Evaluation of pharmacokinetics and toxicology of biosimilar APZ001 antibody in &lt;i&gt;Macaca cynomolgus&lt;/i&gt;

Xiaofei Wang,Xinyu Deng,Yuankeng Huang,Huiqing Liang,Caiguo Ye,Jianmin Guo,Wei Yang,Xialing Lei

doi:10.4314/tjpr.v17i9.30

Abstract

Purpose: To compare the pharmacokinetics of APZ001 antibody with those of cetuximab (Erbitux®) and to evaluate the toxicology of the former. Methods: To evaluate cetuximab’s biosimilar APZ001, Crl:CD1(ICR) (CD-1) mice and Macaca fascicularis (cynomolgus monkey) were chosen for the studies on acute toxicity, chronic toxicity, pharmacokinetics in chronic toxicity and immunogenicity toxicity. The study also compared the pharmacokinetic parameters of APZ001 with those of cetuximab upon single and multiple drug administrations in cynomolgus monkeys. Results: Pharmacokinetic parameters including maximum concentration (C max ) and time to attain maximum drug concentration (T max ), clearance rate and apparent volume of distribution of APZ001 were compared with those of cetuximab in both single and multiple administration studies. Difference of pharmacokinetics from weekly administration of APZ001 and cetuximab in cynomolgus monkeys was insignificant (p > 0.05), with relative bioavailability of 116.9 %. Both APZ001-treated and cetuximabtreated CD-1 mice showed the same level of food intake and body weight. Hematological and serological data were similar from APZ001 antibody and cetuximab treatments, so were the acute and chronic toxicity. Weekly transfusion of APZ001 did not alter its pharmacokinetic parameters. The administered drug was hardly detected in the serum in the 31st and 37th week of recovery; no accumulation of drug was observed upon withdrawal. Conclusion: APZ001 has extremely similar characteristics as cetuximab in terms of pharmacokinetics and toxicity. Keywords: Cetuximab, Pharmacokinetics, Acute toxicity, Chronic toxicity, Immunogenicity, Biosimilar

Highlights

Aberrant overexpression and malfunction of epidermal growth factor receptor (EGFR) have been observed in many cancers, of which proliferation, apoptosis, angiogenesis and metastasis were mediated by it [1,2]
Suppressing cancer EGFR signaling via anti-EGFR monoclonal antibody blocking is, an attractive therapeutic strategy [4]
Several monoclonal antibody (mAb)-targeting cancer therapies have been approved by the Food and Drug Administration (FDA), including Erbitux and Vectibix, which are used to treat colorectal cancer (CRC) and/or squamous cell carcinoma of the head and neck (SCCHN) by targeting EGFR [5,6]; Herceptin and pertuzumab, on the other hand, are used to treat gastric cancers by targeting EGFR2 [7,8]

Summary

Introduction

Aberrant overexpression and malfunction of epidermal growth factor receptor (EGFR) have been observed in many cancers, of which proliferation, apoptosis, angiogenesis and metastasis were mediated by it [1,2]. Suppressing cancer EGFR signaling via anti-EGFR monoclonal antibody (mAb) blocking is, an attractive therapeutic strategy [4]. Several mAbs-targeting cancer therapies have been approved by the Food and Drug Administration (FDA), including Erbitux (cetuximab) and Vectibix (panitumumab), which are used to treat colorectal cancer (CRC) and/or squamous cell carcinoma of the head and neck (SCCHN) by targeting EGFR [5,6]; Herceptin (trastuzumab) and pertuzumab, on the other hand, are used to treat gastric cancers by targeting EGFR2 [7,8]. Due to the economic consideration, use of Erbitux and Herceptin are limited in the less developed countries. This work focused on developing a substitute of Erbitux and Herceptin for a more affordable therapy option. The cetuximab biosimilar antibody APZ001, of which the protein sequence and biological functions bear similarity to cetuximab, was investigated, with its preclinical pharmacokinetics and pharmacovigilance evaluated

Results

Discussion

Conclusion