Flavie Audy 1, Maud Hennion 1, Thomas Wagner 2, Jannie Ausma 3, Ronald Brempt 3, Katleen Swinnen 3, Carole Guillonneau 3, Elisabeth Rouits 1
1 Cencora Pharmalex (, Belgium), 2 ThinkQ2 (, ), 3 Aboleris (, )
Objectives:
ABO21009 is a humanized IgG1 monoclonal antibody targeting human CD45RC, currently developed for the treatment of rheumatoid arthritis.
The pharmacokinetic (PK) of ABO21009 was investigated in a preclinical study in Balb/c mice. Due to limited amino acid sequence homology between the murine and human extracellular domains of CD45RC, ABO21009 did not bind to mouse T cells. In contrast, the binding of ABO21009 to CD45RC in humans is expected to alter its distribution and elimination through TMDD.
This absence of target binding in mice presented a significant challenge to obtain extrapolated data in humans, where target binding dynamics and their influence on drug disposition had to be anticipated.
Methods:
ABO21009 plasma concentrations were obtained in Balb/c mice after single dose of 1 mg/kg and 10 mg/kg. PK profiles were adequately described by a two-compartmental model with linear elimination (Phoenix WinNonin™). Some humanized PK parameters were then derived from this murine model using simple allometric scaling approach.
Based on the binding pattern of ABO21009, it is expected that the distribution and disposition of ABO21009 can be effectively described using a TMDD mechanism. This TMDD mechanism was structured to include three distinct target compartments [1], reflecting the main sites of CD45RC cells expression: blood, lymph nodes and spleen.
Parameters required for the TMDD component were sourced from a combination of in-house data, in vitro experiments and literature related to the target [2-4]. It was assumed that the antibody-receptor binding and the dynamics of the receptor and complex are the same in all three target sites.
Results:
The humanized PK model consisted in a set of linear PK parameters and non-linear PK parameters. The linear PK parameters were derived from the murine PK model by simple allometric scaling. The non-linear part of the model consisted in TMDD parameters quantifying antibody-receptor binding affinity, the target levels for the three target sites (blood, lymph nodes and spleen) the synthesis and degradation rate for the receptor and the internalization rate of the complex. Consequently, PK profiles in humans were simulated using NONMEM based on this translational semi-mechanistic TMDD approach.
To avoid over-parameterization, a simplified model comprising a single TMDD compartment was also developed. This approach helps to balance model complexity with the available data, potentially improving the robustness of the PK predictions.
Conclusions:
This methodology provides a robust framework for extrapolating murine PK data to human predictions, while accurately accounting for the anticipated binding patterns in humans. This approach enables more reliable predictions of drug disposition in human, bridging the gap between preclinical animal studies and human clinical trials.
The limited amino acid sequence homology with the human extracellular domains of CD45RC is not exclusive to mice but extends to all conventional toxicology species (mice, rats, dogs, monkeys). In the absence of a relevant species, the selection of the FIH dose for ABO21009 should be based on the Minimal Anticipated Biological Effect Level (MABEL) approach, using this humanized model and leveraging with in vitro/in vivo efficacy data and in vitro safety data.
References:
[1] A Tutorial on Target-Mediated Drug Disposition (TMDD) Models. Dua et al., CPT Pharmacometrics Syst Pharmacolo, 2015
[2] Population pharmacokinetics of therapeutic monoclonal antibodies. Dirks & Meibohm, Clin Pharmacokinet, 2010
[3] Target-mediated drug disposition model for drugs that bind to more than one target. Gibiansky & Gibiansky, J Pharmacokinet Pharmacodyn, 2010
[4] Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human. Shah & Betts, J Pharmacokinet Pharmacodyn, 2012
Reference: PAGE 34 (2026) Abstr 12267 [www.page-meeting.org/?abstract=12267]
Poster: Drug/Disease Modelling - Other Topics