New Binding Mechanism Science Driving Therapeutic Insight in Immune-Mediated Diseases


The ability of an anti-interleukin-23 antibody to bind to key immune system components may help neutralize a key driver of inflammation right at its cellular source.

While the pathogeneses of psoriasis (PsO) and psoriatic arthritis (PsA) are not completely understood, the cytokine interleukin (IL)-23 has proven to play a central role in these and other inflammatory diseases.1,2 Cytokines, such as IL-23, mediate how immune system cells “talk” to each other and specialized receptors help modulate these intercellular communications.3

One receptor that is intimately involved in inflammation is CD64. This receptor is highly expressed on the surface of certain immune cells that are major producers of IL-23.4–6 Recent studies have suggested that the ability of an anti-IL-23 antibody to bind to both of these key immune system components may help neutralize IL-23, a key driver of inflammation, right at its cellular source.7

To understand the mechanisms of binding to both IL-23 and CD64, we first need to understand the basics of antibody structure and binding. The structure of an antibody plays a key role in its function and has been the focus of developing antibody-related biologics.8

Also known as an immunoglobulin (Ig), an antibody is structurally a large, Y-shaped protein where the top of the antibody (the fragment antigen-binding, or Fab region) binds to an antigen, and the other end (the fragment crystallizable, or Fc region) binds and signals immune cells (see Figure 1).9

Each tip of the Fab region is responsible for target binding and is specific to an antigen, allowing only these 2 structures to bind.9 The Fc region modulates immune cell activity, dictating how the antibody interacts with other parts of the immune system.8,10

IL-23, CD64 and the importance of localizing treatments within inflamed tissues

One target for antibody therapies is IL-23, an inflammation-inducing cytokine. IL-23 is known to be a driver of immune-mediated diseases, including PsO, PsA, and inflammatory bowel disease (IBD).11 Antibody therapies targeting these diseases may bind to IL-23 through their Fab regions, preventing IL-23 from binding and activating specific cellular pathways.2,12

Within the inflamed tissue, IL-23 is secreted from certain immune cells. In vitro, in vivo and ex vivo studies have shown immune cells at sites of chronic inflammation have an increased expression of CD64 receptors.19 The CD64 receptor can bind the Fc region of immunoglobulin G (IgG), and is associated with many immune-mediated diseases.4–6,13,14

Recent in vitro data from Janssen’s ongoing research program showed that the Fc region of our cytokine-targeting antibody is able to bind to the CD64 receptor on IL-23-producing cells.7 The ability to bind to cells with CD64 receptors may physically place these cytokine inhibitors right on the surface of major IL-23-producing immune cells.4–7

This suggests the potential ability of these therapies to neutralize IL-23 at its source and prevent the cytokine from acting within the local tissue microenvironment.7

Potential for improving durable responses to treat inflammatory diseases

The ability of an antibody to bind to CD64 through its Fc region, in areas where more CD64 receptors are active, raises the hypothesis that anti-IL-23 treatments that also bind to CD64 may be enriched at the intercellular interface between IL-23-producing and IL-23-responsive cells within the inflamed tissue. For inflammatory disease, this may enhance the treatment’s ability to neutralize IL-23 where it is produced.7

The ability to capture IL-23 where it is produced, preventing the chronic activation of IL-23-responsive cells, may help explain clinical efficacy in psoriatic disease. Further in vitro and in vivo research will focus on the hypothesis of inhibiting IL-23 at the source of production as we seek to better understand IL-23 pathway mechanisms, biodistribution patterns, and clinical outcomes.

New approaches to antibody-based molecules that provide enhanced potency, specificity, localization, and safety are continually being developed.8 As researchers continue to investigate IL-23 pathway mechanisms and research other pathways that underly immune-mediated diseases, they are working toward the goal of improving the regulation of the immune system and effectively addressing the root cause of immune-mediated disease.

The hope is that this research can provide patients with more efficacious and lasting treatments across inflammatory diseases.


