Tackling COVID-19 with neutralizing monoclonal antibodies

“All mAbs authorized or in development are directed to the RBD, which interacts with the target receptor angiotensin-converting enzyme 2 (ACE2) (Hoffmann et al., 2020; Letko et al., 2020; Walls et al., 2020b; Zhou et al., 2020).”

“All mAbs authorized or in development are directed to the RBD, which interacts with the target receptor angiotensin-converting enzyme 2 (ACE2) (Hoffmann et al., 2020; Letko et al., 2020; Walls et al., 2020b; Zhou et al., 2020).”

“The rapid spread of the disease has prompted the development of several effective vaccines at an unprecedented pace (Jackson et al., 2020; Polack et al., 2020), as well as the intense research for potential novel treatments, including the reuse of existing drugs approved for other indications.”

“The S glycoprotein has two functional subunits that respectively mediate host cell attachment (S1 subunit, formed by four domains, the most relevant being the N-terminal domain [NTD] and receptor-binding domain [RBD]) and fusion of the viral and cellular membranes (S2 subunit) (Tortorici and Veesler, 2019; Walls et al…”

“…hypothesis that protection from infection and disease can be mediated by neutralizing mAbs, furthermore indicating that vaccine-elicited antibodies are likely the major correlate of protection, as observed in non-human primates (Arunachalam et al., 2021; McMahan et al., 2021; Walls et al., 2020a).”

“The rapid spread of the disease has prompted the development of several effective vaccines at an unprecedented pace (Jackson et al., 2020; Polack et al., 2020), as well as the intense research for potential novel treatments, including the reuse of existing drugs approved for other indications.”

“All mAbs authorized or in development are directed to the RBD, which interacts with the target receptor angiotensin-converting enzyme 2 (ACE2) (Hoffmann et al., 2020; Letko et al., 2020; Walls et al., 2020b; Zhou et al., 2020).”

“The Phylogenetic Assignment of Named Global Outbreak (PANGO) lineage designation (Rambaut et al., 2020) of each variant, along with the location where they were first identified, is indicated on the right. ll Review SARS-CoV-2 on mink farms observed in Denmark in late 2020 (Oude Munnink et al.,…”

“…regdanvimab) are sensitive to one ormore of themutations found in RBD residues at positions 417, 452, or 484 that are carried by multiple circulating VOCs, including the recently emerging B.1.617 (Hoffmann et al., 2021; McCallum et al., 2021a; Starr et al., 2021b; Wang et al., 2021b) (Figure 5C).”

“This approach failed and was even detrimental to patients, resulting in vaccine-associated enhanced respiratory disease (Kim et al., 1969), possibly associated with the elicitation of high levels of non-neutralizing antibodies.”

“The RBD, and also the NTD, have been proposed to also interact with other receptors or co-receptors, including neuropilin-1 (NRP-1), dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN or CD209), and liver-/lymph-node-specific intracellular adhesion molecules-3 grabbing non-integri…”

“…data have indicated thus far a lack of clear synergy for cocktails of mAbs targeting noncompeting sites, with the exceptions of S309 and S304 (Pinto et al., 2020) or COV2-2195 and COV2-2130 mAbs (Zost et al., 2020), with the latter combination showing enhanced neutralization potency in…”

“S2M11 was not further developed, while C144 mAb is in early clinical development by Bristol Myers Squibb (phase 1, NCT04700163) in combination with another RBM mAb named C135 (both developed with LS mutations in Fc for half-life extension) (Robbiani et al., 2020; Weisblum et al., 2020).”

“Both have shown similar efficacy in a randomized control trial whereas two other products tested in parallel failed, including one product based on a cocktail of three mAbs (ZMapp) (Mulangu et al., 2019).”

“These classes of mAbs was found to trigger S rearrangement to the post-fusion state, likely due to conformational selection for open RBDs, and promotemembrane fusion (Lempp et al., 2021).”

