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Generation and evaluation of antibody agents for molecular imaging of CD44v6-expressing cancers
KTH, School of Biotechnology (BIO), Protein Technology.
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 39, p. 65152-65170Article in journal (Refereed) Published
Abstract [en]

Aim: The aim of this study was to generate and characterize scFv antibodies directed to human CD44v6, as well as to radiolabel and evaluate top candidates in vitro and in vivo for their potential use in CD44v6-targeted molecular imaging in cancer patients. Materials and methods: Phage display selections were used to isolate CD44v6-specific scFvs. A chain shuffling strategy was employed for affinity maturation based on a set of CD44v6-specific first-generation clones. Two second-generation scFv clones were then chosen for labeling with 111In or 125I and assessed for CD44v6-specific binding on cultured tumor cells. In vivo uptake and distribution was evaluated in tumor-bearing mice using a dual tumor model. Finally, a proof-of-concept small animal PET-CT study was performed on one of the candidates labeled with 124I. Results: Two affinity-matured clones, CD44v6-scFv-A11 and CD44v6-scFv-H12, displayed promising binding kinetics. Seven out of eight radiolabeled conjugates demonstrated CD44v6-specific binding. In vivo studies on selected candidates demonstrated very advantageous tumor-to-organ ratios, in particular for iodinated conjugates, where 125I-labeled scFvs exhibited favorable kinetics and tumor-to-blood ratios above five already at 24 hours p. i.. The small animal PET-CT study using 124I-labeled CD44v6-scFv-H12 was in line with the biodistribution data, clearly visualizing the high CD44v6-expressing tumor. Conclusion: The single chain fragments, CD44v6-scFv-A11 and CD44v6-scFv-H12 specifically bind to CD44v6, and the radiolabeled counterparts provide high tumor-to-blood ratios and fast clearance from organs and blood. We conclude that radioiodinated CD44v6-scFv-A11 and CD44v6-scFv-H12 possess features highly suitable for stringent molecular imaging.

Place, publisher, year, edition, pages
Impact Journals LLC , 2017. Vol. 8, no 39, p. 65152-65170
Keywords [en]
scFv, recombinant antibody formats, CD44v6, squamous cell carcinoma, molecular imaging
National Category
Cell Biology Cancer and Oncology
Identifiers
URN: urn:nbn:se:kth:diva-215366DOI: 10.18632/oncotarget.17996ISI: 000410291200039Scopus ID: 2-s2.0-85021933853OAI: oai:DiVA.org:kth-215366DiVA, id: diva2:1147906
Funder
Swedish Cancer Society, CAN 2015/1080 CAN 2015/385Swedish Research Council, 2013-30876-104113-30 637-2013-468Swedish Society for Medical Research (SSMF)Knut and Alice Wallenberg Foundation, 2008.0133
Note

QC 20171009

Available from: 2017-10-09 Created: 2017-10-09 Last updated: 2017-11-29Bibliographically approved

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