作者: Almeida, Juliana Franco ; Brigido, Marcelo Macedo ; de Souza Vianna, Leonora Maciel ; Jerônimo, Márcio Sousa ; de Castro, Raffael Júnio Araújo ; Pereira, Vanessa Bastos ; Chiabai, Maria José ; Sousa, Isabel Garcia ; de Azevedo, Mariana Gabriela Dantas ; Miyoshi, Anderson ; Fernandes, Suelen Soares ; Bocca, Anamelia Lorenzetti ; Maranhão, Andrea Queiroz

BACKGROUNDAnti-Tumor Necrosis Factor-alpha therapy has become clinically important for treating inflammatory bowel disease. However, the use of conventional immunotherapy requires a systemic exposure of patients and collateral side effects. Lactic acid bacteria have been shown to be effective as mucosal delivering system for cytokine and single domain antibodies, and it is amenable to clinical purposes. Therefore, lactic acid bacteria may function as vehicles for delivery of therapeutic antibodies molecules to the gastrointestinal tract restricting the pharmacological effect towards the gut. Here, we use the mucosal delivery of Lactococcus lactis carrying an anti-TNFα scFv expression plasmid on a DSS-induced colitis model in mice.RESULTSExperimental colitis was induced with DSS administered in drinking water. L. lactis carrying the scFv expression vector was introduced by gavage. After four days of treatment, animals showed a significant improvement in histological score and disease activity index compared to those of untreated animals. Moreover, treated mice display IL-6, IL17A, IL1β, IL10 and FOXP3 mRNA levels similar to health control mice. Therefore, morphological and molecular markers suggest amelioration of the experimentally induced colitis.CONCLUSIONThese results provide evidence for the use of this alternative system for delivering therapeutic biopharmaceuticals in loco for treating inflammatory bowel disease, paving the way for a novel low-cost and site-specific biotechnological route for the treatment of inflammatory disorders.

2019-01-02·Preparative Biochemistry and Biotechnology4区 · 工程技术

Characterization of the novel anti-TNF-α single-chain fragment antibodies using experimental and computational approaches

4区 · 工程技术

Article

作者: Alizadeh, Ali Akbar ; Hamzeh-Mivehroud, Maryam ; Pourtaghi-Anvarian, Samira ; Mohammadi, Samin ; Dastmalchi, Siavoush

Single-chain fragment variable (scFv) antibodies are antibody fragments consist of variable domains of full antibodies known to retain antigen binding properties while having much lower molecular weights granting some beneficial properties to them. In our previous study, three phage particles each displaying an individual scFv antibody (i.e. J43, J44, and J48) were identified as tumor necrosis factor alpha (TNF-α) binders. The current study aimed to produce previously identified anti-TNF-α scFv antibodies and to investigate their abilities to bind and inhibit TNF-α biological effect. The estimated free energy of folding determined using spectrofluorimetry method for the prepared scFv proteins was in the range of 6.35-12.45 kJ mol^-1 indicating their proper folding in the solution. In ELISA experiment, the produced scFvs showed an appropriate affinity towards TNF-α with K_d values in the range of 0.5-2.18 µM. They also inhibited the TNF-α-induced cytotoxicity on L929 cells with sub-micromolar IC₅₀ values (0.12 and 0.73 μM for J44 and J48, respectively). Molecular docking studies showed that J44 could mimic adalimumab interactions with TNF-α, confirming its relatively high TNF-α inhibitory effect compared to J43 and J48. It seems that the findings in the current study can be useful for designing more potent anti-TNF-α antibodies.

2015-07-01·Immunologic Research4区 · 医学

A novel anti-TNF scFv constructed with human antibody frameworks and antagonistic peptides

4区 · 医学

Article

作者: Shusheng Geng ; Jiannan Feng ; Yan Li ; Weisong Qin ; Ming Lv ; Hong Chang ; Beifen Shen

The introduction of TNF inhibitors has revolutionized the treatment of some chronic inflammatory diseases, e.g., rheumatoid arthritis and Crohn's disease. However, immunogenicity is one of the important mechanisms behind treatment failure, and generally, switching to another TNF inhibitor will be the first choice for patients and doctors, which results in unmet need for novel anti-TNF agents. Small antibody molecules with less number of epitope may be valuable in less immunogenicity. In this study, with the help of computer-guided molecular design, single-chain variable fragment (scFv) TSA2 was designed using consensus frameworks of human antibody variable region as scaffold to display anti-TNF antagonistic peptides. TSA2 showed evidently improved bioactivity over TSA1 (anti-TNF scFv explored before) and almost similar activity as S-Remicade (the scFv form of Remicade, anti-TNF antibody approved by FDA), especially in inhibiting TNF-induced cytotoxicity and NF-κB activation. Human antibody consensus frameworks with less immunogenicity have been used in the designing of VH domain antibody, scFv TSA1 and TSA2. A serial of TNF-related works convinced us that the novel design strategy was feasible and could be used to design inhibitors targeting more other molecules than TNF-α. More importantly, these designed inhibitors derived from computer modeling may form a virtual antibody library whose size depends on the number of candidate antagonistic peptides. It will be molecular-targeted virtual antibody library because of the specific antagonistic peptides and the potential antibodies could be determined by virtual screening and then confirmed by biologic experiments.

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适应症	最高研发状态	国家/地区	公司	日期
强直性脊柱炎	药物发现	中国台湾	免疫功坊股份有限公司	-
银屑病关节炎	药物发现	中国台湾	免疫功坊股份有限公司	-
类风湿关节炎	药物发现	中国台湾	免疫功坊股份有限公司	-