  1. Chen L, Deshpande M, Grisotto M, et al. Skin expression of IL-23 drives the development of psoriasis and psoriatic arthritis in mice. Scientific Reports. 2020;10(1):8259. doi:10.1038/s41598-020-65269-6
  2. Jeon C, Sekhon S, Yan D, Afifi L, Nakamura M, Bhutani T. Monoclonal antibodies inhibiting IL-12, -23, and -17 for the treatment of psoriasis. Human Vaccines & Immunotherapeutics. 2017;13(10):2247-2259. doi:10.1080/21645515.2017.1356498
  3. Altan-Bonnet G, Mukherjee R. Cytokine-mediated communication: a quantitative appraisal of immune complexity. Nature Reviews Immunology. 2019;19(4):205-217. doi:10.1038/s41577-019-0131-x
  4. Mehta H, Mashiko S, Angsana J, et al. Differential Changes in Inflammatory Mononuclear Phagocyte and T-Cell Profiles within Psoriatic Skin during Treatment with Guselkumab vs. Secukinumab. Journal of Investigative Dermatology. 2021;141(7):1707-1718.e9. doi:10.1016/j.jid.2021.01.005
  5. Matt P, Lindqvist U, Kleinau S. Up-regulation of CD64-expressing monocytes with impaired FcγR function reflects disease activity in polyarticular psoriatic arthritis. Scandinavian Journal of Rheumatology. 2015;44(6):464-473. doi:10.3109/03009742.2015.1020864
  6. Chapuy L, Bsat M, Sarkizova S, et al. Two distinct colonic CD14+ subsets characterized by single-cell RNA profiling in Crohn’s disease. Mucosal Immunology. 2019;12(3):703-719. doi:10.1038/s41385-018-0126-0
  7. Krueger J, et al. Differentiation of therapeutic antibodies targeting IL-23 . Presented at the Society for Investigative Dermatology (SID) 2022 annual meeting 2022 AAD Annual Meeting, May 18-21 .
  8. Chiu ML, Goulet DR, Teplyakov A, Gilliland GL. Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies. 2019;8(4):55. doi:10.3390/antib8040055
  9. Nicholson LB. The immune system. Essays in Biochemistry. 2016;60(3):275-301. doi:10.1042/EBC20160017
  10. Saunders KO. Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life. Frontiers in Immunology. 2019;10. doi:10.3389/fimmu.2019.01296
  11. Schinocca C, Rizzo C, Fasano S, et al. Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview. Frontiers in Immunology. 2021;12. doi:10.3389/fimmu.2021.637829
  12. Eldirany SA, Ho M, Bunick CG. Structural Basis for How Biologic Medicines Bind Their Targets in Psoriasis Therapy. Vol 93.; 2020.
  13. Dixon KJ, Wu J, Walcheck B. Engineering Anti-Tumor Monoclonal Antibodies and Fc Receptors to Enhance ADCC by Human NK Cells. Cancers (Basel). 2021;13(2):312. doi:10.3390/cancers13020312
  14. Boes M, Schmidt T, Linkemann K, Beaudette BC, Marshak-Rothstein A, Chen J. Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. Proceedings of the National Academy of Sciences. 2000;97(3):1184-1189. doi:10.1073/pnas.97.3.1184
Related Videos
Pharmacist holding medicine box in pharmacy drugstore. | Image Credit: I Viewfinder -
Pharmacy Drugstore Checkout Cashier Counter | Image Credit: Gorodenkoff -
Medicine tablets on counting tray with counting spatula at pharmacy | Image Credit: sutlafk -
Capsules medicine and white medicine bottles on table | Image Credit: Satawat -
Human cell or Embryonic stem cell microscope background | Image Credit: Anusorn -
Concept of health care, pharmaceutical business, drug prices, pharmacy, medicine and economics | Image Credit: Oleg -
Biosimilar pharmaceutical drug bottle on blue background. | Image Credit: Carl -
Pharmaceutical manufacture background with glass bottles with clear liquid on automatic conveyor line. | Image Credit: wacomka -
© 2024 MJH Life Sciences

All rights reserved.