Potent human monoclonal antibodies against SARS CoV, Nipah and Hendra viruses

Abstract

Background: Recently, several potently neutralizing fully human monoclonal antibodies (hmAbs) targeting the severe acute respiratory syndrome-associated coronavirus (SARS CoV) S glycoprotein, and the G glycoprotein of the paramyxoviruses Hendra virus (HeV) and Nipah virus (NiV) have been discovered [corrected].

Objective: To examine, compare and contrast the functional characteristics of hmAbs with the potential for prophylaxis and treatment of diseases caused by SARS CoV, HeV and NiV.

Methods: A review of relevant literature.

Results/conclusions: Structural, functional and biochemical analyses [corrected] have provided insights into the molecular mechanisms of receptor recognition and antibody neutralization, and suggested that these antibodies alone or in combination could fight the viruses' heterogeneity and mutability, which is a major problem in the development of effective therapeutic agents against viruses, including therapeutic antibodies.

Figure 1. Crystal structures of S RBD-receptor and S RBD-antibody complexes

A.S RBD (green) in complex of the human ACE2 receptor (magenta). B.S RBD-Fab m396 antibody (blue-heavy chain and cyan-light chain) complex. C.S RBD-sc Fv 80R antibody (orange-heavy chain and yellow-light chain) complex. S RBD complex structures are projected in the same orientation with respect to the S RBD (green). The receptor and antibody binding sites on the S RBD are colored in red. D.A close-up view of the S RBD-ACE2 interface. Tyr491 of β6–β7 loop from S RBD makes a key contact with Lys353 of ACE2. E.Tyr491 of S RBD is involved in the critical interaction with Fab m396 antibody through cation-pi and hydrogen bond interactions, respectively, with Thr52 and Asn58 of CDR H2. F.A close-up view showing the S RBD-sc Fv 80R antibody interface where Try491 of S RBD interacts with Asp99, Arg100 and Ser101 of CDR H3, and Tyr32 of CDR H1.

Figure 2. Comparison of the complex structures of Nipah and Hendra attachment G glycoproteins, and HIV-1 gp120 glycoprotein

A.NiV G – ephrin-B3 complex (NiV G in magenta and ephrin-B3 in yellow) showing the dominant virus-receptor interaction involving Tyr120 in the G–H loop of ephrin-B3 which snugly fits into the hydrophobic pocket as shown in gray on the surface portion of NiV G glycoprotein. B.HeV G – ephrin-B2 complex (HeV G in green and ephrin-B2 in cyan) in which Phe120 in the G–H ephrin loop inserts into a channel shown in red on the surface of NiV G. C.HIV gp120 glycoprotein (red) complex with its receptor CD4 (yellow) extracted from the HIV gp120-CD4-17b ternary complex (D1 domain of CD4 and 17b antibody are not shown). Phe43 of C'C" loop in CD4 makes a critical contact with gp120, and reaches the hydrophobic pocket, shown as gray surface, formed in between the inner and outer domains of gp120. D.HIV-1 gp120 (red) in complex with the b12 antibody (partly shown, heavy chain in blue, light chain in pink). Tyr53 from the CDR H2 loop of b12 antibody fits into the hydrophobic pocket on the gp120 surface (gray) in a similar manner as “Phe43” of CD4 receptor interacts with the gp120.