Near infrared photoimmunotherapy targeting DLL3 for small cell lung cancer

Abstract

Background: Small cell lung cancer (SCLC) has a poor prognosis, and its treatment options are limited. Deltalike protein 3 (DLL3) is expressed specifically in SCLC and is considered a promising therapeutic target for patients with this disease. Rovalpituzumab tesirine (Rova-T) was the first antibody-drug conjugate targeting DLL3. Although Rova-T development was unfortunately terminated, DLL3 remains an ideal target for SCLC. Near infrared photoimmunotherapy (NIR-PIT) is a new form of cancer treatment that employs an antibodyphotosensitiser conjugate followed by NIR light exposure and damage target cells specifically. In this study, we demonstrate DLL3-targeted NIR-PIT to develop a novel molecularly targeted treatment for SCLC. Methods: The anti-DLL3 monoclonal antibody rovalpituzumab was conjugated to an IR700 photosensitiser (termed 'rova-IR700'). SCLC cells overexpressing DLL3 as well as non-DLL3-expressing controls were incubated with rova-IR700 and then exposed to NIR-light. Next, mice with SCLC xenografts were injected with rova-IR700 and irradiated with NIR-light. Findings: DLL3-overexpressing cells underwent immediate destruction upon NIR-light exposure, whereas the control cells remained intact. The xenograft in mice treated with rova-IR700 and NIR-light shrank markedly, whereas neither rova-IR700 injection nor NIR-light irradiation alone affected tumour size. Interpretation: Our data suggest that targeting of DLL3 using NIR-PIT could be a novel and promising treatment for SCLC.

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

“…In vivo experiments have confirmed that DLL3-overexpressing SCLC tumors are immediately destroyed upon NIR-light exposure. 37 Immunohistochemistry is used to assess DLL3 expression from SCLC biopsies and predict the effects of DLL3targeted agents; however, several practical limitations remain. 38 The application of immuno-positron emission tomography (immunoPET) can non-invasively provide real-time information regarding the status of in vivo DLL3 expression in tumors, facilitating the selection of patients for treatment with DLL3-targeted agents.…”

Cancer photo-immunotherapy: from bench to bedside

“…PIT led to significant reductions in tumor volume in both the flank model and the pleural dissemination model 84 - 89 . Similarly, the delta-like protein 3 (DLL3) mAb rovalpituzumab was conjugated to IRDye 700DX to form rova-IR700, which decreased tumor burden markedly by PIT 90 . An anti-podoplanin antibody, NZ-1, was also synthesized with IRDye 700DX to treat a malignant pleural mesothelioma (MPM) model 74 .…”

Targeted Phototherapy for Malignant Pleural Mesothelioma: Near-Infrared Photoimmunotherapy Targeting Podoplanin

“…We abbreviate IR700 conjugated to NZ-1 as NZ-1-IR700. The detection of binding of NZ-1-IR700 on PDPN was evaluated with immunoblot according to previous reports [21,29].…”

“…Among the organs in the human body, the lung and thoracic cavity can most effectively transmit NIR-light, because it consists of a large amount of air [21][22][23]. Thus, MPM is a potentially good target for NIR-PIT.…”