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.
Highlights
Antibodies are today among the most attractive cancer therapeutic agents due to their target specificity, and for their ability to be engineered, improving their cytotoxic properties against the targeted cancer cells [1, 2]
BiJ591 binding to prostate specific membrane antigen (PSMA) and CD3 was compared with the two parental mAbs used to design this bispecific antibody, HuJ591, which is a deimmunized version of anti-PSMA J591 antibody [20, 22], and OKT-3, a murine mAb targeting CD3 [23]
BiJ591 was shown to bind to PSMA-positive LNCaP PCa cell line and CD3-positive Jurkat T cells, keeping the binding properties of the parental mAbs with an apparent lower affinity to CD3, which could be explained by the proximity of the 6ÂHis-Tag used to detect the BiJ591 and binding site to CD3 (Fig. 1C)
Summary
Antibodies are today among the most attractive cancer therapeutic agents due to their target specificity, and for their ability to be engineered, improving their cytotoxic properties against the targeted cancer cells [1, 2]. There are two bispecific antibodies that have been approved in the clinic, blinatumomab and catumaxomab (discontinued in 2014 for commercial reasons), which have the ability to target a cancer cell marker (CD19 and EpCAM, respectively) and CD3, a T-cell coreceptor well-known to activate and promote T-cell killing of tumor cells [4, 5]. These recombinant antibodies act as a bridge to create an immune synapse and retarget immune effector T cells from the host toward the cancer cells, inducing the latter's lysis by delivery of perforin and granzyme.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
