Oncotarget

Research Papers:

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

Vijay R. Gupta, Adam Root, Timothy Fisher, Rand Norberg, John David, Tracey Clark, Justin Cohen, Chad May and Anand Giddabasappa _

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Oncotarget. 2020; 11:1344-1357. https://doi.org/10.18632/oncotarget.27544

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Abstract

Vijay R. Gupta1, Adam Root2, Timothy Fisher3, Rand Norberg1, John David1, Tracey Clark4, Justin Cohen2, Chad May3 and Anand Giddabasappa1

1 Global Science & Technology (GST) – Comparative Medicine, Pfizer Global Research Development and Medical, San Diego, CA 92121, USA

2 BioMedicine Design, Cambridge, MA 02139, USA

3 Oncology Research and Development, San Diego, CA 92121, USA

4 PDM Biotherapeutics, Pfizer Inc., San Diego, CA 92121, USA

Correspondence to:

Anand Giddabasappa,email: anand.giddabasappa@pfizer.com

Keywords: bispecific antibody; tumor targeting; biodistribution; T cells; molecular imaging

Received: November 03, 2019     Accepted: March 14, 2020     Published: April 14, 2020

ABSTRACT

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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