An intravenous DNA-binding priming agent protects cell-free DNA and improves the sensitivity of liquid biopsies
Tabrizi, S.; Martin-Alonso, C.; Xiong, K.; Blewett, T.; Sridhar, S.; An, Z.; Patel, S.; Rodriguez-Aponte, S. A.; Naranjo, C. A.; Wang, S.-T.; Shea, D.; Golub, T.; Bhatia, S.; Adalsteinsson, V.; Love, J. C.
Show abstract
Blood-based, or "liquid," biopsies enable minimally invasive diagnostics but have limits on sensitivity due to scarce cell-free DNA (cfDNA). Improvements to sensitivity have primarily relied on enhancing sequencing technology ex vivo. Here, we sought to augment the level of circulating tumor DNA (ctDNA) detected in a blood draw by attenuating the clearance of cfDNA in vivo. We report a first-in-class intravenous DNA-binding priming agent given 2 hours prior to a blood draw to recover more cfDNA. The DNA-binding antibody minimizes nuclease digestion and organ uptake of cfDNA, decreasing its clearance at 1 hour by over 150-fold. To improve plasma persistence and limit potential immune interactions, we abrogated its Fc-effector function. We found that it protects GC-rich sequences and DNase-hypersensitive sites, which are ordinarily underrepresented in cfDNA. In tumor-bearing mice, priming improved tumor DNA recovery by 19-fold and sensitivity for detecting cancer from 6% to 84%. These results suggest a novel method to enhance the sensitivity of existing DNA-based cancer testing using blood biopsies.
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