Abstract
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.
Highlights
Prostate cancer (PCa) is one of the major causes of death among men in the western world
In addition to grafting the complementarity determining regions (CDRs) sequences from murine 5A10 to a suitable human framework, the development of the humanized 5A10 (h5A10) involved the introduction of human-to-mouse and some mouse-to-human backmutations in the framework regions of the CDRs
We showed that the humanized 5A10 antibody could efficiently target the fPSA in the same manner as the murine 5A10
Summary
Prostate cancer (PCa) is one of the major causes of death among men in the western world. First-line hormonal therapy of metastatic PCa is initially a very effective treatment for metastatic PCa. Androgen ablation, with e.g., anti-androgens and GnRHagonists/antagonists, inhibits the androgen receptor (AR) pathway central to survival, proliferation, and apoptosis of healthy and malignant prostate cells [1,2]. Reactivation of the AR signaling axis occurs, which eventually leads to castration-resistant prostate cancer (CRPC), for which there is no curative treatment. Conventional imaging modalities available in the clinic, such as computed tomography (CT), magnetic resonance tomography (MR) and bone scan are of limited use for the detection of metastatic PCa. Conventional imaging modalities available in the clinic, such as computed tomography (CT), magnetic resonance tomography (MR) and bone scan are of limited use for the detection of metastatic PCa This contributes to a lack of clinical insight into the biomolecular
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