100P - RS-0139, a novel tumor-targeted delivery of docetaxel, with potent anti-tumor activity in a broad spectrum of tumor cell lines and xenograft models

Background

Docetaxel (DTX), an anti-microtubule agent, suffers from limitations due to its toxicity profile, which includes hypersensitivity reactions, neutropenia, neuropathy, fatigue, and nausea. Sagitta^TM platform technology is discovered to reduce toxicity while maximizing the efficacy of cytotoxic drugs. Sagitta™ Bir, a water-soluble polymeric carrier, allows covalent binding of multiple active substances and targeting moieties to the polymer backbone. RS-0139 is the first drug candidate developed with this platform.

Methods

RS-0139 is a tumor-targeted, DTX-releasing prodrug. The active molecule (DTX) is covalently bound to the polymer backbone via a short peptide releasing only upon entry to the cell via endocytosis. The carrier is also equipped with a targeting peptide which shows high affinity to α_vβ₃, α_vβ₅, and α_vβ₆ integrin receptors highly expressed on the tumor cell. A comprehensive set of in vivo studies are conducted to assess potential anti-tumor activity on A549, NCI-H460, MDA-MB-231, 22Rv1 cell lines.

Results

Physical properties of RS-0139 such as enhanced aqueous solubility provide an advantage over the currently used taxanes. Also, the pharmacokinetic profile is not only improved in terms of half-life and AUC but also is demonstrated to be translatable across species. In preclinical studies, the enzymatically cleavable covalent conjugation of DTX enabled sustained release, reducing adverse effects due to limited circulating free DTX. Hence, RS-0139 showed superior tolerability in healthy mice, rats, and rabbits compared to DTX. Besides, the dosing frequency was reduced due to the 5-fold increase in the half-life. Preclinical data strongly supported the clinical translation of this novel nanomedicine for the treatment of solid tumors. The phase I clinical trial is ongoing on NSCLC patients.

Conclusions

Tumor cell expression of the integrins is correlated with disease progression in various tumor types such as breast, pancreatic, prostate, non-small cell lung cancers and glioblastoma. Preclinical studies demonstrate promising results for NSCL, breast and prostate cancers.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

RS Research.

Funding

RS Research.

Disclosure

G. Nomak, R. Sanyal: Financial Interests, Personal, Member of the Board of Directors: RS Research. M. Karacivi, S. Kutlu Ozkaya, B. Sumer Bolu, T. Karatas: Financial Interests, Personal, Full or part-time Employment: RS Research. H.S. Orer: Financial Interests, Personal, Principal Investigator: RS Research. All other authors have declared no conflicts of interest.