Abstract 3618: Target-specific photo-activatable immunotherapy (PIT) for cancer based on a monoclonal antibody-photosensitizer conjugate

Abstract

Abstract Three modes of cancer therapy, surgery, radiation and chemotherapy, have been central to modern oncologic therapy. Molecular targeted cancer therapies have been introduced to target specific pathways, while minimizing side effects but have had limited success except in several notable cases. The concept of amplifying the effect of molecular targeting by applying physical energy to the bound conjugate is relatively new. In this study, we describe a hydrophilic photosensitizer based on a near infrared (NIR) phthalocyanine dye, IR700, which is covalently conjugated to one of several humanized monoclonal antibodies (MAb) targeting human epidermal growth factor receptor (EGFR) type 1 (HER1) and 2 (HER2). When exposed to light the conjugate induces highly selective cell death in vivo, a process termed “photo-activatable immunotherapy” (PIT). In vitro studies were conducted with Trastuzumab-IR700 bound to HER2-expressing NIH3T3 cells (3T3/HER2) and panitumumab-IR700 bound to HER1-expressing A431 cells which were then irradiated with non harmful NIR light. EGFR-negative Balb3T3 cells were used as controls. In vivo studies were conducted with 3T3/HER2 and A431 xenograft tumors 1 day after intravenous administration of MAb-IR700 followed by non harmful, transcutaneous NIR light. MAb-IR700 demonstrated specific binding to target receptors on the cell membrane, which was followed by gradual internalization into endolysosomal compartments. MAb-IR700 bound target-specific cell death could be induced within 5 minutes of exposure to NIR light and resulted in cellular swelling, bleb formation, and rupture of vesicles indicating necrotic cell death. No phototoxicity was observed in co-cultured receptor-negative Balb3T3 cells after incubation with MAb-IR700, even when MAb-IR700 was not removed from the medium during light exposure. EGFR target-specific accumulation of MAb-IR700 was observed in the mouse xenograft tumors on NIR fluorescence images. Greater than 90% tumor shrinkage within 3 days of the NIR irradiation, was measured, with no apparent side effects, but was only observed in EGFR-expressing tumors. Furthermore, IR700 fluorescence produced by the MAb conjugate permitted guidance of light delivery and allowed for monitoring after therapy. The MAb-IR700 PIT was most effective, when conjugates were bound to the cell membrane, but showed no phototoxicity, when unbound, suggesting a novel mechanism for PIT compared with conventional photodynamic therapies. Target selective PIT based on MAb-IR700 conjugate membrane binding enables selective treatment of cancer with no apparent side effect to normal cells or surrounding tissue. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3618. doi:10.1158/1538-7445.AM2011-3618