Abstract
Background VRC01 and related antibodies target the CD4 binding site (CD4bs), are broadly neutralizing and highly potent, and have undergone high levels of somatic hypermutation. To optimize such antibodies for passive immunization and to further understand antibody development, we reverted three CD4bs antibodies towards their putative germlines and analyzed the effects on breadth and potency. Interestingly, we also identified key germline reversion mutations that increased neutralization potential.
Highlights
VRC01 and related antibodies target the CD4 binding site (CD4bs), are broadly neutralizing and highly potent, and have undergone high levels of somatic hypermutation. To optimize such antibodies for passive immunization and to further understand antibody development, we reverted three CD4bs antibodies towards their putative germlines and analyzed the effects on breadth and potency
Structure/function-based analyses were used to design partially reverted heavy and light chains based on the clonally-related antibodies VRC01, NIH45-46, and VRC07
Here, we showed that in most cases mature framework regions in addition to mature CDRs were required for highest neutralization potency and breadth
Summary
VRC01 and related antibodies target the CD4 binding site (CD4bs), are broadly neutralizing and highly potent, and have undergone high levels of somatic hypermutation. To optimize such antibodies for passive immunization and to further understand antibody development, we reverted three CD4bs antibodies towards their putative germlines and analyzed the effects on breadth and potency. We identified key germline reversion mutations that increased neutralization potential
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