title: Evaluation of a novel hexavalent humanized anti-IGF-1R antibody and its bivalent parental IgG in diverse cancer cell lines.
abstract: 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.
authors.affiliation: Immunomedics, Inc, Morris Plains, New Jersey, United States of America.
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Chang
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Preeti
authors.initials: P
authors.lastname: Trisal
authors.forename: Rongxiu
authors.initials: R
authors.lastname: Li
authors.forename: Diane L
authors.initials: DL
authors.lastname: Rossi
authors.forename: Anju
authors.initials: A
authors.lastname: Nair
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: Michele
authors.initials: M
authors.lastname: Losman
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Cardillo
authors.forename: Edmund A
authors.initials: EA
authors.lastname: Rossi
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D016895:Culture Media, Serum-Free; D015536:Down-Regulation / Q000187:drug effects; D000939:Epitopes / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D008027:Light; D051379:Mice; D008970:Molecular Weight; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000276:immunology*; D012542:Scattering, Radiation; D021241:Spectrometry, Mass, Electrospray Ionization; D014410:Tumor Stem Cell Assay; D014746:Vimentin / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D000970:Antineoplastic Agents; D015820:Cadherins; D016895:Culture Media, Serum-Free; D000939:Epitopes; D007074:Immunoglobulin G; D014746:Vimentin; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt