The intraperitoneal delivery of radiolabeled monoclonal antibodies: studies on the regional delivery advantage

Abstract

The i.p. delivery of murine monoclonal antibody was compared with i.v. delivery in normal mice and rats, in normal nude mice and in those with i.p. human ovarian carcinoma xenografts. In normal rats, all classes of antibodies and antibody fragments evaluated were cleared from the peritoneal cavity at comparable rates. The regional delivery (Rd1) advantage to the peritoneal cavity following i.p. delivery was thus most dependent on the rate of clearance of the antibody or fragment from the blood stream. Determining the exact i.p. delivery advantage was problematic due to the difficulty in reliably obtaining peritoneal fluid later than 9-10 h after i.p. injection in normal animals. During the first 9 h following i.p. injection, the Rd(0-9/0-9) was, for a murine IgG2ak Fab greater than F(ab')2 greater than IgG (at 13.6 greater than 10 greater than 7.9). Two murine IgMs evaluated differed in Rd(0-9) at 27.1 and 9.2 respectively. When blood levels were extrapolated to infinity, these Rd (0-9/affinity) values were considerably lower with the Fab having the highest Rd at 4.67. The i.p. Rd advantage was almost solely due to the i.p. antibody levels seen in the first 24 h after injection, as after that time, blood levels become comparable to those seen following i.v. injection. Normal tissues obtained at sacrifice 5-7 days after i.p. injection. Normal tissues obtained at sacrifice 5-7 days after i.p. or i.v. injection in rats showed comparable levels of radioantibody activity, whether the injection was i.p. or i.v. (except for higher diaphragmatic levels following i.p. delivery). In nude mice with i.p. human-derived ovarian tumors, intact IgG clearance from the peritoneal cavity to the blood was considerably slower than in normal animals, and early i.p. tumor uptake of specific antibody was significantly higher than that following i.v. antibody delivery. With higher early tumor uptake and lower systemic exposure, early tumor/nontumor ratios were significantly greater than those for i.v. delivery, though not beyond 48 h after i.p. injection. This study demonstrates the pharmacokinetic rationale for i.p. monoclonal antibody delivery, especially for agents cleared rapidly from the blood, such as antibody fragments. In addition, definite i.p. delivery benefit for antibody specific to i.p. tumors in the i.p. ovarian cancer system was shown soon after injection. These data regarding i.p. antibody delivery should be useful in rationally planning diagnostic and therapeutic studies involving the i.p. delivery of unmodified and immunoconjugated monoclonal antibodies.

Thrombin Binding Predicts the Effects of Sequence Changes in a Human Monoclonal Antiphospholipid Antibody on Its In Vivo Biologic Actions

“…Because the route of administration and suspension buffer were identical for all IgG preparations, one would expect the kinetics of their i.p. absorption into surrounding tissue and the bloodstream to be equal (36,37). It is unlikely that the high binding V H /V L combinations (IS4VH/B3VL and IS4VHi&ii/B3VL) may have fallen in concentration through binding to other structures during their equilibration phase within the peritoneum because the concentration of these IgG in serum was similar to the low/no CL binding IgG such as IS4VHi&ii/ IS4VL.…”

Dual-Receptor–Targeted Radioimmunotherapy of Human Breast Cancer Xenografts in Athymic Mice Coexpressing HER2 and EGFR Using 177Lu- or 111In-Labeled Bispecific Radioimmunoconjugates

“…We have previously found that 111 In-labeled monoclonal antibodies are rapidly absorbed after intraperitoneal injection, with an absorption half-life of 1.9 h that provides a bioavailability of 70% compared with intravenous injection (14). Others have similarly found equivalent blood concentrations at 24 h after intraperitoneal or intravenous injection of radiolabeled antibodies (22). The tumor length and width were measured using calipers.…”

T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells

“…In a third group of experiments, mice bearing Daudi tumor cells and treated with CAR ϩ T cells also received human immunoglobulins (Jackson ImmunoResearch). Based on pharmacokinetic studies, 34 we injected the human immunoglobulin 3 times weekly intraperitoneally (100 L at 11 mg/mL). Mouse experiments were performed in accordance with Baylor College of Medicine Animal Husbandry guidelines.…”