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AB0172 Protection from articular damage by passive or active anti-TNF alpha immunotherapy in human-TNF alpha transgenic mice depends on anti-TNF alpha antibody levels
  1. L. Semerano1,2,
  2. J. Biton1,
  3. L. Delavallee1,
  4. E. Duvallet1,
  5. E. Assier1,
  6. N. Bessis1,
  7. E. Bernier3,
  8. O. Dhellin3,
  9. G. Grouard-Vogel3,4,
  10. M.-C. Boissier1,4
  1. 1Sorbonne Paris Cite-Universite Paris 13, Ea4222
  2. 2Avicenne Hospital (Ap-Hp), Bobigny, France, Bobigny
  3. 3Neovacs S.A., Paris
  4. 4Rheumatology, Avicenne Hospital (Ap-Hp), Bobigny, France, Bobigny, France

Abstract

Background In human TNFα (hTNFα) transgenic mice (TTg), active anti-TNFα immunization with the kinoid of TNFα (TNF-K) induces polyclonal anti-hTNFα antibodies and results in amelioration of arthritis1,2,3

Objectives 1) To compare the efficacy of TNF-K to that of infliximab (IFX) and to that of TNF-K and IFX co-administration. 2) To evaluate whether the titers of anti-hTNFα antibodies (Ab) induced by active immunization are a determinant of TNF-K efficacy.

Methods Forty-eight TTg mice received one of the following treatments: TNF-K immunization (TNFK group); weekly IFX all along study duration (IFXw0-15); TNF-K plus weekly IFX for 4 weeks (TNF-K+IFX), weekly IFX for 4 weeks (IFXw0-4); PBS. Animals were sacrificed at week 16. Anti-hTNFα Ab titers IFX serum levels and clinical and histological scores were compared.

Results All TNF-K immunized mice (TNF-K and TNF-K+IFX) produced anti-hTNFα Ab. Ab titers were higher in the TNF-K group vs. TNF-K+IFX (p<0.001) and inversely correlated to histological inflammation (R=-0.78; p=0.0001) and destruction (R= -0.67; p=0.001). Mice with high vs. low anti-hTNFα Ab titers had less histological inflammation and destruction (p<0.05). Similarly, the serum levels of infliximab in IFX-only treated mice showed inverse correlation with histological inflammation (R= - 0.56; p<0.05) and destruction scores (R -0.57; p<0.05). TNF-K and long-term IFX treatment (IFXw0-15) didn’t differ in clinical and histological amelioration of arthritis. The group that received TNF-K and IFX co-administration (TNF-K+IFX) had a more rapid clinical improvement (p<0.05) but higher histological inflammation and destruction (p<0.05) compared to the group that received solely TNF-K.

Conclusions In a model of TNFα–dependent arthritis, protection from articular damage by TNF-K correlates with the titers anti-hTNFα Ab induced by active anti-hTNFα immunization. TNF-K and IFX have similar efficacy. The co-administration of TNF-K and a short course of IFX does not result in less articular damage vs. solely TNF-K, probably due to lower anti-hTNFα Ab production. These results are relevant for future development of active anti-TNFα immunization in RA.

  1. Le Buanec H, Delavallee L, Bessis N, et al. TNFalpha kinoid vaccination-induced neutralizing antibodies to TNFalpha protect mice from autologous TNFalpha-driven chronic and acute inflammation. Proc Natl Acad Sci U S A 2006;103:19442-7.

  2. Delavallee L, Le Buanec H, Bessis N, et al. Early and long-lasting protection from arthritis in tumour necrosis factor alpha (TNFalpha) transgenic mice vaccinated against TNFalpha. Ann Rheum Dis 2008;67:1332-8.

  3. Delavallee L, Semerano L, Assier E, et al. Active immunization to tumor necrosis factor-alpha is effective in treating chronic established inflammatory disease: a long-term study in a transgenic model of arthritis. Arthritis Res Ther 2009;11:R195.

Disclosure of Interest L. Semerano: None Declared, J. Biton: None Declared, L. Delavallee: None Declared, E. Duvallet: None Declared, E. Assier: None Declared, N. Bessis: None Declared, E. Bernier Employee of: Neovacs S.A., O. Dhellin Employee of: Neovacs S.A., G. Grouard-Vogel Employee of: Neovacs S.A., M.-C. Boissier Grant/Research support from: Neovacs S.A., Consultant for: Neovacs S.A.

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