AVATAR MEDICAL, LLC — Department of Health and Human Services SBIR Phase II: NIAID

Description

<p>DESCRIPTION provided by applicant Avatar is developing HIV vaccine immunogens based on dityrosine DT crosslinking of soluble native Env gp trimers Several of the most potent broadly neutralizing Abs andquot bnAbsandquot preferentially bind native Env trimers and a trimeric immunogen thus would both present a wide range of key neutralizing epitopes and simultaneously focus immune responses away from immunodominant non neutralizing epitopes Developing a soluble trimeric immunogen however remains hampered by instability of the Env trimer complex Avatarandapos s DT trimers are stabilized at the apex of the spike thereby enabling full cleavage while locking key metastable neutralizing epitopes in their neutralizing conformation thus focusing and optimizing the Ab response In our Phase I studies we introduced targeted DT crosslinks into gp trimers and demonstrated that our DT Env trimers retain native antigenicity Our Phase II studies will further optimize the design of DT Env trimer immunogens by transferring DT crosslinking into Envs from multiple Clade A B and C strains and testing mutations that affect conformational heterogeneity These studies and accompanying optimization of expression purification and crosslinking processes will enable the selection of optimized candidate immunogen s for preclinical testing in Phase III The project breaks into three Specific Aims i immunogenicity testing of Phase I DT Env trimers ii immunogen optimzation including strain and conformational optimization of the variable regions at the apex of the spike followed by further immunogenicity testing and iii production optimization including optimization of expression purification and the DT crosslinking reaction Innovations Avatar for the first time has rendered targeted DT crosslinking feasible while retaining the structural and functional integrity of the gp Env trimer and also improving thermostability Targeted crosslinks are introduced after the protein complex is fully folded at th apex of the trimer immunogens are locked in antigenically favorable conformations designed to optimize the display of key protective epitopes while focusing the immune response away from immunodominant non neutralizing epitopes Significance the design of compact and stable DT gp trimeric immunogens will focus immune responses toward broadly neutralizing and away from non neutralizing epitopes DT mediated conformational locking of select Env conformers may further have the potential to enable andapos single conformerandapos immunogens The project will be executed in collaboration between Avatar Medical LLC and the Pinter lab at PHRI UMDNJ The main goal is to select and produce high qualify candidate DT Env gp trimeric immunogens during Phase II in preparation for preclinical development and final down selection of a final clinical candidate in Phase III The goal of this project is to generate an injectable vaccine product that will trigger immune responses that protect against infection by the Human Immunodeficiency Virus by taking a novel approach to protein engineering The product will specifically trigger production of antibodies in vaccinated individuals that will bind to and neutralize the virus when it enters the body The goal is to develop a product that triggers production of antibodies that will bind to any HIV particle and therefore protect vaccinated individuals regardless of the strain of virus they are exposed to</p>