Anticytokine (Ligand) Antibody Versus Antireceptor Antibody in Treating Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Diseases

Abstract

Intracellular signaling through specific ligand-receptor interactions on the cellular membrane is essential for network communication among various immune cells in immune-mediated inflammatory diseases (IMIDs) [1]. Therapeutic agents extracellularly inhibit this signaling through biological agents and intracellular inhibition via synthetic compounds such as kinase inhibitors (Figure 1). Although the differences between biological agents and kinase inhibitors, as well as among targeted cytokines, have been widely discussed, comparisons between anticytokines (ligands) and antireceptor antibodies remain limited.

Interleukin-6 (IL-6) inhibition is an example of a distinction between these antibodies. The discovery and cDNA cloning of IL-6 and its receptor, as well as the signaling molecule glycoprotein 130 (gp130), have been pivotal for the successful management of various IMIDs through the inhibition of IL-6 signaling [2]. Tocilizumab, an anti-IL-6 receptor (IL-6R) antibody, was first developed in Japan and approved for the treatment of Castleman disease in 2005, followed by rheumatoid arthritis (RA) and juvenile idiopathic arthritis (both polyarticular and systemic) in 2008. Tocilizumab has been globally approved for various IMIDs, including giant cell arteritis and chimeric antigen receptor (CAR) T-cell-induced cytokine release syndrome [3].

The subsequent development of biological agents targeting IL-6R, such as sarilumab, and those targeting IL-6 ligands, including sirukumab, clazakizumab, and olokizumab, has provided valuable insights into the difference between anticytokine and antireceptor antibodies [3]. RA treatment with sarilumab has been successful in clinical trials [4-8], with acceptable safety profiles identified through postmarketing surveillance [9, 10]. However, the clinical development of biological agents targeting IL-6 ligands presents several challenges [3].

The most notable difference between anti-IL-6 and anti-IL-6R blockades lies in the efficiency of neutralizing the target functions within the selected dosing regimens. In our Japanese cohort, the median (interquartile range) serum IL-6 and IL-6R concentrations in treatment-naïve patients with RA were 4.70 (1.51–8.54) pg/mL and 84.2 (62.2–98.0) ng/mL, respectively [11]. Similarly, an RA study in Poland reported median (range) serum IL-6 and IL-6R concentrations of 34.1 (1.5–234.0) pg/mL and 45.366 (17.288–81.760) ng/mL, respectively [12]. Therefore, optimal dosing with limited dosing ranges is feasible for anti-IL-6R but not for anti-IL-6 ligands. For example, IL-6 receptor occupancy at steady-state trough levels was 98% or above with 200 mg of subcutaneous sarilumab every 2 weeks and 162 mg of tocilizumab weekly [13]. Another example is the failure of treatment in people with RA with extremely high serum tumor necrosis factor (TNF) concentrations before treatment with an anti-TNF monoclonal antibody (infliximab) [14].

Concerns regarding the development of antireceptor antibodies for the treatment of RA and other IMIDs include the potential activation of receptor signaling by the antibody, as observed in the development of the anti-CD28 antibody TGN1412 [15]. Therefore, the binding site of the antibody on the cytokine receptor should be carefully considered and tested before proceeding with clinical trials. Nevertheless, therapeutic antibodies targeting cytokine receptors may have some advantages over anticytokine antibodies because receptor expression levels are more stable than cytokine levels.

H.K. wrote the manuscript draft and all other authors provided critical feedback and approved the final version of the manuscript.

Hideto Kameda is an Editorial Board member of the International Journal of Rheumatic Diseases and a co-author of this article. To minimize bias, He was excluded from all editorial decision-making related to the acceptance of this article for publication. Hideto Kameda received consulting and/or speaker fees from AbbVie, Asahi Kasei, Bristol-Myers Squibb, Eisai, Eli Lilly, Janssen, Mitsubishi Tanabe, and UCB, and has received research/educational grants from Asahi Kasei, Pfizer, and Taisho. The other authors declare no conflicts of interest.