Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy

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Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy

Mortensen, Anja (author): Uppsala universitet,Medicinsk strålningsvetenskap,Marika Nestor

Spiegelberg, Diana, 1982- (author): Uppsala universitet,Öron-, näs- och halssjukdomar

Haylock, Anna-Karin (author): Uppsala universitet,Öron-, näs- och halssjukdomar

Lundqvist, Hans (author): Uppsala universitet,Medicinsk strålningsvetenskap

Nestor, Marika, 1976- (author): Uppsala universitet,Medicinsk strålningsvetenskap

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(creator_code:org_t)

2018-04-11
2018
English.
In: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 52:6, s. 1875-1885

Related links:: https://doi.org/10.3...; show more...; https://uu.diva-port... (primary) (Raw object); https://www.spandido...; https://urn.kb.se/re...; https://doi.org/10.3...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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 recombinant monoclonal anti-CD44v6 antibody, AbN44v6, and assessed its potential for use in RIT using either Lu-177 or I-131 as therapeutic radionuclides. In vitro affinity and specificity assays characterized the binding of the antibody labeled with Lu-177, I-125 or I-131. The therapeutic effects of Lu-177-AbN44v6 and I-131-AbN44v6 were investigated using two in vitro 3D tumor models with different CD44v6 expression. Finally, the normal tissue biodistribution and dosimetry for Lu-177-AbN44v6 and I-125-AbN44v6/I-131-AbN44v6 were assessed in vivo using a mouse model. All AbN44v6 radioconjugates demonstrated CD44v6-specific binding in vitro. In the in vitro 3D tumor models, dose-dependent therapeutic effects were observed with both Lu-177-AbN44v6 and I-131-AbN44v6, with a greater significant therapeutic effect observed on the cells with a higher CD44v6 expression. Biodistribution experiments demonstrated a greater uptake of Lu-177-AbN44v6 in the liver, spleen and bone, compared to I-125-AbN44v6, whereas I-125-AbN44v6 demonstrated a longer circulation time. In dosimetric calculations, the critical organs for Lu-177-AbN44v6 were the liver and spleen, whereas the kidneys and red marrow were considered the critical organs for I-131-AbN44v6. The effective dose was in the order of 0.1 mSv/MBq for both labels. In conclusion, AbN44v6 bound specifically 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 Lu-177-AbN44v6 and I-131-AbN44v6 may be promising RIT candidates. Furthermore, biodistribution and dosimetric analysis supported the applicability of both conjugates for RIT. The CD44v6-specific therapeutic effects observed with radiolabeled AbN44v6 in the 3D tumor models in vitro, combined with the beneficial dosimetry in vivo, render AbN44v6 a potential candidate for RIT.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Andra medicinska och farmaceutiska grundvetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Other Basic Medicine (hsv//eng)

Keyword

radio-immunotherapy
3D tumor models
dosimetry
biodistribution
177Lu
131I

Publication and Content Type

ref (subject category)
art (subject category)

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