Gregory Z. Ferl, Reina N. Fuji, Jasvinder Atwal, Jitendra Kanodia, Lee Honigberg, Saroja Ramanujan, Angelica L. Quartino
Genentech, Inc. 1 DNA Way, South San Francisco, CA, USA.
Objectives: Our goal was to develop a mechanistic mathematical model capable of predicting neutralization of multiple Aβ species in the brain, cerebrospinal fluid (CSF) and plasma during the course of Alzheimer’s disease therapy with anti-Aβ monoclonal antibodies (mAbs) that possess varying PK/PD properties.
Methods: We utilized physiological and biochemical values from the literature and internal experiments and studies, including in vitro Crenezumab Biacore affinity data (Kd=5 nM for monomeric Aβ, 0.5 nM for oligomeric Aβ), to develop a model structure and estimate values for model parameters. Within the model structure we include mechanisms that describe mAb binding to soluble and insoluble Aβ species, efflux rates of Aβ and the mAb-Aβ complex from brain to CSF, degradation rates of Aβ and the mAb-Aβ complex within the brain and transport of Aβ across the blood brain barrier. Specifically, we consider scenarios in which the soluble Aβ pool is entirely composed of monomeric Aβ and scenarios in which the soluble Aβ pool is entirely composed of oligomeric Aβ and the impact that binding to insoluble Aβ may have on binding kinetics to each soluble species. Results generated under these scenarios are supported by further extending the model to dynamically simulate the interconversion of soluble monomeric and oligomeric Aβ species. The model is evaluated by its ability to recapitulate the observed plasma PK/PD data from Solanezumab [1] and Crenezumab [2] clinical studies.
Results: The model was able to describe the observed plasma PK/PD data following estimation of the baseline plasma Aβ, plasma Aβ clearance, PK and Kd parameters. The estimated in vivo mAb/Aβ binding affinity for Crenezumab is consistent with the in vitro Kd value (5.7 vs. 5 nM). The impact on the neutralization of soluble Aβ in brain given the affinity of the mAb to insoluble Aβ pool is also demonstrated, where, during the first ~12 months of treatment, the insoluble Aβ pool acts as a significant sink for mAb at affinities significantly greater than 5 nM.
Conclusions: Our model generated predictions that yield insight into neutralization of soluble and insoluble Aβ species in brain during anti-Aβ mAb therapy. We also developed hypotheses regarding mechanisms such as the potentially significant impact of mAb binding to insoluble Aβ pools in the brain on overall mAb/Aβ dynamics.
References:
[1] Uenaka, K. et al. Clin Neuropharmacology 2012.
[2] Boxer, AL. et al. Alzheimer’s & Dementia 2010.
Reference: PAGE 25 (2016) Abstr 5737 [www.page-meeting.org/?abstract=5737]
Poster: Drug/Disease modeling - CNS