Broadly neutralizing antibodies (
bNAbs) are the focus of increasing interest for human immunodeficiency virus type 1 (HIV-1) prevention and treatment. Although several
bNAbs are already under clinical evaluation, the development of
antibodies with even greater potency and breadth remains a priority. Recently, we reported a novel strategy for improving
bNAbs against the CD4-binding site (CD4bs) of gp120 by engraftment of the elongated framework region 3 (FR3) from VRC03, which confers the ability to establish quaternary interactions with a second gp120
protomer. Here, we applied this strategy to a new series of anti-CD4bs
bNAbs (N49 lineage) that already possess high potency and breadth. The resultant chimeric
antibodies bound the HIV-1 envelope (Env) trimer with a higher affinity than their parental forms. Likewise, their neutralizing capacity against a global panel of HIV-1 Envs was also increased. The introduction of additional modifications further enhanced the neutralization potency. We also tried engrafting the elongated CDR1 of the heavy chain from
bNAb 1-18, another highly potent quaternary-binding antibody, onto several VRC01-class
bNAbs, but none of them was improved. These findings point to the highly selective requirements for the establishment of quaternary contact with the HIV-1 Env trimer. The improved anti-CD4bs
antibodies reported here may provide a helpful
complement to current antibody-based protocols for the
therapy and prevention of HIV-1
infection.IMPORTANCE
Monoclonal antibodies represent one of the most important recent innovations in the fight against
infectious diseases. Although potent
antibodies can be cloned from infected individuals, various strategies can be employed to improve their activity or pharmacological features. Here, we improved a lineage of very potent
antibodies that target the receptor-binding site of HIV-1 by engineering chimeric molecules containing a fragment from a different
monoclonal antibody. These engineered
antibodies are promising candidates for development of therapeutic or preventive approaches against HIV/
AIDS.