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

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

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.

MeSH terms

  • Adipocytes
  • Animals
  • Antigens, CD / metabolism
  • Biosimilar Pharmaceuticals / pharmacology*
  • CHO Cells
  • Cell Line
  • Cricetulus
  • Drug Evaluation, Preclinical
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Insulin / metabolism
  • Insulin Lispro / pharmacology*
  • Lipolysis / drug effects
  • Mitosis / drug effects
  • Receptor, Insulin / metabolism
  • Recombinant Proteins / metabolism

Substances

  • Antigens, CD
  • Biosimilar Pharmaceuticals
  • Hypoglycemic Agents
  • Insulin
  • Insulin Lispro
  • Recombinant Proteins
  • SAR342434
  • INSR protein, human
  • Receptor, Insulin