PI-033 - A MECHANISTIC PK/PD MODEL OF AZD0171 (ANTI-LIF) TO SUPPORT PHASE 2 DOSE SELECTION.

A. Shahraz¹, H. Liu¹, F. Hua², O. Ojo³, C. Stovold³, N. Luheshi³, A. Phipps³, K. Vishwanathan¹; ¹AstraZeneca, Waltham, MA, USA, ²Applied Biomath, Concord, MA, USA, ³AstraZeneca, Cambridge, United Kingdom.

Background: AZD0171 is a first -in-class humanized monoclonal antibody, which binds to the human cytokine leukemia inhibitory factor (LIF), promoting immune-mediated antitumor activity through tumor-associated macrophages (TAMs) modulation and inhibition of cancer stem cells [1]. In this study, the effect of AZD0171 on tumor LIF levels was investigated using a mechanistic PK/PD model.

Methods: A mechanistic population PK/PD model was developed in MATLAB SimBiology by incorporating the interactions between AZD0171 and its soluble target (LIF) as well as LIF binding to its membrane receptors: LIF receptor (LIFR) and glycoprotein 130 (gp130). The model includes 3-compartments: central, tissue and tumor with mechanistic tumor disposition using the Krogh model [2]. Free LIF, and trimeric signaling receptor complex LIF: LIFR:gp130 levels were simulated to assess receptor occupancy and dose-response relationship. Clearance of the drug from central (CL), volumes of central (Vc) and tissue compartment (Vt), synthesis rate of LIF in tumor (Ksyn), steady-state LIFR (LIFRss), and intercompartmental clearance (Q) were estimated by fitting to PK and total LIF data from the Phase 1 study.

Results: The goodness of fit plots show that the model describes both PK of AZD0171 and total LIF level well. The population value for Vc, Vt, CL, Ksyn, LIFR, Q are 4.5 L, 2.8 L, 12.6 mL/h, 5.7 pmol/hr, 9.3 nM, and 75 mL/hr, respectively. Modeling results show that tumor LIF is inhibited in a dose-response manner with >90% inhibition for population at the 1500 mg Q2W dose.

Conclusion: A mechanistic PK/PD model was developed to describe inhibition of LIF pathway by AZD0171 and inform recommended phase 2 dose and schedule.

1) Christianson, J. et al. Emerging Perspectives on Leukemia Inhibitory Factor and its Receptor in Cancer. Front Oncol. 11 (2021)
2) Bench to bedside translation of antibody drug conjugates using a multiscale mechanistic PK/PD model: a case study
with brentuximab-vedotin. J Pharmacokinet Pharmacodyn. 39, 643–659 (2012)