“The removal of this glycosylation site by mutagenesis resulted in impaired RBD folding, decreased expression, and reduced infectivity (Li et al., 2020; Starr et al., 2020, 2021a), most likely explaining its strict conservation.”

“NomAbs directed to the cryptic site IIc/class 3 represented by the CR3022 or S304 mAbs (poorly or not neutralizing) are currently under consideration for development (Piccoli et al., 2020; Yuan et al., 2020).”

“The NTD is also a target of neutralizing mAbs (Cerutti et al., 2021; Chi et al., 2020; McCallum et al., 2021b; Suryadevara et al., 2021; Voss et al., 2020; Wu et al., 2021) that were shown to be potent in vitro and were all directed toward the same antigenic site of vulnerability (designated site i).”

“…regdanvimab) are sensitive to one ormore of themutations found in RBD residues at positions 417, 452, or 484 that are carried by multiple circulating VOCs, including the recently emerging B.1.617 (Hoffmann et al., 2021; McCallum et al., 2021a; Starr et al., 2021b; Wang et al., 2021b) (Figure 5C).”

“Importantly, most of the RBD mutations found in current VOCs/VOIs were already previously identified as resistant variants in vitro by using mAbs and convalescent or vaccine-elicited serum antibodies (Andreano et al., 2020; Baum et al., 2020b; Liu et al., 2021b; Weisblum et al., 2020), suggesting that the emergence of…”

“Ia/class 1 Shi et al., 2020 LY-CoV555 Ab169 LY3819253 bamlanivimab 1 NCT04411628 (healthy volunteer) adults IV BLAZE-5 WT 7KMG SARS-CoV-2- immune donor VH1–69 (99.7”

“…to 5 Å distance from ACE2- or mAbs are labeled using both their original and generic (nonproprietary) names. t al., 2020a, Cohen et al. (2021), and Piccoli et al. (2020) and colored as in (A). mAb footprints are highlighted in blue and light green, respectively, as in (A) and OVID-19 mAbs in…”

“Ia/class 1 Baum et al., 2020a, 2020b; Copin et al., 2021; Hansen et al., 2020; Weinreich et al., 2021 8 3 NCT04452318 (household contact prevention) adults/ pediatrics SC/IM 1.2 Study 2069 3 NCT04381936 (late treatment) 12 years and older (hospitalized) IV 8 RECOVERY 1/2/3 EUA NCT04425629 (early…”

“The RBD, and also the NTD, have been proposed to also interact with other receptors or co-receptors, including neuropilin-1 (NRP-1), dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN or CD209), and liver-/lymph-node-specific intracellular adhesion molecules-3 grabbing non-integri…”

“However, this may not necessarily apply to acute viral infections and be a consideration in the treatment of prolonged infections in immunocompromised individuals, such as has been observed with COVID-19 (Avanzato et al., 2020; Choi et al., 2020; Kemp et al., 2021; McCarthy et al., 2021).”

“…mAbs at limiting doses to reach sub-neutralizing levels did not provide evidence for enhancement of disease, even when the Fc was modified to match the target host Fc receptors (e.g., hamsterized in hamsters) (Baum et al., 2020a; Cathcart et al., 2021; Lempp et al., 2021; Rogers et al., 2020).”

“Ia/class 1 Baum et al., 2020a, 2020b; Copin et al., 2021; Hansen et al., 2020; Weinreich et al., 2021 8 3 NCT04452318 (household contact prevention) adults/ pediatrics SC/IM 1.2 Study 2069 3 NCT04381936 (late treatment) 12 years and older (hospitalized) IV 8 RECOVERY 1/2/3 EUA NCT04425629 (early treatment) adult/pedia…”

“, 2020), (2) a phase 2 study of the single RBM mAb BGB-DXP593 tested at three undisclosed doses administered intravenously (Cao et al., 2020), and (3) a phase 1/2/3 study of the single mAb ADG20 recognizing a conserved site on RBD tested as a single undisclosed dose administered either intravenously or intramuscularly…”

“…some that are in the clinic (imdevimab, casirivimab, sotrovimab, bamlanivimab, etesevimab, AZD8895, and AZD1061 mAbs; see Figure 2A or Table 1 for correspondence between initial and generic names of mAbs) (Dong et al., 2021; Greaney et al., 2021a, 2021b; Starr et al., 2021a, 2021b, 2021c).”

