ArticleArthritis research & therapy2015
The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis.
Article in Arthritis research & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers, 2 of them syntheses that pooled it.
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Who cites it
80 citing papers in PubMed, 2 syntheses or guidelines pooled it, 177 citations in OpenAlex.
- Bispecific Antibodies: From Research to Clinical Application.Frontiers in immunology · 2021Pooled it
- Research Progress and Applications of Multivalent, Multispecific and Modified Nanobodies for Disease Treatment.Frontiers in immunology · 2021Pooled it
- Refining therapeutic targeting of interleukin-6 by signalling mode selectivity.Nature reviews. Drug discovery · 2026Review
- Therapeutic Applications of Immunobiologics in Autoimmune and Inflammatory Diseases.Pharmaceutics · 2026Review
- Delving into the innate and adaptive immunity of camelids: a paradigm of interspecies adaptation and evolutionary innovation.Frontiers in immunology · 2026Review
- Research progress on the application of nanobodies in immunity and infectious skin diseases.Frontiers in immunology · 2025Review
- A hTfR1 Receptor-Specific VHH Antibody Neutralizes Pseudoviruses Expressing Glycoproteins from Junín and Machupo Viruses.Viruses · 2024Article
- Exploring the therapeutic potential of interleukin-6 receptor blockade in autoimmune diseases using drug target mendelian randomization.Immunogenetics · 2024Article
- Nanobody-Engineered Biohybrid Bacteria Targeting Gastrointestinal Cancers Induce Robust STING-Mediated Anti-Tumor Immunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Review
- Directed evolution of genetically encoded LYTACs for cell-mediated delivery.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A simple and effective method to remove pigments from heterologous secretory proteins expressed in Pichia pastoris.Advanced biotechnology · 2024Article
- Crystal structure of human serum albumin in complex with megabody reveals unique human and murine cross-reactive binding site.Protein science : a publication of the Protein Society · 2024Article
- Interleukin 6 Antagonists in Severe COVID-19 Disease: Cardiovascular and Respiratory Outcomes.Protein and peptide letters · 2024Review
- Targeting IL-6 or IL-6 Receptor in Rheumatoid Arthritis: What Have We Learned?BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Review
- The potential role of nanobodies in asthma therapy.Frontiers in pharmacology · 2024Review
- Prospects for the computational humanization of antibodies and nanobodies.Frontiers in immunology · 2024Review
- Influencing factors and solution strategies of chimeric antigen receptor T-cell therapy (CAR-T) cell immunotherapy.Oncology research · 2024Review
- Broadly neutralizing antibodies targeting HIV: Progress and challenges.Clinical immunology (Orlando, Fla.) · 2023Review
- Directed Evolution of Genetically Encoded LYTACs for Cell-Mediated Delivery.bioRxiv : the preprint server for biology · 2023Article
20 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionThe pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody® with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology.
methodsALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control.
resultsALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration.
conclusionsALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.