Tolerogenic synthetic nanoparticles for the prevention of anti-drug antibodies against biologic therapies (TECH3P.936)

Abstract

The development of anti-drug antibodies (ADAs) is a common cause for treatment failure and adverse events, such as hypersensitivity reactions, associated with biologic therapies. Therefore, prevention of ADAs in an antigen-specific manner would be highly desirable in order to improve the safety and efficacy of marketed products. Here we describe the use of SVP: polymeric, synthetic, biodegradable nanoparticles carrying a tolerogenic immunomodulator, rapamycin, to induce durable, antigen-specific immune tolerance. In mice, intravenous or subcutaneous co-injections of SVP with free antigen results in robust CD4+ T cell and B cell tolerance (i.e. the inhibition of their activation over multiple challenges), an increase in regulatory cells and the inhibition of antigen-specific hypersensitivity reactions. Only encapsulated rapamycin, not the free form, could induce immunological tolerance to a variety of antigens. Co-injections of SVP and antigen in both rats and cynomologous monkeys also results in B cell tolerance. In mice that spontaneously develop rheumatoid arthritis (RA), we show that treatment with SVP and adalimumab prevents the formation of anti-adalimumab ADAs therefore normalizing adalimumab pharmacokinetics and improving the clinical and histological manifestations of RA. SVP therapy represents a novel antigen-specific approach for the prevention of ADAs against biologic therapies, as well as the treatment of allergies and autoimmune diseases.