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

Abstract

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.

Population pharmacokinetic and pharmacodynamic modeling of MNRP1685A in cynomolgus monkeys using two-target quasi-steady-state (QSS) model

“…The estimated nonspecific CL was 3.26 mL/day/kg in the current PKPD analysis. This is consistent with the CL value (3.22 mL/ day/kg) estimated in the previous PK analysis [9], where only the kinetics of MNRP1685A was described using a two-compartment model comprised of parallel linear and nonlinear (approximated by a Michaelis-Menten equation) clearance pathways. The V 1 is also similar from either PKPD (38.2 mL/kg) or PK (37.8 mL/kg) analysis.…”

“…Consistent with the wide expression pattern of NRP1, MNRP1685A showed strong target-mediated nonlinear pharmacokinetics (PK) across a wide dose range in preclinical species including mice, rats, and monkeys [9]. The total cNRP1 was reported to increase in a dose-dependent manner following an anti-NRP1 antibody administration in these species [3].…”

Immunoglobulin Fc-fused, neuropilin-1-specific peptide shows efficient tumor tissue penetration and inhibits tumor growth via anti-angiogenesis

“…During the initial phase, 125 I-Fc-TPP11 showed slightly faster whole body clearance rate (T 1/2 α = 9.0 ± 0.9 h) than 125 I-Fc (T 1/2 α = 11.1 ± 1.4 h) (Fig. 4A), most likely due to additional degradation after NRP1-mediated intracellular internalization, as has been observed for a human anti-NRP1 mAb [40]. However, in the serum elimination phase, 125 IFc-TPP11 showed a prolonged half-life (T 1/2 β = 66.3 ± 14.5 h) comparable to that of the parent 125 I-Fc (T 1/2 β = 56.4 ± 15.5 h) (Fig.…”

Antibody–Drug Conjugates as Cancer Therapeutics: Past, Present, and Future

“…However, in vivo studies used to assess ADCs in these organs are also limited, as the PK of ADCs can be species dependent. 39 Notwithstanding the complexities discussed above, the accepted consensus based on previous ADC experience is that the most useful parameters and information about E-R relationships can be derived by analysis of the ADC, total antibody, and/or unconjugated payload. 25,37 However, total antibody is typically analyzed in early clinical trials (for example, FIH) and subsequently dropped in later clinical studies because of strong correlation with ADC.…”