Structural and functional insights into a novel pre-clinical-stage antibody targeting IL-17A for treatment of autoimmune diseases

Xu, Jin-Gen; Jia, Huifeng; Chen, Shi; Xu, Jingyue; Zhan, Yifan; Yu, Haijia; Wang, Wei; Xi, Kang; Cui, Xiaopei; Feng, Yujie; Chen, Xiaofang; Xu, Wei; Pan, Xianfei; Wei, Xu; Li, Hui; Wang, Yanting; Xia, Simin; Liu, Xiaoyan; Yang, Lixiang; He, Yang; Zhu, Xiangyang

doi:10.1016/j.ijbiomac.2022.01.119

Cited by 6 publications

(2 citation statements)

References 34 publications

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“…However, the data on the affinity of the Fab 6785 for IL-17A and IC 50 are missing; the affinity of the Fab fragment h142 for the cytokine is reduced as compared to that of other tested antibodies [ 33 ]. Since the HB0017 has the highest affinity for IL-17A among the known IL-17A-specific antibodies [ 32 ] ( Table 5 ), we carried out a comparative structural analysis of the interactions of IL-17A with the HB0017 Fab fragment and the anti-IL-17A-76.…”

Section: Discussionmentioning

confidence: 99%

Two Epitope Regions Revealed in the Complex of IL-17A and Anti-IL-17A VHH Domain

Kostareva

Svoeglazova

Kolyadenko

et al. 2022

IJMS

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Interleukin-17 (IL-17) is a cytokine produced by the Th17 cells. It is involved in chronic inflammation in patients with autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and psoriasis. The antibodies targeting IL-17 and/or IL-17R are therapy tools for these diseases. Netakimab is an IL-17A-specific antibody containing a Lama glama VHH derivative domain and a VL variable domain. We have determined the crystal structure of the IL-17A-specific VHH domain in complex with IL-17A at 2.85 Å resolution. Certain amino acid residues of the three complementary-determining regions of the VHH domain form a network of solvent-inaccessible hydrogen bonds with two epitope regions of IL-17A. The β-turn of IL-17A, which forms the so-called epitope-1, appears to be the main region of IL-17A interaction with the antibody. Contacts formed by the IL-17A mobile C-terminal region residues (epitope-2) further stabilize the antibody–antigen complex.

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Section: Discussionmentioning

confidence: 99%

Two Epitope Regions Revealed in the Complex of IL-17A and Anti-IL-17A VHH Domain

Kostareva

Svoeglazova

Kolyadenko

et al. 2022

IJMS

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“…However, in the last decade or so, more targeted biotherapeutics, notably monoclonal antibodies directed at specific cytokine targets, have been developed and shown to be highly effective therapies for a range of autoimmune diseases (Lefebvre and McAuliffe, 2016;Jung and Kim, 2022). Some of the clinically available monoclonal antibodies are directed at tumor necrosis factor-alpha (TNFα) (Abramovits and Gupta, 2004;von Richter et al, 2019;Coghlan et al, 2021) and (Raychaudhuri, 2013;Kolbinger et al, 2022;Wohlrab et al, 2022;Xu et al, 2022;Yun et al, 2022) which underlie inflammatory responses in many autoimmune diseases. However, as with all biotherapeutics, the pain associated with frequently injecting these antibodies impacts patient compliance and disease management and several pharmaceutical companies have attempted to address this issue by developing infrequent dosing regimens with less painful and more convenient pen injectors for delivering these antibodies (Kivitz and Segurado, 2007;Karlsdottir et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Transenteric delivery of antibodies via an orally ingestible robotic pill yields high bioavailability comparable to parenteral administration in awake canines

Yamaguchi

Dam²,

Dhalla³

et al. 2022

Front. Drug. Deliv.

