Evaluation of a novel hexavalent humanized anti-IGF-1R antibody and its bivalent parental IgG in diverse cancer cell lines.
A major mechanism of monoclonal antibodies that selectively target the insulin-like growth factor type 1 receptor (IGF-1R) to inhibit tumor growth is by downregulating the receptor, regardless whether they are capable (antagonistic) or incapable (agonistic) of blocking the binding of cognate ligands...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3432068?pdf=render |
| _version_ | 1828429803270701056 |
|---|---|
| author | Chien-Hsing Chang Yang Wang Preeti Trisal Rongxiu Li Diane L Rossi Anju Nair Pankaj Gupta Michele Losman Thomas M Cardillo Edmund A Rossi David M Goldenberg |
| author_facet | Chien-Hsing Chang Yang Wang Preeti Trisal Rongxiu Li Diane L Rossi Anju Nair Pankaj Gupta Michele Losman Thomas M Cardillo Edmund A Rossi David M Goldenberg |
| author_sort | Chien-Hsing Chang |
| collection | DOAJ |
| description | A major mechanism of monoclonal antibodies that selectively target the insulin-like growth factor type 1 receptor (IGF-1R) to inhibit tumor growth is by downregulating the receptor, regardless whether they are capable (antagonistic) or incapable (agonistic) of blocking the binding of cognate ligands. We have developed and characterized a novel agonistic anti-IGF-1R humanized antibody, hR1, and used the Dock-and-Lock (DNL) method to construct Hex-hR1, the first multivalent antibody comprising 6 functional Fabs of hR1, with the aim of enhancing potency of hR1. Based on cross-blocking experiments, hR1 recognizes a region of cysteine-rich domain on the α-subunit, different from the epitopes mapped for existing anti-IGF-1R antibodies, yet hR1 is similar to other anti-IGF-1R antibodies in downregulating IGF-1R and inhibiting proliferation, colony formation, or invasion of selected cancer cell lines in vitro, as well as suppressing growth of the RH-30 rhabdomyosarcoma xenograft in nude mice when combined with the mTOR inhibitor, rapamycin. Hex-hR1 and hR1 are generally comparable in their bioactivities under the in-intro and in-vivo conditions investigated. Nevertheless, in selective experiments involving a direct comparison of potency, Hex-hR1 demonstrated a stronger effect on inhibiting cell proliferation stimulated by IGF-1 and could effectively downregulate IGF-1R at a concentration as low as 20 pM. |
| first_indexed | 2024-12-10T17:38:29Z |
| format | Article |
| id | doaj.art-911314e583d9433abb57d0f3190e46a9 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T17:38:29Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-911314e583d9433abb57d0f3190e46a92022-12-22T01:39:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0178e4423510.1371/journal.pone.0044235Evaluation of a novel hexavalent humanized anti-IGF-1R antibody and its bivalent parental IgG in diverse cancer cell lines.Chien-Hsing ChangYang WangPreeti TrisalRongxiu LiDiane L RossiAnju NairPankaj GuptaMichele LosmanThomas M CardilloEdmund A RossiDavid M GoldenbergA major mechanism of monoclonal antibodies that selectively target the insulin-like growth factor type 1 receptor (IGF-1R) to inhibit tumor growth is by downregulating the receptor, regardless whether they are capable (antagonistic) or incapable (agonistic) of blocking the binding of cognate ligands. We have developed and characterized a novel agonistic anti-IGF-1R humanized antibody, hR1, and used the Dock-and-Lock (DNL) method to construct Hex-hR1, the first multivalent antibody comprising 6 functional Fabs of hR1, with the aim of enhancing potency of hR1. Based on cross-blocking experiments, hR1 recognizes a region of cysteine-rich domain on the α-subunit, different from the epitopes mapped for existing anti-IGF-1R antibodies, yet hR1 is similar to other anti-IGF-1R antibodies in downregulating IGF-1R and inhibiting proliferation, colony formation, or invasion of selected cancer cell lines in vitro, as well as suppressing growth of the RH-30 rhabdomyosarcoma xenograft in nude mice when combined with the mTOR inhibitor, rapamycin. Hex-hR1 and hR1 are generally comparable in their bioactivities under the in-intro and in-vivo conditions investigated. Nevertheless, in selective experiments involving a direct comparison of potency, Hex-hR1 demonstrated a stronger effect on inhibiting cell proliferation stimulated by IGF-1 and could effectively downregulate IGF-1R at a concentration as low as 20 pM.http://europepmc.org/articles/PMC3432068?pdf=render |
| spellingShingle | Chien-Hsing Chang Yang Wang Preeti Trisal Rongxiu Li Diane L Rossi Anju Nair Pankaj Gupta Michele Losman Thomas M Cardillo Edmund A Rossi David M Goldenberg Evaluation of a novel hexavalent humanized anti-IGF-1R antibody and its bivalent parental IgG in diverse cancer cell lines. PLoS ONE |
| title | Evaluation of a novel hexavalent humanized anti-IGF-1R antibody and its bivalent parental IgG in diverse cancer cell lines. |
| title_full | Evaluation of a novel hexavalent humanized anti-IGF-1R antibody and its bivalent parental IgG in diverse cancer cell lines. |
| title_fullStr | Evaluation of a novel hexavalent humanized anti-IGF-1R antibody and its bivalent parental IgG in diverse cancer cell lines. |
| title_full_unstemmed | Evaluation of a novel hexavalent humanized anti-IGF-1R antibody and its bivalent parental IgG in diverse cancer cell lines. |
| title_short | Evaluation of a novel hexavalent humanized anti-IGF-1R antibody and its bivalent parental IgG in diverse cancer cell lines. |
| title_sort | evaluation of a novel hexavalent humanized anti igf 1r antibody and its bivalent parental igg in diverse cancer cell lines |
| url | http://europepmc.org/articles/PMC3432068?pdf=render |
| work_keys_str_mv | AT chienhsingchang evaluationofanovelhexavalenthumanizedantiigf1rantibodyanditsbivalentparentaliggindiversecancercelllines AT yangwang evaluationofanovelhexavalenthumanizedantiigf1rantibodyanditsbivalentparentaliggindiversecancercelllines AT preetitrisal evaluationofanovelhexavalenthumanizedantiigf1rantibodyanditsbivalentparentaliggindiversecancercelllines AT rongxiuli evaluationofanovelhexavalenthumanizedantiigf1rantibodyanditsbivalentparentaliggindiversecancercelllines AT dianelrossi evaluationofanovelhexavalenthumanizedantiigf1rantibodyanditsbivalentparentaliggindiversecancercelllines AT anjunair evaluationofanovelhexavalenthumanizedantiigf1rantibodyanditsbivalentparentaliggindiversecancercelllines AT pankajgupta evaluationofanovelhexavalenthumanizedantiigf1rantibodyanditsbivalentparentaliggindiversecancercelllines AT michelelosman evaluationofanovelhexavalenthumanizedantiigf1rantibodyanditsbivalentparentaliggindiversecancercelllines AT thomasmcardillo evaluationofanovelhexavalenthumanizedantiigf1rantibodyanditsbivalentparentaliggindiversecancercelllines AT edmundarossi evaluationofanovelhexavalenthumanizedantiigf1rantibodyanditsbivalentparentaliggindiversecancercelllines AT davidmgoldenberg evaluationofanovelhexavalenthumanizedantiigf1rantibodyanditsbivalentparentaliggindiversecancercelllines |