Anti-PSMA/CD3 Bispecific Antibody Delivery and Antitumor Activity Using a Polymeric Depot Formulation

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 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..

<p>Blinatumomab for the Treatment of Adult B-Cell Acute Lymphoblastic Leukemia: Toward a New Era of Targeted Immunotherapy</p>

“…This is particularly a challenge in resource-limited settings where outpatient blinatumomab administration is not feasible due to the required frequency of bag changes. Polymer-based depot formulation of a bispecific antibody has been reported previously, 58 and a current Phase I trial is investigating the potential for intermittent subcutaneous administration of blinatumomab, albeit in lymphoma (NCT02961881). Future advancements in the drug product formulation of blinatumomab may produce an increased plasma half-life with less frequent dosing.…”

Polymers for extended-release administration

“…Oncogel, an injectable hydrogel for extended release of the chemotherapy drug paclitaxel, made it to phase II clinical trials (Elstad and Fowers, 2009). In a similar fashion, the French company MedinCell is developing a platform for the extended release of drugs based on the biodegradable DB PEG-PLA and TB PLA-PEG-PLA copolymers dissolved in a bio-compatible solvent, tripropionin (Leconet et al, 2018).…”

Improved Efficacy of Antibody Cancer Immunotherapeutics through Local and Sustained Delivery

“…Although local delivery of BiTEs has not been reported, subcutaneous injections of BiTE‐loaded hydrogels overcomes their short plasma half lives and improves efficacy. In situ gelling triblock PEG–PLA hydrogels encapsulating BiTEs targeting prostate‐specific membrane antigen (PSMA) were injected subcutaneously . In a LNCaP xenograft prostate cancer mouse model, the hydrogel improved BiTE half‐life, T cell tumor infiltration, and survival to >50 % at 55 days.…”