Anti-neuropilin-1 (MNRP1685A): unexpected pharmacokinetic differences across species, from preclinical models to humans.
OBJECTIVE
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.
Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, USA.
Yan
Y
Xin
Shuang
S
Bai
Lisa A
LA
Damico-Beyer
Denise
D
Jin
Wei-Ching
WC
Liang
Yan
Y
Wu
Frank-Peter
FP
Theil
Amita
A
Joshi
Yanmei
Y
Lu
John
J
Lowe
Mauricio
M
Maia
Rainer K
RK
Brachmann
Hong
H
Xiang
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D006801:Humans; D008954:Models, Biological; D039942:Neuropilin-1 / Q000276:immunology*; D013045:Species Specificity
D000911:Antibodies, Monoclonal; D039942:Neuropilin-1; C574067:vesencumab