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Selection, characterization and in vivo evaluation of novel CD44v6-targeting antibodies for targeted molecular radiotherapy

Mortensen, A. C.L. ; Berglund, H. ; Segerström, L. ; Walle, M. LU ; Hofström, C. ; Persson, H. ; Nygren, Per-Åke ; Nilvebrant, J. ; Frejd, F. Y. and Nestor, M. (2023) In Scientific Reports 13(1).
Abstract

Molecular radiotherapy combines the advantages of systemic administration of highly specific antibodies or peptides and the localized potency of ionizing radiation. A potential target for molecular radiotherapy is the cell surface antigen CD44v6, which is overexpressed in numerous cancers, with limited expression in normal tissues. The aim of the present study was to generate and characterize a panel of human anti-CD44v6 antibodies and identify a suitable candidate for future use in molecular radiotherapy of CD44v6-expressing cancers. Binders were first isolated from large synthetic phage display libraries containing human scFv and Fab antibody fragments. The antibodies were extensively analyzed through in vitro investigations of... (More)

Molecular radiotherapy combines the advantages of systemic administration of highly specific antibodies or peptides and the localized potency of ionizing radiation. A potential target for molecular radiotherapy is the cell surface antigen CD44v6, which is overexpressed in numerous cancers, with limited expression in normal tissues. The aim of the present study was to generate and characterize a panel of human anti-CD44v6 antibodies and identify a suitable candidate for future use in molecular radiotherapy of CD44v6-expressing cancers. Binders were first isolated from large synthetic phage display libraries containing human scFv and Fab antibody fragments. The antibodies were extensively analyzed through in vitro investigations of binding kinetics, affinity, off-target binding, and cell binding. Lead candidates were further subjected to in vivo biodistribution studies in mice bearing anaplastic thyroid cancer xenografts that express high levels of CD44v6. Additionally, antigen-dependent tumor uptake of the lead candidate was verified in additional xenograft models with varying levels of target expression. Interestingly, although only small differences were observed among the top antibody candidates in vitro, significant differences in tumor uptake and retention were uncovered in in vivo experiments. A high-affinity anti-CD44v6 lead drug candidate was identified, mAb UU-40, which exhibited favorable target binding properties and in vivo distribution. In conclusion, a panel of human anti-CD44v6 antibodies was successfully generated and characterized in this study. Through comprehensive evaluation, mAb UU-40 was identified as a promising lead candidate for future molecular radiotherapy of CD44v6-expressing cancers due to its high affinity, excellent target binding properties, and desirable in vivo distribution characteristics.

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publishing date
type
Contribution to journal
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published
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in
Scientific Reports
volume
13
issue
1
article number
20648
publisher
Nature Publishing Group
external identifiers
  • pmid:38001360
  • scopus:85177659141
ISSN
2045-2322
DOI
10.1038/s41598-023-47891-2
language
English
LU publication?
yes
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Funding Information: Open access funding provided by Karolinska Institute. Funding was provided by The Swedish Cancer Society (Cancerfonden), Svenska Sällskapet för Medicinsk Forskning (SSMF), The Swedish Research Council (Vetenskapsrådet), VINNOVA and The Swedish Childhood Cancer Fund (Barncancerfonden). Publisher Copyright: © 2023, The Author(s).
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05b3aba5-b10e-4ae2-892e-0b4363272988
date added to LUP
2023-12-21 10:52:50
date last changed
2024-06-15 01:37:45
@article{05b3aba5-b10e-4ae2-892e-0b4363272988,
  abstract     = {{<p>Molecular radiotherapy combines the advantages of systemic administration of highly specific antibodies or peptides and the localized potency of ionizing radiation. A potential target for molecular radiotherapy is the cell surface antigen CD44v6, which is overexpressed in numerous cancers, with limited expression in normal tissues. The aim of the present study was to generate and characterize a panel of human anti-CD44v6 antibodies and identify a suitable candidate for future use in molecular radiotherapy of CD44v6-expressing cancers. Binders were first isolated from large synthetic phage display libraries containing human scFv and Fab antibody fragments. The antibodies were extensively analyzed through in vitro investigations of binding kinetics, affinity, off-target binding, and cell binding. Lead candidates were further subjected to in vivo biodistribution studies in mice bearing anaplastic thyroid cancer xenografts that express high levels of CD44v6. Additionally, antigen-dependent tumor uptake of the lead candidate was verified in additional xenograft models with varying levels of target expression. Interestingly, although only small differences were observed among the top antibody candidates in vitro, significant differences in tumor uptake and retention were uncovered in in vivo experiments. A high-affinity anti-CD44v6 lead drug candidate was identified, mAb UU-40, which exhibited favorable target binding properties and in vivo distribution. In conclusion, a panel of human anti-CD44v6 antibodies was successfully generated and characterized in this study. Through comprehensive evaluation, mAb UU-40 was identified as a promising lead candidate for future molecular radiotherapy of CD44v6-expressing cancers due to its high affinity, excellent target binding properties, and desirable in vivo distribution characteristics.</p>}},
  author       = {{Mortensen, A. C.L. and Berglund, H. and Segerström, L. and Walle, M. and Hofström, C. and Persson, H. and Nygren, Per-Åke and Nilvebrant, J. and Frejd, F. Y. and Nestor, M.}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Selection, characterization and in vivo evaluation of novel CD44v6-targeting antibodies for targeted molecular radiotherapy}},
  url          = {{http://dx.doi.org/10.1038/s41598-023-47891-2}},
  doi          = {{10.1038/s41598-023-47891-2}},
  volume       = {{13}},
  year         = {{2023}},
}