Background: Platelet Derived Growth Factor Receptor α (PDGFRα) is a target of the autoimmune response in systemic sclerosis (SSc). Human anti-PDGFRα monoclonal antibodies (huPDGFRα mAbs) cloned from memory B cells of SSc patients [1] have shown the ability to increase collagen gene transcription in healthy donor skin fibroblasts and to induce fibrosis in human skin grafts in SCID mice [2]. Moreover, systemic administration of stimulatory huPDGFRα mAbs in a novel human PDGFRα-transgenic mouse effectively induced both skin and lung fibrosis.

Objectives: We tested the well known anti-fibrotic activity of nintedanib in our humanized mouse model, to assess whether PDGFRα is a key target of this drug and if this animal model is suitable for drug discovery and preclinical validation.

Methods: Two cohorts of C57BL/6-huPDGFRα transgenic mice were treated subcutaneously for 28 days with ALZET mini-osmotic pumps containing a mixture of stimulatory huPDGFRα mAbs VH _PAM -V _κ 16F4 and VH _PAM -V _λ 16F4. One mouse cohort was simultaneously treated with 60 mg/kg/day of nintedanib, administered orally once daily, starting at day 0 (following minipumps implant) to day 28. Vehicle only (PBS) administration control was included. On day 28 minipumps were removed and animals underwent whole-body plethysmography before sacrifice; skin and lung tissues were then harvested for histological and molecular analyses, and synchrotron propagation-based phase-contrast microtomography (ELETTRA, Trieste, Italy).

Results: Continuous subcutaneous administration, for 28 days, of a mixture of stimulatory huPDGFRα mAbs VH _PAM -V _κ 16F4 and VH _PAM -V _λ 16F4 in C57BL/6-huPDGFRα transgenic mice caused relevant dermal thickening and increased collagen deposition in the skin. Skin fibrosis was accompanied by lung fibrosis, characterized by marked alveolar thickening (Th), reduced alveolar space (Sp), augmented alveolar volume density (VD), and upregulated Col1A1 mRNA levels. In vivo whole-body plethysmography revealed a decline of mouse respiratory function, measured as a discrete reduction of lung tidal volume (TV) and expired volume (EV) in mAbs-treated mice compared with PBS-treated mice. HuPDGFRα mAbs-induced lung fibrosis was significantly reduced by nintedanib, with all histological, molecular and physical parameters staying closer to the values measured in PBS-treated mice. Conversely, nintedanib treatment showed limited efficacy on skin fibrosis.

Conclusion: We generated a novel humanized mouse model of skin and lung fibrosis based on the concomitant expression of huPDGFRα and the systemic transfer of stimulatory huPDGFRα mAbs. Simultaneous nintedanib treatment partially prevented antibody-induced lung fibrosis, but not skin fibrosis, indicating that PDGFRα in lung is a target of this drug. This animal model may serve to identify and preclinically validate new therapeutic strategies for SSc and other PDGFRα-related diseases.

REFERENCES: [1] Moroncini G et al. Epitope Specificity Determines Pathogenicity and Detectability of Anti-Platelet-Derived Growth Factor Receptor alpha Autoantibodies in Systemic Sclerosis. Arthritis Rheumatol . 2015; 67(7):1891-1903.

[2] Luchetti MM et al. Induction of Scleroderma Fibrosis in Skin-Humanized Mice by Administration of Anti-Platelet-Derived Growth Factor Receptor Agonistic Autoantibodies. Arthritis Rheumatol. 2016; 68(9): 2263-2273.

Acknowledgements: This research has received funding from the project Heal Italia – Project Code PE00000019, CUP I33C22006900006 - funded under the National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3 - Creation of “Extended Partnerships with Universities, Research Centers, and Companies for the Funding of Basic Research Projects” – Project “Health Extended Alliance for Innovative Therapies, Advanced Lab Research, and Integrated Approaches of Precision Medicine (HEAL ITALIA)” Call for tender No. 341 of 15/03/2022, and Concession Decree No. 0001559.11-10-2022 of Italian Ministry of University funded by the European Union – NextGenerationEU.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.