Jungyeon Hwang

Preclinical to clinical development of the novel camptothecin nanopharmaceutical CRLX101

Camptothecin (CPT) is a potent broad-spectrum anticancer agent that acts through inhibition of topoisomerase 1. Clinical development of CPT was unsuccessful due to poor drug solubility, insufficient in vivo stability of the active form, and toxicity. In order to address these issues, a polymeric nanoparticle comprised of cyclodextrin-poly(ethylene glycol) copolymer (CDP) conjugated to CPT (CRLX101) has been developed and Phase 2 clinical studies are ongoing. Camptothecin is conjugated to the polymer in its active form at 10-12 wt.% loading. CRLX101 self-assembles in solution into nanoparticles with an apparent solubility increase of >1000-fold as compared to the parent drug camptothecin. Preclinical studies exhibited CRLX101 pharmacokinetics superior to the parent drug. Drug concentration in tumor relative to plasma and other major organs is consistent with the enhanced permeation and retention (EPR) anticipated from a nanoparticle. Significant anti-tumor activity was observed that is superior when compared to irinotecan across a broad range of xenograft models. Pharmacokinetic data are consistent with the prolonged half-life and increased AUC. The CRLX101 preclinical and clinical data confirm that CDP can address not only solubility, formulation, toxicity, and pharmacokinetic challenges associated with administration of CPT, but more importantly, can impart unique biological properties, that enhance pharmacodynamics and efficacy of camptothecin.

CRLX101 (formerly IT-101)-A Novel Nanopharmaceutical of Camptothecin in Clinical Development.

CRLX101 (formerly IT-101) is a first-in-class nanopharmaceutical, currently in Phase 2a development, which has been developed by covalently conjugating camptothecin (CPT) to a linear, cyclodextrin-polyethylene glycol (CD-PEG) co-polymer that self-assembles into nanoparticles. As a nanometer-scale drug carrier system, the cyclodextrin polymeric nanoparticle technology, referred to as “CDP”, has unique design features and capabilities. Specifically, CRLX101 preclinical and clinical data confirm that CDP can address not only solubility, formulation, toxicity, and pharmacokinetic challenges associated with administration of CPT, but more importantly, can impart unique biological properties that enhance CPT pharmacodynamics and efficacy.

Reactive block copolymer scaffolds

Block copolymers with sequences of differential reactivity were synthesized, and the step-wise and selective derivatization to form a new block copolymer was demonstrated.

Abstract B176: In vitro and in vivo studies demonstrating sustained drug release for multiple anticancer payloads and improved anticancer effects of a cabazitaxel β-cyclodextrin-PEG copolymer-based nanoparticle-drug conjugate (NDC)

We have demonstrated the ability to generate nanoparticle-drug conjugates (NDCs) with tunable and diverse in vitro and in vivo drug release kinetics by the conjugation of multiple anticancer agents (docetaxel, cabazitaxel, and gemcitabine) to a β-cyclodextrin-PEG (CDP) copolymer through a variety of linker strategies. Linker molecules included glycinate, alaninate, hexanoate, and diester linker β-alanine-glycolate, which were conjugated via ester linkages to the anticancer payloads. In vitro release studies demonstrated that the β-alanine-glycolate linker released drug from the CDP copolymer relatively faster than the glycinate and alaninate linkers, while the hexanoate linker showed much slower drug release. Release studies in native and heat-inactivated plasma had no influence on the release kinetics, indicating that drug release was pH- but not enzyme-triggered. The in vitro release profiles for the respective linkers varied slightly (more so in vivo) depending on the API (Active Pharmaceutical Ingredient) payload, demonstrating that release kinetics can be varied through selection of linker molecules and that NDC chemistry is customizable with respect to API. In vivo PK studies with cabazitaxel (CBTX) NDCs demonstrated that the hexanoate-containing NDC (slower releasing linker) led to higher total (conjugated drug + released) drug levels and lower released drug levels compared to the glycinate NDC (faster releasing linker) and the separately dosed cabazitaxel. This likely led to the greater tolerability (i.e., higher MTD) observed for the CBTX-hexanoate NDC. Both the CBTX-hexanoate and -glycinate NDCs led to high and sustained levels of released drug in tumor tissues (>72 hrs). The maximum drug concentrations in the blood (Cmax) of released drug was lower for all NDCs tested compared to similarly dosed parent drug, thereby addressing Cmax-related toxicities. Two CBTX NDCs (hexanoate and glycinate) were chosen for in vivo efficacy studies in mouse tumor models. Both demonstrated vastly improved efficacy (and survival) over the parent drug, cabazitaxel, at similar doses including efficacy against docetaxel-resistant UISO-BCA-1 tumor cells. The CBTX-hexanoate NDC showed a greater therapeutic index (TI) compared to parent drug as well as the CBTX-glycinate NDC. Citation Format: Chester Metcalf, III, Donna Brown, Jungyeon Hwang, Sujan Kabir, Douglas Lazarus, Pochi Shum, Snehlata Tripathi, Scott Eliasof. In vitro and in vivo studies demonstrating sustained drug release for multiple anticancer payloads and improved anticancer effects of a cabazitaxel β-cyclodextrin-PEG copolymer-based nanoparticle-drug conjugate (NDC). [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 B176.