An anti-TNF receptor one-specific antagonistic antibody for the therapy of inflammatory diseases

Tumor necrosis factor (TNF) has been recognized as the driving pathological mediator of inflammatory diseases. The development and use of antagonists of TNF has proven over the past ten years to be a great clinical and commercial success. However, the current anti-TNFs are first-generation drugs and their limitations have become apparent over years of clinical use. Aside from being effective in only a fraction of patients, their limitations most notably include a universal "black box" warning regarding increased risk of tuberculosis and other infections, as well as warnings regarding increased susceptibility to demyelinating disorders and lymphomas. All approved anti-TNF biologics are essentially "me-too" drugs with respect to target specificity and selectivity (Pfizenmaier and Szymkowski 2011). However, in the past 20 years the role of TNF in both health and disease has been re-evaluated. Especially the role of mTNF/TNFR2 signaling in immune regulation and tissue homeostasis changed the understanding of what constitutes an optimal therapeutic profile for a TNF inhibitor. Selective inhibition of sTNF/TNFR1 signaling seems to be a more promising therapeutic approach and may help to improve the safety and efficacy profile of anti-TNF therapies.

Earlier findings at our institute demonstrated that the monoclonal antibody H398 serves as a universal inhibitor of TNFR1-mediated TNF responses (Thoma et al., 1990; Moosmayer et al., 1995). For the intended therapeutic application we first humanized H398 (IZI-06.1; Kontermann et al., 2008) and then subsequently generated a humanized IgG1 of this human TNFR1-specific reagent (Atrosab; Zettlitz et al., 2010).

In vitro, Atrosab shows similar antagonistic properties as H398. The epitope recognized on TNFR1 by H398 and ATROSAB includes the membrane-distal CRD1 and subdomain A1 of CRD2. The structure of TNFR1 with bound TNF shows that the identified epitope region at least partially overlaps with the TNF binding site, which is mainly located in CRD2 and CRD3. The finding that subdomain A1 of CRD2 is also required for antibody binding hints toward steric blockage as cause for neutralization of TNF action (Zettlitz et al., 2010). Importantly, ATROSAB showed protective activity in a pilot trial of acute arthritis in a non-human primate model (CIA), with delayed onset and reduction of disease severity, demonstrating the therapeutic potential of antibody-mediated specific TNFR1 inhibition in inflammatory disease. Atrosab is currently under development for further clinical studies.

Related publications

Kontermann RE, Münkel S, Neumeyer J, Müller D, Branschädel M, Scheurich P, Pfizenmaier K, A humanized tumor necrosis factor receptor 1 (TNFR1)-specific antagonistic antibody for selective inhibition of tumor necrosis factor (TNF) action. J Immunother. 2008; 31:225-234.

Moosmayer D, Dübel S, Brocks B, Watzka H, Hampp C, Scheurich P, Little M, Pfizenmaier K, A single-chain TNF receptor antagonist is an effective inhibitor of TNF mediated cytotoxicity. Ther Immunol. 1995; 2:31-40.

Pfizenmaier K, Szymkowski DE, Workshop Summary: Introduction to Rational Design of New Means for Therapeutic Modulation of Function of the TNF Family. Adv Exp Med Biol. 2011; 691:487-491.

Thoma B, Grell M, Pfizenmaier K, Scheurich P, Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses. J Exp Med. 1990; 172:1019-1023.

Zettlitz KA, Lorenz V, Landauer K, Münkel S, Herrmann A, Scheurich P, Pfizenmaier K, Kontermann R, ATROSAB, a humanized antagonistic anti-tumor necrosis factor receptor one-specific antibody. MAbs. 2010; 2:639-647.