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Anti-Neuropilin-1 (MNRP1685A): Unexpected Pharmacokinetic Differences Across Species, from Preclinical Models to Humans

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Abstract

Purpose

To compare the pharmacokinetics (PK) of MNRP1685A, a human monoclonal antibody (mAb) against neuropilin-1 (NRP1), in mice, rats, monkeys, and cancer patients from a Phase I study to model with parallel linear and nonlinear clearances.

Methods

Binding characteristics of MNRP1685A in different species were evaluated using surface plasmon resonance technology. PK profiles of MNRP1685A after single and/or multiple doses in different species were analyzed using population analysis. PK parameters were compared across species.

Results

MNRP1685A binds to NRP1 in all four species tested. Consistent with the wide expression of NRP1, MNRP1685A demonstrated pronounced non-linear PK over a wide dose range. PK profiles are best described by a two-compartment model with parallel linear and nonlinear clearances. Model-derived PK parameters suggest similar in-vivo target expression levels and binding affinity to target across all species tested. However, compared to typical human/humanized mAbs, non-specific clearance of MNRP1685A was faster in mice, rats, and humans (60.3, 19.4, and 8.5 ml/day/kg), but not in monkeys (3.22 ml/day/kg).

Conclusions

Monkey PK properly predicted the target-mediated clearance of MNRP1685A but underestimated its non-specific clearance in humans. This unique PK property warrants further investigation of underlying mechanisms.

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Abbreviations

ATA:

anti-therapeutic antibody

CHO cells:

Chinese hamster ovary cells

CL:

non-specific clearance

CLd :

distribution clearance

CV:

coefficient of variation

ELISA:

enzyme-linked immunosorbent assay

FC:

flow cell

FcRn:

neonatal Fc receptor

HRP:

horseradish peroxidase

IV:

intravenous

KD :

equilibrium dissociation constant

kg:

kilogram

Km :

drug concentration at 50 % Vmax

koff :

off-rate

kon :

on-rate

LLOQ:

lower limit of quantitation

mAbs:

monoclonal antibodies

mg:

milligram

min:

minute

ml:

milliliter

mM:

millimolar

ng:

nanogram

nM:

nanomolar

NRP1:

neuropilin-1

PBS:

phosphate-buffered saline

PK:

pharmacokinetics

q3w:

every three weeks

RSE:

relative standard error of estimation

RU:

response unit

SD:

standard deviation

V1 :

apparent volume of central compartment

V2 :

peripheral compartment distribution volume

VEGF:

vascular endothelial growth factor

Vmax :

maximum drug elimination by nonlinear (or specific) clearance

μg:

microgram

μl:

microliter

σprop :

proportional residual error

ωCL :

inter-subject variability on CL

ωKm :

inter-subject variability on Km

ωV1 :

inter-subject variability on V1

ωVmax :

inter-subject variability on Vmax

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Acknowledgments and Disclosures

The authors acknowledge the valuable technical advice from Drs Rong Deng and Saileta Prabhu from Genentech Inc. in reviewing the work. The authors thank In Vivo Studies Group at Genentech for conducting the mouse and rat PK study, Derek Kennedy for coordinating the monkey studies, and Rashell Kinard for bioanalytic contributions. We would like to extend our thanks to Drs Christina de Zafra, Rodney Prell, Gary Cain, Ryan Watts, and Y. Gloria Meng for their contribution to the program.

Authors are employees at Genentech/Roche and hold Roche stocks.

Author information

Authors and Affiliations

  1. Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, USA

    Yan Xin, Shuang Bai, Denise Jin, Frank-Peter Theil, Amita Joshi & Hong Xiang

  2. Portfolio Management and Operations, Genentech, Inc., 1 DNA Way, South San Francisco, California, USA

    Lisa A. Damico-Beyer

  3. Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California, USA

    Wei-Ching Liang & Yan Wu

  4. Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, California, USA

    Yanmei Lu

  5. Department of Bioanalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, USA

    John Lowe & Mauricio Maia

  6. Oncology Exploratory Clinical Development, Genentech, Inc., 1 DNA Way, South San Francisco, California, USA

    Rainer K. Brachmann

  7. Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., 1 DNA Way, MS 46-3A, South San Francisco, California, 94080, USA

    Hong Xiang

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  1. Yan Xin
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Corresponding author

Correspondence to Hong Xiang.

Electronic Supplementary Material

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ESM 1

Goodness-of-fit model evaluation for mouse, rat, monkey, and human PK fittings. The open blue circles are observed concentrations. The black solid lines are lines of unity. The red solid lines are lines of linear regression. DV: dependent variable; PRED: population prediction from NONMEM analysis; IPRED; individual prediction from NONMEM analysis; WRES: weighted residuals for population in NONMEM analysis. (PPT 300 kb)

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Xin, Y., Bai, S., Damico-Beyer, L.A. et al. Anti-Neuropilin-1 (MNRP1685A): Unexpected Pharmacokinetic Differences Across Species, from Preclinical Models to Humans. Pharm Res 29, 2512–2521 (2012). https://doi.org/10.1007/s11095-012-0781-x

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  • DOI: https://doi.org/10.1007/s11095-012-0781-x

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