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Pharmacokinetics and Immune Response of ¹³¹I-Chimeric Mouse/Human B72.3 (Human 4) Monoclonal Antibody in Humans¹

Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294 [M. B. K., M. N. S., T. P. L., R. F. M., R. H. W., L. A., K. R., A. F. L.]; Veterans Administration Medical Center, Birmingham, Alabama 35233 [M. B. K.]; Celltech, Ltd., Slough, United Kingdom [T. S. B., D. K.]; National Cancer Institute, Bethesda, Maryland 20892 [D. S., D. C., J. S.]; and American Cyanamid, Pearl River, New York 10965 [D. S.]

Chimeric B72.3, composed of the V-regions of murine B72.3 and the constant regions of human immunoglobulin G4 heavy and light chain, was administered as a ¹³¹I-labeled conjugate to 12 patients with metastatic colon cancer. Seven of these patients had an antibody response after initial infusion, and the immune response was primarily directed to the murine V-region, although a small proportion of the antibody response was directed to topographical epitopes requiring the presence of both murine V-region and human CH-1 and constant regions (neo-epitopes). The pharmacokinetics included a plasma disappearance curve best fit by a two-compartmental model with an t_1/2 of 18 ± 7 h and a ß t_1/2 of 224 ± 66 h. A second infusion of the same dose of ¹³¹I-chimeric B72.3 was administered to four of these patients 8 wk after the first infusion. Two patients who had a high antibody response to initial infusion had an anamnestic antibody response, and the infused ch-B72.3 rapidly disappeared from the circulation with associated immune complexes and free ¹³¹I in the plasma. One patient with no initial antibody response had no antibody response and identical pharmacokinetics on second infusion. One patient with a modest transient antibody response to initial infusion had no antibody response on second infusion and a modest shortening of plasma circulation. Thus, the human immunoglobulin G4 isotype chimeric B72.3 monoclonal antibody has a plasma half-life 6 to 8 times as long as murine B72.3 and retains considerable immunogenicity in some patients which can adversely affect repetitive infusions.

¹ Supported by National Cancer Institute Grants CM87215 and R01-CA34232 and by NIH Grant M01-RR00032.

² To whom requests for reprints should be addressed, at University of Alabama at Birmingham, Comprehensive Cancer Center, L. B. Wallace Tumor Institute-262B, UAB Station, Birmingham, AL 35294.

Received 5/29/91. Accepted 8/ 2/91.

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