Table 3.

Examples of VHH formats for targeting SARS-CoV-2

Name	Format	Development stage	Affinity to RBD (KD)	ACE2 block	IC50 pseudovirus	IC50 live virus	Epitope	Notes	Reference
VHH72 (original)	VHH monomer	See below	39 nM	No	200 ng/mL (~ 12 nM)	ND	Class 4 (Margulies et al.); RBD-6	Binds MERS, SARS1 and SARS2—neutralizes SARS1 but not MERS	[238, 239]
XVR011 (from VHH72)	Fc-VHH72 fusion	Phase I/II (NCT04884295 [R])	8 nM; 47 pM a	No	840 ng/mL (~ 12 nM)	130 ng/mL	Class 4 (Margulies et al.); RBD-6	Humanized and optimized VHH72; muted Fc; (HumVHH72_S56A/LALA-Fc/Gen2)	[239]
Nb21	VHH monomer	Preclinical	ND	Yes	ND	ND	Class 1 (Margulies et al.); RBD-2	Precursor to PiN-21, which is in preclinical development	[252, 253, 342]
VHH-EV	VHH-VHH dimer-Fc	Preclinical	ND	Yes	2.9 nM	0.7 nM	RBD-2/RBD-6	Fused to Fc; May be DIOS-202 or DIOS-203	[249]
VHH-VE	VHH-VHH dimer-Fc	Preclinical	ND	Yes	4.1 nM	1.32 nM	RBD-6/RBD-2	Fused to Fc; May be DIOS-202 or DIOS-203	[249]
VHH-E	VHH monomer	Preclinical	2 nM	Yes	60 nM	48 nM	Class 1 (Margulies et al. [345]); RBD-2	Blocks ACE2	[249]
VHH-EE	VHH-VHH dimer	Research	ND	Yes	0.93 nM	0.18 nM	Class 1 (Margulies et al. [345]); RBD-2	Blocks ACE2	[249]
VHH-EEE	VHH-VHH-VHH trimer	Research	ND	Yes	0.52 nM	0.17 nM	Class 1 (Margulies et al. [345]); RBD-2	Blocks ACE2	[249]
VHH-V	VHH monomer	Research	9 nM	No	198 nM	142 nM	Class 4 (Margulies et al. [345]); RBD-6	ND	[249]
Re5D06	VHH monomer	Research	2 pM	Yes	ND	ND	RBD-2	Blocks ACE2	[343]
Ty1	VHH monomer	Research	ND	Yes	0.77 μg/ml (54 nM)	12 ng/mL as Fc fusion	RBD-2	Blocks ACE2	[344]

ACE2 angiotensin-converting enzyme-2, K_D affinity (M), MERS Middle East Respiratory Syndrome, ND no data, R recruiting, RBD receptor binding domain, SARS Severe Acute Respiratory Syndrome, VHH single domain antibody (ca. 12 kDa in size)

^a8 nM monomeric; 47 pM as dimeric Fc fusion so avidity also is in play