Charting New Frontiers in GvHD Treatment: Insights from Niktimvo? FDA approval

On August 14, 2024, Syndax and Incyte announced the FDA approval of Niktimvo? (axatilimab-csfr), a CSF-1R monoclonal antibody, for the treatment of chronic graft-versus-host disease (GvHD). Axatilimab is the first CSF-1R monoclonal antibody to receive approval, specifically targeting the drivers of inflammation and fibrosis in chronic GvHD (Business Wire, 2024).?

CSF-1R, a cell surface protein, plays a critical role in regulating the survival and function of monocytes and macrophages. Preclinical studies have demonstrated that inhibiting CSF-1R signaling can significantly reduce the population of disease-mediating macrophages and their monocyte precursors. This reduction is crucial for combating the fibrosis seen in chronic GvHD and other potential disorders, such as idiopathic pulmonary fibrosis (IPF).

About GvHD

First reported by Barnes et al. in 1962 and later defined by Billingham (1996), GvHD is a complex, multi-organ systemic disorder in which donor lymphocytes attack the recipient’s organs during immune reconstitution and hematopoietic recovery following transplantation. Between 30% and 50% of transplant patients develop acute GvHD (aGvHD) post-transplantation. As one of the most common and severe complications of allogeneic hematopoietic stem cell transplantation, GvHD significantly affects patient mortality and post-transplant outcomes. The primary treatment, typically involving corticosteroids and other immunosuppressants, often yields suboptimal results. This highlights the critical need to develop more effective treatment strategies.

Mouse models have been instrumental in providing vital insights into the pathophysiological mechanisms of GvHD, thereby improving the success rates of human hematopoietic stem cell transplants (HSCT). These models have revealed significant differences in the pathophysiology of acute and chronic GvHD, enhancing our understanding of the immune responses involved, including antigen processing and presentation, the role of the thymus, and immune reconstitution post-transplant (Schroeder et al., 2011).

Left image: Stages of Acute GvHD in Mice. This diagram illustrates the sequence of events during the development of aGvHD in mice. The five stages include: immune priming (A), activation (B), T-cell expansion (C), T-cell trafficking (D), and host tissue injury (E). (Source: Schroeder et al., 2011)

Right image: Stages of Chronic GvHD (cGvHD) in Mice. The diagram details the sequence of events during the development of cGvHD in mice. The stages are as follows: immune priming (A), activation of T cells and B cells (B), T cells expansion and B cell autoantibody production (C), trafficking to sited of tissue damage (D), and end organ damage resulting from chronic inflammation and fibrosis (E). (Source: Schroeder et al., 2011)

GvHD Mouse Models at Biocytogen

Biocytogen has developed a range of GvHD mouse models leveraging its proprietary B-NDG immunodeficient mice and humanized mouse models developed based on these B-NDG mice.?

Establishment of GvHD mouse models

These models are assessed biweekly for symptoms of GvHD including weight loss, posture, activity levels, fur texture, and skin damage, with the most relevant metric being animal survival rates.?

Evaluation of GvHD mouse models

Survival curves, weight changes and clinical scores in humanized GvHD mouse models created using different human peripheral blood mononuclear cell (hPBMC) donors. Variations in GvHD severity may occur depending on the hPBMC donor used. Prior to selecting PBMC donors for preclinical efficacy testing, it is crucial to pre-characterize these donors by assessing survival rates, weight changes, and clinical GvHD scores.

Preclinical efficacy of OX40 antibodies (telazorlimab) in B-NDG mice transplanted with human PBMCs. Studies have shown that OX40 antibodies enhance survival rates compared to control groups.

Clinical scoring criteria for GvHD in mouse models

Impact of radiation doses and PBMC injection volumes on GvHD model construction

Effects of different PBMCs and injection volumes on GvHD model development

Hematoxylin and eosin (H&E) staining in GvHD mouse models

On day 7, G1 mice show no significant pathological changes, while G2 and G3 mice exhibit reductions in splenic lymphocyte counts due to radiation, with substantial monocyte and granulocyte presence in G3 spleens. By day 14, G1 and G2 mice continue to exhibit no significant pathology; however, G3 mice display increased splenic granulocytes/lymphocytes and mixed inflammatory cell infiltration in the liver, lungs, and kidneys. Additionally, scattered patchy necrosis is observed in these organs, along with congestion and bleeding in the duodenum and jejunum, and patchy bleeding and necrosis in the spleen.

?

The FDA’s approval of Niktimvo? marks a significant breakthrough in the treatment of chronic GvHD, offering new hope to patients. At Biocytogen, we are committed to supporting this progress by equipping researchers with the tools necessary to further explore and improve GvHD therapies. Contact us today to learn more about our products and services!

References

[1] Business Wire. Incyte and Syndax Announce U.S. FDA Approval of Niktimvo? (axatilimab-csfr) for the Treatment of Chronic Graft-Versus-Host Disease (GVHD).

[2] Barnes, D. W. H., J. F. Loutit, and H. S. Micklem. ““Secondary disease” of radiation chimeras: a syndrome due to lymphoid aplasia.” Annals of the New York Academy of Sciences 99.3 (1962): 374-385.

[3] Billingham, Rupert E. “The biology of graft-versus-host reaction.” Harvey Lect. 62 (1996): 21-78.

[4] Schroeder, Mark A., and John F. DiPersio. “Mouse models of graft-versus-host disease: advances and limitations.” Disease models & mechanisms 4.3 (2011): 318-333.