The immune repertoire of healthy individuals contains a fraction of antibodies (Abs) that bind with high affinity various endogenous or exogenous low molecular weight compounds, including some cofactor molecules essential for the aerobic life, such as riboflavin, heme and adenosine triphosphate (ATP). Despite identification of cofactor-binding Abs as a constituent of normal immune repertoires, their fundamental characteristics have never been systematically investigated. Thus, we do not know the origin, prevalence and physiopathological significance of cofactor-binding Abs. Moreover, the molecular mechanisms of interaction of cofactors with Abs are ill defined. Different proteins use cofactors to extend the chemistry intrinsic to the amino acid sequence of their polypeptide chain. Thus, one can speculate that the association of Abs with cofactors would results in the emergence of untypical properties for Abs. Indeed the binding of heme to certain Abs result in acquisition of new antigen-binding specificities i.e. this interaction can contribute to diversification of the immune repertoires. The principal goal of the present proposal is to gain a basic understanding about the fraction of cofactor-binding Abs in immune repertoires of healthy individuals and to use this knowledge for rational design of novel classes of therapeutic Abs. In this project, we have been addressing the following questions: 1) understanding of the origin and prevalence of cofactor-binding Abs in immune repertoires; 2) characterization of the molecular mechanisms of interaction of cofactors with Abs; 3) understanding of the physiopathological roles of cofactor-binding Abs, and 4) using the cofactor binding for the development of novel types of therapeutic Abs. A comprehensive understanding of various aspects of cofactor-binding Abs should lead to advances in the fundamental knowledge and in the development of innovative therapeutic strategies and diagnostic tools.