aston.martin schreef op 28 oktober 2013 07:58:
Pre-Clinical Proof-Of-Concept Of ALX-0761, a Nanobody® Neutralizing Both IL-17A and F In a Cynomolgus Monkey Collagen Induced Arthritis Model
Abstract:
#1287
Presenter:
Vanheusden, Katrien PhD
Co-Authors:
Detalle, Laurent PhD; Hemeryck, Alex PhD; Vicari, Alain PhD; Grenningloh, Roland PhD; Poelmans, Sofie PhD; Wouters, Heidi PhD; Stöhr, Thomas PhD
Date:
Monday, October 28, 2013
Presenter Available:
9:00 am - 11:00 am
Poster Available:
8:30 am - 4:00 pm
Location:
Exhibit Hall B2-C-D
Session Title:
Rheumatoid Arthritis-Animal Models I
Abstract Category:
Rheumatoid Arthritis - Animal Models
Type:
Poster
Description:
Background/Purpose:
Interleukin (IL)-17 and Th17 cells are implicated in many auto-immune diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis. Although IL-17(A) is the most characterized IL-17 family member, IL-17F may play a non-redundant role in Th17 driven diseases as it is secreted by other cell types. Therefore, a trivalent half-life extended Nanobody® ALX-0761 (MSB0010841) has been developed that neutralizes both IL-17A and IL-17F. A collagen induced arthritis model in cynomolgus monkey was used to demonstrate proof-of-concept.
Methods:
Cynomolgus monkeys were immunized twice intra-dermally with bovine collagen type II to induce an arthritic disease mimicking human RA. Prophylactic ALX-0761 treatment was compared to vehicle: ALX-0761 was administered weekly for eight consecutive weeks and dosed subcutaneously at 2.8mg/kg or 10mg/kg. A tocilizumab treatment group (IV administration, 10mg/kg) was included as positive control. The preventive effect of ALX-0761 on arthritis development was evaluated by the measurement of arthritis score (AS) of the joints, general condition score, X-ray examination scores of the affected joints, C-reactive protein (CRP) concentrations and body weight. In addition, total target levels (both IL-17A and IL-17F), pharmacodynamic biomarkers, immunogenicity and drug exposure were analyzed.
Results:
Immunisation with collagen type II established an arthritis-like disease in all animals. This was observed by worsening of the arthritis and general condition score and X-ray scores A and B, indicative of an increase in joint space narrowing and architectural joint destruction respectively. In addition, body weight loss and prevalence of high-CRP animals was most pronounced in the vehicle group. The levels of IL-17A and IL-17F increased during the establishment of the disease in the vehicle group, supporting a role for these cytokines in the onset and/or maintenance of the disease.
Treatment with ALX-0761 attenuated the disease symptoms when compared to the vehicle group. For the arthritis score as well as for the X-ray score B, ALX-0761 reached statistical significance. Clinical improvement was also observed based on the general condition score, X-ray score A, CRP levels and body weight, although no statistical significance was reached. Serum levels of the inflammatory cytokines IL-6, TNF-a, IL-15 and the cartilage degradation marker MMP-3 decreased in ALX-0761-treated animals, at day 28 or day 56, when compared to vehicle albeit not statistically significant. Serum IL-17A and IL-17F levels increased markedly upon first ALX-0761 administration and reached a plateau after two to three injections.
Conclusion:
This model, responsive to the anti-rheumatic effect of tocilizumab proved to be at least partially dependent on IL-17 as evidenced by increased IL-17A and IL-17F levels in the vehicle group. We emphasize that ALX-0761 significantly improved the clinical endpoints, X-ray score B and the arthritis score and that promising biomarkers (IL-6, IL-15, MMP-3, TNFa) were identified to aid further clinical development.
Disclosure:
K. Vanheusden, Ablynx, 3; L. Detalle, Ablynx, 3; A. Hemeryck, Ablynx, 3; A. Vicari, Merck Serono, 3; R. Grenningloh, Merck Serono, 3; S. Poelmans, Ablynx, 3; H. Wouters, Ablynx, 3; T. Stöhr, Ablynx, 3.