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TitleHighly protective antimalarial antibodies via precision library generation and yeast display screening.
Journal, issue, pagesJ Exp Med, Vol. 219, Issue 8, Year 2022
Publish dateAug 1, 2022
AuthorsBailey B Banach / Prabhanshu Tripathi / Lais Da Silva Pereira / Jason Gorman / Thuy Duong Nguyen / Marlon Dillon / Ahmed S Fahad / Patience K Kiyuka / Bharat Madan / Jacy R Wolfe / Brian Bonilla / Barbara Flynn / Joseph R Francica / Nicholas K Hurlburt / Neville K Kisalu / Tracy Liu / Li Ou / Reda Rawi / Arne Schön / Chen-Hsiang Shen / I-Ting Teng / Baoshan Zhang / Marie Pancera / Azza H Idris / Robert A Seder / Peter D Kwong / Brandon J DeKosky /
PubMed AbstractThe monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. ...The monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. To enhance the potency and clinical utility of CIS43, we used iterative site-saturation mutagenesis and DNA shuffling to screen precise gene-variant yeast display libraries for improved PfCSP antigen recognition. We identified several mutations that improved recognition, predominately in framework regions, and combined these to produce a panel of antibody variants. The most improved antibody, CIS43_Var10, had three mutations and showed approximately sixfold enhanced protective potency in vivo compared to CIS43. Co-crystal and cryo-electron microscopy structures of CIS43_Var10 with the peptide epitope or with PfCSP, respectively, revealed functional roles for each of these mutations. The unbiased site-directed mutagenesis and screening pipeline described here represent a powerful approach to enhance protective potency and to enable broader clinical use of antimalarial antibodies.
External linksJ Exp Med / PubMed:35736810 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.4 - 10.9 Å
Structure data

EMDB-27194: CIS43 Variant 10 bound to pfCSP Class 4
Method: EM (single particle) / Resolution: 10.9 Å

EMDB-27195: CIS43 Variant 10 bound to pfCSP Class 2
Method: EM (single particle) / Resolution: 7.1 Å

EMDB-27202: CIS43 Variant 10 bound to pfCSP Class 1
Method: EM (single particle) / Resolution: 6.1 Å

EMDB-27222: CIS43 Variant 10 bound to pfCSP Class 3
Method: EM (single particle) / Resolution: 9.8 Å

PDB-7sg5:
Structure of PfCSP peptide 21 with antibody CIS43_Var2
Method: X-RAY DIFFRACTION / Resolution: 1.4 Å

PDB-7sg6:
Structure of PfCSP peptide 21 with antibody CIS43_Var10
Method: X-RAY DIFFRACTION / Resolution: 1.55 Å

Chemicals

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-HOH:
WATER / Water

Source
  • Plasmodium falciparum (malaria parasite P. falciparum)
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsIMMUNE SYSTEM / Antibody / Plasmodium falciparum

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