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<p>The monoclonal antibody L9 mediates high-level protection against malaria in children for up to 6 months in Africa. L9 preferentially binds with high affinity to a triplicate of NVDP-minor repeats on the <i>P. falciparum</i> circumsporozoite protein (PfCSP). Here, we sought to improve the affinity of L9 to enhance protection against rare strains with two spatially separated minor repeats or a single minor repeat. Site saturation mutagenesis and yeast display-screening identified a panel of affinity-improved variants. In vivo challenge showed one variant, L9_yd19, to be modestly more potent against a transgenic <i>Plasmodium</i> encoding chimeric CSP with two widely spaced minor repeats from a Kenyan parasite strain, with no loss in potency against the benchmark 3D7 strain with its standard complement of minor repeats. L9_yd19 also had high affinity against NANP-major repeats and was protective against transgenic <i>Plasmodium</i> expressing CSP with a NANP<sub>12</sub> knock-in lacking NVDP. Cryo-EM studies revealed L9_yd19 to recognize PfCSP with two distinct homotypic interfaces, which combined to yield two trimeric layers of antibodies comprising asymmetric trimers that dimerized in a head-to-head fashion. These data reveal a new antibody mechanism that utilizes interfaces involving dual homotypic symmetry elements, a 2-fold and an asymmetric 3-fold, for improved malaria prevention.</p>

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Anti-malaria antibody engineering broadens recognition motifs and reveals new homotypic interactions that enhance protective breadth

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月28日

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  • Jihwan Chun,
  • Prabhanshu Tripathi,
  • Yevel Flores-Garcia,
  • Bharat Madan,
  • Gene A. Lee,
  • Ahmed S. Fahad,
  • Haotian Lei,
  • I-Ting Teng,
  • Nicholas K. Hurlburt,
  • Barbara J. Flynn,
  • Marie Pancera,
  • Kazutoyo Miura,
  • Tongqing Zhou,
  • Azza H. Idris,
  • Fidel Zavala,
  • Robert A. Seder,
  • Peter D. Kwong,
  • Brandon J. DeKosky

摘要

The monoclonal antibody L9 mediates high-level protection against malaria in children for up to 6 months in Africa. L9 preferentially binds with high affinity to a triplicate of NVDP-minor repeats on the P. falciparum circumsporozoite protein (PfCSP). Here, we sought to improve the affinity of L9 to enhance protection against rare strains with two spatially separated minor repeats or a single minor repeat. Site saturation mutagenesis and yeast display-screening identified a panel of affinity-improved variants. In vivo challenge showed one variant, L9_yd19, to be modestly more potent against a transgenic Plasmodium encoding chimeric CSP with two widely spaced minor repeats from a Kenyan parasite strain, with no loss in potency against the benchmark 3D7 strain with its standard complement of minor repeats. L9_yd19 also had high affinity against NANP-major repeats and was protective against transgenic Plasmodium expressing CSP with a NANP12 knock-in lacking NVDP. Cryo-EM studies revealed L9_yd19 to recognize PfCSP with two distinct homotypic interfaces, which combined to yield two trimeric layers of antibodies comprising asymmetric trimers that dimerized in a head-to-head fashion. These data reveal a new antibody mechanism that utilizes interfaces involving dual homotypic symmetry elements, a 2-fold and an asymmetric 3-fold, for improved malaria prevention.