Evidence map›Paper›PMID 42183362›Full record

ArticleResearch square2026

A first-in-class precision antibody conjugate targeting EGFR, mTOR, and PI3K to treat head and neck cancers.

Xiaoyi Li, Meghri Katerji, Lily M Klapper, Siddharth Matikonda, Nick Brill-Edwards, Aamna Siddiqui, Chathuranga Rathnamalala, Mo Yang, Jungwuk Lee, Ryan Bensen and 6 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Research square, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Xiaoyi LiChemical and Biological Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Meghri KaterjiDepartment of Surgery, Pharmacology, and Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, Syracuse, NY 13210.
Lily M KlapperLaboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Siddharth MatikondaChemical and Biological Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Nick Brill-EdwardsLaboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Aamna SiddiquiLaboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Chathuranga RathnamalalaChemical and Biological Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Mo YangChemical and Biological Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Jungwuk LeeLaboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Ryan BensenLaboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
Lai ThangAnimal Technical Support, Laboratory Animal Sciences Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
Simone DifilippantonioAnimal Technical Support, Laboratory Animal Sciences Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
Julien Dugal-TessierNJ Bio Inc., Princeton, NJ 08540.
Shengzong LiangNJ Bio Inc., Princeton, NJ 08540.
John BrognardDepartment of Surgery, Pharmacology, and Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, Syracuse, NY 13210.ORCID 0000-0002-9243-6615
Martin SchnermannChemical and Biological Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.

Funding

CCR NIH HHS HHSN261200800001CNIH HHS HHSN261200800001E
6 · The paper itself

Abstract

Head and neck squamous cell carcinoma (HNSCC) exhibits limited response to EGFR blockade with cetuximab, largely due to constant activation of the PI3K/AKT/mTOR pathways. Despite the development of numerous PI3K/mTOR inhibitors, their clinical application remains constrained by dose-limiting on-target toxicities. Here we report PAC-XL, a precision antibody conjugate linking the PI3K/mTOR inhibitor BGT226 to cetuximab through a β-glucuronidase-cleavable benzyl-ammonium carbamate (BAC) linker. Unlike conventional linkers, the BAC chemistry enabled a homogeneous, high drug-to-antibody ratio (DAR=8) conjugate that preserved EGFR binding, antigen-mediated uptake, lysosomal trafficking, plasma stability, and enzyme-dependent payload release. PAC-XL induced EGFR- and PI3K/mTOR-dependent cytotoxicity, suppressed PI3K/mTOR signaling, and triggered apoptosis in PIK3CA-altered HNSCC models. In xenografts, PAC-XL outperformed cetuximab, BGT226 and alpelisib, including complete regressions, while reducing hyperglycemia and weight loss caused by systemic PI3K/mTOR inhibition. These findings establish targeted delivery of PI3K/mTOR inhibitors as a strategy to enhance efficacy while improving tolerability in HNSCC.

Identifiers

PMID42183362
PMCPMC13193103

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.