# In vivo enrichment of cell-free DNA to boost sensitivity of circulating nucleic-acid based diagnostics

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $193,901

## Abstract

PROJECT SUMMARY/ABSTRACT
Robust diagnostics are critical to healthcare. Analysis of circulating nucleic acids such as cell-free DNA
(cfDNA) is a rapidly expanding class of diagnostics in several fields of medicine, including cancer and
infectious diseases. In oncology, detection of circulating tumor DNA (ctDNA) often precedes appearance of
disease on imaging, raising the possibility that it can be used for early detection of cancer. But despite
significant improvements in the accuracy and cost of next-generation sequencing, routine use of cfDNA in most
clinical settings remains limited by low sensitivity. The cause of low sensitivity is the intrinsic low level of ctDNA
in plasma. ctDNA fragments bearing tumor-specific features are often absent from a blood draw due to
stochastic partitioning at low ctDNA concentrations. This physical absence of ctDNA fragments cannot be
overcome with more accurate sequencing or better computational approaches after a sample has been
collected. We have developed a novel approach to directly address this limitation at time of sample collection.
Our preliminary results show that an engineered DNA-binding monoclonal antibody (mAb) can protect cfDNA in
plasma and increase recovery of ctDNA by 20-fold. This proposal expands on this finding to understand what
factors are important for improving recovery of ctDNA using mAbs, to engineer mAbs that can recover even
more ctDNA, and to extend this concept to target epigenetic features of cfDNA. Our hypothesis is that
engineering the binding affinity, binding specificity, and pharmacokinetics of mAbs can further improve the
recovery of ctDNA, and that mAbs that target methylated cfDNA can help enrich ctDNA from highly methylated
regions of the tumor genome. In Aim 1, we will test a custom-designed panel of engineered mAbs with different
binding relationships to cfDNA and different Fc modifications to determine what factors influence their
performance. In Aim 2, we will extend this approach to epigenetic markers, focusing on cfDNA methylation.
Taking advantage of the fact that CpG islands are hypermethylated in many tumors, we will develop agents
that can enrich DNA with methylated CpGs, and hence enrich hypermethylated tumor DNA at CpG islands.
The candidate is a radiation oncologist and physician-scientist at Massachusetts General Hospital (MGH) and
a post-doctoral scientist at Massachusetts Institute of Technology (MIT) and the Broad Institute, where the
work outlined in this proposal will be conducted. A diverse team of mentors (Dr. J. Christopher Love, Dr.
Sangeeta Bhatia, Dr. Viktor Adalsteinsson) and advisors (Dr. Theodore Hong, Dr. David Miyamoto), spanning
three world-class institutions (MIT, Broad Institute, MGH), will support the candidate in successful completion of
the research goals and training plan outlined in this proposal. The proposed work includes a career
development plan that will enable the candidate to gain the necessary technical, scientific, and leade...

## Key facts

- **NIH application ID:** 10947415
- **Project number:** 1K08EB036081-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** SHERVIN TABRIZI
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $193,901
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10947415

## Citation

> US National Institutes of Health, RePORTER application 10947415, In vivo enrichment of cell-free DNA to boost sensitivity of circulating nucleic-acid based diagnostics (1K08EB036081-01). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/10947415. Licensed CC0.

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