470P - Preclinical assessment of the pharmacokinetics, disposition, and duration of action of the dual alphav-integrin and neuropilin-1 targeting peptide CEND-1

Background

CEND-1 (iRGD), a bifunctional cyclic peptide, enhances delivery of co-administered anti-cancer agents by transforming the solid tumour microenvironment into a temporary drug conduit. The present study explored the pharmacokinetic (PK) properties of CEND-1, as well as its distribution, tumor selectivity and duration of action in preclinical tumor models.

Methods

PK was assessed in mouse plasma after intravenous infusion of CEND-1 at various dose levels. To measure tissue ligand concentration, [³H]-CEND-1 radioligand was administered intravenously to mice bearing orthotopic 4T1 tumors and measured by quantitative whole-body autoradiography (QWBA) or quantitative radiography (QRA). The duration of the tumor-penetrating effect of CEND-1 was evaluated by assessing tumor accumulation of Evans Blue and Doxorubicin in two different models of hepatocellular carcinoma (HCC): TGFα/c-myc-double transgenic mice and HepG2 xenografted mice.

Results

Systemic exposure of CEND-1 in mice generally increased with dose in a more than dose proportional manner. The systemic half-life was approximately 30 minutes. The radiolabelled [³H]-CEND-1 localised to the tumour and several healthy tissues shortly after administration, but it was cleared from most healthy tissues by 3 hours. Despite the rapid systemic clearance, the tumors still had significant amounts of [³H]-CEND-1 several hours after i.v. administration. In mice with HCC, the tumor penetrability remained elevated for at least 24 hours after the injection of a single dose of CEND-1.

Conclusions

These results indicate a favourable in vivo PK profile of CEND-1 after intravenous administration and demonstrate a specific and long-lasting tumour homing and tumor penetrability. Therefore, even single injections of CEND-1 may elicit long-lasting tumor PK improvements for co-administered anti-cancer agents.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Cend Therapeutics, Inc.

Disclosure

H.A. Järveläinen: Financial Interests, Institutional, Leadership Role: Cend Therapeutics. C. Henson: Financial Interests, Institutional, Full or part-time Employment: Pharmaron UK. G. Bullen-Clerkson: Financial Interests, Institutional, Full or part-time Employment: Pharmaron UK. S. Harris: Financial Interests, Institutional, Full or part-time Employment: Pharmaron UK. All other authors have declared no conflicts of interest.