Abstract B026: Targeting the novel tumor antigen MT1-MMP with Bicycle® Drug Conjugates (BDC®) for the potential treatment of NSCLC and other solid tumor indications

Abstract Background The membrane-type 1 matrix metalloproteinase MT1-MMP (or MMP14) is a member of the type 1 transmembrane proteinase family, highly overexpressed in several solid tumors and associated with poor prognosis (e.g. non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, breast cancer, gastric cancer, and osteosarcoma). Its expression profile makes this target amenable to novel precision targeting with a toxin drug conjugate across a broad spectrum of solid tumors. Bicycle® drug conjugates (BDC®) intrinsically possess several advantages over other targeted cytotoxic modalities such as antibody-drug conjugates (ADCs). This Bicycle® advantage includes improved kinetics of extravasation and tumor penetration, fast renal clearance, and a lack of engagement of Fc receptors. Targeting MT1-MMP with a BDC® molecule represents an attractive potential approach for targeted tumor therapy. Method and materials Bicycle® binders for MT1-MMP were identified using a proprietary phage display peptide technology consisting of highly diverse phage libraries of Bicycle® molecules, then conjugated to cleavable linkers and toxins to form Bicycle® Drug Conjugates (BDC®). Tool molecules were identified, containing an MT1-MMP binding Bicycle® conjugated to the cytotoxic auristatin derivative maleimidocaprolyl-monomethyl auristatin E (MMAE) via a proteolytically cleavable valine-citrulline (Val-Cit) linker. The properties of tool molecules were evaluated using a range of in vitro and in vivo models assessing MT1-MMP binding and specificity/selectivity, internalisation, in vitro cytotoxicity, and in vivo antitumor activity using xenograft models (cell and patient derived). Toxicology studies were performed in Han Wistar rats and Cynomologous monkeys. Results In vitro, tool molecules bound to MT1-MMP with high affinity (KD ∼3nM), and demonstrated both, cross-reactivity to species orthologues of MT1-MMP and selectivity over related human MMP family members by surface plasmon resonance (SPR) measurements. A fluorescent version of the MT1-MMP binding Bicycle® bound to cell lines dependent on expression levels of MT1-MMP, effectively internalised, and the tool BDC® molecule (MMAE containing) demonstrated MT1-MMP dependent cytotoxicity in an in vitro cell model.In vivo, the tool BDC® molecule demonstrated the expected PK profile in pre-clinical species of a short half life, and was effective in MT1-MMP expressing cell line (CDX) xenograft models in both mice and rats, showing complete tumor regression at 3mg/kg weekly dosing. The molecule also showed antitumor activity in a panel of NSCLC patient-derived xenograft models (PDX). Finally, in vivo toxicology (2 doses 1 week apart) demonstrated a similar tolerated range to other clinical stage BDC® molecules. Conclusions Targeting MT1-MMP with a BDC® molecule shows potent antitumour activity in a range of solid tumour xenograft models, with a focus on NSCLC, and represents an attractive opportunity to target this novel tumor antigen for therapeutic benefit in this indication. Citation Format: Steve B. Ludbrook, Stephen Walsh, Gemma Mudd, Johanna Lahdenranta, Philip Huxley, Luca Mascheroni, Maximillian Harman, Jennifer Bré, Inma Rioja, Michael Skynner, Gavin Bennett. Targeting the novel tumor antigen MT1-MMP with Bicycle® Drug Conjugates (BDC®) for the potential treatment of NSCLC and other solid tumor indications [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B026.