Broadly Neutralizing Antibodies
Vulnerable sites of virus are often shielded by glycosylation and thus deeply buried within cavity conformations, which are not accessible for common antibodies generated by human repertoires. Interestingly, many broadly neutralizing Abs (bnAbs) - e.g. isolated from HIV infected patients who don’t progress to AIDS - have very long CDR-H3s. Structural biology suggested these long loops mediate recognition of the critical but hidden viral epitopes. However, molecular immunology tells us that eliciting antibodies with ultra long CDR-H3 is difficult and rare – 3.5% and 0.4% of human naïve B cells carry long (24 aa) or very long (28 aa) CDR-H3s, respectively. To bypass the limitation given by nature, we design and construct synthetic antibody libraries carrying convex paratopes encoded by long CDR-H3. We hypothesize such antibody library design will greatly increase our chance to isolate bnAbs.