New Tremfya data shows it binds to CD64 cells & interleukin (IL)-23

[Fred]

New data shows Tremfya binds to CD64 positive (CD64+) cells in addition to interleukin (IL)-23 both of which are key components of the immune system.

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Janssen Pharmaceutical announced the first results of the in vitro MODIF-Y studies, supporting a hypothesis that may differentiate the mechanism of first-in-class TREMFYA® (guselkumab) from risankizumab due to the ability of TREMFYA to bind to CD64 positive (CD64+) cells in addition to interleukin (IL)-23 — both of which are key components of the immune system. These findings, which are being presented at the Society for Investigative Dermatology (SID) annual meeting May 18-21, 2022 in Portland, Oregon, demonstrate TREMFYA binds simultaneously to CD64 via its native fragment crystallizable (Fc) region and to IL-23 via its antigen-binding region, suggesting the potential to neutralize IL-23 right at the site where it is secreted.  Further studies will be conducted in vitro and in vivo to generate additional evidence supporting this hypothesis.

IL-23, a cytokine secreted by activated monocyte/macrophage and dendritic cells, is known to be a driver of inflammatory diseases, including plaque psoriasis (PsO), psoriatic arthritis (PsA), and inflammatory bowel disease (IBD). CD64 is a receptor that binds the Fc region of immunoglobulin G4 and is highly expressed on the surface of certain immune cells that are major producers of IL-23.

“The initial results of these studies show the potential differentiating mechanism of TREMFYA,” said presenting study author James G. Krueger, M.D., Ph.D., D. Martin Carter Professor in Clinical Investigation and Co-director, Center for Clinical and Translational Science, The Rockefeller University in New York. “Its ability to bind to CD64+ cells may physically place TREMFYA right on the surface of these major IL-23-producing immune cells, which are key drivers of inflammation in diseases such as psoriasis and psoriatic arthritis. This potentially allows TREMFYA to neutralize IL-23 where it is being produced and prevent IL-23 from acting in the local tissue microenvironment.”

The MODIF-Y studies explored mechanisms potentially underpinning therapeutic profile differences between TREMFYA, a fully human monoclonal antibody specific for the p19 subunit of IL-23 with a native Fc region, and risankizumab, a humanized anti-IL-23 monoclonal antibody with a mutated Fc region.

Differentiated, Local Neutralization of IL-23 at its Source

    The results from these studies show that TREMFYA is differentiated from risankizumab by the capacity of TREMFYA to bind via its native Fc region to CD64, which is expressed on IL-23-producing cells.1This raises the possibility that TREMFYA may bind to IL-23 while also being localized to IL-23-producing cells through its binding to CD64, thus neutralizing IL-23 at its cellular source.1Risankizumab shows negligible binding to CD64 due to its mutated Fc region.

    CD64+ mononuclear phagocytes represent the predominant IL-23 source in psoriatic skin and IBD, and increased frequency of CD64+ monocytes correlates with markers of joint disease activity in active PsA.

    These studies also showed that TREMFYA and risankizumab display comparable affinity for binding IL-23 and potency for inhibiting IL-23-mediated signaling.

Potential for Enrichment in Inflamed Tissues

    Binding to CD64 raises the hypothesis that the presence of TREMFYA may be enriched at the intercellular interface between IL-23-producing and -responsive cells within the inflamed tissue. This may in turn enhance the ability of TREMFYA to neutralize IL-23 where it is produced in inflammatory diseases.

The results of these molecular investigations follow previous publications of Phase 3 clinical trials demonstrating the durable, long-term efficacy and safety profile of TREMFYA based on five years of data in plaque PsO and two years of data in PsA.

“This ability of TREMFYA to capture IL-23 right where it is produced, preventing permanent activation of IL-23-responsive cells, may help explain its durable clinical efficacy in psoriatic disease,” said Dan Cua, Ph.D., Vice President, IL-23 Pathway Leader, Janssen Research & Development, LLC. “These molecular studies also inform current and future research that fuel our critical understanding of IL-23 pathway mechanisms, biodistribution patterns, and clinical outcomes, as we seek to provide patients with more efficacious and lasting treatments across a number of inflammatory diseases.”

Further in vivo research is being conducted on the biodistribution of TREMFYA and its correlation to efficacy in the treatment of patients with PsA and IBD, which includes ongoing Phase 3 trials in Crohn’s disease and ulcerative colitis. Janssen is dedicated to continuing to investigate the pathways underlying immune-mediated diseases, focusing on improving the regulation of the immune system to create novel treatments that can effectively address the root cause of disease.

Source: janssen.com

Tremfya (guselkumab)

Skyrizi (risankizumab)