Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

An Fc-Engineered Glycomodified Antibody Supports Proinflammatory Activation of Immune Effector Cells and Restricts Progression of Breast Cancer.

Show less

Author information

Affiliations

  • 1. Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom.
      Authors
    • Chenoweth AM 1, 2
    • Cheung A 1, 2
    • Trendell J 1
    • Navarro-Llinas B 1
    • Suriawinata E 1
    • McCraw A 1, 2
    • Ilieva KM 1, 2
    • Irshad S 1
    • Grigoriadis A 1, 5
    • Tutt ANJ 1, 4
    • Karagiannis SN 1, 2
    (11 authors)
  • 2. St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, Guy's Hospital, London, United Kingdom.
      Authors
    • Chenoweth AM 1, 2
    • Cheung A 1, 2
    • Chauhan J 2
    • Adams R 2
    • Osborn G 2
    • Stoker K 2, 8
    • Grandits M 2
    • Laddach R 2, 8
    • McCraw A 1, 2
    • Esapa B 2
    • Ilieva KM 1, 2
    • Romero-Clavijo P 2
    • Karagiannis SN 1, 2
    (13 authors)
  • 3. SeromYx Systems, Inc., Woburn, Massachusetts.
      Authors
    • Gross A 3
    • Clarke A 3
    • Brown L 3
    • Cserny J 3
    • Moise L 3
    • Jatiani S 3
    (6 authors)
  • 4. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.
      Authors
    • Haider S 4
    • Tutt ANJ 1, 4
    (2 authors)
  • 5. Cancer Bioinformatics, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom.
      Authors
    • Quist J 5
    • Grigoriadis A 1, 5
    (2 authors)
    • Show all (8)

ORCIDs linked to this article

Show all (34)

Cancer Research, 01 Nov 2025, 85(22):4521-4540
https://doi.org/10.1158/0008-5472.can-24-3174 PMID: 41128663 PMCID: PMC12616241

This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC

Abstract 

Fc engineering to enhance antibody effector functions harbors the potential to improve therapeutic effects. Understanding FcγR expression and distribution in the tumor microenvironment prior to and following treatment may help guide immune-engaging antibody design and patient stratification. In this study, we investigated FcR-expressing immune effector cells in HER2+ and triple-negative breast cancers (TNBC), including neoadjuvant chemotherapy-resistant disease. FcγRIIIa expression, FcγRIIIa+ NK cells, and classically activated (M1-like) macrophages correlated with improved anti-HER2 antibody efficacy. FcγRIIIa protein and FcγRIIIa+ NK cells and macrophages were present in primary TNBC and retained in treatment-resistant tumors. FcγRIIIa was spatially associated with folate receptor alpha-positive (FRα+) tumor areas at baseline and in residual tumors following neoadjuvant chemotherapy. Wild-type and Fc-engineered antibodies recognizing two breast cancer-associated antigens, HER2 and the emerging TNBC target FRα, were designed and generated to have increased FcγRIIIa-expressing effector cell engagement. The combination of glycoengineering, including fucose removal from the N-linked Fc glycan, and Fc point mutations greatly increased antibody affinity for and retention on FcγRIIIa. The Fc-engineered antibodies enhanced immune effector activity against HER2+ breast cancer and TNBC, altering proinflammatory cytokine production by NK cells and tumor-conditioned macrophages and skewing macrophages toward proinflammatory states. Furthermore, the Fc-engineered antibodies restricted orthotopic HER2+ and FRα+ breast cancer xenograft growth at doses suboptimal for equivalent wild-type antibodies and recruited FcγRIIIa-expressing cells into tumors. Antibody design through combined glycoengineering and Fc point mutations to enhance FcγRIIIa engagement of tumor-infiltrating effector cells may be a promising strategy for developing therapies for patients with aggressive and treatment-resistant breast cancers.

Significance

Assessment of Fc receptors and immune cells in breast cancer enables development of tailored engineering strategies for tumor-targeting monoclonal antibodies with enhanced immune-stimulating and anticancer attributes by combining glycoengineering and Fc mutations.

Free full text 

loading

Full text links 

Read article at publisher's site: https://doi.org/10.1158/0008-5472.can-24-3174

Citations & impact 

This article has not been cited yet.

Data 

Data behind the article

This data has been text mined from the article, or deposited into data resources.

Nucleotide Sequences

RRID - Resource Identification Portal (Showing 25 of 25)

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

    Funding 

    Funders who supported this work.

    Biotechnology and Biological Sciences Research Council (1)

    • Grant ID: BB/T008709/1

      Loading publications

    Breast Cancer Now (1)

    • Grant ID: 147KL-Q3

      Loading publications

    Cancer Research UK (1)

    • Grant ID: C7893/A29290

      Loading publications

    Medical Research Council (1)

    • Grant ID: MR/R015643/1

      Loading publications

    Worldwide Cancer Research (1)

    Worldwide Cancer Research (WCR) (1)

    • Grant ID: 24-0087

      Loading publications

    • Annotations
      In full text (1050)
    • Save
    • Open PDF
    • Claim to ORCID