{
  "abstract": "Targeting highly abundant stromal antigens in solid tumors is often limited by antigen sink effects, which reduce therapeutic exposure and compromise efficacy. Transforming growth factor beta-induced protein ig-h3 (TGFBI/BIGH3) is a secreted extracellular matrix (ECM) protein overexpressed in multiple malignancies and involved in tumor progression and immune modulation, yet its high circulating levels present a major challenge for antibody-based targeting. Here, we report that structural characterization suggested an increased oligomerization of BIGH3 in the tumor microenvironment (TME)-mimicking conditions without detectable loss of antibody binding and affinity (Equilibrium dissociation constant (KD) or half-maximal effective concentration (EC50)). We also demonstrate that pH-sensitive anti-BIGH3 antibodies can be engineered to preferentially bind under acidic conditions that mimics the TME while reducing binding under physiological pH. Through iterative humanization, oligomerization assessment, fragment crystallizable region (Fc) optimization, and structure-guided mutagenesis, we generated variants exhibiting robust tumor-relevant binding combined with reduced affinity at neutral pH. Biophysical analyses confirmed preserved stability and manufacturability profiles, while in vitro studies demonstrated pH-dependent target engagement and in vivo studies showed anti-tumor effect in colorectal cancer mouse model. These findings support the feasibility of a strategy aimed at mitigating antigen sink by exploiting tumor-associated pH gradients, although direct in vivo pharmacokinetic (PK), biodistribution and tumor accumulation studies remain to be performed. Collectively, this work provides a proof-of-concept (PoC) framework for the development of conditionally active antibodies targeting highly expressed extracellular antigens in solid tumors and highlights pH-dependent engineering as a potentially generalizable approach to improve therapeutic index.",
  "abstract_shown": true,
  "affiliations": [
    "StromaCare SAS, Department of Research and Development, Lyon, France; Corresponding author.",
    "StromaCare SAS, Department of Research and Development, Lyon, France",
    "Abzena, Department of Research and Development, Cambridge, United Kingdom",
    "GCLIPS Biotech, Department of Research and Development, Toulouse, France"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Karine Aguéra"
    },
    {
      "affs": [
        1
      ],
      "name": "Sahar Kassem"
    },
    {
      "affs": [
        1
      ],
      "name": "Sophie Bachy"
    },
    {
      "affs": [
        2
      ],
      "name": "Arron Hearn"
    },
    {
      "affs": [
        2
      ],
      "name": "Dawn Bembridge"
    },
    {
      "affs": [
        2
      ],
      "name": "Farnoush Masoudzadeh"
    },
    {
      "affs": [
        3
      ],
      "name": "Héliciane Palenzuela"
    },
    {
      "affs": [
        3
      ],
      "name": "Rosie Dawaliby"
    },
    {
      "affs": [
        0
      ],
      "name": "Georges Rawadi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8b1tqzf21bt5d.bib",
  "cited_by": 0,
  "doi": "10.1016/j.bbrep.2026.102769",
  "fulltext_url": "http://www.sciencedirect.com/science/article/pii/S2405580826003298",
  "id": "8b1tqzf21bt5d",
  "issns": [
    "2405-5808"
  ],
  "landing_url": "https://doi.org/10.1016/j.bbrep.2026.102769",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "lcc",
      "QD415-436"
    ],
    [
      "lcc",
      "QH301-705.5"
    ],
    [
      "openalex",
      "2741|Monoclonal and Polyclonal Antibodies Research"
    ]
  ],
  "openalex": "W7222586228",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13718408/pdf/?tool=EBI",
  "pmcid": "PMC13718408",
  "pmid": "42959777",
  "published": "2026-10-16",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/8b1tqzf21bt5d.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:44:30Z",
      "native_id": "4e1a93ead1834e4ea191e7151377fd5e",
      "source": "doaj",
      "url": "https://doi.org/10.1016/j.bbrep.2026.102769"
    },
    {
      "first_seen": "2026-10-31T00:20:38Z",
      "native_id": "PMC:PMC13718408",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13718408"
    },
    {
      "first_seen": "2026-11-01T00:20:50Z",
      "native_id": "MED:42959777",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42959777"
    },
    {
      "first_seen": "2026-11-02T12:22:26Z",
      "native_id": "PMC13718408",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.bbrep.2026.102769"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2741|Monoclonal and Polyclonal Antibodies Research",
      "subfield": "imaging"
    }
  ],
  "title": "Targeting BIGH3 in selected solid tumors through a pH-Dependent antibody engineering strategy",
  "title_text": "Targeting BIGH3 in selected solid tumors through a pH-Dependent antibody engineering strategy",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T12:22:26Z",
  "url": "https://research.draconitic.com/paper/8b1tqzf21bt5d",
  "venue": "Biochemistry and Biophysics Reports",
  "versions": []
}