Evidence map›Paper›PMID 41106435›Full record

ArticleJournal of controlled release : official journal of the Controlled Release Society2025

Structure-guided design and engineering of a biparatopic antibody targeting CCR2 in triple negative breast cancer.

Timothy S Little, Yuyan Wang, Ameya P Chaudhari, Omar M Budayr, Jessica G Tetterton-Kellner, Alexander G Bastian, Adam D Brown, Natalie E Jasiewicz, Amelia C McCue, H Shelton Earp and 2 more

Abstract read
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In one paragraph

Article in Journal of controlled release : official journal of the Controlled Release Society, 2025. 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

12 authors.

Timothy S LittleDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Yuyan WangDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Ameya P ChaudhariDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Omar M BudayrDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jessica G Tetterton-KellnerDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Alexander G BastianLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Adam D BrownDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Natalie E JasiewiczDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Amelia C McCueDepartment of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
H Shelton EarpLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Medicine, Division of Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Brian C MillerDepartment of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Medicine, Division of Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Juliane NguyenDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: julianen@email.unc.edu.

Funding

Polarizing Macrophages to Tumor Suppressors by Blocking Multiple CCR2 Chemokine Receptor EpitopesR01CA241679 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI NGUYEN, JULIANE · 2020 to 2024
$1.9M
NCI NIH HHS R01 CA241679
6 · The paper itself

Abstract

Chemokine signaling plays a pivotal role in cancer progression, shaping the tumor microenvironment and influencing disease outcomes. Among these, interactions between the chemokine CCR2 receptor and its ligand CCL2 has been shown to be a key driver of cancer progression by recruiting immune-suppressive cells to the tumor microenvironment. Most CCR2-targeting antibodies block the N-terminal domain (NTD) of the receptor as this is the primary binding site of its ligand CCL2. However, CCR2 contains three additional extracellular loops that also participate in binding interactions, thus mediating downstream signaling. Here, we developed a biparatopic antibody that targets two distinct, non-overlapping epitopes on CCR2: the NTD and the extracellular loop 3 (ECL3). We hypothesized that simultaneously blocking two distinct epitopes on CCR2 would more effectively inhibit the CCR2/CCL2 signaling axis, thus curtailing tumor progression. Binding interactions were modeled using AlphaFold and HADDOCK and validated by ELISA and surface plasmon resonance assays. When compared to monospecific constructs, the biparatopic antibody demonstrated stronger binding affinity to a CCR2-mimicking peptide. Functional studies showed that treatment with the biparatopic antibody enhanced macrophage polarization to a pro-inflammatory (anti-tumor) state, with up to 70-fold improvement in M1/M2 ratios in bone marrow-derived macrophages relative to single-epitope blockers. In a murine model of triple-negative breast cancer, the biparatopic antibody demonstrated a significant reduction in tumor growth. These findings highlight its potential as a therapeutic agent for reshaping macrophage polarization and inhibiting tumor progression.

Indexed as

Receptors, CCR2Triple Negative Breast NeoplasmsAnimalsCell Line, TumorChemokine CCL2EpitopesFemaleHumansMiceCCR2 protein, humanChemokine CCL2EpitopesReceptors, CCR2Bispecific antibodyChemokine receptorsMacrophage polarizationTNBC immunotherapy

Identifiers

PMID41106435
PMCPMC12951773

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

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.