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.

doi:10.1101/2023.01.13.523947

bioRxiv · 10.1101/2023.01.13.523947

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.

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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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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.. 2023-01-14. An intravenous DNA-binding priming agent protects cell-free DNA and improves the sensitivity of liquid biopsies. https://doi.org/10.1101/2023.01.13.523947

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