Mathematical PKPD and safety model of bispecific TfR/BACE1 antibodies for the optimization of antibody uptake in brain

Gadkar, Kapil; Yadav, Daniela Bumbaca; Zuchero, Joy Yu; Couch, Jessica A.; Kanodia, Jitendra; Kenrick, Margaret; Atwal, Jasvinder K.; Dennis, Mark S.; Prabhu, Saileta; Watts, Ryan J.; Joseph, Sean B.; Ramanujan, Saroja

doi:10.1016/j.ejpb.2016.01.009

Cited by 41 publications

(43 citation statements)

References 17 publications

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“…One of the most active areas of bsAbs application is in the field of cancer immunotherapy . Cancer immunotherapy works by unleashing the body's own immune system to eliminate or control cancer.…”

Section: Next‐generation Antibody‐based Therapeutics and Their Uniquementioning

confidence: 99%

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Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

Ovacik¹,

Lin

2018

Clinical Translational Sci

198

154

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The tutorial introduces the readers to the fundamentals of antibody pharmacokinetics (PK) in the context of drug development. Topics covered include an overview of antibody development, PK characteristics, and the application of antibody PK/pharmacodynamics (PD) in research and development decision‐making. We also discuss the general considerations for planning a nonclinical PK program and describe the types of PK studies that should be performed during early development of monoclonal antibodies.

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Section: Next‐generation Antibody‐based Therapeutics and Their Uniquementioning

confidence: 99%

“…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 …”

Section: Next‐generation Antibody‐based Therapeutics and Their Uniquementioning

confidence: 99%

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

Ovacik¹,

Lin

2018

Clinical Translational Sci

198

154

View full text Add to dashboard Cite

show abstract

“…A new bispecific antibody with the same anti‐TfR1 arm and a higher affinity anti‐BACE1 arm (anti‐nBACE1) with four‐times greater potency against BACE1 than the original anti‐TfR/BACE1 was generated . The two anti‐TfR1 antibodies exhibited the same plasma PK, supporting the assumption that binding to TfR is the major driver for target‐mediated clearance and that binding to BACE1 does not have a measurable impact.…”

Section: Resultsmentioning

confidence: 70%

“…Gadkar et al . previously presented a PK‐PD model for the behavior of murine anti‐TfR bispecifics in mice to address the complex systemic and brain PK‐PD relationships observed.…”

Section: Discussionmentioning

confidence: 99%

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Prospective Design of Anti‐Transferrin Receptor Bispecific Antibodies for Optimal Delivery into the Human Brain

Kanodia

Gadkar

Bumbaca

et al. 2016

CPT Pharmacom & Syst Pharma

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Anti‐transferrin receptor (TfR)‐based bispecific antibodies have shown promise for boosting antibody uptake in the brain. Nevertheless, there are limited data on the molecular properties, including affinity required for successful development of TfR‐based therapeutics. A complex nonmonotonic relationship exists between affinity of the anti‐TfR arm and brain uptake at therapeutically relevant doses. However, the quantitative nature of this relationship and its translatability to humans is heretofore unexplored. Therefore, we developed a mechanistic pharmacokinetic‐pharmacodynamic (PK‐PD) model for bispecific anti‐TfR/BACE1 antibodies that accounts for antibody‐TfR interactions at the blood‐brain barrier (BBB) as well as the pharmacodynamic (PD) effect of anti‐BACE1 arm. The calibrated model correctly predicted the optimal anti‐TfR affinity required to maximize brain exposure of therapeutic antibodies in the cynomolgus monkey and was scaled to predict the optimal affinity of anti‐TfR bispecifics in humans. Thus, this model provides a framework for testing critical translational predictions for anti‐TfR bispecific antibodies, including choice of candidate molecule for clinical development.

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Approaches Towards Prediction of CNS PK and PD

Lange

Chang

Shah

2022

Drug Delivery to the Brain

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Mathematical PKPD and safety model of bispecific TfR/BACE1 antibodies for the optimization of antibody uptake in brain

Cited by 41 publications

References 17 publications

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

Prospective Design of Anti‐Transferrin Receptor Bispecific Antibodies for Optimal Delivery into the Human Brain

Approaches Towards Prediction of CNS PK and PD

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