Effect of pre-irradiation on radiopharmaceutical localization in human colon tumor xenografts using mono- and bispecific monoclonal antibodies.

In previous investigations we found that pre-irradiation of a tumor can significantly increase site-specific accumulation of radiolabeled monoclonal antibodies (MAb). The aims of the present study were to compare the effects of radiation on the localization of conventional MAb and a bifunctional delivery system and to evaluate a new time-dose schedule. T380 human colon tumors in athymic nude mice were irradiated (60Co, 10 Gy single dose) and the antibodies were injected 2 hours later.

Biodistribution of monoclonal antibodies: scale-up from mouse to human using a physiologically based pharmacokinetic model.

The efficacy of a novel diagnostic or therapeutic agent depends on its selective localization in a target tissue. Biodistribution studies are expensive and difficult to carry out in humans, but such data can be obtained easily in rodents. We have developed a physiologically based pharmacokinetic model for scaling up data from mice to humans, the first such model for genetically engineered macromolecules that bind to their targets in vivo, such as mAbs.

Prediction of tumor response to experimental radioimmunotherapy with 90Y in nude mice.

Purpose: To identify those factors that predict variability in tumor response to 90Y-radioimmunotherapy based on measurement of incorporated activity and physical dimensions of individual tumors and to apply the concept of effective dose to radioimmunotherapy.

Methods And Materials: Human colon carcinoma xenografts growing in nude mice were treated with anti-CEA antibodies labeled with 90Y directly or through a bispecific antibody/labeled hapten system. Tumor response was measured as the delay in growth to eight times the treatment volume.

Effects of proton irradiation on radiolabeled monoclonal antibody uptake in human colon tumor xenografts.

A major limitation of radiolabeled monoclonal antibodies (MAbs) for cancer imaging and therapy is their low accumulation within solid tumors. We, and others, have previously shown that pretreatment of a tumor mass with gamma radiation can increase the level of radiolabeled MAb at the tumor site. Unlike that of conventional radiation, the dose distribution of protons allows for increasing the dose to the cancer volume while reducing the normal tissue dose.

Association of intestinal peptide transport with a protein related to the cadherin superfamily.

The first step in oral absorption of many medically important peptide-based drugs is mediated by an intestinal proton-dependent peptide transporter. This transporter facilitates the oral absorption of beta-lactam antibiotics and angiotensin-converting enzyme inhibitors from the intestine into enterocytes lining the luminal wall. A monoclonal antibody that blocked uptake of cephalexin was used to identify and clone a gene that encodes an approximately 92-kilodalton membrane protein that was associated with the acquisition of peptide transport activity by transport-deficient cells.