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Biotherapeutics such as peptides and antibodies are highly efficacious clinically but, unlike conventional medications, cannot be administered orally as they get digested and inactivated. Thus, biotherapeutics require parenteral routes for delivery, such as intravenous, intramuscular or subcutaneous administration. However, these delivery methods have limitations such as poor patient compliance or may require clinical supervision compared to oral therapies. We explored whether a novel, orally administered transenteric delivery system (Robotic Pill) could provide equivalent bioavailability to parenterally administered drugs. Utilizing an awake canine model, we demonstrated that orally administered Robotic Pills containing either human IgG or an anti-cytokine monoclonal antibody directed against either TNFα or interleukin-17A yielded bioavailability equivalent to parenterally administered controls. The ability to achieve clinically relevant blood levels of biotherapeutics via any orally administered preparation represents an important advance in drug delivery.

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Safety, tolerability, pharmacokinetics and efficacy of HB0017, a humanized monoclonal antibody that targets interleukin-17A, in healthy participants and patients with moderate-to-severe plaque psoriasis

Jiang,

Du,

Liu

et al. 2023

British Journal of Dermatology

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Background Several interleukin (IL)-17 inhibitors have been approved for the treatment of moderate-to-severe plaque psoriasis (PsO). There is still scope for the development of affordable treatments for PsO. Objectives To assess, in a phase Ia study, the safety, tolerability and pharmacokinetics (PK) of HB0017, a humanized monoclonal antibody that targets IL-17A, in healthy participants and patients with moderate-to-severe plaque PsO; and, in a phase Ib study, to assess the efficacy of HB0017 in patients with moderate-to-severe plaque PsO. Methods The phase Ia study (NCT04505033) was a randomized double-blind placebo-controlled dose-escalation study in healthy participants. Each cohort of 10 volunteers was randomly assigned to receive either a single dose of HB0017 (50 mg, 150 mg, 300 mg or 450 mg) or the matching placebo at a ratio of 4 : 1. The phase Ib study (NCT05442788) was a randomized double-blind placebo-controlled dose-escalation study in enrolled patients with moderate-to-severe plaque PsO. Each cohort of 10 patients was randomly assigned to receive either multiple doses of HB0017 (150 mg, 300 mg or 450 mg) or the matching placebo at a ratio of 4 : 1. Results HB0017 demonstrated dose-proportional linear PK and was tolerated across the dose range assessed. In the phase Ia and Ib studies, participants in both the HB0017 and placebo groups experienced treatment-emergent adverse events (69% vs. 87%, 96% vs. 100%, respectively). HB0017 demonstrated clinically meaningful effects in patients with moderate-to-severe plaque PsO. PASI 75 [≥ 75% improvement in Psoriasis Area and Severity Index (PASI)], PASI 90 (≥ 90% improvement in PASI) and static Physician Global Assessment (sPGA) 0/1 (i.e. ‘clear’ or ‘almost clear’) responses were 100% for the HB0017 300-mg group, with maximal improvements (100% or near 100% reductions from baseline) in PASI score observed at week 12, while the duration of effect was evident up to week 20. There was no clinical response in any participant in the placebo group in the phase Ib study. Conclusions Overall, HB0017 showed acceptable safety and tolerability in both healthy participants and patients with moderate-to-severe plaque PsO. An encouraging signal of efficacy with a longer half-life provides HB0017 with the potential to be added to the currently available range of biologics targeting IL-17A.

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Structural and functional insights into a novel pre-clinical-stage antibody targeting IL-17A for treatment of autoimmune diseases

Cited by 6 publications

References 34 publications

Two Epitope Regions Revealed in the Complex of IL-17A and Anti-IL-17A VHH Domain

Two Epitope Regions Revealed in the Complex of IL-17A and Anti-IL-17A VHH Domain

Transenteric delivery of antibodies via an orally ingestible robotic pill yields high bioavailability comparable to parenteral administration in awake canines

Safety, tolerability, pharmacokinetics and efficacy of HB0017, a humanized monoclonal antibody that targets interleukin-17A, in healthy participants and patients with moderate-to-severe plaque psoriasis

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