2. Academic Validation
  3. The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis

The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis

  • Arthritis Res Ther. 2015 May 20;17(1):135. doi: 10.1186/s13075-015-0651-0.
Maarten Van Roy 1,  Cedric Ververken 2,  Els Beirnaert 3 4,  Sven Hoefman 5,  Joost Kolkman 6 7,  Michel Vierboom 8,  Elia Breedveld 9,  Bert 't Hart 10 11,  Sofie Poelmans 12,  Lieselot Bontinck 13,  Alex Hemeryck 14,  Sandy Jacobs 15,  Judith Baumeister 16,  Hans Ulrichts 17
Affiliations

Affiliations

  • 1 Ablynx NV, Technologiepark 21, 9052, Zwijnaarde, Belgium. [email protected].
  • 2 Ablynx NV, Technologiepark 21, 9052, Zwijnaarde, Belgium. [email protected].
  • 3 Ablynx NV, Technologiepark 21, 9052, Zwijnaarde, Belgium. [email protected].
  • 4 VIB, Rijvisschestraat 120, 9052, Zwijnaarde, Belgium. [email protected].
  • 5 Ablynx NV, Technologiepark 21, 9052, Zwijnaarde, Belgium. [email protected].
  • 6 Ablynx NV, Technologiepark 21, 9052, Zwijnaarde, Belgium. [email protected].
  • 7 Crucell, Archimedesweg 4-6, 2333, CA, Leiden, The Netherlands. [email protected].
  • 8 Department of Immunobiology, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288 GJ, Rijswijk, The Netherlands. [email protected].
  • 9 Department of Immunobiology, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288 GJ, Rijswijk, The Netherlands. [email protected].
  • 10 Department of Immunobiology, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288 GJ, Rijswijk, The Netherlands. [email protected].
  • 11 Department of Neuroscience, University of Groningen, University Medical Center, Hanzeplein 1, 9700 RB, Groningen, The Netherlands. [email protected].
  • 12 Ablynx NV, Technologiepark 21, 9052, Zwijnaarde, Belgium. [email protected].
  • 13 Ablynx NV, Technologiepark 21, 9052, Zwijnaarde, Belgium. [email protected].
  • 14 Ablynx NV, Technologiepark 21, 9052, Zwijnaarde, Belgium. [email protected].
  • 15 Ablynx NV, Technologiepark 21, 9052, Zwijnaarde, Belgium. [email protected].
  • 16 Ablynx NV, Technologiepark 21, 9052, Zwijnaarde, Belgium. [email protected].
  • 17 Ablynx NV, Technologiepark 21, 9052, Zwijnaarde, Belgium. [email protected].
PMID: 25994180 DOI: 10.1186/s13075-015-0651-0
Abstract

Introduction: The 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.

Methods: ALX-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.

Results: ALX-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.

Conclusions: ALX-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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