Pharmacokinetic and pharmacodynamic analysis of circulating biomarkers of anti-NRP1, a novel anti-angiogenesis agent, in two phase I trials in patients with advanced solid tumors.

Xin Y, Li J, Wu J, Kinard R, Weekes CD, Patnaik A, Lorusso PM, Brachmann R, Tong RK, Yan Y, Watts R, Bai S, Hegde PS.
Journal   Clin Cancer Res.
Species  
Analytes Measured   PlGF , Flt-1 VEGFR1
Matrix Tested   Plasma
Year   2012
Volume  
Page Numbers  
Application   Angiogenesis and Vascular
Abstract
PURPOSE: MNRP1685A is a monoclonal antibody to neuropilin-1 (NRP1). We evaluated blood-based pharmacodynamic (PD) biomarkers of MNRP1685A in two Phase I studies to assess exposure/response relationships to inform target dose and regimen selection.

EXPERIMENTAL DESIGN: The Phase I studies evaluated escalating doses of MNRP1685A as a single agent or in combination with bevacizumab. Plasma Placental Growth Factor (P1GF), 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 Emax 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 P1GF. 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 appears to enhance bevacizumab-mediated VEGF pathway blockade, as demonstrated 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.

View Publications

Related Products

Human Growth Factor I Kit
FGF (basic), PlGF, VEGF-A, VEGFR-1/Flt-1 | Human
Multiplex
Angiogenesis Control Pack 1
FGF (basic), PlGF, Tie-2, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1
V-PLEX Human Biomarker 54-Plex Kit
CRP, Eotaxin, Eotaxin-3, FGF (basic), GM-CSF, ICAM-1, IFN-γ, IL-1α, IL-1β, IL-1RA, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-9, IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-17A/F, IL-17B, IL-17C, IL-17D, IL-21, IL-22, IL-23, IL-27, IL-31, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, MIP-3α, PlGF, SAA, TARC, Tie-2, TNF-α, TNF-β, TSLP, VCAM-1, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1 | Human
Multiplex
V-PLEX Plus Human Biomarker 54-Plex Kit
CRP, Eotaxin, Eotaxin-3, FGF (basic), GM-CSF, ICAM-1, IFN-γ, IL-1α, IL-1β, IL-1RA, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-9, IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-17A/F, IL-17B, IL-17C, IL-17D, IL-21, IL-22, IL-23, IL-27, IL-31, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, MIP-3α, PlGF, SAA, TARC, Tie-2, TNF-α, TNF-β, TSLP, VCAM-1, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1 | Human
Multiplex
R-PLEX Human PlGF Antibody Set
PlGF | Human
Singleplex
V-PLEX Angiogenesis Panel 1 Human Kit
FGF (basic), PlGF, Tie-2, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1 | Human
Multiplex
V-PLEX Human PlGF Kit
PlGF | Human
Singleplex
V-PLEX Plus Angiogenesis Panel 1 Human Kit
FGF (basic), PlGF, Tie-2, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1 | Human
Multiplex
V-PLEX Plus Human PlGF Kit
PlGF | Human
Singleplex
V-PLEX Human Biomarker 46-Plex Kit
CRP, Eotaxin, Eotaxin-3, FGF (basic), GM-CSF, ICAM-1, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-21, IL-22, IL-23, IL-27, IL-31, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, MIP-3α, PlGF, SAA, TARC, Tie-2, TNF-α, TNF-β, VCAM-1, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1 | Human
Multiplex
V-PLEX Plus Human Biomarker 46-Plex Kit
CRP, Eotaxin, Eotaxin-3, FGF (basic), GM-CSF, ICAM-1, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-21, IL-22, IL-23, IL-27, IL-31, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, MIP-3α, PlGF, SAA, TARC, Tie-2, TNF-α, TNF-β, VCAM-1, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1 | Human
Multiplex
V-PLEX Human Biomarker 40-Plex Kit
CRP, Eotaxin, Eotaxin-3, FGF (basic), GM-CSF, ICAM-1, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, PlGF, SAA, TARC, Tie-2, TNF-α, TNF-β, VCAM-1, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1 | Human
Multiplex
V-PLEX Plus Human Biomarker 40-Plex Kit
CRP, Eotaxin, Eotaxin-3, FGF (basic), GM-CSF, ICAM-1, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, PlGF, SAA, TARC, Tie-2, TNF-α, TNF-β, VCAM-1, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1 | Human
Multiplex
Human Flt-1 Antibody
VEGFR-1/Flt-1
V-PLEX Neuroinflammation Panel 1 Human Kit
CRP, Eotaxin, Eotaxin-3, FGF (basic), ICAM-1, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-13, IL-15, IL-16, IL-17A, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, PlGF, SAA, TARC, Tie-2, TNF-α, TNF-β, VCAM-1, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1 | Human
Multiplex
V-PLEX Plus Neuroinflammation Panel 1 Human Kit
CRP, Eotaxin, Eotaxin-3, FGF (basic), ICAM-1, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-13, IL-15, IL-16, IL-17A, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, PlGF, SAA, TARC, Tie-2, TNF-α, TNF-β, VCAM-1, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1 | Human
Multiplex
V-PLEX Human Flt-1 Kit
VEGFR-1/Flt-1 | Human
Singleplex
V-PLEX Plus Human Flt-1 Kit
VEGFR-1/Flt-1 | Human
Singleplex
Human PlGF Antibody
PlGF
Browse Our Products

By Analytes
By Applications
Search
Customer Service/Orders


Scientific/Technical Support


Instrument Support


Company Headquarters