Enhanced clearance of radiolabeled murine monoclonal antibody by a syngeneic anti-idiotype antibody in tumor-bearing nude mice.
A syngeneic anti-idiotype monoclonal antibody (MAb) (CM-11) directed against an anti-carcinoembryonic antigen (CEA) murine MAb (NP-4) was evaluated as a second antibody (SA) to promote the rapid clearance of radiolabeled NP-4 from the blood. Initial studies confirmed that CM-11 IgG removed 131I-NP-4 IgG from the blood as effectively as a polyclonal donkey anti-goat IgG removed 131I-goat IgG. However, use of an F(ab')2 in place of either the NP-4 or CM-11 IgG was not as effective in removing primary radiolabeled antibody, despite the formation of high-molecular-weight complexes. In accordance with previous results, the timing and dose of the SA injection was critical for optimizing tumor uptake and improving tumor/non-tumor ratios. In nude mice bearing GW-39 human colonic tumor xenografts, a delay in the injection of CM-11 by 48 hr after injection of radiolabeled NP-4 was optimal, since this allowed maximum tumor accretion. At a 200:1 CM-11:NP-4 ratio, tumor uptake was reduced, suggesting inhibition of NP-4 binding to CEA within the tumor. Despite optimizing tumor uptake by delaying SA injection and adjusting its dose, the percentage of 131I-NP-4 in the tumor decreased 2- to 3-fold within 2 days after CM-11 injection. A similar effect was seen for 111In-labeled NP-4 IgG with CM-11. Injection of excess unlabeled NP-4 given to block CM-11 shortly after its injection failed to curtail the loss of NP-4 from the tumor. Our results suggest that high blood levels of MAb are important for sustaining NP-4 in the tumor. Radiation-dose predictions derived from biodistribution studies indicate that a higher tumor dose may be delivered using the SA method than with either 131I-NP-4 IgG or F(ab')2 alone. Use of the SA method with 90Y-labeled NP-4 IgG, as modeled from biodistribution studies with 111In-NP-4 IgG, would likely be limited by liver toxicity.
Sharkey
R M
RM
Garden State Cancer Center, Newark, NJ.
Boerman
O C
OC
Natale
A
A
Pawlyk
D
D
Monestier
M
M
Losman
M J
MJ
Goldenberg
D M
DM
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage / Q000097:blood*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000097:blood / Q000378:metabolism / Q000532:radiotherapy; D005260:Female; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000097:blood*; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000097:blood*; D007205:Indium Radioisotopes / Q000097:blood* / Q000627:therapeutic use; D007457:Iodine Radioisotopes / Q000097:blood* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008970:Molecular Weight; D011829:Radiation Dosage; D013997:Time Factors
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes