Abstract 1167: Development of BT1718, a novel Bicycle Drug Conjugate for the treatment of lung cancer
Authors: Gavin Bennett, Robert Lutz, Peter Park, Helen Harrison, Kevin Lee
Journal: Cancer Research (2017)

Abstract BT1718 is a Bicycle Drug Conjugate (BDC®) comprising a constrained bicyclic peptide (Bicycle®) that binds with high affinity and specificity to membrane type 1-matrix metalloprotease (MT1-MMP; MMP14) covalently linked through a hindered disulfide linker to the potent anti-tubulin agent DM1. MT1-MMP is involved in normal tissue remodeling and is also expressed in tumor associated stromal cells. However, overexpression is linked to increased tumor aggression and metastasis. Specifically, over-expression of MT1-MMP is also associated with poor clinical prognosis and shorter survival times in patients with NSCLC and a range of other solid tumors. The Bicycle MT1-MMP binding element within BT1718 was identified using a proprietary phage display peptide technology consisting of highly diverse phage libraries of linear amino acid sequences constrained into two loops by a central tri-functional chemical scaffold. These MT1-MMP binding Bicycles exhibit a profound affinity and specificity, more often associated with monoclonal antibodies, whilst their low molecular weight (1.5-3 kDa), akin to that of a small molecule, aids in rapid extravasation and tumor penetration. Together these attributes make Bicycles an ideal format for the targeted delivery of cytotoxic payloads. We evaluated the ability of BT1718 to bind to and kill tumor cells in vitro and in vivo in a panel of tumor cells. BT1718 demonstrated MT1-MMP target-specific binding and MT1-MMP-dependent cell killing of lung tumor cells in vitro as well as efficacy across a panel of lung tumor xenograft mouse models. For example, in the Met-amplified squamous NSCLC lung EBC-1 model, complete regressions were observed in all mice at doses as low as 5 mg/kg (iv) twice weekly and across a range of other dosing schedules, from daily to weekly. MT1-MMP-dependent activity was demonstrated by blocking target specific interactions through co-administration of an excess of unconjugated Bicycle binder, which inhibited tumour regression, or a non-binding Bicycle, which had no effect. Further evaluation in patient-derived lung xenograft (PDX) models indicates a similar activity to that seen in cell-line derived xenografts, with efficacy seen from 3mg/kg twice weekly and rapid full regression of tumors at higher doses. The molecular attributes of these Bicycles: rapid tumor penetration and specific binding, makes them ideal therapeutics for targeted delivery of toxins as Bicycle drug conjugates (BDCs). The small size of the BDC may offer a significant advantage to other targeted cytotoxic approaches such as antibody-drug conjugates due to rapid extravasation and improved tumor penetration. BT1718, a Bicycle Drug Conjugate, shows potent anti-tumor activity in human lung tumor xenograft models and IND-enabling studies are underway. Citation Format: Gavin Bennett, Robert Lutz, Peter Park, Helen Harrison, Kevin Lee. Development of BT1718, a novel Bicycle Drug Conjugate for the treatment of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1167. doi:10.1158/1538-7445.AM2017-1167