Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific and trafficking of adoptively transferred T cells in mouse xenograft model

P-cadherin-LP-DART is a bispecific antibody targeting P-cadherin expressed on the tumor cells and CD3 on the T-cells. Previously we demonstrated the development and efficacy of P-cadherin-LP-DART in in vitro and in vivo models. Here, we evaluated the three pillars: exposure, targeting specificity an...

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Autores principales: Gupta, Vijay R., Root, Adam, Fisher, Timothy, Norberg, Rand, David, John, Clark, Tracey, Cohen, Justin, May, Chad, Giddabasappa, Anand
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170501/
https://www.ncbi.nlm.nih.gov/pubmed/32341754
http://dx.doi.org/10.18632/oncotarget.27544
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author Gupta, Vijay R.
Root, Adam
Fisher, Timothy
Norberg, Rand
David, John
Clark, Tracey
Cohen, Justin
May, Chad
Giddabasappa, Anand
author_facet Gupta, Vijay R.
Root, Adam
Fisher, Timothy
Norberg, Rand
David, John
Clark, Tracey
Cohen, Justin
May, Chad
Giddabasappa, Anand
author_sort Gupta, Vijay R.
collection PubMed
description P-cadherin-LP-DART is a bispecific antibody targeting P-cadherin expressed on the tumor cells and CD3 on the T-cells. Previously we demonstrated the development and efficacy of P-cadherin-LP-DART in in vitro and in vivo models. Here, we evaluated the three pillars: exposure, targeting specificity and pharmacodynamic modulation for P-cadherin-LP-DART using fluorescence molecular tomography (FMT). Bispecific antibodies and T-cells were conjugated with a near-infrared fluorophores: VivoTag(®)680XL (VT680) and CellVue(®)NIR815 (CV815), respectively. In vitro binding and cytotoxic T-lymphocyte assay demonstrated that P-cadherin-LP-DART significantly retained its properties after VT680 conjugation. In vivo FMT imaging was performed to determine the bispecific biodistribution and T-cell trafficking in HCT-116 xenograft model. Peak tumor exposure (2.71%ID) was observed at 96 hr post-injection with measurable quantity even at 240 hr (1.46%ID) (Pillar 1). P-cadherin-LP-DART accumulation in tumor was 20-25 fold higher compared to Control-LP-DART demonstrating the targeting specificity (Pillar 2). Imaging after engraftment of CV815 labeled T-cells showed P-cadherin-LP-DART mediated T-cell trafficking in tumors (Pillar 3). This study harnessed the multichannel capability of FMT and demonstrated the targeting of drug and trafficking of T cells to tumors, simultaneously. Our results show the impact of molecular imaging in demonstrating three pillars of pharmacology, longitudinally and non-invasively.
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spelling pubmed-71705012020-04-27 Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific and trafficking of adoptively transferred T cells in mouse xenograft model Gupta, Vijay R. Root, Adam Fisher, Timothy Norberg, Rand David, John Clark, Tracey Cohen, Justin May, Chad Giddabasappa, Anand Oncotarget Research Paper P-cadherin-LP-DART is a bispecific antibody targeting P-cadherin expressed on the tumor cells and CD3 on the T-cells. Previously we demonstrated the development and efficacy of P-cadherin-LP-DART in in vitro and in vivo models. Here, we evaluated the three pillars: exposure, targeting specificity and pharmacodynamic modulation for P-cadherin-LP-DART using fluorescence molecular tomography (FMT). Bispecific antibodies and T-cells were conjugated with a near-infrared fluorophores: VivoTag(®)680XL (VT680) and CellVue(®)NIR815 (CV815), respectively. In vitro binding and cytotoxic T-lymphocyte assay demonstrated that P-cadherin-LP-DART significantly retained its properties after VT680 conjugation. In vivo FMT imaging was performed to determine the bispecific biodistribution and T-cell trafficking in HCT-116 xenograft model. Peak tumor exposure (2.71%ID) was observed at 96 hr post-injection with measurable quantity even at 240 hr (1.46%ID) (Pillar 1). P-cadherin-LP-DART accumulation in tumor was 20-25 fold higher compared to Control-LP-DART demonstrating the targeting specificity (Pillar 2). Imaging after engraftment of CV815 labeled T-cells showed P-cadherin-LP-DART mediated T-cell trafficking in tumors (Pillar 3). This study harnessed the multichannel capability of FMT and demonstrated the targeting of drug and trafficking of T cells to tumors, simultaneously. Our results show the impact of molecular imaging in demonstrating three pillars of pharmacology, longitudinally and non-invasively. Impact Journals LLC 2020-04-14 /pmc/articles/PMC7170501/ /pubmed/32341754 http://dx.doi.org/10.18632/oncotarget.27544 Text en http://creativecommons.org/licenses/by/3.0/ Copyright: Gupta et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Gupta, Vijay R.
Root, Adam
Fisher, Timothy
Norberg, Rand
David, John
Clark, Tracey
Cohen, Justin
May, Chad
Giddabasappa, Anand
Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific and trafficking of adoptively transferred T cells in mouse xenograft model
title Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific and trafficking of adoptively transferred T cells in mouse xenograft model
title_full Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific and trafficking of adoptively transferred T cells in mouse xenograft model
title_fullStr Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific and trafficking of adoptively transferred T cells in mouse xenograft model
title_full_unstemmed Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific and trafficking of adoptively transferred T cells in mouse xenograft model
title_short Molecular imaging reveals biodistribution of P-cadherin LP-DART bispecific and trafficking of adoptively transferred T cells in mouse xenograft model
title_sort molecular imaging reveals biodistribution of p-cadherin lp-dart bispecific and trafficking of adoptively transferred t cells in mouse xenograft model
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170501/
https://www.ncbi.nlm.nih.gov/pubmed/32341754
http://dx.doi.org/10.18632/oncotarget.27544
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