| Autor: |
Mateo Reveiz, Prabhanshu Tripathi, Lais Da Silva Pereira, Patience Kiyuka, Tracy Liu, Baoshan Zhang, Yongping Yang, Brian G. Bonilla, Marlon Dillon, Myungjin Lee, Chen-Hsiang Shen, Arne Schön, Sven Kratochvil, Facundo D. Batista, Azza H. Idris, Robert A. Seder, Peter D. Kwong, Reda Rawi |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.04.08.487687 |
| Popis: |
SUMMARYAntibody 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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