Preclinical Dosimetry, Imaging, and Targeted Radionuclide Therapy Studies of Lu-177-Labeled Albumin-Binding, PSMA-Targeted CTT1403

• Published in: Molecular imaging and biology Vol. 22; no. 2; pp. 274 - 284
• Main Authors: Ling, Xiaoxi, Latoche, Joseph D., Choy, Cindy J., Kurland, Brenda F., Laymon, Charles M., Wu, Yijen, Salamacha, Nathan, Shen, Ding, Geruntho, Jonathan J., Rigatti, Lora H., Windish, Hillarie P., Langton-Webster, Beatrice, Berkman, Clifford E., Anderson, Carolyn J.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-04-2020; Springer Nature B.V
• Subjects: Albumin; Albumins; Animal models; Animals; Antigens; Antigens, Surface - chemistry; Bearing; Binding; Biomarkers; Blood circulation; Castration; Clinical trials; Computed tomography; Dosimeters; Dosimetry; Drug Screening Assays, Antitumor; Glutamate Carboxypeptidase II - chemistry; Growth inhibition; Humans; Imaging; Internalization; Kidneys; Lutetium - pharmacology; Male; Medical imaging; Medical research; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms - drug therapy; Optimization; Photon emission; Pollution monitoring; Prostate; Prostate cancer; Radiation therapy; Radioisotopes; Radioisotopes - chemistry; Radioisotopes - pharmacology; Radiology; Radiometry - methods; Radiopharmaceuticals - pharmacology; Rats; Rats, Sprague-Dawley; Research Article; Single photon emission computed tomography; Single Photon Emission Computed Tomography Computed Tomography; Tissue Distribution; Tomography; Tumors; X ray imagery; Xenograft Model Antitumor Assays; Targeted radionuclide therapy; Lu-177; Albumin binder; Prostate-specific membrane antigen
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-019-01404-8

Purpose
Prostate-specific membrane antigen (PSMA) continues to be the hallmark biomarker for prostate cancer as it is expressed on nearly all prostatic tumors. In addition, increased PSMA expression correlates with castration resistance and progression to the metastatic stage of the disease. Recently, we combined both an albumin-binding motif and an irreversible PSMA inhibitor to develop the novel PSMA-targeted radiotherapeutic agent, CTT1403. This molecule was novel in the field of PSMA-targeted agents as its key motifs resulted in extended blood circulation time and tumor uptake, rapid and extensive internalization into PSMA+ cells, and promising therapeutic efficacy. The objective of this study was to perform IND-enabling translational studies on CTT1403 in rodent models.
Procedures
A dose optimization study was performed in PC3-PIP (PSMA+) tumor-bearing mice. Treatment groups were randomly selected to receive one to three 14-MBq injections of CTT1403. Control groups included (1) saline, (2) non-radioactive [
175
Lu]CTT1403, or (3) two injections of 14 MBq CTT1751, a Lu-177-labeled non-targeted albumin-binding moiety. Tumor growth was monitored up to 120 days. Small-animal single photon emission tomography/X-ray computed tomography imaging was performed with CTT1403 and CTT1751 in PC3-PIP tumor-bearing mice to visualize infiltration of the Lu-177-labeled agent into the tumor. In preparation for a first-in-human study, human absorbed doses were estimated based on rat biodistribution out to 5 weeks to determine a safe CTT1403 therapy dose in humans.
Results
Two to 3 injections of 14 MBq CTT1403 yielded significant tumor growth inhibition and increased survival compared with all control groups and mice receiving 1 injection of 14 MBq CTT1403. Five of 12 mice receiving 2 or 3 injections of CTT1403 survived to the 120-day post-treatment study endpoint. Dosimetry identified the kidneys as the dose-limiting organ, with an equivalent dose of 5.18 mSv/MBq, resulting in a planned maximum dose of 4.4 GBq for phase 1 clinical trials.
Conclusions
The preclinical efficacy and dosimetry of CTT1403 suggest that this agent has significant potential to be safe and effective in humans.