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9. Phase I-II safety, immunogenicity and clinical results of TNFα-kinoid immunotherapeutic immunization in Crohn's disease patients

P. Vandepapeliere1, F. Malan2, G. Rogler3, A. van der Bijl2, F.C. Kruger4, D. Kruger2, G. Grouard-Vogel1, O. Dhellin1, B. Fanget1, P. Michetti5

1Neovacs SA, Paris, France; 2Parexel, Bloemfontein, South Africa; 3Universitätsspital Zürich, Zürich, Switzerland; 4Durbanville Clinic, Cape Town, South Africa; 5Gastro-entérologie La Source Beaulieu, Lausanne, Switzerland

Treatment of Crohn's disease (CD) with monoclonal antibodies (MAbs) against TNFα has demonstrated efficacy but also limitations, primarily the frequent lack of a sustained therapeutic effect. Induction of endogenous polyclonal antibodies to TNFα through active immunization may be an attractive alternative for sustained control of CD. We evaluated the safety, immune responses and clinical effects of active immunization against TNFα using a TNFα-Kinoid in CD patients.

TNFα-Kinoid (TNF-K, Neovacs SA, Paris, France) is an immunotherapeutic composed of recombinant human TNFα (hTNFα) conjugated to KLH as a carrier protein, inactivated and adjuvanted with ISA-51 emulsion.

Patients with moderate to severe Crohn's disease (CDAI 220–400) were enrolled in an open label, phase 1–2 dose escalation study to evaluate the safety and immunogenicity of three doses of TNF-K (60, 180 or 360 mcg) administered intramuscularly on Days 0, 7 and 28 with a fourth dose on Day 168 for some patients. Safety evaluation included recording of adverse events, monitoring of haematological and biochemical parameters as well as the evaluation of immune responsiveness to recall antigens in vivo. Immune responses were evaluated through regular titration of anti-TNFα and anti-KLH antibodies with isotyping and cellular lymphoproliferation. Clinical response was assessed by repeated complete clinical evaluation, Crohn's Disease Activity Index (CDAI), quantification of fecal calprotectin, and measurements of serum biomarkers.

21 patients were enrolled, 3 in the 60 mcg group and 9 in each of the 180 and 360 mcg groups. Four patients (1 from 60, 2 from 180 and 1 from 360 mcg groups) were administered a maintenance dose at month 6. No related serious adverse event was observed and all patients completed the trial. A few minor and transient local and systemic reactions have been reported following immunization and the laboratory safety parameters were not altered. Anti-TNFα antibodies were measured in 1/3 patients at 60 mcg, and in 8/9 patients at both 180 and 360 mcg. This antibody response was variable in intensity but on average persisted 3–4 months and was boosted by a further TNF-K injection at month 6. No T cell response specific to TNFα was detected. Overall, 66–78% of the patients presented a clinical response (CDAI-70) from week 4 to 12. At weeks 4, 8 and 12, 36%, 50% and 45% of the patients, respectively, were in clinical remission (CDAI ≤ 150). Clinical remission was associated with anti-TNFα antibody seropositivity. Calprotectin levels decreased concomitantly.

In this trial, active immunization with a TNFα-Kinoid safely induced anti-TNFα antibodies with indication of a positive clinical response. These promising preliminary results suggest for the first time that active immunization against TNFα could represent a new therapeutic strategy in Inflammatory Bowel Diseases.