A Systems Pharmacology Model for Drug Delivery to Solid Tumors by Antibody-Drug Conjugates: Implications for Bystander Effects

Jackson K. Burton, Dean Bottino, Timothy W. Secomb

Research output: Contribution to journalArticle

Abstract

Antibody-drug conjugates (ADCs) are cancer drugs composed of a humanized antibody linked to a cytotoxic payload, allowing preferential release of payload in cancer cells expressing the antibody-targeted antigen. Here, a systems pharmacology model is used to simulate ADC transport from blood to tumor tissue and ADC uptake by tumor cells. The model includes effects of spatial gradients in drug concentration in a three-dimensional network of tumor blood vessels with realistic geometry and accounts for diffusion of ADC in the tumor extracellular space, binding to antigen, internalization, intracellular processing, and payload efflux from cells. Cells that process an internalized ADC-antigen complex may release payload that can be taken up by other “bystander” cells. Such bystander effects are included in the model. The model is used to simulate conditions in previous experiments, showing good agreement with experimental results. Simulations are used to analyze the relationship of bystander effects to payload properties and single-dose administrations. The model indicates that exposure of payload to cells distant from vessels is sensitive to the free payload diffusivity in the extracellular space. When antigen expression is heterogeneous, the model indicates that the amount of payload accumulating in non-antigen-expressing cells increases linearly with dose but depends only weakly on the percentage of antigen-expressing cells. The model provides an integrated mechanistic framework for understanding the effects of spatial gradients on drug distribution using ADCs and for designing ADCs to achieve more effective payload distribution in solid tumors, thereby increasing the therapeutic index of the ADC.

Original languageEnglish (US)
Article number12
JournalAAPS Journal
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2020

Fingerprint

Bystander Effect
Neoplasm Antibodies
Pharmacology
Pharmaceutical Preparations
Antibodies
Antigens
Extracellular Space
Neoplasms
Vascular Tissue Neoplasms
Antibodies, Monoclonal, Humanized

Keywords

  • capillaries
  • diffusion
  • drug transport
  • mathematical model
  • vascular permeability

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

A Systems Pharmacology Model for Drug Delivery to Solid Tumors by Antibody-Drug Conjugates : Implications for Bystander Effects. / Burton, Jackson K.; Bottino, Dean; Secomb, Timothy W.

In: AAPS Journal, Vol. 22, No. 1, 12, 01.01.2020.

Research output: Contribution to journalArticle

@article{90979bd588464710b9379d930e9b1bcd,
title = "A Systems Pharmacology Model for Drug Delivery to Solid Tumors by Antibody-Drug Conjugates: Implications for Bystander Effects",
abstract = "Antibody-drug conjugates (ADCs) are cancer drugs composed of a humanized antibody linked to a cytotoxic payload, allowing preferential release of payload in cancer cells expressing the antibody-targeted antigen. Here, a systems pharmacology model is used to simulate ADC transport from blood to tumor tissue and ADC uptake by tumor cells. The model includes effects of spatial gradients in drug concentration in a three-dimensional network of tumor blood vessels with realistic geometry and accounts for diffusion of ADC in the tumor extracellular space, binding to antigen, internalization, intracellular processing, and payload efflux from cells. Cells that process an internalized ADC-antigen complex may release payload that can be taken up by other “bystander” cells. Such bystander effects are included in the model. The model is used to simulate conditions in previous experiments, showing good agreement with experimental results. Simulations are used to analyze the relationship of bystander effects to payload properties and single-dose administrations. The model indicates that exposure of payload to cells distant from vessels is sensitive to the free payload diffusivity in the extracellular space. When antigen expression is heterogeneous, the model indicates that the amount of payload accumulating in non-antigen-expressing cells increases linearly with dose but depends only weakly on the percentage of antigen-expressing cells. The model provides an integrated mechanistic framework for understanding the effects of spatial gradients on drug distribution using ADCs and for designing ADCs to achieve more effective payload distribution in solid tumors, thereby increasing the therapeutic index of the ADC.",
keywords = "capillaries, diffusion, drug transport, mathematical model, vascular permeability",
author = "Burton, {Jackson K.} and Dean Bottino and Secomb, {Timothy W.}",
year = "2020",
month = "1",
day = "1",
doi = "10.1208/s12248-019-0390-2",
language = "English (US)",
volume = "22",
journal = "AAPS Journal",
issn = "1550-7416",
publisher = "Springer New York",
number = "1",

