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Preclinical evaluation of a novel engineered recombinant humananti-CD44v6 antibody for potential use in radio-immunotherapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Marika Nestor)ORCID iD: 0000-0002-6771-3289
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.ORCID iD: 0000-0002-1509-2142
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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2018 (English)In: International Journal of Oncology, ISSN 1019-6439Article in journal (Refereed) In press
Abstract [en]

CD44v6 is overexpressed in a variety of cancers,rendering it a promising target for radio-immunotherapy (RIT).In this study, we have characterized a novel engineered recombinantmonoclonal anti-CD44v6 antibody, AbN44v6, andassessed its potential for use in RIT using either 177Lu or 131Ias therapeutic radionuclides. In vitro affinity and specificityassays characterized the binding of the antibody labeled with177Lu, 125I or 131I. The therapeutic effects of 177Lu-AbN44v6 and131I-AbN44v6 were investigated using two in vitro 3D tumormodels with different CD44v6 expression. Finally, the normaltissue biodistribution and dosimetry for 177Lu-AbN44v6 and125I-AbN44v6/131I-AbN44v6 were assessed in vivo using amouse model. All AbN44v6 radioconjugates demonstratedCD44v6-specific binding in vitro. In the in vitro 3D tumormodels, dose-dependent therapeutic effects were observedwith both 177Lu-AbN44v6 and 131I-AbN44v6, with a greatersignificant therapeutic effect observed on the cells with a higherCD44v6 expression. Biodistribution experiments demonstrateda greater uptake of 177Lu-AbN44v6 in the liver, spleen and bone,compared to 125I-AbN44v6, whereas 125I-AbN44v6 demonstrateda longer circulation time. In dosimetric calculations, thecritical organs for 177Lu-AbN44v6 were the liver and spleen,whereas the kidneys and red marrow were considered the criticalorgans for 131I-AbN44v6. The effective dose was in the order of0.1 mSv/MBq for both labels. In conclusion, AbN44v6 boundspecifically and with high affinity to CD44v6. Furthermore,in vitro RIT demonstrated growth inhibition in a CD44v6-specific activity-dependent manner for both radioconjugates,demonstrating that both 177Lu-AbN44v6 and 131I-AbN44v6 maybe promising RIT candidates. Furthermore, biodistributionand dosimetric analysis supported the applicability of bothconjugates for RIT. The CD44v6-specific therapeutic effectsobserved with radiolabeled AbN44v6 in the 3D tumor modelsin vitro, combined with the beneficial dosimetry

Place, publisher, year, edition, pages
2018.
Keyword [en]
radio-immunotherapy, 3D tumor models, dosimetry, biodistribution, 177Lu, 131I
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-341765OAI: oai:DiVA.org:uu-341765DiVA, id: diva2:1182763
Available from: 2018-02-14 Created: 2018-02-14 Last updated: 2018-02-18
In thesis
1. Precision medicine and targeted therapy: Turning the tables on cancer
Open this publication in new window or tab >>Precision medicine and targeted therapy: Turning the tables on cancer
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

An extended understanding of the molecular characteristics of cancer has led to a revolution within the field of precision medicine. This thesis explores the utilization of two targets for precision medicine, namely, CD44v6 and murine double-minute 2 and X (MDM2/X).

A novel mini-antibody construct targeting CD44v6 (AbD19384), was assessed for possible use in radiodiagnostics, while a recombinant full-length anti-CD44v6 antibody based on the same construct, AbN44v6, was evaluated for radio-immunotherapy (RIT) following labeling with 177Lu and 131I. Additionally, normal tissue biodistribution and dosimetry was assessed for radiolabeled AbN44v6. The efficacy and mechanisms behind the observed effects of PM2 therapy, a novel stapled peptide that inhibits MDM2/X, were assessed in vitro and in vivo both as monotherapy and in combination with external beam radiotherapy (EBRT). Lastly, combination therapy using RIT (177Lu-AbN44v6) and PM2 was evaluated in an in vitro 3D tumor spheroid model.

AbD19384 successfully visualized CD44v6-positive xenografts. Similarly, radiolabeled AbN44v6 bound specifically to CD44v6, and RIT resulted in antigen-dependent, activity-dependent growth inhibition of in vitro 3D tumor spheroids. Biodistribution and dosimetry revealed low-level accumulation in normal tissues and low total effective doses of 0.1 mSv/MBq of injected radioconjugate. PM2-based therapy increased pro-apoptotic protein levels and caused growth inhibition of wt p53 cancer cell lines, which was amplified in combination with radiotherapy. In vivo studies of wt p53 and p53-knockout xenografts demonstrated the specificity of PM2 towards wt p53 cancers and established the potency of combining PM2-based therapy with EBRT.

The work presented in this thesis exemplifies the potency of combination treatments based on a precise understanding of the targeted cancer. Utilizing not one but several of the molecular characteristics of a specific cancer will help turn the tables on cancer and improve patient outcomes in the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 56
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1430
Keyword
p53 cancers, PM2, radiosensitization, radio-immunotherapy, MDM2/X inhibition, combination therapy, targeted radionuclide therapy, CD44v6
National Category
Medical and Health Sciences
Research subject
Biomedical Radiation Science
Identifiers
urn:nbn:se:uu:diva-342030 (URN)978-91-513-0239-3 (ISBN)
Public defence
2018-04-06, Rudbecksalen, Dag Hammarskjölds Väg 20, Uppsala, 13:00 (English)
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Supervisors
Available from: 2018-03-13 Created: 2018-02-18 Last updated: 2018-04-24

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