Evidence map›Paper›PMID 27287046›Full record

ArticleThe AAPS journal2016

Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy.

Cornelius Cilliers, Hans Guo, Jianshan Liao, Nikolas Christodolu, Greg M Thurber

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In one paragraph

Article in The AAPS journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
79citing papers in PubMed, 1 pooled it
–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

79 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Review
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  4. Antibody-drug conjugate engineering: from design to efficacy and safety.Signal transduction and targeted therapy · 2026
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19 more citing papers are in PubMed but not listed here.

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

5 authors.

Cornelius CilliersDepartment of Chemical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, Michigan, 48109, USA.
Hans GuoDepartment of Chemical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, Michigan, 48109, USA.
Jianshan LiaoDepartment of Chemical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, Michigan, 48109, USA.
Nikolas ChristodoluDepartment of Chemical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, Michigan, 48109, USA.
Greg M ThurberDepartment of Chemical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, Michigan, 48109, USA. gthurber@umich.edu.

Funding

XenograftP30CA046592 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI THEODORE S LAWRENCE · 1988 to 2026
$178.2M
NCI NIH HHS P30 CA046592
6 · The paper itself

Abstract

Antibody-drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from nonspecific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody-drug conjugate Kadcyla in HER2-positive mouse xenografts. This model is able to capture the impact of the drug-antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs.

Indexed as

Models, TheoreticalAdo-Trastuzumab EmtansineAnimalsAntibodies, Monoclonal, HumanizedAntineoplastic AgentsCell Line, TumorDose-Response Relationship, DrugImmunotoxinsMaytansineMiceMice, NudeTissue DistributionTrastuzumabTreatment OutcomeTumor BurdenXenograft Model Antitumor AssaysAdo-Trastuzumab EmtansineAntibodies, Monoclonal, HumanizedAntineoplastic AgentsImmunotoxinsMaytansineTrastuzumabado-trastuzumab emtansineantibody tissue penetrationdrug-antibody ratio (DAR)HerceptinKadcylaKrogh cylinder

Identifiers

PMID27287046
PMCPMC4996726

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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.