Selection of a DTPA chelate conjugate for monoclonal antibody targeting to a human colonic tumor in nude mice.
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.
Sharkey
R M
RM
Center For Molecular Medicine and Immunology, University of Medicine and Dentistry, Newark, NJ 07103.
Motta-Hennessy
C
C
Gansow
O A
OA
Brechbiel
M W
MW
Fand
I
I
Griffiths
G L
GL
Jones
A L
AL
Goldenberg
D M
DM
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
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D002614:Chelating Agents; D000922:Immunotoxins; D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes; D004369:Pentetic Acid