Mathematical PKPD and safety model of bispecific TfR/BACE1 antibodies for the optimization of antibody uptake in brain
Abstract
Treatment of diseases of the central nervous system by monoclonal antibodies may be limited by the restricted uptake of antibodies across the blood-brain barrier (BBB). An antibody targeting transferrin receptor (TfR) has been shown to take advantage of the receptor-mediated transcytosis properties of TfR in order to cross the BBB in mice, with the uptake in the brain being dependent on the affinity to TfR. In the bispecific format with arms targeting both TfR and β-secretase 1 (BACE1), altering the affinity to TfR has been shown to impact systemic exposure and safety profiles. In this work, a mathematical model incorporating pharmacokinetic/pharmacodynamic (PKPD) and safety profiles is developed for bispecific TfR/BACE1 antibodies with a range of affinities to TfR in order to guide candidate selection. The model captures the dependence of both systemic and brain exposure on TfR affinity and the subsequent impact on brain Aβ40 lowering and circulating reticulocyte levels. Model simulations identify the optimal affinity for the TfR arm of the bispecific to maximize Aβ reduction while maintaining reticulocyte levels. The model serves as a useful tool to prioritize and optimize preclinical studies and has been used to support the selection of additional candidates for further development.
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Gadkar et al. built a PK/PD model using data from bsAbs with a range of affinities that captured the dependence of both systemic and brain exposure on TfR affinity and the subsequent impact on efficacy and safety.
“Gadkar et al. built a PK/PD model using data from bsAbs with a range of affinities that captured the dependence of both systemic and brain exposure on TfR affinity and the subsequent impact on efficacy and safety.87”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [87]
One of the most active areas of bsAbs application is in the field of cancer immunotherapy.
“One of the most active areas of bsAbs application is in the field of cancer immunotherapy.85, 86, 87”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [87]
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- Authors
- Gadkar, K., Yadav, D. B., Zuchero, J. Y., Couch, J. A., Kanodia, J., Kenrick, M. K., Atwal, J. K., Dennis, M. S., Prabhu, S., Watts, R. J., Joseph, S. B., & Ramanujan, S.
- Affiliations
- Genentech (US)
- Corresponding author
- Ramanujan, Saroja
- ORCID
- Venue
- European Journal of Pharmaceutics and Biopharmaceutics
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 101
- Pages
- 53-61
- ISSN
- 0939-6411 (ISSN-L)
- OpenAlex
- W2252006103
- Cited by
- 52
- References
- 19
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2023: 9 · 2022: 9 · 2021: 5 · 2020: 3 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 4 · 2015: 1
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmaceutics and Biopharmaceutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- bispecific antibodies, transferrin receptor, BACE1, blood-brain barrier penetration, receptor-mediated transcytosis, pharmacokinetic-pharmacodynamic modeling, safety modeling, brain drug delivery
- MeSH terms
- Animals, Antibodies, Monoclonal, Biological Transport, Blood-Brain Barrier, Brain, Models, Theoretical, Receptors, Transferrin, Reticulocytes, Transferrin, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Antibodies, Bispecific, Mice, Amyloid Precursor Protein Secretases, Transcytosis
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