Therapeutic antibodies elicited by immunization against TNF-α

Dalum, Iben; Butler, Duncan; Jensen, Michael; Hindersson, Peter; Steinaa, Lucilla; Waterston, Ashita; Grell, S. N.; Feldmann, Marc; Elsner, Henrik I.; Mourit­sen, Søren

doi:10.1038/10878

Cited by 125 publications

(111 citation statements)

References 24 publications

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“…Protein-based vaccines have been obtained by cross-linking to OVA (IL-9 [18]) or immunogenic peptides (IL-12 [19], IL-1 [23], CD20 [24]) or by administration of OVA peptide containing fusion protein in the case of TNF-a [25]. DNA vaccines encoding a fusion protein (IL-5-p30 tetanus helper epitope [26]), altered IL-6 sequences [27] or even non-modified naked DNA, as reported for C-C chemokines [28] have also proven successful.…”

Section: Discussionmentioning

confidence: 99%

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

2006

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IL-17 has been associated with multiple inflammatory disorders such as rheumatoid arthritis, asthma and multiple sclerosis. As these diseases require long-term treatment we turned to an auto-vaccine strategy for IL-17 neutralization in vivo. Mouse IL-17A was covalently linked to ovalbumin and used to immunize C57BL/6 mice. This vaccine induced the production of antibodies that blocked IL-17A bioactivity in vitro but did not react with the other IL-17 isoforms, including IL-17F. As the half-life of the Ab titers after the last immunogen administration was approximately 4 months, the vaccine provides for long lasting and selective inhibition of IL-17A activity in vivo. A monoclonal Ab (mAb) derived from these mice showed the same specificity for IL-17A. To test the ability of the vaccine to confer protection against an IL-17-dependent disorder, SJL mice were vaccinated with IL-17-OVA and encephalomyelitis (EAE) was induced by proteolipid protein (PLP) peptide 139-151. Vaccinated mice were completely protected against the disease. The above-mentioned anti-IL-17A mAb also prevented EAE development. The absence of clinical symptoms contrasted with unaltered PLP-induced cytokine production in vitro and unmodified anti-PLP IgG titers and isotypes. These results suggest that an anti-IL-17A auto-vaccine offers new perspectives for therapy of autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

2006

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“…In addition, anti-TNF-␣ antibodies (17,18) and soluble chimeric TNF-␣ receptors (19,20) are widely used in the treatment of autoimmune disease, and a number of approaches are being pursued to develop TNF-␣-specific vaccines for clinical use. The latter include recombinant TNF-␣ molecules containing foreign immunodominant T-helper epitopes, TNF-␣ fusions to virus-like particles of the bacteriophage Q ␤ , and keyhole limpet hemocyanin-TNF-␣ heterocomplexes (4,21,22).…”

Section: Resultsmentioning

confidence: 99%

“…A number of strategies are being pursued to address this challenge including the development of improved adjuvants, the introduction of foreign helper peptides into chimeric antigens, and the use of DNA vaccines (1)(2)(3)(4). Interestingly, almost 50 years ago, Weigle (5) showed that rabbits immunized with a rabbit thyroglobulin that had been nonspecifically labeled with a diazonium derivative produced cross-reactive antibodies to native thyroglobulin.…”

Section: Tnf-␣ ͉ Unnatural Amino Acids ͉ Vaccination ͉ Immunogenicitymentioning

confidence: 99%

Immunochemical termination of self-tolerance

Grünewald

Tsao

Perera

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The ability to selectively induce a strong immune response against self-proteins, or increase the immunogenicity of specific epitopes in foreign antigens, would have a significant impact on the production of vaccines for cancer, protein-misfolding diseases, and infectious diseases. Here, we show that site-specific incorporation of an immunogenic unnatural amino acid into a protein of interest produces high-titer antibodies that cross-react with WT protein. Specifically, mutation of a single tyrosine residue (Tyr 86 ) of murine tumor necrosis factor-␣ (mTNF-␣) to p-nitrophenylalanine (pNO2Phe) induced a hightiter antibody response in mice, whereas no significant antibody response was observed for a Tyr 86 3 Phe mutant. The antibodies generated against the pNO 2Phe are highly cross-reactive with native mTNF-␣ and protect mice against lipopolysaccharide (LPS)-induced death. This approach may provide a general method for inducing an antibody response to specific epitopes of self-and foreign antigens that lead to a neutralizing immune response.TNF-␣ ͉ unnatural amino acids ͉ vaccination ͉ immunogenicity

