Modified human TNF alpha molecules, DNA encoding such modified TNF alpha molecules, process for preparation of modified human TNF alpha molecules, vaccines comprising such modified TNF alpha molecules and DNA and its use

摘要

A modified human TNF alpha molecule capable of raising neutralizing antibodies towards wild-type human TNF alpha following administration of said modified TNF alpha molecule to a human host, wherein at least one peptide fragment of the human TNF alpha molecule has been substituted by at least one peptide known to contain an immunodominant T cell epitope or a truncated form of said molecule containing an immunodominant epitope and one or both flanking regions of the human TNF alpha molecule comprising at least one TNF alpha B cell epitope, wherein the substitution introduces a substantial change in the amino acid sequence of the front beta-sheet, in any one of the connecting loops and/or in any one of the B', I or D strands of the back beta-sheet, wherein the substitution has been made in region of the TNF alpha molecule so as to preserve the beta-sheet structure of the B and G strands, and wherein the substitution leads to inactivation of the biological activity of human TNF alpha when tested in the L929 bioassay. The modified human TNF alpha molecules or DNA encoding them may be formulated as vaccines against TNF alpha optionally with pharmaceutically acceptable adjuvant, for the prevention or treatment of chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel diseases, cancer, disseminated sclerosis, diabetes, psoriasis, osteoporosis or asthma.