4.6 Article

Comparative Evaluation of Novel 177Lu-Labeled PNA Probes for Affibody-Mediated PNA-Based Pretargeting

Journal

CANCERS
Volume 13, Issue 3, Pages -

Publisher

MDPI
DOI: 10.3390/cancers13030500

Keywords

pretargeting; PNA; affibody molecules; radionuclide therapy; HER2-expressing xenografts

Categories

Funding

  1. Swedish Cancer Society (Cancerfonden) [19 0212 Pj 01 H, CAN 2017/425, CAN 2018/436, CAN 2020/181]
  2. Swedish Research Council (Vetenskapsradet) [2019-00986, 2016-05207, 2019-00994]
  3. ProNova VINN Excellence Centre for Protein Technology
  4. Swedish Agency for Innovation (VINNOVA) [2019/00104]
  5. Vinnova [2019-00104, 2019-00994] Funding Source: Vinnova
  6. Swedish Research Council [2016-05207] Funding Source: Swedish Research Council

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The study showed that shortening PNA probes can significantly increase the difference in accumulation of radiometals in tumor xenografts and in kidneys, potentially leading to more efficient cancer therapy. This affibody-mediated PNA-based pretargeting approach holds promise for radionuclide therapy of HER2-expressing tumors.
Simple Summary Affibody molecules are small, engineered affinity proteins based on a nonimmunoglobulin scaffold. Affibody-based radionuclide imaging probes have demonstrated excellent tumor targeting. However, the renal clearance of affibody molecules is accompanied by high reabsorption and retention of activity in the kidney, which prevents their use for radionuclide therapy. We have previously shown the feasibility of overcoming the high renal uptake using a pretargeting approach for affibody-mediated therapy based on peptide nucleic acid (PNA) hybridization. In this study, we test the hypothesis that shortening the PNA pretargeting probes would further increase the difference between the accumulation of radiometals in tumor xenografts and in kidneys. A series of novel PNA probes has been designed and evaluated in vitro and in vivo. We have found that a variant containing 9 nucleobases enables a two-fold increase of the tumor-to-kidney dose ratio compared with a variant containing 15 nucleobases. This creates preconditions for more efficient therapy of cancer. Affibody-mediated PNA-based pretargeting is a promising approach to radionuclide therapy of HER2-expressing tumors. In this study, we test the hypothesis that shortening the PNA pretargeting probes would increase the tumor-to-kidney dose ratio. The primary probe Z(HER2:342)-SR-HP15 and the complementary secondary probes HP16, HP17, and HP18, containing 9, 12, and 15 nucleobases, respectively, and carrying a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator were designed, synthesized, characterized in vitro, and labeled with Lu-177. In vitro pretargeting was studied in HER2-expressing SKOV3 and BT474 cell lines. The biodistribution of these novel probes was evaluated in immunodeficient mice bearing SKOV3 xenografts and compared to the previously studied [Lu-177]Lu-HP2. Characterization confirmed the formation of high-affinity duplexes between HP15 and the secondary probes, with the affinity correlating with the length of the complementary PNA sequences. All the PNA-based probes were bound specifically to HER2-expressing cells in vitro. In vivo studies demonstrated HER2-specific uptake of all Lu-177-labeled probes in xenografts in a pretargeting setting. The ratio of cumulated radioactivity in the tumor to the radioactivity in kidneys was dependent on the secondary probe's size and decreased with an increased number of nucleobases. The shortest PNA probe, [Lu-177]Lu-HP16, showed the highest tumor-to-kidney ratio. [Lu-177]Lu-HP16 is the most promising secondary probe for affibody-mediated tumor pretargeting.

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