Abstract 1076: The peptide-drug conjugate TH1902 inhibits growth of subcutaneous melanoma xenografts and formation of lung metastases in a syngeneic mouse model

Abstract

Syngeneic mouse models provide an effective approach for studying how cancer therapies perform in the presence of a functional immune system. Here TH1902, a peptide-drug conjugate (PDC) which consists of two molecules of docetaxel attached by a cleavable succinyl linker to a peptide (TH19P01) that targets the scavenger receptor sortilin (SORT1), was investigated using subcutaneous implantation of murine B16-F10 melanoma cells within the flanks of syngeneic C57BL/6 mice. Tumor growth was at most inhibited by half upon weekly administration of docetaxel compared to vehicle-treated mice, while administration of TH1902 was well tolerated and led to tumor regression. The B16-F10 SORT1-expressing melanoma cell line is also known to produce distant lung metastases when injected intravenously into the mice. Tail vein injection of these cells (1.25x105 cells per implantation) created a model system for evaluating TH1902’s effects on metastatic nodules formation. Each implantation produced 70 to 100 visible, black surface nodules on the lungs at 13 days following cancer cell implantation, appropriate for nodule quantification. No black nodules were detected elsewhere within the mice tissues other than those detected in the lungs. This model was next used to demonstrate that the formation of lung metastases could be sharply curtailed by bi-weekly intravenous administration of either 10 mg/kg docetaxel or 23 mg/kg TH1902 (equivalent to the docetaxel injection in terms of docetaxel content) during this period. Administration of docetaxel routinely decreased the number of metastatic lung nodules by about 50%, whereas administration of TH1902 decreased the number of nodules by more than 85%. Similar results were obtained whether the test articles were administered i) one time as a bolus at one hour prior to implantation of the cells, ii) as a bolus twice weekly beginning 3 days post-implantation, or iii) both prior to and following implantation as described. Although little weight loss was recorded over the 13-day treatment duration, all TH1902-treated mice showed better tolerability profile in terms of weight compared to docetaxel for all conditions tested. In a subsequent experiment using prolonged administration at the same dosage (up to 24 days of treatment), TH1902 was able to inhibit metastatic formation over a longer period compared to docetaxel. In fact, after six cycles of treatment, TH1902-treated mice significantly sustained its inhibitory effect on melanoma lungs metastasis formation (-77%) whereas docetaxel was unable to maintain its effect (-7%). Moreover, considerable weight loss was associated with docetaxel treatment over 24 days while TH1902 treatments resulted in no net change in mouse body weights. In this syngeneic model, TH1902 is more tolerated and effective than docetaxel at inhibiting both melanoma xenograft growth and metastatic formation. Citation Format: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Larocque, Alain Zgheib, Sophie Kozelko, Richard Béliveau, Christian Marsolais, Borhane Annabi. The peptide-drug conjugate TH1902 inhibits growth of subcutaneous melanoma xenografts and formation of lung metastases in a syngeneic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1076.