Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Interleukin-6 (IL-6) is a pleiotropic cytokine inducing a wide range of biological activities via its receptor IL-6R. IL-6 plays an important role in the pathogenesis of a variety of diseases, including rheumatoid arthritis (RA), and blocking of IL-6R results in clinical benefit as shown with tocilizumab (TCZ), a monoclonal antibody targeting IL-6R.
Nanobodies are therapeutic proteins based on the smallest functional fragments of heavy chain-only antibodies, naturally occurring in the Camelidae family. ALX-0061 is a bispecific anti-IL-6R Nanobody engineered to obtain an extended half-life in vivo by targeting human serum albumin, in combination with a high in vitro affinity and potency for the anti-IL-6R building block.
The presented work was aimed at determining the ALX-0061 in vitro and in vivo profile and at translating these results to a first-in-man (FIM) dose.
Methods:
ALX‑0061 was characterized extensively using in vitro systems: biological activity, specificity and affinity was assessed and compared to TCZ. Due to very tight target binding, the affinity of ALX‑0061 for IL‑6R could not be accurately determined via surface plasmon resonance and the new and more sensitive GyrolabTM platform was used.
The PK/PD properties of ALX‑0061 were examined in naive cynomolgus monkeys and in an human (h)IL-6-induced acute phase response model in the same species in which platelet numbers and plasma concentrations of CRP and fibrinogen were monitored as disease parameters.
In vivo efficacy of ALX-0061 was assessed in a collagen-induced arthritis (CIA) rhesus monkey model. In this model, inflammation of the joints was induced via sensitization with collagen type II, after which clinical endpoints were assessed in correlation to biomarker deregulation.
Results:
ALX‑0061 neutralized specifically both soluble and membrane IL‑6R with a comparable in vitro potency to TCZ. However, affinity of ALX-0061 for IL-6R (0.19 pM ± 0.08 pM) was 2000-fold superior compared to TCZ (462 pM ± 138 pM).
In the cynomolgus monkey, ALX‑0061 showed a dose‑dependent and complete inhibition of three hIL-6-induced inflammation parameters. PK analysis in the same species demonstrated a half-life (5.7 to 7.4 days) similar to that reported for serum albumin which was predicted to translate into a convenient iv dosing regimen in humans. Measurement of total sIL-6R levels in these studies supported the calculation of the FIM dose.
Although emergence of neutralising anti-drug antibodies was observed in most of the ALX-0061- or TCZ-treated animals in the CIA disease study, both drugs demonstrated a clear biological effect as shown on CRP levels. A clinical effect was obvious in animals with active drug exposure throughout the course of the study.
Conclusion:
ALX-0061 combines high in vitro affinity and potency with favorable PK/PD properties in non-human primates and has the potential to be an effective treatment for RA in humans. A Phase I/II clinical trial is ongoing. Interim analysis of the single ascending dose part were encouraging, results from the multiple dose part are expected in H2 2012.
Disclosure:
M. Van Roy,
Ablynx N.V.,
3,
Ablynx N.V.,
1;
H. Ulrichts,
Ablynx N.V.,
3,
Ablynx N.V.,
1;
S. Rossenu,
Ablynx N.V.,
3;
S. Jacobs,
Ablynx N.V.,
3,
Ablynx N.V.,
1;
S. Poelmans,
Ablynx N.V.,
3;
G. Verheyden,
Ablynx N.V.,
3,
Ablynx N.V.,
1;
M. Vierboom,
None;
B. ‘t Hart,
None;
J. Baumeister,
Ablynx N.V.,
1,
Ablynx N.V.,
3;
J. B. Holz,
Ablynx N.V.,
1,
Ablynx N.V.,
3,
Ablynx N.V.,
6.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/preclinical-development-of-alx-0061-an-anti-il-6r-nanobody-for-therapeutic-use-in-rheumatoid-arthritis-with-a-high-in-vitro-affinity-and-potency-and-a-competitive-in-vivo-pharmacological-p/