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.
Highlights
Antibody-based therapeutic platforms have revolutionized the biopharmaceutical landscape in last two decades [1]
Target co-engagement by bispecific antibodies leads to activation of the T cell receptor (TCR) signaling cascade resulting in release of granzymes and perforin molecules that results in tumor cytotoxicity
Dose-dependent binding curves demonstrate that VT680 labeling of P-cadherin LP-Dualaffinity re-targeting (DART) minimally affect binding to P-cadherin when compared to unlabeled antibody
Summary
Antibody-based therapeutic platforms have revolutionized the biopharmaceutical landscape in last two decades [1]. Bispecific antibodies are one of these innovative platforms that can co-engage two different antigens at the same time [2, 3]. Renewed interest in cancer immunotherapy has focused on bispecific antibodies as a preferred therapeutic modality used to direct immune effector cells to tumors expressing a target antigen to trigger an anti-tumor cytotoxic response [2, 4]. Target co-engagement by bispecific antibodies leads to activation of the T cell receptor (TCR) signaling cascade resulting in release of granzymes and perforin molecules that results in tumor cytotoxicity. Two T cell targeting bispecific antibodies have been approved to treat cancer and an additional 50 molecules are in different stages of clinical development [3, 6,7,8]
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