Assessing the Feasibility of Neutralizing Osteopontin with Various Therapeutic Antibody Modalities

Scientific Reports
Vahid FarrokhiZhiyong Yang

Abstract

Osteopontin is a secreted glycophosphoprotein that is highly implicated in many physiological and pathological processes such as biomineralization, cell-mediated immunity, inflammation, fibrosis, cell survival, tumorigenesis and metastasis. Antibodies against osteopontin have been actively pursued as potential therapeutics for various diseases by pharmaceutical companies and academic laboratories. Many studies have demonstrated the efficacy of osteopontin inhibition in a variety of preclinical models of diseases such as rheumatoid arthritis, cancer, nonalcoholic steatohepatitis, but clinical utility has not yet been demonstrated. To evaluate the feasibility of osteopontin neutralization with antibodies in a clinical setting, we measured its physiological turnover rate in humans, a sensitive parameter required for mechanistic pharmacokinetic and pharmacodynamic (PK/PD) modeling of biotherapeutics. Results from a stable isotope-labelled amino acid pulse-chase study in healthy human subjects followed by mass spectrometry showed that osteopontin undergoes very rapid turnover. PK/PD modeling and simulation of different theoretical scenarios reveal that achieving sufficient target coverage using antibodies can be very challenging mos...Continue Reading

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Citations

Feb 28, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ali NazmiDanyvid Olivares-Villagómez
Aug 25, 2019·Biomolecules·Yao-Yun FanHendrik Neubert
May 16, 2020·European Journal of Internal Medicine·Federico CarboneFabrizio Montecucco
Nov 19, 2020·Cancers·Hannah R MoormanKebin Liu
Feb 18, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Andrew J ArmstrongSusan Halabi
Aug 20, 2021·Naunyn-Schmiedeberg's Archives of Pharmacology·Manja NeweStephan R Künzel

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