Background/Purpose:

Tumor necrosis factor alpha (TNFa) and interleukin (IL)-17A are pleiotropic cytokines implicated in the pathogenesis of several autoimmune diseases including Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA). It has been suggested that TNFa and IL-17A drive independent actions on cellular inflammatory responses resulting in significantly increased proinflammatory mediator output. Targeting both TNFa and IL-17A has been proposed to have potential to achieve better and long lasting efficacy with a favorable safety profile in RA and PsA.

Methods:

JNJ-61178104 is a novel human anti-TNF-a and anti-IL‑17A bispecific antibody. The affinities of JNJ-61178104 binding to TNFa and IL-17A were assessed by surface plasmon resonance. The functional activity of JNJ 61178104 was evaluated in several preclinical cell based assays to characterize neutralization in the conditions where only one or both cytokines were present. Given the bispecific nature of JNJ‑61178104, the ability to neutralize both TNFa and IL-17A simultaneously was assessed in a co-culture model. To evaluate pharmacodynamics (PD) activity of JNJ-61178104 in vivo, Balb/c mice were treated with intranasal instillation of TNFa and IL-17A to induced acute lung inflammation. Proinflammatory cytokine production was assessed by ELISA and cellular influx was enumerated in lung lavage.

Results:

JNJ-61178104 binds to both TNFa (KD= 1.88~2.11 x 10^-11 M) and IL-17A (KD= 2.20~4.53 x 10^-11 M) with high affinity and inhibits binding of human TNFa to its receptors (IC₅₀ = 0.92~1.96 nM) or human IL-17A to IL-17RA receptor (IC₅₀ = 1.18 nM). JNJ-61178104 also potently neutralizes soluble TNFa (IC₅₀ = 0.22~1.33 nM), transmembrane TNFa (IC₅₀ = 0.74 nM), IL-17A- and IL 17A/F heterodimer (IC₅₀ = 0.32~3.06 nM) -mediated responses in multiple cell based assays.

In a co-culture system consisting of human synovial-like-fibroblast cells isolated from an RA donor and activated human Th1/Th17 cells, either parental anti-TNFa antibody or parental anti-IL-17A antibody only partially inhibit cytokines production, while JNJ-61178104 inhibited IL-6 and GROa production in a dose dependent manner similarly to the combination of parental antibodies.

In the acute pharmacodynamics model, while the parental anti-TNFa antibody or parental anti-IL-17A antibody dosed at 10 mg/kg partially attenuated cell accumulation in the lung, treatment with the JNJ 61178104 at 1 mg/kg, 3 mg/kg, and 10 mg/kg resulted in a significant, dose dependent inhibition of cell influx, with a near complete ablation of total cells/neutrophils in the lung with the highest dose of 10 mg/kg.

Conclusion:

Overall, JNJ-61178104 demonstrated potent functional neutralization of both TNFa and IL-17A driven inflammatory responses in vitro and in vivo preclinical models. Favorable pharmacological profile of JNJ-61178104, i.e., along with significant clinical experience with both TNFα and IL-17A pathways in RA and PsA subjects support the clinical investigation of JNJ-61178104 in autoimmune and inflammatory disease.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovery-and-characterization-of-jnj-61178104-a-bispecific-antibody-against-human-tumor-necrosis-factor-tnf-alpha-and-interleukin-il-17a/