Evidence map›Paper›PMID 27299941›Full record

ArticleCPT: pharmacometrics & systems pharmacology2016

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

J S Kanodia, K Gadkar, D Bumbaca, Y Zhang, R K Tong, W Luk, K Hoyte, Y Lu, K R Wildsmith, J A Couch and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in CPT: pharmacometrics & systems pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

17 citing papers in PubMed.

  1. Article
  2. Article
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  5. Article
  6. Review
  7. Article
  8. Review
  9. Review
  10. Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood-brain barrier.Proceedings of the National Academy of Sciences of the United States of America · 2020
    Article
  11. A translational platform PBPK model for antibody disposition in the brain.Journal of pharmacokinetics and pharmacodynamics · 2019
    Article
  12. Review
  13. Review
  14. Nanotherapeutics for Gene Modulation that Prevents Apoptosis in the Brain and Fatal Neuroinflammation.Molecular therapy : the journal of the American Society of Gene Therapy · 2018
    Article
  15. Review
  16. Review
  17. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

J S KanodiaPreclinical and Translational Pharmacokinetics Department, Genentech, South San Francisco, California, USA.
K GadkarPreclinical and Translational Pharmacokinetics Department, Genentech, South San Francisco, California, USA.
D BumbacaPreclinical and Translational Pharmacokinetics Department, Genentech, South San Francisco, California, USA.
Y ZhangAntibody Engineering Department, Genentech, South San Francisco, California, USA.
R K TongProtein Sciences, Genentech, South San Francisco, California, USA.
W LukBiochemical and Cellular Pharmacology, Genentech, South San Francisco, California, USA.
K HoyteBiochemical and Cellular Pharmacology, Genentech, South San Francisco, California, USA.
Y LuBiochemical and Cellular Pharmacology, Genentech, South San Francisco, California, USA.
K R WildsmithBiomarker Development, Genentech, South San Francisco, California, USA.
J A CouchSafety Assessment, Genentech, South San Francisco, California, USA.
R J WattsDepartment of Neuroscience, Genentech, South San Francisco, California, USA.
M S DennisAntibody Engineering Department, Genentech, South San Francisco, California, USA.
J A ErnstProtein Sciences, Genentech, South San Francisco, California, USA.
K Scearce-LevieDepartment of Neuroscience, Genentech, South San Francisco, California, USA.
J K AtwalDepartment of Neuroscience, Genentech, South San Francisco, California, USA.
S RamanujanPreclinical and Translational Pharmacokinetics Department, Genentech, South San Francisco, California, USA.
S JosephPreclinical and Translational Pharmacokinetics Department, Genentech, South San Francisco, California, USA.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

Drug DesignAnimalsAntibodies, BispecificBlood-Brain BarrierBrainDrug Delivery SystemsHumansMacaca fascicularisProspective StudiesReceptors, TransferrinAntibodies, BispecificReceptors, Transferrin

Identifiers

PMID27299941
PMCPMC4879477

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LicenceCC BY-NC-ND
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.