Biotech Values

[DonShimoda]

XOMA -- Is Gevokizumab a “best-in-class” anti-IL-1ß therapeutic antibody?

These articles discuss the role that IL-1ß plays in the development of many inflammatory, autoimmune, metabolic and oncological diseases and make the case that Gevokizumab is a “best-in-class” anti-IL-1ß therapeutic antibody,

XOMA 052, a potent, high-affinity monoclonal antibody for the treatment of IL-1ß-mediated diseases

Interleukin-1ß (IL-1ß) is a potent mediator of inflammatory responses and plays a role in the differentiation of a number of lymphoid cells. In several inflammatory and autoimmune diseases, serum levels of IL-1ß are elevated and correlate with disease development and severity. The central role of the IL-1 pathway in several diseases has been validated by inhibitors currently in clinical development or approved by the FDA. However, the need to effectively modulate IL-1ß-mediated local inflammation with the systemic delivery of an efficacious, safe and convenient drug still exists.

Several inhibitors of the IL-1 pathway have been developed and have provided important proof of concept to illustrate that this pathway has great potential for the development of new therapeutic drugs. While providing proof of concept in many diseases, these inhibitors require frequent or high dosing regimens to achieve and maintain efficacy, which is possibly due to their mechanism of inhibition together with their pharmacokinetic properties. This is particularly true for diseases like rheumatoid arthritis, where a therapeutic agent, in order to exert its inhibitory effect, must penetrate the synovial compartment and maintain a steady-state of local efficacious levels.

To overcome these limitations, we sought to design and develop a “best-in-class” anti-IL-1ß therapeutic antibody, XOMA 052. This high affinity antibody specifically inhibits IL-1ß activity
with a unique mechanism of action. Such specificity for IL-1ß alone will have the added advantage of sparing both IL-1a, which could provide a safety margin for protection against potential infections and IL-1Ra, which is the natural antagonist of the IL-1 signaling pathway. Indeed, inactivation of IL-1Ra would work against the very purpose of the therapeutic drug.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038011/

One Target-Two Different Binding Modes: Structural Insights into Gevokizumab and Canakinumab Interactions to Interleukin-1ß
Blech M, Peter D, Fischer P, Bauer MM, Hafner M, Zeeb M, Nar H.
Source
Department of Lead Identification and Optimization Support, Structural Research Group, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany; Department of NBE Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany; Institut für Medizintechnologie der Ruprecht-Karls-Universität Heidelberg & Hochschule Mannheim, Heidelberg und Mannheim, Germany. Electronic address: [e-mail].
Abstract
Interleukin-1ß (IL-1ß) is a key orchestrator in inflammatory and several immune responses. IL-1ß exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1ß monoclonal antibodies. Canakinumab is known to neutralize IL-1ß by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1ß bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1ß signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1ß. Furthermore, we characterized the epitopes on IL-1ß employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1ß and provide insight into the mechanisms leading to their distinct modulation of IL-1ß signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1ß causes competitive inhibition of the association of IL-1ß and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1ß and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1ß pathway attenuation.
http://www.ncbi.nlm.nih.gov/pubmed/23041424