Balancing the Affinity and Pharmacokinetics of Antibodies by Modulating the Size of Charge Patches on Complementarity-Determining Regions

Cai, Hao; Hu, Zhilan; Boswell, C. Andrew; Diao, Jinpian; Li, Charlene; Zhang, Liangyi; Shen, Amy; Teske, Christopher A.; Zhang, Boyan; Kamath, Amrita V.; Jiang, Guoying

doi:10.1016/j.xphs.2020.09.003

Cited by 5 publications

(2 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Disrupting positive charge patches on complementarity-determining regions (CDRs) of an antibody without altering pI could improve its plasma exposure. 13 , 14 Generally speaking, the relationships between clearance and antibody charge have been reported to be monotonic, bell-shaped, or uncorrelated, using various metrics for charge and charge distribution. One caveat of these studies is that only one or two variants derived from each parental antibody were used for PK comparison, making it challenging to demonstrate a continuous quantitative structure-pharmacokinetic relationship (QSPKR) over a wide range of antibody charge.…”

Section: Introductionmentioning

confidence: 99%

Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies

Liu

Verma

Kettenberger

et al. 2021

mAbs

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies

Liu

Verma

Kettenberger

et al. 2021

mAbs

View full text Add to dashboard Cite

“… 66 The results from the current study are consistent with the latter. Other reports have demonstrated that disrupting surface charge distribution without changing pI may also alter a mAb’s plasma exposure, 71 , 72 or that reducing pI whilst more evenly distributing surface charge can significantly reduce clearance. 73 Positive charges on the mAb surface may interact with the negatively charged cell membrane leading to higher nonspecific tissue uptake.…”

Section: Discussionmentioning

confidence: 99%

Development of in silico models to predict viscosity and mouse clearance using a comprehensive analytical data set collected on 83 scaffold-consistent monoclonal antibodies

Mock,

Jacobitz,

Langmead

et al. 2023

mAbs

View full text Add to dashboard Cite

Biologic drug discovery pipelines are designed to deliver protein therapeutics that have exquisite functional potency and selectivity while also manifesting biophysical characteristics suitable for manufacturing, storage, and convenient administration to patients. The ability to use computational methods to predict biophysical properties from protein sequence, potentially in combination with high throughput assays, could decrease timelines and increase the success rates for therapeutic developability engineering by eliminating lengthy and expensive cycles of recombinant protein production and testing. To support development of high-quality predictive models for antibody developability, we designed a sequence-diverse panel of 83 effector functionless IgG1 antibodies displaying a range of biophysical properties, produced and formulated each protein under standard platform conditions, and collected a comprehensive package of analytical data, including in vitro assays and in vivo mouse pharmacokinetics. We used this robust training data set to build machine learning classifier models that can predict complex protein behavior from these data and features derived from predicted and/or experimental structures. Our models predict with 87% accuracy whether viscosity at 150 mg/mL is above or below a threshold of 15 centipoise (cP) and with 75% accuracy whether the area under the plasma drug concentration–time curve (AUC 0–672 h ) in normal mouse is above or below a threshold of 3.9 × 10 6 h x ng/mL.

show abstract

Model-Based Assessment of the Contribution of Monocytes and Macrophages to the Pharmacokinetics of Monoclonal Antibodies

2022

View full text Add to dashboard Cite

Balancing the Affinity and Pharmacokinetics of Antibodies by Modulating the Size of Charge Patches on Complementarity-Determining Regions

Cited by 5 publications

References 36 publications

Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies

Effect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies

Development of in silico models to predict viscosity and mouse clearance using a comprehensive analytical data set collected on 83 scaffold-consistent monoclonal antibodies

Model-Based Assessment of the Contribution of Monocytes and Macrophages to the Pharmacokinetics of Monoclonal Antibodies

Contact Info

Product

Resources

About