An experimental and theoretical evaluation of the influence of pretargeting antibody on the tumor accumulation of effector

Abstract

In treating tumors by pretargeting, the antitumor antibody and the cytotoxic effector (e.g., toxins and radioactivity) are separately administered. Therefore, pretargeting is more complicated with many variables. We are conducting studies to understand the influence of each variable using a novel recognition pair of mutually complementary phosphorodiamidate morpholino oligomers (MORF/ cMORF). Earlier we developed a semi-empirical model capable of accurately predicting the behavior of a radiolabeled cMORF effector with variations in dosages and timing. We have now extended the model to predict the effector behavior, in particular, its maximum percent tumor accumulation (MPTA) in mice pretargeted with three different MORF-conjugated antibodies (MN14, B72.3, and CC49). The MN14 and the CC49 target different antigens in the same tumor, whereas the CC49 and the B72.3 target the same antigen but with very different tumor accumulation. By comparing the pretargeting results of these three antibodies with our prediction, we confirmed that the MPTA of the radiolabeled cMORF effector in the LS174T tumor is independent of the antibodies. In conclusion, the MPTA cannot be improved through the use of different pretargeting antibodies, although different antibodies may improve the maximum absolute tumor accumulation, the heterogeneity, and/or the tumor-to-normal tissue ratios of the effector. This conclusion will apply equally well to effectors carrying a fluorescent probe, an anticancer agent, or a radioactive imaging agent.

Rules of thumb for maximum percent tumor accumulation

“…The influence of the pretargeting agent can only be reflected by its effect on the number of artificial binding sites in connection to the condition that holds the MPTA expression. This lack of direct influence has been confirmed experimentally [4]. …”

A Semiempirical Model of Tumor Pretargeting

“…effector in circulation not bound to circulating antibody) (33). This equation may be used to describe how the radiolabeled effector, tumor model, and pretargeting antibody influence the tumor accumulations of effector.…”

“…By equation 2, the MPTA will vary with the tumor host (via F ), tumor type and size (via f, W and E ) and the effector (via E and the integral of C) (33). The MPTA will not change with different antibodies provided that each antibody is not entirely inaccessible.…”

Adding a Clearing Agent to Pretargeting Does Not Lower the Tumor Accumulation of the Effector as Predicted

“…[13][14][15][16] In the present study, the authors intended to confirm whether this model can correctly predict the influence of a clearing agent on the tumor accumulation of the effector. Predictions on the effector levels in normal tissues would have required accurate measurements of the pharmacokinetics of the pretargeting antibody following the addition of the clearing agent, and were beyond the scope of this limited study.…”