Theranostics 2016; 6(1):93-103. doi:10.7150/thno.12766 This issue Cite

Research Paper

Feasibility of Affibody Molecule-Based PNA-Mediated Radionuclide Pretargeting of Malignant Tumors

Hadis Honarvar1*, Kristina Westerlund2*, Mohamed Altai1, Mattias Sandström3, Anna Orlova4, Vladimir Tolmachev1#, Amelie Eriksson Karlström2#✉

1. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2. School of Biotechnology, Division of Protein Technology, KTH Royal Institute of Technology, Stockholm, Sweden
3. Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
4. Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
*These authors contributed equally
# Shared senior authorship

Citation:
Honarvar H, Westerlund K, Altai M, Sandström M, Orlova A, Tolmachev V, Karlström AE. Feasibility of Affibody Molecule-Based PNA-Mediated Radionuclide Pretargeting of Malignant Tumors. Theranostics 2016; 6(1):93-103. doi:10.7150/thno.12766. https://www.thno.org/v06p0093.htm
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Abstract

Graphic abstract

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 125I and 111In. 111In-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 111In-/125I-HP2 to ZHER2:342-SR-HP1 pre-treated cells was demonstrated. 111In-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 111In-ZHER2:342-SR-HP1. The complementary PNA probe 111In/125I-HP2 accumulated in SKOV-3 xenografts when ZHER2:342-SR-HP1 was injected 4 h earlier. The tumor accumulation of 111In/125I-HP2 was negligible without ZHER2:342-SR-HP1 pre-injection. The uptake of 111In-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.

Keywords: Affibody, peptide nucleic acid, radionuclide pretargeting, scaffold protein, HER2


Citation styles

APA
Honarvar, H., Westerlund, K., Altai, M., Sandström, M., Orlova, A., Tolmachev, V., Karlström, A.E. (2016). Feasibility of Affibody Molecule-Based PNA-Mediated Radionuclide Pretargeting of Malignant Tumors. Theranostics, 6(1), 93-103. https://doi.org/10.7150/thno.12766.

ACS
Honarvar, H.; Westerlund, K.; Altai, M.; Sandström, M.; Orlova, A.; Tolmachev, V.; Karlström, A.E. Feasibility of Affibody Molecule-Based PNA-Mediated Radionuclide Pretargeting of Malignant Tumors. Theranostics 2016, 6 (1), 93-103. DOI: 10.7150/thno.12766.

NLM
Honarvar H, Westerlund K, Altai M, Sandström M, Orlova A, Tolmachev V, Karlström AE. Feasibility of Affibody Molecule-Based PNA-Mediated Radionuclide Pretargeting of Malignant Tumors. Theranostics 2016; 6(1):93-103. doi:10.7150/thno.12766. https://www.thno.org/v06p0093.htm

CSE
Honarvar H, Westerlund K, Altai M, Sandström M, Orlova A, Tolmachev V, Karlström AE. 2016. Feasibility of Affibody Molecule-Based PNA-Mediated Radionuclide Pretargeting of Malignant Tumors. Theranostics. 6(1):93-103.

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