title: Selection of a DTPA chelate conjugate for monoclonal antibody targeting to a human colonic tumor in nude mice.
abstract: Our previous studies with a 90Y-labelled antibody against carcinoembryonic antigen (CEA) conjugated to the cyclic anhydride-DTPA (CA-DTPA) indicated that the accretion of 90Y in the bone may limit the application of 90Y-labelled antibodies for therapy. In this report, we have compared the tumor targeting of CA-DTPA-conjugated antibody to antibody conjugated with 4 isothiocyanatobenzyl (ITC-Bz) derivatives of DTPA in nude mice bearing a human colonic tumor xenograft. In biodistribution studies using an 111In-labelled anti-CEA murine monoclonal antibody (MAb), the CA-DTPA-conjugated MAb showed lower tumor uptake, faster blood clearance, and higher accretion in the liver than any of the 4 ITC-Bz-DTPA-conjugated MAbs. There were smaller differences among the 4 ITC-Bz-DTPA conjugates. Whole-body autoradiography of animals given 90Y-MAb prepared with the CA-DTPA or the ITC-Bz-DTPA showed less radioactivity in the bone with the ITC-Bz-DTPA-MAb than the CA-DTPA-MAb. 90Y uptake in the bone corresponded with regions of low proliferative activity as defined by 3H-labelled thymidine, suggesting that the 90Y was in the cortex rather than the marrow. These studies clearly show an advantage of the ITC-Bz-DTPA derivatives for 90Y and 111In labelling of MAbs.
authors.affiliation: Center For Molecular Medicine and Immunology, University of Medicine and Dentistry, Newark, NJ 07103.
authors.forename: R M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: C
authors.initials: C
authors.lastname: Motta-Hennessy
authors.forename: O A
authors.initials: OA
authors.lastname: Gansow
authors.forename: M W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: I
authors.initials: I
authors.lastname: Fand
authors.forename: G L
authors.initials: GL
authors.lastname: Griffiths
authors.forename: A L
authors.initials: AL
authors.lastname: Jones
authors.forename: D M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001345:Autoradiography; D002272:Carcinoembryonic Antigen / Q000276:immunology; D002614:Chelating Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D000922:Immunotoxins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007205:Indium Radioisotopes; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D004369:Pentetic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D014915:Whole-Body Counting; D015021:Yttrium Radioisotopes
chemical_list: D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D002614:Chelating Agents; D000922:Immunotoxins; D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes; D004369:Pentetic Acid