Safety, Immunogenicity and Clinical Phase I-II Results of TNFα-Kinoid Immunotherapeutic in Crohn's Disease Patients

Vandepapelière, Pierre; Malan, François; Rogler, Gerhard; Bijl, Anina van der; Kruger, Frederik C.; Kruger, Dawid S.; Grouard-Vogel, Géraldine; Dhellin, Olivier; Fanget, B.; Michetti, Pierre

doi:10.1016/s0016-5085(11)60501-5

Cited by 15 publications

(5 citation statements)

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“…The drug was also investigated to treat CD patients, and a high clinical response was reported with remission rates in half of the patients. However, the clinical efficacy needs to be weighed against the potential harmful consequences of life-long ablation of TNF and probably for that reason further development was suspended [264]. The same holds true for CYT007-TNFQb of which the phase I/II clinical trial was discontinued in psoriasis patients [265].…”

Section: Tnf Inhibitorsmentioning

confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

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Section: Tnf Inhibitorsmentioning

confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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“…Based on the proof of concept established in experimental arthritis, TNF-K entered clinical development. A Phase I clinical trial, performed in Crohn’s disease patients, showed it was well tolerated and immunogenic [17] . Here we report the results of a phase IIa pilot study, performed in RA patients, who previously experienced a secondary failure of anti-TNF biologics.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Vaccination with TNF-Kinoid in TNF Antagonist-Resistant Rheumatoid Arthritis: A Phase II Randomized, Controlled Clinical Trial

et al. 2014

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ObjectivesActive immunization, or vaccination, with tumor necrosis factor (TNF)-Kinoid (TNF-K) is a novel approach to induce polyclonal anti-TNF antibodies in immune-mediated inflammatory diseases. This study was performed to transfer the proof of concept obtained in mice model of rheumatoid arthritis (RA) into human. We designed a pilot study to demonstrate the feasibility of therapeutic vaccination in RA.MethodsThis was a phase IIa, placebo-controlled, multicenter study in adults with RA who previously experienced secondary failure of TNF antagonists. Patients were immunized intramuscularly with 2 or 3 doses of placebo (n = 10) or 90 (n = 6), 180 (n = 12), or 360 µg TNF-K (n = 12). The primary objective was to identify the best dose and schedule based on anti-TNF antibody titers. Clinical symptoms and safety were assessed during 12 months and solicited reactions for 7 days after each injection.ResultsThe highest anti-TNF antibody response was detected in patients immunized with 360 µg TNF-K and with 3 injections, although this difference was not significant with all other groups. Similar proportions of patients receiving TNF-K and placebo reported adverse events up to month 12. Serious adverse events were reported by 4 patients treated with TNF-K (13.3%) and 3 treated with placebo (30.0%), all unrelated to treatment. At month 12, DAS28-CRP, tender and swollen joint counts, and HAQ scores decreased significantly more in patients who exhibited anti-TNF antibody response than in patients who did not.ConclusionsTNF-K therapeutic vaccination induced dose- and schedule-dependent anti-TNF antibodies in RA patients and was well tolerated. Patients who developed anti-TNF antibodies showed a trend toward clinical improvement. Although the most aggressive dose and schedule, i.e. 360 mg dose administered 3 times, did show a strong trend of higher antibody response, further studies are warranted to examine even higher and more frequent doses in order to establish the best conditions for clinical improvement.Trial RegistrationClinicalTrials.gov NCT01040715

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“…The drug was also investigated to treat CD patients, and a high clinical response was reported with remission rates in half of the patients. However, the clinical efficacy needs to be weighed against the potential harmful consequences of life-long ablation of TNF and probably for that reason further development was suspended [ 273 ]. The same holds true for CYT007-TNFQb of which the phase I/II clinical trial was discontinued in psoriasis patients [ 274 ].…”

Section: Other Anti-tnf and Tnf-modulating Drugsmentioning

confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

IJMS

104

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The first Food and Drug Administration-(FDA)-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects, followed by protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-tumor necrosis factor (TNF) drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class, whereas others are linked with their mechanism of action, being pan-TNF inhibition. The effects of TNF can diverge at the level of TNF format or receptor, and we discuss the consequences of this in sepsis, autoimmunity and neurodegeneration. Recently, researchers tried to design drugs with reduced side effects. These include molecules with more specificity targeting one specific TNF format or receptor, or that neutralize TNF in specific cells. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the benefits of selective approaches in different diseases.

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Safety, Immunogenicity and Clinical Phase I-II Results of TNFα-Kinoid Immunotherapeutic in Crohn's Disease Patients

Cited by 15 publications

References 0 publications

A New Venue of TNF Targeting

A New Venue of TNF Targeting

Therapeutic Vaccination with TNF-Kinoid in TNF Antagonist-Resistant Rheumatoid Arthritis: A Phase II Randomized, Controlled Clinical Trial

A New Venue of TNF Targeting

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