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 mostly due to osteopontin’s fast turnover, as well as its relatively high plasma concentrations in human. Therapeutic antibodies against osteopontin would need to be engineered to have much extended PK than conventional antibodies, and be administered at high doses and with short dosing intervals.
Highlights
Inc.) recognizes the same epitope and inhibits RGD as well as α9β1 integrin-dependent cell binding to human osteopontin
Immunoaffinity enrichment combined with LC-MS/MS detection of D3-leucine tracer incorporation into osteopontin derived tryptic peptides enabled the turnover measurement (Fig. 1a)
High analytical sensitivity enabled by targeted immunoaffinity enrichment of osteopontin and multiple reaction monitoring (MRM) MS analysis was critical for high confidence turnover measurement
Summary
Inc.) recognizes the same epitope and inhibits RGD as well as α9β1 integrin-dependent cell binding to human osteopontin. ASK8007 was evaluated in a double-blind, multi-center, combined first-in-man, single-dose escalation (phase I, part A) and proof-of-concept, multiple-dose (phase IIA, part B) study, in RA patients with active disease[21]. The effects of ASK8007 treatment on OPN-R were not measured Another monoclonal antibody developed against osteopontin is AOM1 (Pfizer Inc.). AOM1 efficiently inhibited osteopontin binding to recombinant integrin αvβ[3] with an IC50 of 65 nM This antibody was evaluated in a metastatic model of non-small cell lung adenocarcinoma (NSCLC), the KrasG12D-LSLp53fl/fl GEMM (genetically engineered mouse model). Modeling and simulation was performed to compare different theoretical scenarios using the measured physiological turnover rate, to estimate the reduction in plasma levels of free osteopontin in human treated with various doses of antibodies. To expand the set of possible therapeutic solutions, antibodies with different properties and much improved PK (pH dependent antigen binding; active uptake by FcRn-expressing cells) were explored using the model
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