Abstract 1820: Efficacy and safety of the TLR7 agonist micelles MBS8(1V270) tested in pre-clinical models

Abstract

Abstract TLR7 agonists have shown efficacy in pre-clinical cancer models, however, their clinical use is restricted to topical treatment due to a high systemic toxicity. We have developed a micellar formulation of the TLR7 agonist MBS8(1V270) which demonstrated low toxicity and high efficacy in multiple murine cancer models when administered intravenously as monotherapy. In combination treatment, MBS8(1V270) showed a synergistic effect with PD-1 and PD-L1 inhibitors. Moreover, in several models resistant to anti-PD-1 treatment, MBS8(1V270) co-administration restored sensitivity to anti-PD-1 thus indicating potential for combination treatment in clinical setting. GLP toxicology studies in SD rats and cynomolgus monkeys did not reveal significant toxicities up to the human equivalent dose level of ~1.3 mg/kg which is above anticipated therapeutic dose. Additionally, ex vivo stimulation of human whole blood demonstrated significantly lower IL-6 induction by MBS8(1V270) as compared to the benchmark drug resiquimod. Tissue distribution and excretion of MBS8(1V270) was investigated in SD rats. No signs of drug accumulation were observed in any of the analyzed organs with nearly complete clearance of the drug 24 hours post-end of infusion. The major route of the MBS8(1V270) elimination was via faeces. Cellular uptake of MBS8(1V270) by human blood cells was investigated ex vivo using whole blood from healthy donors. The main cell populations taking up the drug were monocytes and B cells followed by NK cells. No MBS8(1V270) was detected in neutrophils or T cells.In conclusion, MBS8(1V270) was well tolerated in rodents and cynomolgus monkeys at dose levels above therapeutic effective doses identified in mice, thus providing a good therapeutic window. It showed significant anti-cancer activity in multiple murine tumor models when administered either alone or in combination with PD-1/PD-L1 inhibitors. Together, these data provide a rationale for clinical studies of MBS8(1V270) as monotherapy and in combination with immune checkpoint inhibitors. MBS8(1V270) is currently under clinical investigation in the clinical trial MBS8-101 (ClinicalTrials.gov identifier NCT04855435). Citation Format: Simon Skjøde Jensen, Esben Christensen, Martin Bak Winther, Anders Elias Hansen, Jonas Rosager Henriksen, Thomas Lars Andersen, Morten Just Petersen, Svetlana Panina. Efficacy and safety of the TLR7 agonist micelles MBS8(1V270) tested in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1820.