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

• Published in: Molecular cancer therapeutics Vol. 17; no. 9; pp. 1927 - 1940
• Main Authors: Leconet, Wilhem, Liu, He, Guo, Ming, Le Lamer-Déchamps, Sophie, Molinier, Charlotte, Kim, Sae, Vrlinic, Tjasa, Oster, Murielle, Liu, Fang, Navarro, Vicente, Batra, Jaspreet S, Noriega, Adolfo Lopez, Grizot, Sylvestre, Bander, Neil H
• Format: Journal Article
• Language: English
• Published: United States 01-09-2018
• Subjects: Animals; Antibodies, Bispecific - administration & dosage; Antibodies, Bispecific - immunology; Antibodies, Bispecific - pharmacology; Antigens, Surface - immunology; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; CD3 Complex - immunology; Cell Line, Tumor; Drug Delivery Systems - methods; Drug Liberation; Glutamate Carboxypeptidase II - immunology; Humans; Male; Mice, SCID; Polymers - chemistry; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Survival Analysis; Tumor Burden - drug effects; Xenograft Model Antitumor Assays - methods
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-17-1138

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.
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