Anti-neuropilin-1 (MNRP1685A): unexpected pharmacokinetic differences across species, from preclinical models to humans.

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.

• Authors: Yan Xin, Shuang Bai, Lisa A Damico-Beyer, Denise Jin, Wei-Ching Liang, Yan Wu, Frank-Peter Theil, Amita Joshi, Yanmei Lu, John Lowe, Mauricio Maia, Rainer K Brachmann, Hong Xiang
• Journal: Pharmaceutical research (Pharm Res) Vol. 29 Issue 9 Pg. 2512-21 (Sep 2012) ISSN: 1573-904X [Electronic] United States
• PMID: 22707361 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Neuropilin-1
• vesencumab

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacokinetics)
• Humans
• Models, Biological
• Neuropilin-1 (immunology)
• Species Specificity