Non-agonistic bivalent antibodies that promote c-MET degradation and inhibit tumor growth and others specific for tumor related c-MET.
The c-MET receptor has a function in many human cancers and is a proven therapeutic target. Generating antagonistic or therapeutic monoclonal antibodies (mAbs) targeting c-MET has been difficult because bivalent, intact anti-Met antibodies frequently display agonistic activity, necessitating the use...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3325269?pdf=render |
| _version_ | 1818193024510853120 |
|---|---|
| author | Sameer A Greenall Ermanno Gherardi Zhanqi Liu Jacqueline F Donoghue Angela A Vitali Qian Li Roger Murphy Luisa Iamele Andrew M Scott Terrance G Johns |
| author_facet | Sameer A Greenall Ermanno Gherardi Zhanqi Liu Jacqueline F Donoghue Angela A Vitali Qian Li Roger Murphy Luisa Iamele Andrew M Scott Terrance G Johns |
| author_sort | Sameer A Greenall |
| collection | DOAJ |
| description | The c-MET receptor has a function in many human cancers and is a proven therapeutic target. Generating antagonistic or therapeutic monoclonal antibodies (mAbs) targeting c-MET has been difficult because bivalent, intact anti-Met antibodies frequently display agonistic activity, necessitating the use of monovalent antibody fragments for therapy. By using a novel strategy that included immunizing with cells expressing c-MET, we obtained a range of mAbs. These c-MET mAbs were tested for binding specificity and anti-tumor activity using a range of cell-based techniques and in silico modeling. The LMH 80 antibody bound an epitope, contained in the small cysteine-rich domain of c-MET (amino acids 519-561), that was preferentially exposed on the c-MET precursor. Since the c-MET precursor is only expressed on the surface of cancer cells and not normal cells, this antibody is potentially tumor specific. An interesting subset of our antibodies displayed profound activities on c-MET internalization and degradation. LMH 87, an antibody binding the loop connecting strands 3d and 4a of the 7-bladed β-propeller domain of c-MET, displayed no intrinsic agonistic activity but promoted receptor internalization and degradation. LMH 87 inhibited HGF/SF-induced migration of SK-OV-3 ovarian carcinoma cells, the proliferation of A549 lung cancer cells and the growth of human U87MG glioma cells in a mouse xenograft model. These results indicate that c-MET antibodies targeting epitopes controlling receptor internalization and degradation provide new ways of controlling c-MET expression and activity and may enable the therapeutic targeting of c-MET by intact, bivalent antibodies. |
| first_indexed | 2024-12-12T00:39:49Z |
| format | Article |
| id | doaj.art-3215250fd70647869da99e78f2d5188a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T00:39:49Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3215250fd70647869da99e78f2d5188a2022-12-22T00:44:16ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0174e3465810.1371/journal.pone.0034658Non-agonistic bivalent antibodies that promote c-MET degradation and inhibit tumor growth and others specific for tumor related c-MET.Sameer A GreenallErmanno GherardiZhanqi LiuJacqueline F DonoghueAngela A VitaliQian LiRoger MurphyLuisa IameleAndrew M ScottTerrance G JohnsThe c-MET receptor has a function in many human cancers and is a proven therapeutic target. Generating antagonistic or therapeutic monoclonal antibodies (mAbs) targeting c-MET has been difficult because bivalent, intact anti-Met antibodies frequently display agonistic activity, necessitating the use of monovalent antibody fragments for therapy. By using a novel strategy that included immunizing with cells expressing c-MET, we obtained a range of mAbs. These c-MET mAbs were tested for binding specificity and anti-tumor activity using a range of cell-based techniques and in silico modeling. The LMH 80 antibody bound an epitope, contained in the small cysteine-rich domain of c-MET (amino acids 519-561), that was preferentially exposed on the c-MET precursor. Since the c-MET precursor is only expressed on the surface of cancer cells and not normal cells, this antibody is potentially tumor specific. An interesting subset of our antibodies displayed profound activities on c-MET internalization and degradation. LMH 87, an antibody binding the loop connecting strands 3d and 4a of the 7-bladed β-propeller domain of c-MET, displayed no intrinsic agonistic activity but promoted receptor internalization and degradation. LMH 87 inhibited HGF/SF-induced migration of SK-OV-3 ovarian carcinoma cells, the proliferation of A549 lung cancer cells and the growth of human U87MG glioma cells in a mouse xenograft model. These results indicate that c-MET antibodies targeting epitopes controlling receptor internalization and degradation provide new ways of controlling c-MET expression and activity and may enable the therapeutic targeting of c-MET by intact, bivalent antibodies.http://europepmc.org/articles/PMC3325269?pdf=render |
| spellingShingle | Sameer A Greenall Ermanno Gherardi Zhanqi Liu Jacqueline F Donoghue Angela A Vitali Qian Li Roger Murphy Luisa Iamele Andrew M Scott Terrance G Johns Non-agonistic bivalent antibodies that promote c-MET degradation and inhibit tumor growth and others specific for tumor related c-MET. PLoS ONE |
| title | Non-agonistic bivalent antibodies that promote c-MET degradation and inhibit tumor growth and others specific for tumor related c-MET. |
| title_full | Non-agonistic bivalent antibodies that promote c-MET degradation and inhibit tumor growth and others specific for tumor related c-MET. |
| title_fullStr | Non-agonistic bivalent antibodies that promote c-MET degradation and inhibit tumor growth and others specific for tumor related c-MET. |
| title_full_unstemmed | Non-agonistic bivalent antibodies that promote c-MET degradation and inhibit tumor growth and others specific for tumor related c-MET. |
| title_short | Non-agonistic bivalent antibodies that promote c-MET degradation and inhibit tumor growth and others specific for tumor related c-MET. |
| title_sort | non agonistic bivalent antibodies that promote c met degradation and inhibit tumor growth and others specific for tumor related c met |
| url | http://europepmc.org/articles/PMC3325269?pdf=render |
| work_keys_str_mv | AT sameeragreenall nonagonisticbivalentantibodiesthatpromotecmetdegradationandinhibittumorgrowthandothersspecificfortumorrelatedcmet AT ermannogherardi nonagonisticbivalentantibodiesthatpromotecmetdegradationandinhibittumorgrowthandothersspecificfortumorrelatedcmet AT zhanqiliu nonagonisticbivalentantibodiesthatpromotecmetdegradationandinhibittumorgrowthandothersspecificfortumorrelatedcmet AT jacquelinefdonoghue nonagonisticbivalentantibodiesthatpromotecmetdegradationandinhibittumorgrowthandothersspecificfortumorrelatedcmet AT angelaavitali nonagonisticbivalentantibodiesthatpromotecmetdegradationandinhibittumorgrowthandothersspecificfortumorrelatedcmet AT qianli nonagonisticbivalentantibodiesthatpromotecmetdegradationandinhibittumorgrowthandothersspecificfortumorrelatedcmet AT rogermurphy nonagonisticbivalentantibodiesthatpromotecmetdegradationandinhibittumorgrowthandothersspecificfortumorrelatedcmet AT luisaiamele nonagonisticbivalentantibodiesthatpromotecmetdegradationandinhibittumorgrowthandothersspecificfortumorrelatedcmet AT andrewmscott nonagonisticbivalentantibodiesthatpromotecmetdegradationandinhibittumorgrowthandothersspecificfortumorrelatedcmet AT terrancegjohns nonagonisticbivalentantibodiesthatpromotecmetdegradationandinhibittumorgrowthandothersspecificfortumorrelatedcmet |