Preclinical Safety Evaluation of Intraperitoneally Administered Cu-Conjugated Anti-EGFR Antibody NCAB001 for the Early Diagnosis of Pancreatic Cancer Using PET

Detecting tumor lesions <1 cm in size using current imaging methods remains a clinical challenge, especially in pancreatic cancer. Previously, we developed a method to identify pancreatic tumor lesions >= 3 mm using positron emission tomography (PET) with an intraperitoneally administered Cu-64-labeled anti-epidermal growth factor receptor (EGFR) antibody (Cu-64-NCAB001 ipPET). Here, we conducted an extended single-dose toxicity study of Cu-64-NCAB001 ipPET in mice based on approach 1 of the current ICH M3 [R2] guideline, as our new drug formulation contains 45 mu g of the antibody. We used NCAB001 labeled with stable copper isotope instead of Cu-64. The total content of size variants was approximately 6.0% throughout the study. The relative binding potency of Cu-NCAB001 to recombinant human EGFR was comparable to that of cetuximab. The general and neurological toxicities of Cu-NCAB001 ipPET at 62.5 or 625 mu g/kg were assessed in mice. The no-observed-adverse-effect level of Cu-NCAB001 was 625 mu g/kg, a dose approximately 1000-fold higher at the mu g/kg level than the dose of Cu-64-NCAB001 in our formulation (45 mu g). The size variants did not affect the safety of the formulation. Therefore, clinical studies on the efficacy of Cu-64-NCAB001 ipPET for early detection of pancreatic cancer using PET imaging can be safely conducted.