Rheumatoid arthritis (RA) is one of the most common autoimmune diseases affecting primarily the joints. Despite successful therapies including antibodies against tumor necrosis factor (TNF) and interleukin-6 (IL-6) receptor, only 20 to 30% of patients experience remission. We studied whether inhibiting both TNF and IL-6 would result in improved efficacy. Using backtranslation from single-cell RNA sequencing (scRNA-seq) data from individuals with RA, we hypothesized that TNF and IL-6 act synergistically on fibroblast-like synoviocytes (FLS) and T cells. Coculture of FLS from individuals with RA and T cells supported this hypothesis, revealing effects on both disease-driving pathways and biomarkers. Combining anti-TNF and anti–IL-6 antibodies in collagen-induced arthritis (CIA) mouse models resulted in sustained long-term remission, improved histology, and effects on bone remodeling pathways. These promising data initiated the development of an anti–TNF/IL-6 bispecific nanobody compound 1, with similar potencies against TNF and IL-6. We observed additive efficacy of compound 1 in a FLS/T cell coculture affecting arthritis and T helper 17 (T_H17) pathways. This nanobody compound transcript signature inversely overlapped with described RA endotypes, indicating a potential efficacy in a broader patient population. In summary, we showed superiority of a bispecific anti–TNF/IL-6 nanobody compound or combination treatment over monospecific treatments in both in vitro and in vivo models. We anticipate improved efficacy in upcoming clinical studies.

Biomedcode scientists have coauthored a paper published in Scientific Reports  that provides for the first time a possible mechanistic explanation to the growth retardation commonly observed in children with chronic inflammatory diseases treated with glucocorticoids. The Tg197 human TNF transgenic mice were used as a tool to show that TNF overexpression and dexamethasone treatment impair bone growth separately and in an additive manner.

Biomedcode is in search  of an individual or company with proven experience in Intellectual Property  exploitation to take over the management of the IP of its drug discovery projects. The ideal candidate will lead initiatives to generate and engage with business partners to exploit the company’s IP portfolio. Critical thinking and a demonstrated ability to execute a particular IP exploitation strategy, identify partnerships and financing opportunities in the life sciences industry  as well as develop and manage IP commercialization strategies are required.

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 Ig

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.

Biomedcode has been recognized by the  Pharma Tech Outlook magazine as one of the top 10 CROs of the year 2020. An interview with Biomedcode’s CEO and CSO is published in this month’s special edition on Europe’s CROs.

 

 

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Biomedcode is excited to participate as one of the 63 European companies that have been selected to join the EUGATEWAY Healthcare and Medical Technologies Business Mission to Singapore on 8-11 December 2020. Due to the COVID-19 pandemic this will be a virtual event and we look forward to discussing with potential new partners and clients about future collaborations!

 

During rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor α antibodies (anti-TNFα Abs) may induce on-target toxicities, including severe infections (tuberculosis [TB] or septic arthritis) and malignancy. Here, we used an immunoglobulin
G1 (IgG1) hinge as an Ab lock to cover the TNFα-binding site of Infliximab by linking it with matrix metalloproteinase (MMP) -2/9 substrate to generate pro-Infliximab that can be specif- ically activated in the RA region to enhance the selectivity and safety of treatment. The Ab lock significantly inhibits the TNFα binding and reduces the anti-idiotypic (anti-Id) Ab binding to pro-Infliximab by 395-fold, 108-fold compared with Infliximab, respectively, and MMP-2/9 can completely restore the TNFα neutralizing ability of pro-Infliximab to block TNFα down- stream signaling. Pro-Infliximab was only selectively activated in the disease site (mouse paws) and presented similar pharmacokinetics (PKs) and bio-distribution to Infliximab. Fur- thermore, pro-Infliximab not only provided equivalent therapeutic efficacy to Infliximab but also maintained mouse immunity against Listeria infection in the RA mouse model, leading to a significantly higher survival rate (71%) than that of the Infliximab treatment group (0%). The high-selectivity pro-Infliximab maintains host immunity and keeps the original therapeu- tic efficiency, providing a novel strategy for RA therapy.