Fig. 1: Structure of CD388 and universal activity against influenza A and B in cell-based CPE and microneutralization assays.
From: Drug–Fc conjugate CD388 targets influenza virus neuraminidase and is broadly protective in mice
a, Molecular surface representation of the full-length hIgG1 (PDB code 1HZH) structure redacted to show only the Fc construct boundaries used in CD388. Positions of lysine residues that were preferentially conjugated in CD388 are shown in green (based on proteolytic digestion and peptide mapping using a conjugate with wild-type hIgG1; Methods). CD388 is a multivalent conjugate of a ZAN dimer (shown in blowup) stably conjugated to lysines on the N-terminal extended hIgG1 Fc with an average drug:antibody ratio (DAR) of 4.5:1. The spatial disposition of conjugated lysine residues on the Fc domain surface and the length and flexibility of the PEG linkers result in ZAN dimer constellations on CD388 where sufficient separation (>90 Å) exists between ZAN dimers to allow simultaneous engagement of a single CD388 molecule with multiple active sites within an NA tetramer, between neighbouring NA tetramers on the same virus particle, or between NA tetramers on different virus particles. b–f, EC50 values [nM] of CD388, OST, ZAN or BXA against a panel of influenza strains A/H1N1 (b), A/H3N2 (c), B in a cell-based cytopathic effect assay (d), and A/H5N1 (e) and A/H7N9 (f) in a cell-based microneutralization assay. In b–f, data points in box and whiskers plots represent mean EC50 values for different influenza strains derived from dose-response curves measured in duplicate. The boxes bound the 25th and 75th percentile, with median values shown in the boxes. Whiskers highlight strains with the highest and lowest EC50s.
