Evaluation of Aminopolycarboxylate Chelators for Whole-Body Clearance of Free Ac: A Feasibility Study to Reduce Unexpected Radiation Exposure during Targeted Alpha Therapy.

Actinium-225 (Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free Ac can be released from the drugs and that such free Ac is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of Ac TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free Ac and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free Ac were examined in mice before an in vivo chelating study. The liver exhibited pronounced Ac uptake, with an estimated human absorbed dose of 4.76 Sv/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced Ac retention in the liver (22% and 30%, respectively). Significant Ac reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free Ac. This feasibility study provides useful information for reducing undesirable radiation exposure from free Ac

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 64Cu-labeled anti-epidermal growth factor receptor (EGFR) antibody (64Cu-NCAB001 ipPET). Here, we conducted an extended single-dose toxicity study of 64Cu-NCAB001 ipPET in mice based on approach 1 of the current ICH M3 [R2] guideline, as our new drug formulation contains 45 μg of the antibody. We used NCAB001 labeled with stable copper isotope instead of 64Cu. 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 μg/kg were assessed in mice. The no-observed-adverse-effect level of Cu-NCAB001 was 625 μg/kg, a dose approximately 1000-fold higher at the μg/kg level than the dose of 64Cu-NCAB001 in our formulation (45 µg). The size variants did not affect the safety of the formulation. Therefore, clinical studies on the efficacy of 64Cu-NCAB001 ipPET for early detection of pancreatic cancer using PET imaging can be safely conducted

In Vitro Tumor Cell-Binding Assay to Select High-Binding Antibody and Predict Therapy Response for Personalized ⁶⁴Cu-Intraperitoneal Radioimmunotherapy against Peritoneal Dissemination of Pancreatic Cancer: A Feasibility Study

Peritoneal dissemination of pancreatic cancer has a poor prognosis. We have reported that intraperitoneal radioimmunotherapy using a 64Cu-labeled antibody (64Cu-ipRIT) is a promising adjuvant therapy option to prevent this complication. To achieve personalized 64Cu-ipRIT, we developed a new in vitro tumor cell-binding assay (64Cu-TuBA) system with a panel containing nine candidate 64Cu-labeled antibodies targeting seven antigens (EGFR, HER2, HER3, TfR, EpCAM, LAT1, and CD98), which are reportedly overexpressed in patients with pancreatic cancer. We investigated the feasibility of 64Cu-TuBA to select the highest-binding antibody for individual cancer cell lines and predict the treatment response in vivo for 64Cu-ipRIT. 64Cu-TuBA was performed using six human pancreatic cancer cell lines. For three cell lines, an in vivo treatment study was performed with 64Cu-ipRIT using high-, middle-, or low-binding antibodies in each peritoneal dissemination mouse model. The high-binding antibodies significantly prolonged survival in each mouse model, while low-and middle-binding antibodies were ineffective. There was a correlation between in vitro cell binding and in vivo therapeutic efficacy. Our findings suggest that 64Cu-TuBA can be used for patient selection to enable personalized 64Cu-ipRIT. Tumor cells isolated from surgically resected tumor tissues would be suitable for analysis with the 64Cu-TuBA system in future clinical studies