title: A universal pretargeting system for cancer detection and therapy using bispecific antibody.
abstract: Multistep targeting systems represent highly selective alternatives to targeting systems using directly radiolabeled antibodies for diagnostic and therapeutic applications. A flexible bispecific antibody (bsMAb) multistep, pretargeting system that potentially can be developed for use with a variety of different imaging or therapeutic agents is described herein. The flexibility of this system is based on use of an antibody directed against histamine-succinyl-glycine (HSG) and the development of peptides containing the HSG residue. HSG-containing peptides were synthesized with either 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid for the chelation of 111In, 90Y, or 177Lu, or a technetium/rhenium chelate. The peptides can be radiolabeled to a high specific activity in a facile manner that avoids the need for purification. In vivo studies in nude mice bearing human colon tumor xenografts showed that the radiolabeled peptides cleared rapidly from the body with minimal retention in tumor or normal tissues. For pretargeting, these peptides were used in combination with a bsMAb composed of the anti-HSG Fab' that was covalently coupled with the Fab' of either an anticarcinoembryonic antigen or an anticolon-specific antigen-p antibody to provide tumor targeting capability. When the radiolabeled peptides were administered 1-2 days after a pretargeting dose of the bsMAbs, tumor uptake of the radiolabeled peptides increased as much as 28-175-fold over that seen with the peptides alone with tumor:nontumor ratios exceeding 2:1 to 8:1 within just 3 h of the peptide injection, which was a marked improvement over the tumor:nontumor ratios seen with a directly radiolabeled 99mTc-anti-anticarcinoembryonic antigen Fab' at this same time. The anticolon-specific antigen-p x anti-HSG F(ab')2 bsMAb had the highest and longest retention in the tumor, and when used in combination with the 111In-labeled peptide, radiation dose estimates for therapeutic radionuclides, such as 90Y and 177Lu, suggested that antitumor effects would be expected with tolerable radiation exposure to the normal tissues. These results suggest that this multistep, pretargeting system has diagnostic imaging and therapeutic potential.
authors.affiliation: Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: William J
authors.initials: WJ
authors.lastname: McBride
authors.forename: Habibe
authors.initials: H
authors.lastname: Karacay
authors.forename: Ken
authors.initials: K
authors.lastname: Chang
authors.forename: Gary L
authors.initials: GL
authors.lastname: Griffiths
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Hansen
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism / Q000532:radiotherapy; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000008:administration & dosage* / Q000627:therapeutic use; D011877:Radionuclide Imaging; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D018796:Immunoconjugates; D009842:Oligopeptides; D011868:Radioisotopes; C030139:colon-specific antigen