“…the recent emergence of several SARS-CoV-2 variants of concern (VOCs) has shown limitation in the coverage by some of these mAbs that target epitopes mutating rapidly (Chen et al., 2021c; Collier et al., 2021; Davies et al., 2021a; McCallum et al., 2021a; Tegally et al., 2021; Wibmer et al., 2021).”

“Three major studies (REMACCAP, COVACTA, and RECOVERY) have published the validity of this approach in COVID-19 hospitalized patients, with contrasting results (Horby et al., 2021; REMAP-CAP Investigators et al., 2021; Rosas et al., 2021).”

“AbbVie is also testing ABBV-47D11 and ABBV-2B04 mAbs (Alsoussi et al., 2020; Wang et al., 2020) alone and in combination for treating adults hospitalized with COVID-19 in a phase 1 study.”

“…constrained access to their cognate epitope, as 50% of S trimers have all three RBDs closed, whereas the remaining half possess a single open RBD (Ke et al., 2020; Walls et al., 2020b), and the proximity of the epitopes on neighboring RBDs might not be compatible with multiple immunoglobulin G…”

“However, this may not necessarily apply to acute viral infections and be a consideration in the treatment of prolonged infections in immunocompromised individuals, such as has been observed with COVID-19 (Avanzato et al., 2020; Choi et al., 2020; Kemp et al., 2021; McCarthy et al., 2021).”

“…Phylogenetic Assignment of Named Global Outbreak (PANGO) lineage designation (Rambaut et al., 2020) of each variant, along with the location where they were first identified, is indicated on the right. ll Review SARS-CoV-2 on mink farms observed in Denmark in late 2020 (Oude Munnink et al., 2021).”

“3102 Cell 184, June 10, 2021 cate a high potential for mAb-based immune prophylaxis of COVID-19 and support the hypothesis that protection from infection and disease can be mediated by neutralizing mAbs, furthermore indicating that vaccine-elicited antibodies are likely the major correlate of protection, as observed i…”

“In the following years until the present day, the efficacy of convalescent plasma for the treatment of viral respiratory infections was probed in several studies that have shown some evidence for a reduction in mortality, especially when given early after symptom onset (Mair-Jenkins et al., 2015).”

“…some that are in the clinic (imdevimab, casirivimab, sotrovimab, bamlanivimab, etesevimab, AZD8895, and AZD1061 mAbs; see Figure 2A or Table 1 for correspondence between initial and generic names of mAbs) (Dong et al., 2021; Greaney et al., 2021a, 2021b; Starr et al., 2021a, 2021b, 2021c).”

“…regdanvimab) are sensitive to one ormore of themutations found in RBD residues at positions 417, 452, or 484 that are carried by multiple circulating VOCs, including the recently emerging B.1.617 (Hoffmann et al., 2021; McCallum et al., 2021a; Starr et al., 2021b; Wang et al., 2021b) (Figure 5C).”

“Indeed, the B.1.1.7 variant was found to be more transmissible and cause more severe infections compared to the parental virus (Davies et al., 2021a, 2021b; Munitz et al., 2021).”

“…Cell 184, June 10, 2021 bodies, possibly reducing vaccine effectiveness and the duration of protection (Cele et al., 2021; Chen et al., 2021c; Collier et al., 2021; Kustin et al., 2021; Liu et al., 2021a; McCallum et al., 2021a; Muik et al., 2021; Wang et al., 2021b, 2021c; Wu et al., 2021).”

