Novel Vaccine Ajuvants-CCR4 Antagonists - Isis Project No 3491

Marketing Opportunity

Vaccine efficacy is greatly improved by adjuvants, which enhance and modify immune responses. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants. The most under-explored adjuvants are drug-like molecules targeting specific receptors such as the imidazoquinolines (e.g. Imiquimod), which target Toll-like receptors (TLRs).

The Oxford Invention

Researchers at University of Oxford have used in silico modeling and structure-based drug-design and discovered new adjuvants that act by a novel mechanism of inhibition of CCR4-mediated migration of regulatory T cells. These CCR4 antagonists increase antibody to poorly immunogenic hepatitis B surface antigen and cellular responses to purified protein derivative of Mycobacterium tuberculosis (PPD).

As proof-of-principle, Oxford researchers chose to target the interaction of the chemokines CCL22 and CCL17 with their receptor CCR4. CCR4 was posited as an adjuvant target based on its expression on CD4_CD25_ regulatory T cells (Tregs), which negatively regulate immune responses induced by dendritic cells (DC), whereas CCL17 and CCL22 are chemotactic agents crucial in promoting contact between DC and CCR4_ T cells. A group of adjuvant candidates were identified by virtual screening and molecular docking as CCR4 antagonists. These molecules were further demonstrated to enhance DC-mediated human CD4_ T cell proliferation in an in vitro immune response model and amplify cellular and humoral immune responses in vivo in experimental models when injected in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis (MVA85A) or recombinant hepatitis B virus surface antigen (rHBsAg) vaccines. The significant adjuvant activity observed provides good evidence supporting the hypothesis that CCR4 is a viable target for rational adjuvant design.

Oxford researchers are currently establishing the optimum mode of use for our lead compound, determining whether it synergises with conventional adjuvants, and establishing its ability to enhance protection against influenza virus infection and M. tuberculosis and identifying how it alters specific immune responses.

Patent Status

This work is the subject of a patent application. Interested parties are welcome to discuss with Isis Innovation how to utilise this invention.

 

Request Further Information: Project Number 3491 - Novel Vaccine Ajuvants-CCR4 Antagonists