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Regul Toxicol Pharmacol. 2019 Dec;109:104497. doi: 10.1016/j.yrtph.2019.104497. Epub 2019 Oct 11.

Comparison of metabolic and mitogenic response in vitro of the rapid-acting insulin lispro product SAR342434, and US- and EU-approved Humalog®.

Author information

1
Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926, Frankfurt am Main, Germany.
2
Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926, Frankfurt am Main, Germany. Electronic address: paulus.wohlfart@sanofi.com.
3
Beactica AB, Virdings allé 2, 754 50, Uppsala, Sweden.

Abstract

SAR342434 is a biosimilar of insulin lispro (Humalog® U-100). Batches of SAR342434 were compared with Humalog® batches of either EU or US origin in a panel of in vitro biological assays that included insulin binding to insulin receptor (IR) isoforms A (IR-A) and B (IR-B) and IR-A/IR-B autophosphorylation. A surface plasmon resonance biosensor-based assay was developed to characterize the kinetics of insulin binding to solubilized full-length IR-A or IR-B. Insulin-dependent metabolic activity assays included inhibition of lipolysis in in vitro differentiated human adipocytes, glucose uptake in L6-myocytes, and repression of glucose-6-phosphatase gene expression in human hepatocytes. Mitogenic activity assays included insulin binding to insulin-like growth factor-1 receptor (IGF1R), IGF1R autophosphorylation, and cell proliferation in MCF-7 cells. Weighted geometric means and their respective 95% confidence intervals (CI) were calculated for all 50% inhibitory or effective concentration values and kinetic binding constants for IR-A and IR-B. Statistical evaluation of the data demonstrated that the 90% CIs of the ratio of geometric means between SAR342434 and Humalog® EU or Humalog® US were within the predefined acceptance limits for each assay. Insulin lispro as SAR342434 solution demonstrated similarity to both US- and EU-approved Humalog® based on a side-by-side biological similarity assessment.

KEYWORDS:

Adipocyte lipolysis; Hepatocyte glucose-6-phosphatase gene expression; Insulin lispro; Insulin receptor; Insulin-like growth factor receptor-1; L6 myocyte glucose uptake; MCF-7 cell proliferation; Receptor binding/autophosphorylation; SAR342434; Surface plasmon resonance

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