( Fig. 2B and Fig. 1C ). Importantly, ADG-2 bound with high affinity (KD App 0.24-1.12 nM) to 154 every clade I sarbecovirus RBD that exhibited detectable hACE2 binding in our assay. This 155 finding supports the high degree of ADG-2 epitope conservation among sarbecoviruses that use 156 hACE2 as a receptor.
previously determined high-resolution models of the SARS-CoV-2 spike and a homologous Fab 200 (Fig. 3D, Fig. S8A -D, Table S1 ). Consistent with our fine epitope mapping and competitive 201 binding experiments ( Fig. 3B and Fig. S7C ), the epitope recognized by ADG-2 overlaps with the 202 hACE2-binding site and each position identified by epitope mapping clustered to the cleft 203 between the heavy and light chains of ADG-2 (Fig. 3D ). This epitope also partially overlaps with 204 those recognized by frequently observed "class 1" SARS-CoV-2 nAbs, which are exemplified by 205 VH3-53 antibodies with short CDRH3s and compete with hACE2 in the RBD "up" conformation 206 (32) (Fig. 3E ). However, in contrast to previously reported nAbs in this class, ADG-2 binds with 207 a divergent angle of approach and displays broadly neutralizing activity (32) (Fig. 3E, Fig. 1C , 208 and Fig. S8E ). Thus, ADG-2 binds to a highly conserved motif via a unique angle of approach, 209 providing additional structural insight into its broad recognition of SARS-like CoVs. lung pathology; significantly more than prophylactically-treated mice but significantly less than 244 sham-treated mice (Fig. 5C ). Therapeutic antibody treatment also resulted in a significant reduction in lung viral loads at four dpi, but not at two dpi, relative to sham-treated mice. We 246 conclude that ADG-2 treatment can reduce disease burden in mice infected with both SARS-247 CoV MA15 and SARS-CoV-2 MA10. 248 Since the beginning of the COVID-19 pandemic, a plethora of potently neutralizing 249 SARS-CoV-2 antibodies have been isolated, and some have rapidly advanced into clinical trials 250 (36). However, the epitopes recognized by most of these nAbs are highly variable among other 251 clade 1a and 1b sarbecoviruses, hence limiting their neutralization breadth and increasing their 252 susceptibility to antibody escape mutations (27). Here, we described an engineered antibody that 253 neutralizes SARS-CoV-2 with a potency that rivals current lead SARS-CoV-2 clinical nAbs, but 254 also broadly neutralizes other clade I sarbecoviruses, potently triggers Fc-mediated effector 255 functions, and provides significant protection against SARS and COVID-19 disease in mouse 256 models. Thus, ADG-2 represents a promising candidate for the prevention and treatment of not 257 only COVID-19 but also future respiratory diseases caused by pre-emergent SARS-related 258 CoVs. Furthermore, our fine epitope mapping and structural studies demonstrate that ADG-2 259 employs a unique angle of approach to recognize a highly conserved epitope overlapping the 260 receptor binding site. This epitope represents an Achilles' heel for clade 1a and 1b 261 sarbecoviruses and hence an attractive target for the rational design of "pan-SARS" vaccines that 262 aim to elicit similar broadly protective antibodies.
A to the SARS-CoV-2 RBD. S309 and CR3022, which bind non-overlapping epitopes distinct from 
Binding (% of WT) Polyspecificity reagent binding of antibodies was performed as described previously (37) . Affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) 816 To measure the propensity for antibodies to self-associate, AC-SINS was performed as was generated using maximum likelihood analysis of MAFFT-aligned RBD-SD1 sequences.
Multiple sequence alignment of sarbecovirus RBD sequences was visualized in Jalview. Amino which was used to calculate a 5.94 Å 3D reconstruction using non-uniform refinement (48).
High-resolution crystallographic models of the SARS-CoV-2 RBD (PDB ID: 6M0J) (31) and a 958 homologous Fab (PDB ID: 6APC) (49) were docked into the density using Chimera (50). A full 959 description of the data collection and processing parameters can be found in Table S1 . 