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

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

Mortensen, Anja (author): Uppsala University,Karolinska Institute,Uppsala universitet,Cancerprecisionsmedicin,Science for Life Laboratory, SciLifeLab,Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.

Berglund, Hanna (author): Uppsala University,Uppsala universitet,Cancerprecisionsmedicin,Science for Life Laboratory, SciLifeLab

Segerström, Lova (author): Uppsala University,Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab

Walle, M. (author): Lund University,Lunds universitet,Institutionen för immunteknologi,Institutioner vid LTH,Lunds Tekniska Högskola,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Department of Immunotechnology,Departments at LTH,Faculty of Engineering, LTH,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Science for Life Laboratory (SciLifeLab)

Hofström, Camilla (author): KTH Royal Institute of Technology,KTH,Science for Life Laboratory, SciLifeLab,Läkemedelsutveckling,Karolinska Inst, Drug Discovery & Dev Platform, Stockholm, Sweden.;KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden.,Science for Life Laboratory (SciLifeLab)

Persson, Helena (author): KTH Royal Institute of Technology,KTH,Science for Life Laboratory, SciLifeLab,Läkemedelsutveckling,Karolinska Inst, Drug Discovery & Dev Platform, Stockholm, Sweden.;KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden.,Science for Life Laboratory (SciLifeLab)

Nygren, Per-Åke, 1961- (author): KTH Royal Institute of Technology,KTH,Science for Life Laboratory, SciLifeLab,Läkemedelsutveckling,Drug Discovery and Development Platform, Science for Life Laboratory (SciLifeLab), Stockholm, Sweden.;Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.

Nilvebrant, Johan, 1982- (author): KTH Royal Institute of Technology,KTH,Proteinteknologi,Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden,KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden.

Frejd, Fredrik Y. (author): Uppsala University,Uppsala universitet,Cancerprecisionsmedicin,Science for Life Laboratory, SciLifeLab

Nestor, Marika, 1976- (author): Uppsala University,Uppsala universitet,Cancerprecisionsmedicin,Science for Life Laboratory, SciLifeLab

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Springer Nature, 2023
2023
English.
In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1

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Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)

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By the author/editor: Mortensen, Anja; Berglund, Hanna; Segerström, Lova; Walle, M.; Hofström, Camill ...; Persson, Helena; show more...; Nygren, Per-Åke, ...; Nilvebrant, Joha ...; Frejd, Fredrik Y ...; Nestor, Marika, ...; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Radiology Nuclea ...

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By the university: Royal Institute of Technology; Uppsala University; Karolinska Institutet; Lund University

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