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A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
Anti-PSMA/CD3 Bispecific Antibody Delivery and Antitumor Activity Using a Polymeric Depot Formulation
Wilhem Leconet1, He Liu2, Ming Guo2
1Department of Urology, Weill Cornell Medical College-New York Presbyterian Hospital, New York, New York. wil2011@med.cornell.edu.
Abstract:
Small therapeutic proteins represent a promising novel approach to treat cancer. Nevertheless, their clinical application is often adversely impacted by their short plasma half-life. Controlled long-term delivery of small biologicals has become a challenge because of their hydrophilic properties and in some cases their limited stability. Here, an in situ forming depot-injectable polymeric system was used to deliver BiJ591, a bispecific T-cell engager (BiTE) targeting both prostate-specific membrane antigen (PSMA) and the CD3 T-cell receptor in prostate cancer. BiJ591 induced T-cell activation, prostate cancer-directed cell lysis, and tumor growth inhibition. The use of diblock (DB) and triblock (TB) biodegradable polyethylene glycol-poly(lactic acid; PEG-PLA) copolymers solubilized in tripropionin, a small-chain triglyceride, allowed maintenance of BiJ591 stability and functionality in the formed depot and controlled its release. In mice, after a single subcutaneous injection, one of the polymeric candidates, TB1/DB4, provided the most sustained release of BiJ591 for up to 21 days. Moreover, the use of BiJ591-TB1/DB4 formulation in prostate cancer xenograft models showed significant therapeutic activity in both low and high PSMA-expressing tumors, whereas daily intravenous administration of BiJ591 was less efficient. Collectively, these data provide new insights into the development of controlled delivery of small therapeutic proteins in cancer. Mol Cancer Ther; 17(9); 1927-40. ©2018 AACR.
Insights
A novel injectable polymer system successfully delivered BiJ591, a bispecific T-cell engager, for sustained prostate cancer treatment. This controlled release enhanced therapeutic efficacy compared to daily injections.
Area of Science:
- Oncology
- Biomaterials Science
- Drug Delivery Systems
Background:
- Small therapeutic proteins offer promise for cancer treatment but face challenges due to short plasma half-life and limited stability.
- Controlled long-term delivery of hydrophilic and potentially unstable biologicals remains a significant hurdle in clinical applications.
Purpose of the Study:
- To develop and evaluate an in situ forming, injectable polymeric depot system for the controlled delivery of BiJ591, a bispecific T-cell engager (BiTE).
- To assess the stability, release kinetics, and therapeutic efficacy of BiJ591 delivered via the polymeric system in prostate cancer models.
Main Methods:
- Utilized diblock (DB) and triblock (TB) biodegradable polyethylene glycol-poly(lactic acid) (PEG-PLA) copolymers solubilized in tripropionin to create an injectable depot.
- Administered the BiJ591-loaded polymeric formulation subcutaneously in mice with prostate cancer xenografts.
- Evaluated BiJ591 release profiles, stability, T-cell activation, and tumor growth inhibition.
Main Results:
- The triblock copolymer formulation (TB1/DB4) demonstrated sustained release of BiJ591 for up to 21 days after a single subcutaneous injection.
- The BiJ591-TB1/DB4 formulation showed significant therapeutic activity in both low and high PSMA-expressing prostate cancer xenografts.
- This controlled delivery approach was more effective than daily intravenous administration of BiJ591.
Conclusions:
- Injectable PEG-PLA copolymer depots provide a viable strategy for the controlled, long-term delivery of small therapeutic proteins like BiJ591.
- This formulation enhances the therapeutic efficacy of BiTEs in prostate cancer treatment, offering a promising alternative to conventional administration methods.
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