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Humanization, radiolabeling and biodistribution studies of an igg1-type antibody targeting uncomplexed psa for theranostic applications

Strand, Joanna LU ; Sjöström, Kjell ; Lamminmaki, Urpo J. ; Timmermand, Oskar Vilhelmsson LU ; Strand, Sven Erik LU and Tran, Thuy A. LU (2021) In Pharmaceuticals 14(12).
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... (More)

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.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
5A10, FPSA, Humanization, Imaging, Prostate cancer, Theranostics
in
Pharmaceuticals
volume
14
issue
12
article number
1251
publisher
MDPI AG
external identifiers
  • scopus:85121304426
  • pmid:34959652
ISSN
1424-8247
DOI
10.3390/ph14121251
language
English
LU publication?
yes
id
3fd8f991-c120-47cd-b263-e6b2f9bda772
date added to LUP
2022-01-27 11:54:35
date last changed
2024-06-01 23:57:24
@article{3fd8f991-c120-47cd-b263-e6b2f9bda772,
  abstract     = {{<p>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.</p>}},
  author       = {{Strand, Joanna and Sjöström, Kjell and Lamminmaki, Urpo J. and Timmermand, Oskar Vilhelmsson and Strand, Sven Erik and Tran, Thuy A.}},
  issn         = {{1424-8247}},
  keywords     = {{5A10; FPSA; Humanization; Imaging; Prostate cancer; Theranostics}},
  language     = {{eng}},
  number       = {{12}},
  publisher    = {{MDPI AG}},
  series       = {{Pharmaceuticals}},
  title        = {{Humanization, radiolabeling and biodistribution studies of an igg<sub>1</sub>-type antibody targeting uncomplexed psa for theranostic applications}},
  url          = {{http://dx.doi.org/10.3390/ph14121251}},
  doi          = {{10.3390/ph14121251}},
  volume       = {{14}},
  year         = {{2021}},
}