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“…In particular, the proinflammatory TNF␣ cytokine was shown to be critically involved in the pathogenesis of rheumatoid arthritis (RA) and further its inhibition by anti-TNF␣ Abs controls the disease in experimental models (2,3). These data prompted anti-human TNF␣ (hTNF␣) mAb therapy for RA in humans (4,5).…”

mentioning

confidence: 99%

TNFα kinoid vaccination-induced neutralizing antibodies to TNFα protect mice from autologous TNFα-driven chronic and acute inflammation

Buanec

Delavallée

Bessis

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The proinflammatory cytokine TNF␣ is a potent mediator of septic shock and a therapeutic target for chronic inflammatory pathologies including rheumatoid arthritis and Crohn's disease. As an alternative to anti-human TNF␣ (hTNF␣) mAbs and other hTNF␣ blocker approved drugs, we developed an active anti-hTNF␣ immunotherapy, based on a vaccine comprised of a keyhole limpet hemocyanin-hTNF␣ heterocomplex immunogen (hTNF␣ kinoid) adjuvanted in incomplete Freund's adjuvant. In mice transgenic for hTNF␣ (TTg mice), hTNF␣ kinoid vaccination elicited high titers of Abs that neutralized hTNF␣ bioactivities but did not result in a cellular response to hTNF␣. The vaccine was safe and effective in two experimental models. Kinoid-immunized but not control TTg mice resisted hTNF␣-driven shock in one model and were prevented from spontaneous arthritis, inflammatory synovitis, and articular destruction in a second model. These data demonstrate an anti-cytokine induction of autoimmune protection against both acute and chronic hTNF␣ exposure. They show that active vaccination against a human cytokine can be achieved, and that the immune response can be effective and safe.anticytokine vaccination ͉ rheumatoid arthritis ͉ TNF␣ therapeutic vaccination ͉ TNF␣-dependent shock T he pathogenesis of severe chronic diseases, including rheumatic diseases, autoimmunity, and cachexia, depend at least in part on cytokine dysregulation within altered tissues (1). In particular, the proinflammatory TNF␣ cytokine was shown to be critically involved in the pathogenesis of rheumatoid arthritis (RA) and further its inhibition by anti-TNF␣ Abs controls the disease in experimental models (2, 3). These data prompted anti-human TNF␣ (hTNF␣) mAb therapy for RA in humans (4, 5). Efficacy in preventing RA of either mouse-human chimeric (infliximab; ref. 4) or fully human (adalimumab; ref. 5) mAbs was first demonstrated in the transgenic mouse model expressing hTNF␣. These mice mimic the clinical and histopathological progression of RA in humans (6, 7). Thereafter, clinical trials using infliximab (8, 9) and adalimumab (10) were successfully completed. Today, these approved therapeutic mAbs, as well as soluble hTNF␣ receptor derivative (etanercept) specifically targeting hTNF␣, are used in therapy of autoimmune diseases (11,12). About 1 million patients to date have been treated with these TNF␣ blockers with clinical efficacy in RA (1), Crohn's disease (13), and psoriasis (14). Potential side effects, however, include the risk of infection (sepsis or tuberculosis; ref. 15) and the occurrence of anti-DNA autoAbs (16) and possibly lymphoma (17). Furthermore, these therapeutic approaches are expensive and cumbersome. These limitations prompted investigations of alternative strategies, including active anti-TNF␣ immunization, targeting TNF␣ pathogenic effects (18)(19)(20). In this report, we show that a biologically inactive but immunogenic hTNF␣ derivative, constituted of a keyhole limpet hemocyanin (KLH)-hTNF␣ heterocomplex, called hTNF␣ kinoid (21), successf...

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Therapeutic antibodies elicited by immunization against TNF-α

Cited by 125 publications

References 24 publications

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

Immunochemical termination of self-tolerance

TNFα kinoid vaccination-induced neutralizing antibodies to TNFα protect mice from autologous TNFα-driven chronic and acute inflammation

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