Abstract B135: The mechanism of action of BT1718, a novel small-molecule drug conjugate for the treatment of solid tumors expressing MT1-MMP

Abstract

BT1718 is a small-molecule drug conjugate, also called 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; MT1) covalently linked through a hindered disulfide linker to the potent antitubulin agent DM1. MT1 is naturally involved in tissue remodeling; however, its overexpression is linked to increased tumor aggressiveness and metastasis. Overexpression of MT1 is associated with poor survival in NSCLC, TNBC, and other solid tumors. MT1 expression can also be observed in tumor-associated stromal cells. The Bicycle binder for 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 chemical scaffold. While binding with similar affinity and specificity to that observed with monoclonal antibodies, the small size of a Bicycle (1.5-3 kDa) aids in its rapid extravasation and tumor penetration, making it an ideal format for the targeted delivery of cytotoxic payloads. BT1718 shows profound antitumor activities as a single agent when given at doses as low as 3mg/kg biw, producing complete regression of tumors in cell-line and patient-derived xenograft models. BT1718 is also able to produce rapid complete regression of very large tumors (~1000 mm³). We have evaluated the target dependence of antitumor activities of BT1718 by evaluating tumor response in a range of xenograft models with varying expression of MT1, as measured by mRNA, FACS, and IHC. We evaluated a panel of cell-line derived xenograft (CDX) and patient-derived xenograft (PDX) tumors across various indications including lung, breast, colorectal, stomach, head and neck cancer, and multiple myeloma. In both CDX and PDX models, the efficacy of BT1718 was dependent on the MT1 expression levels. Moderate and high MT1-expressing cell lines showed partial or complete regression when treated with BT1718, while low MT1-expressing lines showed limited or no effect. BT1718 is a first-in-class, cytotoxic small-molecule drug conjugate with great potential for treatment of MT1-expressing solid tumors and is about to begin clinical testing.

Citation Format: Gavin Bennett, Mike Rigby, Bob Lutz, Peter Park, Nicholas Keen. The mechanism of action of BT1718, a novel small-molecule drug conjugate for the treatment of solid tumors expressing MT1-MMP [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B135.