The light chain of the L9 antibody is critical for binding circumsporozoite protein minor repeats and preventing malaria

Structural basis of epitope selectivity and potent protection from malaria by PfCSP antibody L9

“…NA(NPNVDPNA) 3 ; there is no additional density observed that would correspond to N-terminal, C-terminal, or major repeat regions. The L9 Fab and peptide cryo-EM structures correspond well with our recent X-ray structures of two chimeric precursors of L9 (L9 K /F10 H and F10 K /L9 H ) in complex with a short minor repeat peptide (NA NPNV DP) ( 6 ) (fig. S2).…”

“…PfCSP, the primary surface antigen of P. falciparum sporozoites, is a major target for vaccines and mAbs as it is both highly conserved and critical for the initiation of malaria infection. PfCSP contains an immunodominant central repeat region composed of repeating four-amino-acid units, structurally defined as DPNA, NPNV, and NPNA (4)(5)(6)(7)(8)(9)(10)(11). These roughly define the junctional, minor repeat, and major repeat epitopes, respectively.…”

“…Like many of the most potent NPNA-specific mAbs, L9 is also encoded by the IGHV3-33/IGKV1-5 heavy/light chain gene combination. However, L9 is highly specific for the NPNV (minor) repeats and relies on critical contributions from the light chain for both NPNV selectivity and high potency ( 6 ).…”

“…Another unique property of L9 is the ability to “crosslink” two NPNV motifs within the minor repeat region of PfCSP, which improves binding affinity ( 6 ). Our cryo-EM structure reveals that L9 achieves this through multivalent Fab binding to sequential NPNV repeats stabilized by an extensive antibody-antibody, or homotypic, interface between adjacent Fabs (Fig.…”

A vaccine targeting the L9 epitope of the malaria circumsporozoite protein confers protection from blood-stage infection in a mouse challenge model

“…The DPNA motif is found twice in the CIS43 epitope and once in the L9 epitope, whereas NPNV is found twice in the L9 epitope and once in the CIS43 epitope. In addition, the minimal L9 binding peptide (NA NPNV DP) is centered on the NPNV sequence 15 . To examine the specificity of antibodies induced by the L9 and CIS43 VLP vaccines, the binding of sera to peptides representing the L9 and CIS43 epitopes, as well as peptides representing the major repeat (NANP) and non-naturally occurring peptides representing repeat junctions (DPNA and NPNV) was assessed (Supplementary Fig.…”