title: New chelating agent for attaching indium-111 to monoclonal antibodies: in vitro and in vivo evaluation.
abstract: 111In possesses excellent radiophysical properties suitable for use in immunoscintigraphy of cancerous tissues when attached to an antitumor antibody. However, 111In has a tendency to accumulate in normal tissues such as liver. Instability of the linkage between 111In and antibody may contribute to this problem. To avoid this, we developed a new bifunctional chelating agent, 1,3-bis[N-[N-(2-aminoethyl)-2-aminoethyl]-2-aminoacetamido]-2-(4- isothiocyanatobenzyl)propane-N,N,N',N'',N''',N'''',N''''',N'''''- octaacetic acid (LiLo), that forms a kinetically stable chelate with metal ions such as indium. Using LiLo, indium-111 was conjugated to a human monoclonal antibody, 16.88. Competitive binding analysis revealed that the 16.88-LiLo conjugate is as immunoreactive as the unconjugated native antibody. This conjugate was compared with 111In-16.88, where diethylenetriaminepentaacetic acid dianhydride (DTPAa) was used as the chelating agent. In vitro stability studies showed that 111In was more stably bound to 16.88-LiLo than to 16.88-DTPA. Biodistribution studies in athymic mice bearing colorectal tumor xenografts indicated less liver retention with 16.88-LiLo than with 16.88-DTPA. These results demonstrate that LiLo is superior to DTPAa for attachment of 111In to the monoclonal antibodies.
authors.affiliation: Organon Teknika, Biotechnology Research Institute, Rockville, Maryland 20850.
authors.forename: R
authors.initials: R
authors.lastname: Subramanian
authors.forename: J
authors.initials: J
authors.lastname: Colony
authors.forename: S
authors.initials: S
authors.lastname: Shaban
authors.forename: H
authors.initials: H
authors.lastname: Sidrak
authors.forename: M V
authors.initials: MV
authors.lastname: Haspel
authors.forename: N
authors.initials: N
authors.lastname: Pomato
authors.forename: M G
authors.initials: MG
authors.lastname: Hanna
authors.forename: R P
authors.initials: RP
authors.lastname: McCabe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D002460:Cell Line; D002461:Cell Line, Transformed; D002614:Chelating Agents / Q000138:chemical synthesis*; D003110:Colonic Neoplasms / Q000532:radiotherapy*; D006801:Humans; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D007202:Indicators and Reagents; D007205:Indium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D012709:Serum Albumin / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D007202:Indicators and Reagents; D007205:Indium Radioisotopes; D012709:Serum Albumin; C076593:1,3-bis(N-(N-(2-aminoethyl)-2-aminoethyl)-2-aminoacetamido)-2-(4-isothiocyanatobenzyl)propane-N,N,N',N'',N''',N'''',N''''',N'''''-octaaceticacid; D004369:Pentetic Acid