RT Journal Article
SR Electronic
T1 <em>In Silico</em> Improvement of Highly Protective Anti-Malarial Antibodies
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.08.487687
DO 10.1101/2022.04.08.487687
A1 Mateo Reveiz
A1 Prabhanshu Tripathi
A1 Lais Da Silva Pereira
A1 Patience Kiyuka
A1 Tracy Liu
A1 Baoshan Zhang
A1 Yongping Yang
A1 Brian G. Bonilla
A1 Marlon Dillon
A1 Myungjin Lee
A1 Chen-Hsiang Shen
A1 Arne Schön
A1 Sven Kratochvil
A1 Facundo D. Batista
A1 Azza H. Idris
A1 Robert A. Seder
A1 Peter D. Kwong
A1 Reda Rawi
YR 2022
UL http://biorxiv.org/content/early/2022/04/09/2022.04.08.487687.abstract
AB Antibody CIS43 binds Plasmodium falciparum circumsporozoite protein (PfCSP) and protects against malaria, as recently demonstrated clinically. To improve the efficacy of CIS43, we developed an in silico pipeline to optimize the interaction energy of CIS43 to its junctional epitope (peptide 21: PfCSP residues 101-115). Starting from two improved CIS43 variants, recently elicited from a CIS43-germline knock-in mice, single and double amino acid substitutions in the peptide 21-proximal heavy (VH) and light (VL) variable regions were introduced. CIS43-variants, selected on the basis of improved in silico interface and stability energies, showed increased affinity to peptide 21 and superior malaria-protective efficacy. The best designed variant, antibody P3-43, was significantly more protective than its template antibody m43.151, with greater liver-burden protection than the current best-in-class (antibody iGL-CIS43.D3). Crystal structures of improved antibodies revealed atomic-level interactions explaining gains in binding affinity. The reported pipeline provides a powerful in silico approach to improve antibody functionality.Competing Interest StatementS.K., P.T., R.R., M.R., P.D.K., R.A.S. and F.D.B. have submitted a US Provisional Patent Application describing improved CIS43 antibodies (filed November 5, 2021). R.A.S. and A.H.I. hold patents on CIS43 (International Application No. PCT/US2018/017826; US Patent Application No. 16/485,354; issued June 1, 2021).