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A novel xenograft mouse model for testing approaches targeting human kappa light-chain diseases

Gene Therapy volume 26, pages 187–197 (2019)Cite this article

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Abstract

Patients with immunoglobulin (Ig) light-chain (LC) diseases such as LC light-chain amyloidosis die with organ failure and need new therapies. We sought a model to test anti-LC siRNA delivery to human plasma cells, requiring circulating LC, in vivo indicators of tumor presence, and capacity for multiple injections of delivery vehicle. The JJN-3 human myeloma reporter cell line expressing firefly luciferase (FFL) implanted intraperitoneally (IP) in the NOD scid γ (NSG) mouse has a 90% prompt tumor-take, rapid LC production, and in vivo indicators of tumor measurable on day 5 post-implant (κ LC, bioluminescent signal, and soluble B-cell maturation antigen [sBCMA]) with median day 5 serum levels of κ LC of 1482 ng/mL (range, 255–4831) and robust correlations with all in vivo indicators. In preliminary attempts to deliver siRNA against κ LC constant region mRNA, we identified the 306-O18B3 lipidoid nanoparticle (LNP) as promising, safe and efficient in vitro. In vivo in the JJN-3 NSG IP model, after daily IP 306-O18B3:siRNA injections on days 5–10, a reduction in κ LC was observed on day 8 between control and test groups that continued through day 12 at sacrifice. This model is potentially useful as a platform for refining anti-LC therapies.

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Acknowledgements

For their continued support, we thank the Division of Hematology-Oncology and Departments of Medicine and Pathology and Laboratory Medicine at Tufts, the Amyloidosis and Myeloma Research Fund at Tufts, the Cam Neely and John Davis Myeloma Research Fund, the John C. Davis Program for Myeloma and Amyloid at Tufts, the Sidewater Family Fund, the Lavonne Horowitz Trust, the Werner and Elaine Dannheiser Fund for Research on the Biology of Aging of the Lymphoma Foundation, David and Barbara Levine (in memoriam), and the Demarest Lloyd Jr Foundation.

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Authors and Affiliations

  1. John Conant Davis Myeloma and Amyloid Program, Tufts Medical Center, Boston, MA, USA

    Xun Ma, Ping Zhou, Adin Kugelmass, Denis Toskic, Melissa Warner, Lisa Lee, Terry Fogaren, Amandeep Godara & Raymond L. Comenzo

  2. Department of Medicine, Division of Hematology-Oncology, Tufts Medical Center, Boston, MA, USA

    Lisa Lee, Terry Fogaren, Amandeep Godara & Raymond L. Comenzo

  3. Department of Biomedical Engineering, Tufts University School of Medicine, Boston, MA, USA

    Ming Wang, Yamin Li, Liu Yang & Qiaobing Xu

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  1. Xun Ma
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Corresponding author

Correspondence to Raymond L. Comenzo.

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Conflict of interest

Drs Comenzo, Ma, and Zhou have a patent on the siRNA sequences used to knock down expression of the κ light chain constant region. Dr Comenzo has served as a consultant or advisor to Takeda Millennium, Unum, Prothena and Janssen, and has received clinical research funding from Takeda Millennium, Janssen, and Prothena Biotech. Drs Xu and Wang have numerous patents on nanostructure delivery vehicles. The remaining authors declare that they have no conflict of interest.

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Ma, X., Zhou, P., Kugelmass, A. et al. A novel xenograft mouse model for testing approaches targeting human kappa light-chain diseases. Gene Ther 26, 187–197 (2019). https://doi.org/10.1038/s41434-019-0070-y

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