Sajadi: Development of a new family of potent and broad neutralizing antibodies
Given the wealth of structure/function information now available for antibodies and HIV-1 envelopes, it is reasonable to propose that broadly neutralizing antibodies (bNAbs) can be engineered into efficacious antiviral agents with pan-neutralizing activity and clinically relevant pharmacokinetic profiles. This investment will support the rational engineering of near pan-neutralizing bNAbs against the CD4bs, using rare resistance variants of HIV-1 as guides. A family of plasma anti-CD4bs antibodies with extremely broad and potent neutralizing activity has been identified. The most broad and potent member of this family (N49P7) tracks its breadth to a unique CDRH3 loop structure, capable of reaching deep into the CD4bs cavity of gp120 and engaging highly conserved residues of the gp120 inner domain. A second CD4bs mAb (N49P9.3), from the same donor but a separate lineage, is also extremely broad and potent. Antibodies N49P7 and N49P9.3 will serve as the starting point for efforts to rationally engineer bNAbs with pan-neutralizing activity, even covering viruses that are cross-resistant to other anti-CD4bs bNAbs. Engineered derivatives of donor N49 bNAbs should demonstrate prophylactic efficacy with exceptional breadth and potency. Their pharmacokinetic profiles should also be suitable for subcutaneous dosing no more frequently than every three months.
The specific goals of this investment are:
In vitro testing of natural antibodies and existing variants to determine clinical potential: From donor N49, 8 lineages and 38 antibodies have been identified. Further in vitro screening of antibodies from other lineages and time points is needed to determine potential. A second donor with promising bNAbs will be added for antibody discovery and testing, as well as single-cell PCR. While the primary emphasis will be on neutralization potency and breadth, stability will also be considered. Based on these analyses, antibodies from two lineages will be chosen for further engineering.
2) Engineering bNAbs to enhance potency and breadth, and to improve the biophysical properties and pharmacokinetic profiles
in vitro and
in vivo: Antibodies from two lineages will be used to engineer variants with improved neutralization potency, stability, polyreactivity, and immunogenicity. Pharmacokinetic profiles and suitability for mass manufacturing will also be studied. Ultimately, one pre-clinical candidate and one back-up antibody will be engineered for extended half-life (i.e. to produce ‘LS’ versions).
This funding will be used to engineer bNAbs with ≥90% activity against a global panel and a clade C HIV transmitter/founder panel of pseudoviruses. The engineered bNAbs will be designed to have an in vitro potency (IC80) ≤0.02 μg/ml, a tripled half-life, and stability at 2-8°C. These bNAbs may serve as ideal candidates in a variety of platforms for the prevention of HIV-1 infection.