DARPin-based Pretargeting: Zeroing in on Cancer

Conventional targeted radiotherapy often results in unwanted radiation exposure to healthy tissues.Our solution: Two-Step DARPin-Based Pretargeting Aim: Improve tumor-targeting while mimizing off-target effects in mice with HER2-expressing xenografts Key Benefits: Enhanced tumor specificity Reduced radiation to healthy tissues Potential for improved therapeutic window Step1: Primary agent G3-HP1 Non-radioactive DARPin-PNA conjugate Binds specifically to HER2-expressing tumors Carries HP1: a 15-mer PNA-based recognition sequence Is allowed to clear from bloodstreamStep 2: Secondary probe 177 Lu-HP2 Radiolabeled with Lutetium-177 for therapy and imaging Administred after optimized interval Either: Binds specifically to primary agent at tumor site via complementary PNA-sequence, or Rapidly clears through the kidneys Key Conclusions: Our two-step approch achieves an 8-fold increase in tumor uptake of 177 Lu Off-target accumulation is markedly reduced, with up to 370-fold decrease in liver uptake Results suggest potential for improved efficacy and reduced toxicity in treatment of HER2-positive cancers Future Implications:This pretargeting method may pave the way for more effective and safer targeted radionuclide therapies, improving treatment options for HER2-positive cancers.