Cetuximab: Preclinical Evaluation of a Monoclonal Antibody Targeting EGFR for Radioimmunodiagnostic and Radioimmunotherapeutic Applications

Abstract

The monoclonal antibody cetuximab binds to EGFR and thus provides an opportunity to create both imaging and therapies that target this receptor. The potential of cetuximab as a radioimmunoconjugate using the acyclic bifunctional chelator, CHX-A”-DTPA was investigated. The pharmacokinetic behavior in the blood was determined in mice with and without tumors. Tumor targeting and scintigraphic imaging were evaluated in mice bearing xenografts of LS-174T (colorectal), SHAW (pancreatic), SKOV3 (ovarian), DU145 (prostate) and HT-29 (colorectal). Excellent tumor targeting was observed in each of the models with peak tumor uptakes of 59.8±18.1, 22.5±4.7, 33.3±5.7, 18.2±7.8 and 41.7±10.8 %ID/g at 48-72 hr, respectively. In contrast, the highest tumor %ID/g obtained in mice bearing melanoma (A375) xenografts was 6.3±1.1 at 72 hr. The biodistribution of 111In-cetuximab was also evaluated in non-tumor bearing mice. The highest %ID/g was observed in the liver (9.3±1.3 at 24 hr) and the salivary glands 8.1±2.8 at 72 hr). Scintigraphy showed excellent tumor targeting at 24 hr. Blood pool was evident as expected but cleared over time. At 168 hr the tumor was clearly discernible with negligible background.

Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease

“…[23][24][25] These studies were performed with mice bearing subcutaneous (s.c.) tumor xenografts and the radiolabeled cetuximab given by an intravenous (i.v.) route.…”

“…Several imaging investigations have explored the practicality of using cetuximab for monitoring disease, assaying EGFR expression, determining patient selection as well as for performing dosimetric calculations for RIT. [21][22][23][24][25][26] The possibility that cetuximab might be appropriate for RIT applications was demonstrated in a set of studies published by this laboratory. 23 Tumor targeting of 111 In-cetuximab was validated in 5 tumor models by direct quantitation of tumor tissue and with g-scintigraphy.…”

“…[21][22][23][24][25][26] The possibility that cetuximab might be appropriate for RIT applications was demonstrated in a set of studies published by this laboratory. 23 Tumor targeting of 111 In-cetuximab was validated in 5 tumor models by direct quantitation of tumor tissue and with g-scintigraphy. The usefulness of cetuximab was also confirmed in a study in which cetuximab labeled with 86 Y was studied for positron-emission tomography (PET) imaging.…”

Structure-based drug design and biological evaluation of 2-acetamidobenzothiazole derivative as EGFR kinase inhibitor

“…Moreover, colon cancer (HCT-116, HCT-15 and HT-29) cell lines were selected for the comparison since they express high levels of EGFR [28][29][30] , e.g. HCT-116 and HT-29 cell lines express approximately 100 000-150 000 EGFRs per cell 29 .…”

Imaging agents for in vivo molecular profiling of disseminated prostate cancer - targeting EGFR receptors in prostate cancer: Comparison of cellular processing of [111In]-labeled affibody molecule ZEGFR:2377 and cetuximab

“…The use of natural ligands is limited by their physiological activity that can provoke adverse reactions: nausea, vomiting, diarrhea, hypotension, fever and chills (17). Intact mAbs demonstrated their capacity to image EGFR-expressing tumors (18)(19)(20) but the sensitivity of such tracers can be limited by the long biodistribution times, slow tumor penetration, and slow blood clearance of the tracers, which reduces target or non-target contrast. The affibody molecules, a new class of imaging agents combine small size of natural ligands, absence of physiological action, and high affinity to target and can be used for radioimmuno-diagnostic.…”