Grant Number: 3U19AI057234-06S1
PI: Jacques Banchereau, PhD
Funding Organization: National Institute of Allergy and Infectious Diseases
Project Start: October 1, 2009
Project End: September 1, 2011

Abstract:
Several synthetic adenine derivatives have been demonstrated to activate TLR7 - which is highly expressed on pDCs - stimulating the production of type-I IFNs by these cells. The adjuvant activity of the TLR7 ligands as well as their protein conjugates has been demonstrated. In work funded by this supplement, a small library of derivatives of known TLR7 agonists will be synthesized. These organic compounds will be based on well-known TLR agonists (imidazoquinolines) but will be variously functionalized in a manner to facilitate their precise conjugation to engineered antigen-targeting vaccines. In order to optimize the TLR7 agonists in the context of the antibody vaccine, the SAR will be examined for protein conjugates rather than free ligands. Concurrently with the syntheses, conjugation strategies will be explored to determine the optimal linker location and the prefered linker characteristics (length and stability). The synthesis and conjugation of molecules containing multiple copies of the TLR7 ligands will also be explored.

Each TLR7 ligand immunoconjugate will be thoroughly characterized. Mass spec techniques will be used to establish the extent and location of the protein modification, while in vitro immunoassays will reveal the functionality of the conjugates. This supplemental funding will provide full-time summer research experiences to two undergraduate students, who will facilitate the synthesis and study of novel compounds for the creation of improved mucosal vaccines. Supporting Project 1 as well as Tech Development Project 1, these undergraduate researchers will gain valuable laboratory experience while accelerating the pace and expanding the breadth of the U19 research program. This expansion of the synthetic studies will be enabled by the supplemental funding, and represents a significant enhancement to the project. It is anticipated that optimized adjuvant-linked immunoconjugates constructed using these compounds will elicit a significantly enhanced mucosal immune response.