“Protection by antiviral neutralizing antibodies in animal models of influenza A and HIV-1 was shown to require the contribution of effector functions mediated by Fc-FcgR interactions for optimal efficacy (DiLillo et al., 2014; Hessell et al., 2007).”

“Several mutations found in these VOCs/VOIs are found to reduce or abolish the neutralizing activity of several mAbs, including those already approved or in late stages of development (Figure 5).”

“Ib/class 2 Chen et al., 2021a; Gottlieb et al., 2021; ACTIV-3/TICO LY-CoV555 Study Group et al., 2021; Jones et al., 2021 2 NCT04701658 (early treatment) 12 years and older IV BLAZE-5 2/3 NCT04518410 (early treatment) adults IV ACTIV-2 4 NCT04656691 (early treatment, at-home infusion) older adults…”

“Another highly potent RSV mAb (nirsevimab) harboring an Fc fragment engineered for half-life extension recently showed a 78% reduction in hospitalization in pre-term infants in a phase 2b study (Griffin et al., 2020; Zhu et al., 2017).”

“The S glycoprotein has two functional subunits that respectively mediate host cell attachment (S1 subunit, formed by four domains, the most relevant being the N-terminal domain [NTD] and receptor-binding domain [RBD]) and fusion of the viral and cellular membranes (S2 subunit) (Tortorici and Veesler, 2019; Walls et al…”

“…shown to increase by 6-fold the affinity for human ACE2 (Collier et al., 2021) and was also associated to an increased interaction withmurine ACE2 (Gu et al., 2020), raising the possibility thatmutations in S may also emerge as a result of inter-species exchange of SARS-CoV-2, like the two-way…”

“In this context, the resurgence of COVID-19 in Manaus, Brazil is associated with the emergence of the P.1 SARSCoV-2 VOC despite an estimated seroprevalence of 75% in this region (Buss et al., 2021; Sabino et al., 2021).”

“…of anti-RBD mAbs to exert Fc-dependent effector function: (1) epitope specificities of the mAbs, as previously shown for mAbs against IAV HA and NA (DiLillo et al., 2014, 2016); (2) orientation and distance of the Fc fragment relative to the plasma membrane (Dilillo et al., 2016; Pinto et al.,…”

“…Cell 184, June 10, 2021 bodies, possibly reducing vaccine effectiveness and the duration of protection (Cele et al., 2021; Chen et al., 2021c; Collier et al., 2021; Kustin et al., 2021; Liu et al., 2021a; McCallum et al., 2021a; Muik et al., 2021; Wang et al., 2021b, 2021c; Wu et al., 2021).”

“The relevance for antibody-dependent enhancement of disease (ADE) in the context of a range of different viral infections, including SARS-CoV and SARS-CoV-2, is reviewed elsewhere (Arvin et al., 2020; Bournazos et al., 2020b; Lee et al., 2020).”

“, 2000); GAALIE, G236A/A330L/I332E (Weit8L/N434S (Zalevsky et al., 2010); TM, triple mutant in Fc, L234F/L235E/P331S”

“…titers of vaccine-elicited anti- 3094 Cell 184, June 10, 2021 bodies, possibly reducing vaccine effectiveness and the duration of protection (Cele et al., 2021; Chen et al., 2021c; Collier et al., 2021; Kustin et al., 2021; Liu et al., 2021a; McCallum et al., 2021a; Muik et al., 2021;…”

“Preliminary data have suggested increased transmissibility for the B.1.427/B.1.429 VOCs (Deng et al., 2021).”

“It was hypothesized that this control was mediated by T cell immunity (Barouch et al., 2013; Schoofs et al., 2016) and boosted by viral antigen presentation through immune complexes formed between HIV-1 envelope glycoprotein and the infused mAbs, through the so-called antibody vaccinal effect.”

“…regdanvimab) are sensitive to one ormore of themutations found in RBD residues at positions 417, 452, or 484 that are carried by multiple circulating VOCs, including the recently emerging B.1.617 (Hoffmann et al., 2021; McCallum et al., 2021a; Starr et al., 2021b; Wang et al., 2021b) (Figure 5C).”

