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.
Competing Interest Statement
A provisional patent has been filed related to this work (PCT/US2022/013769) (ST, CMA, KX, SNB, VAA, JCL). T.R. Golub has advisor roles (paid) at Foundation Medicine, GlaxoSmithKline and Sherlock Biosciences. V.A. Adalsteinsson is a member of the scientific advisory boards of AGCT GmbH and Bertis Inc., which were not involved in this study. S.N.B. reports compensation for cofounding, consulting for, and/or board member- ship in Glympse Bio, Satellite Bio, CEND Therapeutics, Catalio Capital, Intergalactic Therapeutics, Port Therapeutics, Vertex Pharmaceuticals, and Moderna, and receives sponsored research funding from Johnson & Johnson, Revitope, and Owlstone. J.C.L. has interests in Sunflower Therapeutics PBC, Pfizer, Honeycomb Biotechnologies, OneCyte Biotechnologies, QuantumCyte, Amgen, and Repligen. Interests of J.C.L. are reviewed and managed under MIT policies for potential conflicts of interest. The remaining authors report no conflicts of interest.
Footnotes
↵¶ These authors jointly supervised this work.