Background Neovacs developed the Interferon alpha Kinoid (IFN-K), a therapeutic vaccine composed of IFNα2b coupled to a carrier protein, the keyhole limpet hemocyanin. A placebo-controlled phase I/II study was conducted comparing 3 or 4 injections of 30, 60, 120, 240 μg IFN-K versus placebo in 28 Systemic Lupus Erythematosus (SLE) patients. Anti-IFNα2b binding and neutralizing antibodies were analyzed demonstrating the immunogenicity of IFN-K towards IFNα2b. We further characterized the isotypes, avidity and specificity of anti-IFNα antibodies towards other IFN subtypes. We also compared the neutralizing capacities in sera from two SLE patient to that of 9F3 a murine anti-IFNα monoclonal antibody (Genentech patent # US 7 087 726 B2).
Methods Isotype profile and cross-reactions of anti-IFNα antibodies towards IFNβ or IFNγ were tested by ELISAs. The relative anti-IFNα antibody avidity (RAV) was analyzed by ELISA in the presence of a gradient of sodium isothiocyanate chaotropic agent. Neutralizing capacities of anti-IFN antibodies towards the 13 IFNα subtypes were assessed by the compendial Madin Darby bovine kidney-vesicular stomatitis virus infection assay and were also compared to 9F3 (ATCC#PTA-2917).
Results The main anti-IFNα antibody isotypes produced were IgG1 and IgG3. Anti-IFNα IgA were detected in 4 patients. Some anti-huIFNα IgM were detected mainly at day 38. IgG4 and IgE were never detected. The RAV of anti-IFNα antibodies increased with the appearance of IFNα neutralizing capacity, whereas the RAV of binding anti-IFNα antibodies without neutralizing activity remained low and stable, similar to anti-IFNα auto-antibodies detected before dosing or in the placebo group. Anti-IFNα antibodies induced by IFN-K did not cross-react with IFNβ or IFNγ. The induced anti-IFNα antibodies neutralized most or all IFNα subtypes and the number of subtypes neutralized increased with the level and persistence of neutralizing capacities. The 9F3 mab neutralized 7 IFNα subtypes, of which only two (IFNα2A and IFNα2B) strongly. In contrast, sera from the two patients exhibiting neutralizing capacities 2 years after immunizations, neutralized 13 and 9 subtypes and the neutralizing capacity of the induced polyclonal antibodies is exercised at high serum dilutions and is much more powerful against all IFNα subtypes than monoclonal 9F3 which only strongly neutralized two IFNα sub-types.
Conclusions Anti-IFNα antibodies induced by IFN-K in SLE patients neutralized most or all IFNα subtypes but recognized neither IFNβ nor IFNγ. As opposed to monoclonal antibodies kinoid induced polyclonal antibodies neutralized most IFNα subtypes at high dilution. These preliminary results support the superiority of a polyclonal antibody strategy in a disease such as lupus wherein all IFNα subtypes may play a role.
Disclosure of Interest G. Grouard-Vogel Shareholder of: Neovacs, Employee of: Neovacs, B. Lauwerys Consultant for: Neovacs, P. Vandepapeliere Shareholder of: Neovacs, Employee of: Neovacs, F. Colaone Shareholder of: Neovacs, Employee of: Neovacs, P. Blanco Consultant for: Neovacs, T. Defrance Consultant for: Neovacs, C. Roucairol Shareholder of: Neovacs, Employee of: Neovacs, F. Houssiau Consultant for: Neovacs
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