Intratumoral distribution of two consecutive injections of chimeric antibody G250 in primary renal cell carcinoma: implications for fractionated dose radioimmunotherapy.
Tumor uptake of the chimeric G250 (cG250) monoclonal antibody (mAb) in patients with primary renal cell carcinoma (RCC) is among the highest reported in solid tumors. However, as observed in other tumor types, the intratumoral distribution of the antibody is highly heterogeneous, which may limit the efficacy of radioimmunotherapy. A number of highly dynamic physiological factors have been postulated that may contribute to heterogeneous tumor uptake of antibodies. Their impact on tumor uptake of antibodies may vary from one tumor region to another as well as from one day to the next. Here, we report on a clinical study that was designed to investigate whether the pattern of mAb cG250 uptake within RCC tumors is altered with subsequent injections. Ten patients with a clinical diagnosis of primary RCC were studied. Nine days before surgery, patients received 125I-cG250 (5 mg of cG250, 50 microCi of 125I), followed by a second injection of 131I-cG250 (5 mg of cG250, 3.5 mCi of 131I) 4 days later. Postsurgery, the tumor was cut into (1-cm) thick slices. Slices were imaged on a gamma camera, and the slice with the most pronounced heterogeneity in 131I-cG250 distribution was selected and cut into 1-cm3 cubes. Each cube was analyzed for 121I-cG250 and 131I-cG250 uptake, and the 131I/125I ratio was determined. For each tumor slice, the distribution patterns of both isotopes were reconstructed and compared with each other. All tumors analyzed showed a heterogeneous distribution of both isotopes throughout the tumor slice; focal uptake in some areas of a tumor reached very high levels (up to 0.19% injected dose/g), whereas other tumorous areas of the same slice showed much lower uptake (as low as 0.0047% injected dose/g). Remarkably, in all tumors, the distribution pattern of both injections was identical: without exception, in all samples analyzed (n = 692), the uptake of 125I-cG250 was similar to 131I-cG250 uptake. Overall, the 131I/125I ratio was 1.64+/-0.31 (mean+/-SD). The constant 131I/125I ratios, observed in all tumor samples investigated, indicate that the tumor parameters governing cG250 mAb uptake were not altered significantly within the time period studied. In addition, the results of this study suggest that multiple radiolabeled antibody injections, administered within short time periods, will target the same areas within a tumor and, thus, will not solve the problem of heterogeneous tumor uptake of antibody.
Steffens
M G
MG
Department of Urology, University Hospital Nijmegen, The Netherlands. m.steffens@nugen.azn.nl
Boerman
O C
OC
Oyen
W J
WJ
Kniest
P H
PH
Witjes
J A
JA
Oosterhof
G O
GO
van Leenders
G J
GJ
Debruyne
F M
FM
Corstens
F H
FH
Oosterwijk
E
E
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D007553:Isotope Labeling; D007680:Kidney Neoplasms / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D016499:Radioimmunotherapy; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D011993:Recombinant Fusion Proteins