Characterization of concurrent target suppression by JNJ-61178104, a bispecific antibody against human tumor necrosis factor and interleukin-17A

Abstract

Tumor necrosis factor (TNF) and interleukin (IL)-17A are pleiotropic cytokines implicated in the pathogenesis of several autoimmune diseases including rheumatoid arthritis (RA) and psoriatic arthritis (PsA). JNJ-61178104 is a novel human anti-TNF and anti-IL-17A monovalent, bispecific antibody that binds to both human TNF and human IL-17A with high affinities and blocks the binding of TNF and IL-17A to their receptors in vitro. JNJ-61178104 also potently neutralizes TNF and IL-17A-mediated downstream effects in multiple cell-based assays. In vivo, treatment with JNJ-61178104 resulted in dose-dependent inhibition of cellular influx in a human IL-17A/TNF-induced murine lung neutrophilia model and the inhibitory effects of JNJ-61178104 were more potent than the treatment with bivalent parental anti-TNF or anti-IL-17A antibodies. JNJ-61178104 was shown to engage its targets, TNF and IL-17A, in systemic circulation measured as drug/target complex formation in normal cynomolgus monkeys (cyno). Surprisingly, quantitative target engagement assessment suggested lower apparent in vivo target-binding affinities for JNJ-61178104 compared to its bivalent parental antibodies, despite their similar in vitro target-binding affinities. The target engagement profiles of JNJ-61178104 in humans were in general agreement with the predicted profiles based on cyno data, suggesting similar differences in the apparent in vivo target-binding affinities. These findings show that in vivo target engagement of monovalent bispecific antibody does not necessarily recapitulate that of the molar-equivalent dose of its bivalent parental antibody. Our results also offer valuable insights into the understanding of the pharmacokinetics/pharmacodynamics and target engagement of other bispecific biologics against dimeric and/or trimeric soluble targets in vivo.

Keywords: IL-17A; TNF; bispecific antibody; target engagement; target-mediated drug disposition; translational modeling.

Figure 1.

Inhibition of in vitro inflammatory responses mediated by endogenous TNF and IL-17A. Human rheumatoid arthritis fibroblast-like synovial cells (RA-FLS) were cocultured with in vitro differentiated T_h17/T_h1 cells. Various concentrations of JNJ-8104, CNTO 9809 (parental anti-TNF), CNTO 4782 (parental anti-IL-17A) or equal-molar fixed-ratio combination of CNTO 9809 and CNTO 4782 were incubated with the coculture for 48 hours. Endogenous TNF and IL-17A-mediated production of IL-6 (a) and GROα (b) in the supernatants were measured.

Figure 2.

Inhibition of rhTNF- and rhIL-17A-induced Cellular Influx by JNJ-8104 in the Airway Lumen of Mice. Mice were intranasally instilled with rhTNF- and rhIL-17A in combination. After 6 h their lungs were lavaged and total numbers of BAL cells (a) and neutrophils (b) were enumerated as detailed in “Materials & Methods.” Mice were injected intraperitoneally with the test mAbs or isotype control18 hours prior to cytokines challenge. Data are represented as mean ± SEM; N = 6–7 mice/group.

Figure 3.

Observed serum concentrations versus time profiles of Total mAb (a), total TNF (b), and Total IL-17A (c) following IV administration of golimumab (parental anti-TNF), CNTO 6785 (anti-IL-17A with identical parental Fab arms) or JNJ-8104 at the specified dose levels in cynomolgus monkeys. Data are represented as mean ± SD.

Figure 4.

(a) Schematic representation of the TMDD-based PK/TE model. The model parameter names are as defined in Materials and Methods. (b) Observed serum concentrations versus time profiles of Total TNF following 14 weekly high doses of golimumab, golimumab + CNTO 6785 or JNJ-8104 in cynomolgus monkeys. (c) Observed (symbols) and model-predicted (dashed lines) serum concentrations versus time profiles of Total TNF following high doses of golimumab or JNJ-8104 in cynomolgus monkeys. Data are represented as mean ± SD.

Figure 5.

PK/TE model fitting of PK and Total TNF profiles following IV administration of JNJ-8104 (a) and golimumab (b) in cynomolgus monkeys. Symbols = Observed individual data; Lines = Mean model prediction.

Figure 6.

PK/TE model fitting of PK, total IL-17A and Free IL-17A profiles following IV administration of JNJ-8104 (a) and CNTO 6785 (b) in cynomolgus monkeys. Symbols = Observed individual data; Lines = Mean model prediction.

Figure 7.

Comparison of observed and model-predicted Total TNF profiles (a−e) and serum drug concentrations (f) following a single IV administration of JNJ-8104 at 0.1, 0.3, 1, 3 and 10 mg/kg in normal human subjects. Symbols = Observed individual data; For A-E: Solid lines = Mean model prediction based on cyno PK/TE model parameters and allometric scaling for human PK; Dotted lines = Mean model prediction based on estimated JNJ-8104 human PK parameters from FIH data with cyno-based in vivo KD. The observed mean (SD) concentrations of Total TNF at week 2 trough following 40 mg q2 w SC doses of adalimumab are also shown in Figure 7c. In figure 7f, the colored lines represent the simulated human PK based on allometric scaling from cyno only.

Figure 8.

Comparison of observed and model-predicted Total IL-17A profiles following a single IV administration of JNJ-8104 at 0.1, 0.3, 1, 3 and 10 mg/kg (a−e) normal human subjects. Symbols = Observed individual data; Solid lines = Mean model prediction based on cyno PK/TE model parameters and allometric scaling for human PK; Dotted lines = Mean model prediction based on estimated JNJ-8104 human PK parameters from FIH data with cyno-based in vivo KD.