Table 1.

Fc-region containing bispecific antibody formats that have been generated for viral immunotherapy.

Virus	Targets	Format	Results	Reference
1) Targeting 2 distinct viral epitopes
Influenza	HA protein of different strains	Full-sized IgG antibodies linked via C -termini	Retained activity and stability of original antibodies against various influenza subtypes	[16]
	Head of H5 HA protein	FcDART	Retained activity and efficacy of original antibodies in mice and ferret models	[17]
HIV-1	Various neutralizing epitopes on Env	Asymmetric IgG (CrossMAb)	Retained binding activity of original antibodies; enhanced neutralization of HIV-1 strains; best neutralizer retained pharmacokinetic properties of original antibodies	[18]
	Two subunits of Env	Immunoadhesins (scFv-Fc)	Retained binding activity of original antibodies; enhanced neutralization compared to original antibodies	[19]
	Different epitopes on adjacent GPs	Asymmetric IgG1 molecule with IgG3 hinge domain	Enhanced neutralization and protection in infected humanized mice compared to original antibodies and bispecific antibody without IgG3 hinge domain	[20]
Hepatitis B	Various epitopes on surface antigen	DVD	Enhanced neutralization and inhibition of hepatitis B surface-antigen secretion compared to original antibodies	[21]
Dengue	DII and DIII of surface protein	DVD with mutated Fc-domain	Retained binding activity of original antibodies; enhanced neutralization and protection in mouse model; eliminated ADE of infection in vitro	[22]
	DII and DIIII of surface protein	DART-Ig with mutated Fc-domain	Retained neutralizing activity and therapeutic activity in mice as original antibodies; enhanced avidity for isolated recombinant DENV surface protein	[23]
Ebola	SUDV and EBOV GP	scFvs of EBOV antibody fused to SUDV-IgG	Retained neutralizing activity of original antibodies; post-exposure protection of mice from both viruses	[24]
2) Targeting viral and host epitopes
HIV-1	Env and CD4	scFv of anti-Env antibodies fused to anti-CD4 IgG	Enhanced neutralizing activity and potency compared to original antibodies; neutralization of strains resistant to original antibodies	[14]
	CD4 and CD4 induced epitope on Env	Single-domain antibody (anti-CD4i site) fused to CD4 IgG	Enhanced neutralizing activity and potency compared to original antibodies; neutralization of strains resistant to original antibodies	[25]
	Various neutralizing epitopes on Env and CD4 or CCR5	Asymmetric IgG (CrossMAb)	Enhanced neutralizing activity compared to original antibodies; reduction of viral load in infected humanized mice	[26]
Ebola	Receptor binding site of GP and NPC1	DVD	Neutralization of all known ebolaviruses and post exposure protection against multiple filoviruses in mouse models.	[27]
3) Recruiting host cell machinery
Dengue	Primate CR1 and DENV GP	Thioester Cross-linked IgGs	Facilitated specific and rapid binding of DENV to monkey and human erythryocytes; clearance of DENV viremia in cynomolgus macques	[30]
Marburg	Primate CR1 and Marburg GP	Thioester Cross-linked IgGs	Facilitated specific and rapid binding of MARV-GP to monkey and human erythrocytes	[31]
CMV	CD3 and CMV	Thioester Cross-linked IgGs	Redirected specific cytotoxicity to CMV infected cells	[33]
HIV	CD3 and CD4 induced epitope on Env	scFV of anti-CD3 linked to light chain of anti-Env by GS linker	Increased CD8+ T-cell activation and lysis of infected cells; reduction of latently infected CD4+ T cells ex vivo; in vivo safety in ART-treated SHIV-infected macaques	[36]