Ellis, M. | Search bioRxiv

bioRxiv2018

Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems

Guiding the dose selection for monoclonal antibody oncology drugs is often done using methods for predicting the receptor occupancy of the drug in the tumor. In this manuscript, previous work on characterizing target inhibition at steady state using the AFIR metric [1] is extended to include a \"target-tissue\" compartment and the shedding of membrane-bound targets. A new potency metric AFTIR (Averarge Free Tissue target to Initial target ratio at steady state) is derived, and it depends on only four key quantities: the equilibrium binding constant, the fold-change in target expression at steady state after binding to drug, the biodistribution of target from circulation to target tissue, and the average drug concentration in circulation. The AFTIR metric is useful for guiding dose selection, for efficiently performing sensitivity analyses, and for building intuition for more complex target mediated drug disposition models. In particular, reducing the complex, physiological model to four key parameters needed to predict target inhibition helps to highlight specific parameters that are the most important to estimate in future experiments to guide drug development.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC=\"FIGDIR/small/432500_fig1.gif\" ALT=\"Figure 1\">\nView larger version (30K):\norg.highwire.dtl.DTLVardef@6895d7org.highwire.dtl.DTLVardef@4566e0org.highwire.dtl.DTLVardef@6515e8org.highwire.dtl.DTLVardef@8168ea_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 1C_FLOATNO Graphical Abstract\n\nC_FIG

pharmacology and toxicology↗

bioRxiv2018

LRRK2 kinase inhibitors induce a reversible effect in the lungs of non-human primates with no measurable pulmonary deficits

Putative gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2), resulting in increased kinase activity and cellular toxicity, are a leading genetic cause of Parkinsons disease (PD). Hence, there is strong interest in developing LRRK2 kinase inhibitors as a disease-modifying therapy. Published reports that repeat dosing with two LRRK2 kinase inhibitors (GNE-7915 and GNE-0877) induce histopathological changes in the lung of non-human primates Fuji et al. 2015 (1) raised concerns about potential safety liability of LRRK2 kinase inhibitors. In the present study, we sought to determine whether previously observed effects in the lung: (a) represent on-target pharmacology, but with the potential for margin of safety, (b) are reversible upon drug withdrawal, and (c) are associated with pulmonary function deficits. To this end, we evaluated the histopathological effects, toxicokinetics and target inhibition of three structurally diverse LRRK2 kinase inhibitors, GNE-7915 (30 mg/kg, BID, as a positive control), MLi-2 (15 and 50 mg/kg, QD) and PFE-360 (3 and 6 mg/kg, QD) following 2 weeks of dosing in non-human primates. Subsets of animals dosed with GNE-7915 or MLi-2 were evaluated after 2-week dose-free periods. All three LRRK2 kinase inhibitors induced mild cytoplasmic vacuolation of type II pneumocytes, as reported previously, confirming an on-target effect of these compounds. Interestingly, despite lower doses of both PFE-360 and MLi-2 producing nearly complete inhibition of LRRK2 kinase activity in the brain as assessed by levels of pS935-LRRK2, histopathological changes in lung were absent in animals treated with low-dose PFE-360 and observed only sporadically in the low-dose MLi-2 group. The lung effect was fully reversible at 2 weeks post-dosing of GNE-7915. In a second study of identical dosing with MLi-2 and GNE-7915, no deficits were observed in a battery of translational pulmonary functional tests. In aggregate, these results do not preclude the development of LRRK2 kinase inhibitors for clinical investigation in Parkinsons disease.

pharmacology and toxicology↗