Abstract B33: CRLX101, an investigational nanoparticle-drug conjugate, localizes in human tumors and not in adjacent healthy tissue after intravenous dosing
Authors: Clark Andrew , Wiley Devin T. , Zuckerman Jonathan E. , Webster Paul , Chao Joseph , Lin James , Yen Yun , Davis Mark E. , Eliasof Scott 
Published: May 2016

Abstract
Background: Nanoparticle-based therapeutics are thought to rely on the enhanced permeability and retention effect to preferentially localize in solid tumors and not healthy tissue. These phenomena are rationalized primarily from animal models of the human disease. There is a need to obtain analogous information from humans in order to better understand how nanoparticle-based therapeutics perform in humans. CRLX101 is an investigational nanoparticle drug conjugate (NDC) consisting of a cyclodextrin-containing polymer (CDP) conjugate of the payload camptothecin (CPT). The individual polymer strands self-assemble into nanoparticles (ca. five strands) of approximately 10 to 40 nm diameter and 10 wt% CPT by multiple, interstrand, inclusion complex formation between the cyclodextrin and the CPT molecules. CRLX101 is currently being investigated in phase II trials in patients with renal, ovarian and rectal cancer.
Methods: A phase I clinical trial was performed with CRLX101 at the City of Hope, in patients with advanced or metastatic stomach, gastroesophageal or esophageal cancer. This study was sponsored by City of Hope Medical Center, and funding and CRLX101 was provided by Cerulean Pharma Inc. (ClinicalTrials.gov identifier: NCT01612546). The goal of this study was to test the hypothesis that intact CRLX101 nanoparticles deposit in human tumors and not in normal adjacent tissue after intravenous administration. Tumor and adjacent healthy tissue biopsies were obtained through endoscopic capture from patients who received CRLX101, and analyzed via a number of methodologies.
Results: Both the pre- and post-dosing, healthy tissue samples adjacent to tumors show no evidence of either the NDC or the payload (CPT) contained within the NDC. Similar results are obtained from the pre-dosing tumor samples. However, in 8 of 9 patients that were evaluated, CPT is detected in the tumor tissue by fluorescent microscopy examination of fixed sections. For 3 of these patients, proof of intact CRLX101 NDC is obtained from tissue sections by colocalized, fluorescence from the CPT and a secondary antibody used to stain a PEG specific antibody (binds to the PEG in CRLX101). Following fluorescence imaging, remaining tissues from 3 patients were homogenized and measured for free and CDP conjugated CPT using HPLC. CPT was present in the post-treatment tumor tissue of all 3 patient samples with an average of 96.2±13.1% in the conjugated form, indicating that CRLX101 NDCs are localized in these samples.
Conclusions: Tumor and adjacent healthy tissue biopsies obtained from cancer patients who have received CRLX101show that these NDCs do localize in human tumors and not in adjacent tissues.
Citation Format: Andrew Clark, Devin T. Wiley, Jonathan E. Zuckerman, Paul Webster, Joseph Chao, James Lin, Yun Yen, Mark E. Davis, Scott Eliasof. CRLX101, an investigational nanoparticle-drug conjugate, localizes in human tumors and not in adjacent healthy tissue after intravenous dosing. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B33.