Kinetic and catabolic considerations of monoclonal antibody targeting in erythroleukemic mice

Abstract

The parameters affecting the use of tumor-specific monoclonal antibodies for diagnostic imaging and tumor cell targeting and therapy were quantitatively examined in a murine erythroleukemia model system. Normal and tumor-bearing leukemic BALB/c mice were given injections of 125I-, 131I-, or 111In-labeled specific and control immunoglobulins. At various times after injection, gamma camera images were obtained, and targeting to whole organs and to isolated cells was measured. The following observations were made: (a) tumor-specific monoclonal antibodies rapidly targeted to tumor cells (within hr); (b) the ratio of binding to tumor cells as compared to normal cells was highest (63.7 +/- 7.6) at the earliest times (6 hr after injection); (c) specific targeting was reflected by 20-fold shorter half-lives of antibody in the blood of tumor-bearing mice; (d) bound antibody was rapidly catabolized, and the radiolabel was cleared from the target (within hr) and appeared in organs metabolizing or excreting the radioisotope; (e) optimal images of tumors, using either 131I- or 111In-diethylenetriaminepentaacetic acid-labeled antibodies, were obtained early after extravascular distribution of the antibody because of the rapid targeting, clearance, and excretion or metabolism of isotope; and (f) changing the immunoglobulin isotype class or fragment had large effects on the half-life of the antibody but did not improve cell targeting uptake ratios or image contrast or alleviate the problem of specific catabolism. These results suggest (a) that diagnostic imaging should be obtained immediately after extravascular distribution of the antibody using short-lived isotopes and (b) that tumoricidal agents coupled to antibodies must act quickly upon targeting. In our system, the radiometal chelate-conjugated monoclonal antibodies appear to be the most versatile and effective at satisfying these criteria.