paola
AU - Michieli, Paolo
AU - Comoglio, Paolo M.
AU - Vigna, Elisa
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - Antibody
KW - Cancer targeted therapy
KW - Fab
KW - Half-life
KW - Met
KW - Protein engineering
UR - http://www.scopus.com/inward/record.url?scp=84974814468&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84974814468&partnerID=8YFLogxK
U2 - 10.1016/j.molonc.2016.03.004
DO - 10.1016/j.molonc.2016.03.004
M3 - Article
AN - SCOPUS:84974814468
VL - 10
SP - 938
EP - 948
JO - Molecular Oncology
JF - Molecular Oncology
SN - 1574-7891
IS - 6
ER -