Ozoralizumab, a Humanized Anti-TNFα NANOBODY® Compound, Exhibits Efficacy Not Only at the Onset of Arthritis in a Human TNF Transgenic Mouse but Also During Secondary Failure of Administration of an Anti-TNFα IgG

Abstract

Although the introduction of tumor necrosis factor (TNF) inhibitors represented a significant advance in the treatment of rheumatoid arthritis (RA), traditional anti-TNFα antibodies are somewhat immunogenic, and their use results in the formation of anti-drug antibodies (ADAs) and loss of efficacy (secondary failure). Ozoralizumab is a trivalent, bispecific NANOBODY® compound that differs structurally from IgGs. In this study we investigated the suppressant effect of ozoralizumab and adalimumab, an anti-TNFα IgG, on arthritis and induction of ADAs in human TNF transgenic mice. Ozoralizumab markedly suppressed arthritis progression and did not induce ADAs during long-term administration. We also developed an animal model of secondary failure by repeatedly administering adalimumab and found that switching from adalimumab to ozoralizumab was followed by superior anti-arthritis efficacy in the secondary-failure animal model. Moreover, ozoralizumab did not form large immune complexes that might lead to ADA formation. The results of our studies suggest that ozoralizumab, which exhibited low immunogenicity in the animal model used and has a different antibody structure from that of IgGs, is a promising candidate for the treatment of RA patients not only at the onset of RA but also during secondary failure of anti-TNFα treatment.

Immunotherapeutic progress and application of bispecific antibody in cancer

“…Ozoralizumab is a bi-Nanobody-based bsAb consisting of two anti-TNFα nanobodies and an anti-HSA nanobody. It is a good TNF inhibitor that inhibits arthritis progression ( 45 ) and is currently in phase II clinical studies for the treatment of rheumatoid arthritis.…”

Proinflammatory cytokines and their receptors as druggable targets to alleviate pathological pain

“…231 Tumor necrosis factor-a interfering antibodies like adalimumab and golimumab are in use for RA for several years with a relatively good safety profile and little risk of increased susceptibility to infections or major cardiovascular events. 40,101 Novel nanobody molecules, such as ozoralizumab, structurally differing from the classical IgG mAbs, seem to cause less antidrug antibodies (ADAs) in preclinical studies, 156 and a phosphate-free etanercept formulation exhibited reduced injection site pain scores in patients with arthritis. 68 In spheroid cultures of human osteoarthritic chondrocytes, the inflammatory processes induced by TNF-a could be reversed by anti-TNFa biologics, including adalimumab, infliximab, and etanercept.…”

Selection of single domain anti-transferrin receptor antibodies for blood-brain barrier transcytosis using a neurotensin based assay and histological assessment of target engagement in a mouse model of Alzheimer’s related amyloid-beta pathology

“…Caplacizumab was the first VHH approved by FDA for treatment of acquired thrombotic thrombocytopenic purpura in humans [ 36 ]. There are several more VHHs which are in clinical trials, with safety profiles similar to other antibody therapeutics in humans [ 37 , 38 ]. Importantly, VHHs have been found that can facilitate BBB penetration and allow brain target binding [ 39 – 44 ].…”