}

TY - JOUR

T1 - A Systems Pharmacology Model for Drug Delivery to Solid Tumors by Antibody-Drug Conjugates

T2 - Implications for Bystander Effects

AU - Burton, Jackson K.

AU - Bottino, Dean

AU - Secomb, Timothy W.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - Antibody-drug conjugates (ADCs) are cancer drugs composed of a humanized antibody linked to a cytotoxic payload, allowing preferential release of payload in cancer cells expressing the antibody-targeted antigen. Here, a systems pharmacology model is used to simulate ADC transport from blood to tumor tissue and ADC uptake by tumor cells. The model includes effects of spatial gradients in drug concentration in a three-dimensional network of tumor blood vessels with realistic geometry and accounts for diffusion of ADC in the tumor extracellular space, binding to antigen, internalization, intracellular processing, and payload efflux from cells. Cells that process an internalized ADC-antigen complex may release payload that can be taken up by other “bystander” cells. Such bystander effects are included in the model. The model is used to simulate conditions in previous experiments, showing good agreement with experimental results. Simulations are used to analyze the relationship of bystander effects to payload properties and single-dose administrations. The model indicates that exposure of payload to cells distant from vessels is sensitive to the free payload diffusivity in the extracellular space. When antigen expression is heterogeneous, the model indicates that the amount of payload accumulating in non-antigen-expressing cells increases linearly with dose but depends only weakly on the percentage of antigen-expressing cells. The model provides an integrated mechanistic framework for understanding the effects of spatial gradients on drug distribution using ADCs and for designing ADCs to achieve more effective payload distribution in solid tumors, thereby increasing the therapeutic index of the ADC.

AB - Antibody-drug conjugates (ADCs) are cancer drugs composed of a humanized antibody linked to a cytotoxic payload, allowing preferential release of payload in cancer cells expressing the antibody-targeted antigen. Here, a systems pharmacology model is used to simulate ADC transport from blood to tumor tissue and ADC uptake by tumor cells. The model includes effects of spatial gradients in drug concentration in a three-dimensional network of tumor blood vessels with realistic geometry and accounts for diffusion of ADC in the tumor extracellular space, binding to antigen, internalization, intracellular processing, and payload efflux from cells. Cells that process an internalized ADC-antigen complex may release payload that can be taken up by other “bystander” cells. Such bystander effects are included in the model. The model is used to simulate conditions in previous experiments, showing good agreement with experimental results. Simulations are used to analyze the relationship of bystander effects to payload properties and single-dose administrations. The model indicates that exposure of payload to cells distant from vessels is sensitive to the free payload diffusivity in the extracellular space. When antigen expression is heterogeneous, the model indicates that the amount of payload accumulating in non-antigen-expressing cells increases linearly with dose but depends only weakly on the percentage of antigen-expressing cells. The model provides an integrated mechanistic framework for understanding the effects of spatial gradients on drug distribution using ADCs and for designing ADCs to achieve more effective payload distribution in solid tumors, thereby increasing the therapeutic index of the ADC.

KW - capillaries

KW - diffusion

KW - drug transport

KW - mathematical model

KW - vascular permeability

UR - http://www.scopus.com/inward/record.url?scp=85076406446&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076406446&partnerID=8YFLogxK

U2 - 10.1208/s12248-019-0390-2

DO - 10.1208/s12248-019-0390-2

M3 - Article

C2 - 31828446

AN - SCOPUS:85076406446

VL - 22

JO - AAPS Journal

JF - AAPS Journal

SN - 1550-7416

IS - 1

M1 - 12

ER -