Humanization, Radiolabeling and Biodistribution Studies of an IgG1-Type Antibody Targeting Uncomplexed PSA for Theranostic Applications

Pharmaceuticals

Urpo J. Lamminmaki¹  Thuy A. Tran²  Joanna Strand³  Sven-Erik Strand³  Oskar Vilhelmsson Timmermand³  Kjell Sjöström⁴ 

[1] Department of Biotechnology, University of Turku, 20500 Åbo, Finland;Department of Oncology and Pathology, Karolinska Institutet, 17177 Stockholm, Sweden;Department of Oncology, Department of Clinical Sciences, Lund University, 22243 Lund, Sweden;Innovagen AB, 22362 Lund, Sweden;

关键词: prostate cancer;    imaging;    humanization;    5A10;    fPSA;    theranostics;   

DOI  :  10.3390/ph14121251

来源: DOAJ

【 摘 要 】

Metastatic castration-resistant prostate cancer is today incurable. Conventional imaging methods have limited detection, affecting their ability to give an accurate outcome prognosis, and current therapies for metastatic prostate cancer are insufficient. This inevitably leads to patients relapsing with castration-resistant prostate cancer. Targeting prostate-specific antigens whose expression is closely linked to the activity in the androgen receptor pathway, and thus the pathogenesis of prostate cancer, is a possible way to increase specificity and reduce off-target effects. We have humanized and evaluated radioimmunoconjugates of a previously murine antibody, m5A10, targeting PSA intended for theranostics of hormone-refractory prostate cancer. The humanized antibody h5A10 was expressed in mammalian HEK293 cells transfected with the nucleotide sequences for the heavy and light chains of the antibody. Cell culture medium was filtered and purified by Protein G chromatography, and the buffer was changed to PBS pH 7.4 by dialysis. Murine and humanized 5A10 were conjugated with p-SCN-Bn-CHX-A”-DTPA. Surface plasmon resonance was used to characterize the binding to PSA of the immunoconjugates. Immunoconjugates were labeled with either indium-111 or lutetium-177. Biodistribution studies of murine and humanized 5A10 were performed in mice with LNCaP xenografts. 5A10 was successfully humanized, and in vivo targeting showed specific binding in xenografts. The results thus give an excellent platform for further theranostic development of humanized 5A10 for clinical applications.

【 授权许可】

Unknown