title: Pharmacokinetic and pharmacodynamic analysis of circulating biomarkers of anti-NRP1, a novel antiangiogenesis agent, in two phase I trials in patients with advanced solid tumors.
abstract: OBJECTIVE
  MNRP1685A is a monoclonal antibody to neuropilin-1 (NRP1). We evaluated blood-based pharmacodynamic biomarkers of MNRP1685A in two phase I studies to assess exposure/response relationships to inform target dose and regimen selection.
  
  
  METHODS
  The phase I studies evaluated escalating doses of MNRP1685A as a single agent or in combination with bevacizumab. Plasma placental growth factor (PlGF), VEGF, and circulating NRP1 (cNRP1) were evaluated at multiple time points using meso-scale discovery (MSD) assays and ELISA, respectively. Plasma PlGF was also measured in a phase I/II trial of bevacizumab in metastatic breast cancer (AVF0776). The association between PlGF and MNRP1685A dose was described by a sigmoid E(max) model. cNRP1 and MNRP1685A PK profiles were described using a two-target quasi-steady state (QSS) model.
  
  
  RESULTS
  A dose- and time-dependent increase in plasma PlGF and cNRP1 was observed in all patients treated with MNRP1685A. PK/PD analysis showed that bevacizumab and MNRP1685A had an additive effect in elevating PlGF. Predictions based on the two-target QSS model showed that the free drug concentration to maintain greater than 90% saturation of membrane NRP1 (mNRP1) and cNRP1 is about 8 μg/mL.
  
  
  CONCLUSIONS
  These data show that MNRP1685A inhibits the VEGF pathway in humans as assessed by an increase in plasma PlGF. MNRP1685A seems to enhance bevacizumab-mediated VEGF pathway blockade, as showed by an increase in the magnitude of PlGF elevation when combined with bevacizumab. PK/PD analysis of biomarkers in the phase I population allowed identification of doses at which apparent maximal pathway modulation was observed.
authors.affiliation: Genentech Inc, South San Francisco, California 94080, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xin
authors.forename: Jessica
authors.initials: J
authors.lastname: Li
authors.forename: Jenny
authors.initials: J
authors.lastname: Wu
authors.forename: Rashell
authors.initials: R
authors.lastname: Kinard
authors.forename: Colin D
authors.initials: CD
authors.lastname: Weekes
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Patricia
authors.initials: P
authors.lastname: Lorusso
authors.forename: Rainer
authors.initials: R
authors.lastname: Brachmann
authors.forename: Raymond K
authors.initials: RK
authors.lastname: Tong
authors.forename: Yibing
authors.initials: Y
authors.lastname: Yan
authors.forename: Ryan
authors.initials: R
authors.lastname: Watts
authors.forename: Shuang
authors.initials: S
authors.lastname: Bai
authors.forename: Priti S
authors.initials: PS
authors.lastname: Hegde
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D017261:Glycosylphosphatidylinositols / Q000097:blood; D006801:Humans; D008252:Macaca fascicularis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D039942:Neuropilin-1 / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015415:Biomarkers; D017261:Glycosylphosphatidylinositols; D039942:Neuropilin-1; C574067:vesencumab