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. 2024 Sep 14:17:6375-6388.
doi: 10.2147/JIR.S471963. eCollection 2024.

Preclinical Development of SHR-1819, a Potent Humanized IL-4Rα Antibody for Treating Type 2 Inflammatory Diseases

Guolin Zhao  1   2 , Zhijun Wang  1   2 , Jun Zhang  1   2 , Yuan Lin  1   2 , Tang Zhou  1   2 , Kaili Liu  1   2 , Changyong Yang  1 , Cheng Liao  1
Affiliations

Preclinical Development of SHR-1819, a Potent Humanized IL-4Rα Antibody for Treating Type 2 Inflammatory Diseases

Guolin Zhao et al. J Inflamm Res. .

Abstract

Background: Interleukin (IL)-4 and IL-13 are critical pathogenic factors for type 2 inflammation-related allergic diseases, sharing the mutual receptor subunit IL-4Rα. However, it was ineffective for certain type 2 inflammation diseases by targeting IL-4, IL-13 ligand alone or both in clinical studies. The work presented herein aimed to evaluate the preclinical efficacy and pharmacokinetics profile of a novel monoclonal antibody against IL-4Rα, SHR-1819, as a promising therapy for type 2 inflammation diseases.

Methods: SHR-1819 was generated through immunization by C57BL/6 mice with recombinant hIL-4Rα protein, followed by humanization and affinity maturation. Then, its binding properties with IL-4Rα were determined using surface plasmon resonance (SPR) and ELISA. In vitro inhibitory effects of SHR-1819 were assessed on hIL-4-/hIL-13-induced cell proliferation and signal transducer and activator of transcription 6 (STAT6) signaling activation. In vivo efficacy of SHR-1819 was evaluated in several type 2 inflammatory diseases models, including asthma, atopic dermatitis (AD), and allergic rhinitis (AR) by using hIL-4/hIL-4Rα transgenic mice. Furthermore, the pharmacokinetic (PK) profiles of SHR-1819 were characterized.

Results: SHR-1819 showed high binding affinity to human IL-4Rα and effectively blocked IL-4Rα at sub-nanomolar concentration. In vitro assays indicated that SHR-1819 significantly inhibited TF-1 cell proliferation and STAT6 activation induced by hIL-4/hIL-13. In the asthma model, SHR-1819 could reduce airway hyperresponsiveness, decrease serum IgE levels, and alleviated inflammatory lung cell infiltration. In the AD model, SHR-1819 could significantly alleviate inflammatory and skin symptoms. In the AR model, it could remarkably decrease the frequencies of nasal rubbing and sneezing, and inflammatory cell infiltration in nasal tissues. These in vivo efficacy studies demonstrated the therapeutic potential of SHR-1819 in preclinical disease models. Moreover, subcutaneous administration of SHR-1819 exhibited favorable bioavailability in mice.

Conclusion: The results supported SHR-1819 as a promising preclinical candidate for the treatment of type 2 inflammatory diseases, including asthma, AD and AR.

Keywords: IL-13; IL-4; IL-4Rα; type 2 inflammatory diseases.

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Conflict of interest statement

The authors declare no competing interest in this work.

Figures

Figure 1
Figure 1
Binding and blocking profiles of SHR-1819. (A) and (B) Binding kinetics of SHR-1819 with human IL-4α by SPR. (C) Binding affinity of SHR-1819 to human IL-4Rα by ELISA. (D) and (E) Blocking profiles of SHR-1819 to IL-4Rα on B cells from human and hIL-4/hIL-4Rα transgenic mice by flow cytometry. (F) Blocking effect of SHR-1819 on hIL-4/hIL-4Rα by ELISA. Human IgG4 was used as a negative control.
Figure 2
Figure 2
Cellular inhibitions of SHR-1819 on hIL-4 and hIL-13 signaling. (A) and (B) Inhibition on proliferation of TF-1 cells stimulated by IL-4 or IL-13. (C) and (D) Inhibition on STAT6 activation induced by hIL-4 or hIL-13 in HEK-Blue IL-4/IL-13 cells. Human IgG4 was used as a negative control.
Figure 3
Figure 3
Effects of SHR-1819 on OVA-induced asthma in hIL-4/hIL-4Rα transgenic mice. (A) Protocol for the OVA-induced asthma model study in hIL-4/hIL-4Rα transgenic mice and administration of test articles. (B) Body weights during the treatment period. (C) The curve of Penh change rate against Mch concentration. (D) The area under the curve (AUC) of Penh curve on Day 31. (E) Serum IgE levels on Day 34, determined by ELISA. (F) and (G) Cell count and corresponding percentages of the Eos, Mac, Neu, and Lym cells in BALF, determined by FACS. (H) Representative H&E images of lung tissues. Bar =100 µm. (I) Scores of the histopathological parameters included airway diameter, mucosal thickness, and inflammatory cell infiltration (score 0–4, with 4 indicating the most severe injury). Data were presented as the sum of scores of each parameter. *P < 0.05, **P < 0.01, ***P < 0.001 vs Model Group using Student’s t-test or Dunnett’s multiple comparisons test in GraphPad Prism version 9.
Figure 4
Figure 4
Effects of SHR-1819 on oxazolone-induced AD in hIL-4/hIL-4Rα transgenic mice. (A) Protocol for the oxazolone-induced AD model study in hIL-4/hIL-4Rα transgenic mice. (B) and (C) Ear swelling (thickness) was measured from Day 0 to Day 35. (D) Blood was collected and serum IgE levels were measured by ELISA. (E) Representative H&E images of ear tissues. (F) Scores of the histopathological parameters included inflammatory cell infiltration, dermal thickness, and epidermal thickness (score 0–3, with 3 indicating the most severe injury). Data were presented as the sum of scores of each parameter. **P < 0.01, ***P < 0.001 vs Model Group using Student’s t-test or Dunnett’s multiple comparisons test in GraphPad Prism version 9.
Figure 5
Figure 5
Effects of SHR-1819 on OVA-induced allergic rhinitis in hIL-4/hIL-4Rα transgenic mice. (A) Protocol for the OVA-induced allergic rhinitis mouse model study in hIL-4/hIL-4Rα transgenic mice. (B) and (C) Behavior changes (sneezing and rubbing counts) in OVA-induced model on Day 27. (D) Blood was collected and serum IgE levels were measured by ELISA. (E) and (F) Thickness of olfactory mucosa and olfactory bulb, and histopathological examination included morphology of mucosal epithelial cells and inflammatory cell infiltration (score 0–3, with 3 indicating the most severe injury). (G) Representative of H&E staining pictures of the mucous layer (upper image) and lamina propria (lower image). Yellow, black and red arrows indicated neutrophil and lymphocyte infiltration, epithelial shedding, and macrophage infiltration, respectively. Data were shown as the sum of scores of each parameter. *P < 0.05, **P < 0.01, ***P < 0.001 vs Model Group using Student’s t-test or Dunnett’s multiple comparisons test in GraphPad Prism version 9.
Figure 6
Figure 6
Mean concentration-time curves after a single subcutaneous (SC) or intravenous (IV) injection of SHR-1819 in hIL-4/hIL-4Rα transgenic mice.
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