title: A versatile bifunctional chelate for radiolabeling humanized anti-CEA antibody with In-111 and Cu-64 at either thiol or amino groups: PET imaging of CEA-positive tumors with whole antibodies.
abstract: Radiolabeled anti-carcinoembryonic antigen (CEA) antibodies have the potential to give excellent images of a wide variety of human tumors, including tumors of the colon, breast, lung, and medullar thyroid. In order to realize the goals of routine and repetitive clinical imaging with anti-CEA antibodies, it is necessary that the antibodies have a high affinity for CEA, low cross reactivity and uptake in normal tissues, and low immunogenicity. The humanized anti-CEA antibody hT84.66-M5A (M5A) fulfills these criteria with an affinity constant of >10 (10) M (-1), no reactivity with CEA cross-reacting antigens found in normal tissues, and >90% human protein sequence. A further requirement for routine clinical use of radiolabeled antibodies is a versatile method of radiolabeling that allows the use of multiple radionuclides that differ in their radioemissions and half-lives. We describe a versatile bifunctional chelator, DO3A-VS (1,4,7-tris(carboxymethyl)-10-(vinylsulfone)-1,4,7,10-tetraazacyclododecane) that binds a range of radiometals including 111 In for gamma-ray imaging and 64Cu for positron emission tomography (PET), and which can be conjugated with negligible loss of immunoreactivity either to sulfhydryls (SH) in the hinge region of lightly reduced immunoglobulins or surface lysines (NH) of immunoglobulins. Based on our correlative studies comparing the kinetics of radiolabeled anti-CEA antibodies in murine models with those in man, we predict that 64Cu-labeled intact, humanized antibodies can be used to image CEA positive tumors in the clinic.
authors.affiliation: Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: James
authors.initials: J
authors.lastname: Bading
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Yazaki
authors.forename: Amitkumar H
authors.initials: AH
authors.lastname: Ahuja
authors.forename: Desiree
authors.initials: D
authors.lastname: Crow
authors.forename: David
authors.initials: D
authors.lastname: Colcher
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Williams
authors.forename: Jeffrey Y C
authors.initials: JY
authors.lastname: Wong
authors.forename: Andrew
authors.initials: A
authors.lastname: Raubitschek
authors.forename: John E
authors.initials: JE
authors.lastname: Shively
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002614:Chelating Agents / Q000737:chemistry*; D003301:Copper Radioisotopes; D003432:Cross-Linking Reagents / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D006844:Hydrocarbons, Cyclic / Q000276:immunology*; D018796:Immunoconjugates / Q000737:chemistry*; D007205:Indium Radioisotopes; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014753:Vinyl Compounds / Q000737:chemistry*
chemical_list: C527697:1,4,7-tris(carboxymethyl)-10-(vinylsulfone)-1,4,7,10-tetraazacyclododecane; D002272:Carcinoembryonic Antigen; D002614:Chelating Agents; D003301:Copper Radioisotopes; D003432:Cross-Linking Reagents; D006573:Heterocyclic Compounds, 1-Ring; D006844:Hydrocarbons, Cyclic; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D013438:Sulfhydryl Compounds; D014753:Vinyl Compounds