Comparative Nonclinical Assessments of the Proposed Biosimilar PF-05280014 and Trastuzumab (Herceptin®)

Abstract

Background and ObjectivesTrastuzumab (Herceptin®) is a humanized monoclonal antibody (mAb) that binds to the HER2 protein. PF-05280014 is being developed as a potential biosimilar to trastuzumab products marketed in the United States (trastuzumab-US) and European Union (trastuzumab-EU). Nonclinical studies were designed to evaluate the similarity of PF-05280014 to trastuzumab-US and trastuzumab-EU using in vitro structural and functional analyses, and in vivo pharmacokinetic and immunogenicity assessments.MethodsPeptide mapping was utilized to determine structural similarity. Functional similarity was assessed via an in vitro tumor cell growth inhibition assay. CD-1 male mice were administered a single-dose (0, 1, 10, or 100 mg/kg) of PF-05280014, trastuzumab-US, or trastuzumab-EU. Mice were monitored for clinical signs and body weight changes over a 4-month period. At approximately 720, 1,080, 1,440, 2,160, and 2,880 h post-dose, terminal blood samples were collected and assayed for PF-05280014, trastuzumab-US, or trastuzumab-EU concentrations and anti-drug antibodies (ADA). Values for Cmax, area under the concentration time curve (AUC), clearance (CL), volume of distribution (Vss), half-life (t½), and the presence of ADA were determined.ResultsIn this report, peptide mapping of PF-05280014, trastuzumab-US, and trastuzumab-EU showed similar chromatographic profiles in a side-by-side analysis. The tumor cell growth inhibition of PF-05280014 was similar to trastuzumab-US and trastuzumab-EU. Cmax and AUC0–∞ values in mice were similar and dose-dependent across the mAbs at all doses, and CL and Vss values were similar and dose-independent. The CL values across doses ranged from 0.193 to 0.350 mL/h/kg (PF-05280014), from 0.200 to 0.346 mL/h/kg (trastuzumab-US), and from 0.193 to 0.335 mL/h/kg (trastuzumab-EU). Vss values across doses ranged from 84.9 to 120 mL/kg (PF-05280014), 86.7 to 130 mL/kg (trastuzumab-US), and 85.4 to 116 mL/kg (trastuzumab-EU). The incidence of ADA was low (~10%) and also similar across all dose levels and the three mAbs. The lower exposure generally observed in ADA-positive animals did not impact the overall PK interpretation. All animals survived to their scheduled terminal blood collection with no mAb-related differences in body weight gain or clinical signs.ConclusionsPF-05280014, trastuzumab-US, and trastuzumab-EU were well tolerated during the 4-month observation period following a single dose of up to 100 mg/kg. PF-05280014, trastuzumab-US, and trastuzumab-EU showed similar structural properties, tumor cell growth inhibition properties, and PK profiles. The incidence of ADA was low and similar across the three mAbs. The results of these studies support the development of PF-05280014 as a proposed biosimilar to Herceptin.

Clinical considerations for the development of biosimilars in oncology

“…37 Biosimilars have already improved access to wellestablished therapeutic interventions in Europe and other locations where approvals have occurred. 4,35 Although there are some limitations to the use of biosimilars due to issues with interchangeability and extrapolation of data, in the long-term, biosimilars should offer a wider array of Non-clinical: similar structure, function, chromatographic profile, PK, and immunogenicity to trastuzumab sourced from US and EU 54 Phase 1: comparative PK, PD, safety, tolerability, and immunogenicity to trastuzumab sourced from US and EU, in healthy subjects 14 Mfg, manufacturer; PK, pharmacokinetics; PD, pharmacodynamics; HER2, human epidermal growth factor receptor 2; ORR, overall response rate; MBC, metastatic breast cancer www.tandfonline.com 291 mAbs therapeutic solutions and increase accessibility to effective cancer treatments. Clinicians should understand the importance of biosimilars in clinical practice and how to make informed decisions about their appropriate use.…”

Can we establish a hierarchy among trastuzumab biosimilar candidates?

“…These steps have already been successfully achieved for PF-05280014. 6,7 Treatment with trastuzumab can result in the production of anti-trastuzumab antibodies; therefore, initial phase I trials for PK assessment include healthy male subjects, because they are less likely to require treatment with trastuzumab for breast cancer in the future. Notably, several previous studies have validated the absence of observable discrepancies in PK profiles for trastuzumab between healthy volunteers and patients.…”

“…[1][2][3][4][5] In this issue of the British Journal of Cancer, Lammers et al report evidence establishing another step towards the registration of PF-05280014, a trastuzumab biosimilar candidate developed by Pfizer. 1,[6][7][8] This significant trial has provided clinical efficacy results of this candidate in patients with early breast cancer, and insight into its pharmacokinetic (PK) non-inferiority.The development of a biosimilar drug requires the collation of extensive pre-clinical comparability studies to demonstrate similar structural, physicochemical, and functional biological characteristics with the referent medical product. 9,10 .…”

Cell Culture Technologies in Successful Biosimilar Development

“…Control Strategy the cell culture process are developed based upon scientific and risk management principles because it impact the safety and quality of the therapeutics being produced [26][27][28]. Regulatory agencies emphasize analysis and characterization of products in relation to the cell culture processes; setting process specifications; and identifying critical quality attributes (CQA) and critical process parameters [26,30,31]. Moreover, process analytical technology(PAT) guidance was issued to help design, develop, and implement analytical tools during manufacturing and quality assurance of biologics [32,33].…”