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Feasibility of Affibody Molecule-Based PNA-Mediated Radionuclide Pretargeting of Malignant Tumors
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. (Vladimir Tolmachev)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. (Vladimir Tolmachev)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
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2016 (Engelska)Ingår i: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 6, nr 1, s. 93-103Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Affibody molecules are small (7 kDa), non-immunoglobulin scaffold proteins with a potential as targeting agents for radionuclide imaging of cancer. However, high renal re-absorption of Affibody molecules prevents their use for radionuclide therapy with residualizing radiometals. We hypothesized that the use of Affibody-based peptide nucleic acid (PNA)-mediated pretargeting would enable higher accumulation of radiometals in tumors than in kidneys. To test this hypothesis, we designed an Affibody-PNA chimera ZHER2:342-SR-HP1 containing a 15-mer HP1 PNA recognition tag and a complementary HP2 hybridization probe permitting labeling with both (125)I and (111)In. (111)In-ZHER2:342-SR-HP1 bound specifically to HER2-expressing BT474 and SKOV-3 cancer cells in vitro, with a KD of 6±2 pM for binding to SKOV-3 cells. Specific high affinity binding of the radiolabeled complementary PNA probe (111)In-/(125)I-HP2 to ZHER2:342-SR-HP1 pre-treated cells was demonstrated. (111)In-ZHER2:342-SR-HP1 demonstrated specific accumulation in SKOV-3 xenografts in BALB/C nu/nu mice and rapid clearance from blood. Pre-saturation of SKOV-3 with non-labeled anti-HER2 Affibody or the use of HER2-negative Ramos xenografts resulted in significantly lower tumor uptake of (111)In-ZHER2:342-SR-HP1. The complementary PNA probe (111)In/(125)I-HP2 accumulated in SKOV-3 xenografts when ZHER2:342-SR-HP1 was injected 4 h earlier. The tumor accumulation of (111)In/(125)I-HP2 was negligible without ZHER2:342-SR-HP1 pre-injection. The uptake of (111)In-HP2 in SKOV-3 xenografts was 19±2 %ID/g at 1 h after injection. The uptake in blood and kidneys was approximately 50- and 2-fold lower, respectively. In conclusion, we have shown that the use of Affibody-based PNA-mediated pretargeting enables specific delivery of radiometals to tumors and provides higher radiometal concentration in tumors than in kidneys.

Ort, förlag, år, upplaga, sidor
2016. Vol. 6, nr 1, s. 93-103
Nyckelord [en]
Affibody; peptide nucleic acid; radionuclide pretargeting; scaffold protein; HER2
Nationell ämneskategori
Klinisk medicin
Identifikatorer
URN: urn:nbn:se:uu:diva-273542DOI: 10.7150/thno.12766ISI: 000371806600001PubMedID: 26722376OAI: oai:DiVA.org:uu-273542DiVA, id: diva2:894789
Forskningsfinansiär
Cancerfonden, 2012/354Vetenskapsrådet, 521-2012-2228Vetenskapsrådet, 621-2013-5135
Anmärkning

De två första författarna delar förstaförfattarskapet och de två sista författarna delar sistaförfattarskapet.

Tillgänglig från: 2016-01-15 Skapad: 2016-01-15 Senast uppdaterad: 2017-11-30Bibliografiskt granskad
Ingår i avhandling
1. Development of Affibody molecules for radionuclide molecular imaging and therapy of cancer
Öppna denna publikation i ny flik eller fönster >>Development of Affibody molecules for radionuclide molecular imaging and therapy of cancer
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Affibody molecules are a promising class of scaffold-based targeting proteins for radionuclide-based imaging and therapy of cancer. This thesis work is based on 5 original research articles (papers I-V), which focus on optimization of molecular design of HER2-binding Affibody variants for high contrast imaging of this predictive biomarker as well as development of Affibody molecules suitable for radionuclide-based targeted therapies. 

Papers I and II were dedicated to evaluation of the influence of the macrocyclic chelator DOTA positioning at N-terminus, in the middle of helix-3 and at C terminus of a synthetic Affibody molecule, ZHER2:S1. These synthetic variants were labelled with different radionuclides i.e. 111In and 68Ga to study also the effect of different labels on their biodistribution properties.

In paper III a 2-helix variant, Z342min, was developed using native ligation cyclization to cross-link helices one and two resulting in a stable 2-helix scaffold and characterized in vivo. This study was performed with the aim to obtain structure-properties relationship for development of smaller Affibody molecules.  

Papers IV and V were devoted to development of therapeutic strategies. In paper IV, a series of peptide based chelators was investigated for labelling of Affibody molecules with 188Re to provide low renal retention. In paper V, a pretargeting approach using peptide nucleic acid was investigated. These studies were performed with the aim to overcome the high renal retention of Affibody molecules when labelled with residualizing therapeutic radionuclides. Otherwise, the particle emitting radiometals could damage the kidneys more than the tumours.

The results obtained for anti-HER2 Affibody molecules summarized in this thesis might be of importance for the development of other scaffold protein based targeting agents.

 

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 71
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1237
Nyckelord
Affibody molecules, HER2, Molecular imaging, Radionuclide targeted therapy, Radionuclide molecular imaging, Labeling chemistry
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Biomedicinsk strålningsvetenskap
Identifikatorer
urn:nbn:se:uu:diva-298740 (URN)978-91-554-9624-1 (ISBN)
Externt samarbete:
Disputation
2016-09-24, Fåhraeus Hall, Dag Hammarskjölds väg 20, Uppsala, 09:30 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-08-31 Skapad: 2016-07-06 Senast uppdaterad: 2016-09-05

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