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Twenty-eight patients with metastatic malignant melanoma received anti-p97 murine monoclonal antibody (96.5) infused over 2 h at doses between 1 and 20 mg coupled to either 2.5 or 5.0 mCi of 111In by the bifunctional chelating agent diethyltriaminepentaacetic acid. Clearance of 111In from plasma closely fit an open, one-compartment mathematical model (r2 greater than 0.90). The overall half-life of 111In plasma was approximately 31 h and did not appear to be dependent on the total dose of antibody administered. The apparent volume of distribution of the 111In label approximated the total blood volume (7.8 +/- 0.7 liters) at the 1-mg dose and decreased to 3.0 +/- 0.14 liters at the 20-mg dose, suggesting saturation of antigenic or other extravascular binding sites at higher antibody doses. The clearance of the murine monoclonal antibody itself from plasma was measured by an enzyme-linked immunosorbent assay. The pharmacokinetics for the murine antibody in plasma also fit an open, one-compartment mathematical model. All pharmacokinetic parameters for unlabeled antibody closely paralleled those found for 111In-labeled antibody pharmacokinetics. This suggests that the 111In radiolabel remains complexed to the monoclonal antibody after in vivo administration. The cumulative urinary excretion of the 111In label over 48 h was between 12 and 23% of the total administered dose and is assumed to represent 111In-labeled chelate complex unattached to antibody. Analysis of the 111In label in spleen, liver, heart, and kidney showed that the concentration of label in liver tissue was reduced with increasing antibody doses and coincided with changes in the apparent volume of distribution. These studies show that murine monoclonal antibodies are cleared slowly from the circulation in humans and that early, rapid distribution of labeled antibody to the liver can be reduced by increasing the dose of unlabeled antibody. This may be particularly important in limiting hepatic toxicity when administering antibody coupled to drugs, radionuclides, or toxins.
M G Rosenblum, and
J L Murray, and
T P Haynie, and
H J Glenn, and
M F Jahns, and
R S Benjamin, and
J M Frincke, and
D J Carlo, and
E M Hersh
June 1987,
The Journal of dermatology,
M G Rosenblum, and
J L Murray, and
T P Haynie, and
H J Glenn, and
M F Jahns, and
R S Benjamin, and
J M Frincke, and
D J Carlo, and
E M Hersh
August 1988,
Japanese journal of cancer research : Gann,
M G Rosenblum, and
J L Murray, and
T P Haynie, and
H J Glenn, and
M F Jahns, and
R S Benjamin, and
J M Frincke, and
D J Carlo, and
E M Hersh
April 1997,
Japanese journal of cancer research : Gann,
M G Rosenblum, and
J L Murray, and
T P Haynie, and
H J Glenn, and
M F Jahns, and
R S Benjamin, and
J M Frincke, and
D J Carlo, and
E M Hersh
September 1991,
Kaku igaku. The Japanese journal of nuclear medicine,
M G Rosenblum, and
J L Murray, and
T P Haynie, and
H J Glenn, and
M F Jahns, and
R S Benjamin, and
J M Frincke, and
D J Carlo, and
E M Hersh
January 1995,
Dermatology (Basel, Switzerland),
M G Rosenblum, and
J L Murray, and
T P Haynie, and
H J Glenn, and
M F Jahns, and
R S Benjamin, and
J M Frincke, and
D J Carlo, and
E M Hersh
February 1987,
Cancer research,
M G Rosenblum, and
J L Murray, and
T P Haynie, and
H J Glenn, and
M F Jahns, and
R S Benjamin, and
J M Frincke, and
D J Carlo, and
E M Hersh
April 1991,
American journal of clinical oncology,
M G Rosenblum, and
J L Murray, and
T P Haynie, and
H J Glenn, and
M F Jahns, and
R S Benjamin, and
J M Frincke, and
D J Carlo, and
E M Hersh
January 1987,
European journal of nuclear medicine,
M G Rosenblum, and
J L Murray, and
T P Haynie, and
H J Glenn, and
M F Jahns, and
R S Benjamin, and
J M Frincke, and
D J Carlo, and
E M Hersh
February 1990,
Cancer research,
M G Rosenblum, and
J L Murray, and
T P Haynie, and
H J Glenn, and
M F Jahns, and
R S Benjamin, and
J M Frincke, and
D J Carlo, and
E M Hersh
October 1988,
AJR. American journal of roentgenology,
