486P - Effects of a BBB-penetrating oligonucleotide drug, RBD8088, in mouse models of human glioblastoma

Background

Glioblastoma (GBM) is a vastly lethal cancer with a high unmet clinical need and poor prognosis. Several targeting therapies are under clinical stage development but passing of the blood-brain barrier (BBB) remains one of the biggest hurdles. Here, we report the development and efficacy by systemic delivery of RBD8088, an innovative oligonucleotide drug capable of traversing the BBB and targeting glioblastoma specifically.

Methods

An oligonucleotide compound specific for targeting of glioma tumor cells in vitro was discovered, further developed and optimized. Its targeting effect was verified in vivo in subcutaneous (SC) and orthotopic cell line-derived xenograft (CDX) mouse models using human glioma cell lines U118MG and U87. The oligonucleotide compound was further optimized and derivatized to form RBD8088. RBD8088´s anti-tumor activity was evaluated after repeated dosing in SC and orthotopic CDX mouse models. The stability in serum was quantified by LC-MS and safety assessed in rodents.

Results

RBD8088 demonstrates a specific tumor targeting effect when administered systemically in SC xenograft and in brain orthotopic CDX mouse models. In addition, a dose dependent and long-lasting anti-tumor efficacy was shown. In SC xenograft model, tumor growth was significantly halted, resulted in 162.3 mm³ for RBD8088-treated vs 600.2 mm³ for control drug at study end (p-value <0.05, n=7/group). In brain orthotopic glioma tumor mouse models, tumor size was measured by luciferase radiance resulting in 1.83x10⁶ for RBD8088 vs 158.3x10⁶ p/sec/cm²/sr for a control drug at day 27 (p-value<0.05, n=6/group). RBD8088 is stable in mouse serum in vitro for up to 24 h. Safety studies in mice and rats show that the RBD8088 is well tolerated.

Conclusions

RBD8088 penetrates BBB and express a therapeutic effect in a targeted manner in mouse models of GBM. RBD8088 is currently undergoing further preclinical validation and development aiming for CTA/IND application in the near future.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Suzhou Ribo Life Science, Co. Ltd.

Funding

Suzhou Ribo Life Science, Co. Ltd.

Disclosure

All authors have declared no conflicts of interest.