“The removal of this glycosylation site by mutagenesis resulted in impaired RBD folding, decreased expression, and reduced infectivity (Li et al., 2020; Starr et al., 2020, 2021a), most likely explaining its strict conservation.”

“, receptor mimicry) (Walls et al., 2019), preventing egress of virus from infected cells, or blocking cell-to-cell spread of virus (e.”

“The breadth Cell 184, June 10, 2021 3087 ll Review of reactivity of HA stem mAbs toward all IAVs represents an opportunity to develop an off-the-shelf approach to prepare for future influenza A pandemics.”

“…mediate host cell attachment (S1 subunit, formed by four domains, the most relevant being the N-terminal domain [NTD] and receptor-binding domain [RBD]) and fusion of the viral and cellular membranes (S2 subunit) (Tortorici and Veesler, 2019; Walls et al., 2016, 2020b; Wrapp et al., 2020).”

“The NTD is also a target of neutralizing mAbs (Cerutti et al., 2021; Chi et al., 2020; McCallum et al., 2021b; Suryadevara et al., 2021; Voss et al., 2020; Wu et al., 2021) that were shown to be potent in vitro and were all directed toward the same antigenic site of vulnerability (designated site i).”

“Corey and co-authors have recently shown in two trials that administration of VRC01 did not prevent HIV-1 infection (Corey et al., 2021).”

“…Cell 184, June 10, 2021 bodies, possibly reducing vaccine effectiveness and the duration of protection (Cele et al., 2021; Chen et al., 2021c; Collier et al., 2021; Kustin et al., 2021; Liu et al., 2021a; McCallum et al., 2021a; Muik et al., 2021; Wang et al., 2021b, 2021c; Wu et al., 2021).”

“However, this may not necessarily apply to acute viral infections and be a consideration in the treatment of prolonged infections in immunocompromised individuals, such as has been observed with COVID-19 (Avanzato et al., 2020; Choi et al., 2020; Kemp et al., 2021; McCarthy et al., 2021).”

“…hypothesis that protection from infection and disease can be mediated by neutralizing mAbs, furthermore indicating that vaccine-elicited antibodies are likely the major correlate of protection, as observed in non-human primates (Arunachalam et al., 2021; McMahan et al., 2021; Walls et al., 2020a).”

“The combination of two broadly neutralizing mAbs was shown to be effective in maintaining prolonged suppression after antiretroviral therapy interruption (Mendoza et al., 2018).”

“Ia/class 1 Baum et al., 2020a, 2020b; Copin et al., 2021; Hansen et al., 2020; Weinreich et al., 2021 8 3 NCT04452318 (household contact prevention) adults/ pediatrics SC/IM 1.2 Study 2069 3 NCT04381936 (late treatment) 12 years and older (hospitalized) IV 8 RECOVERY 1/2/3 EUA NCT04425629 (early…”

“…Cell 184, June 10, 2021 bodies, possibly reducing vaccine effectiveness and the duration of protection (Cele et al., 2021; Chen et al., 2021c; Collier et al., 2021; Kustin et al., 2021; Liu et al., 2021a; McCallum et al., 2021a; Muik et al., 2021; Wang et al., 2021b, 2021c; Wu et al., 2021).”

“These classes of mAbs was found to trigger S rearrangement to the post-fusion state, likely due to conformational selection for open RBDs, and promotemembrane fusion (Lempp et al., 2021).”

“In this context, the resurgence of COVID-19 in Manaus, Brazil is associated with the emergence of the P.1 SARSCoV-2 VOC despite an estimated seroprevalence of 75% in this region (Buss et al., 2021; Sabino et al., 2021).”

“The relevance for antibody-dependent enhancement of disease (ADE) in the context of a range of different viral infections, including SARS-CoV and SARS-CoV-2, is reviewed elsewhere (Arvin et al., 2020; Bournazos et al., 2020b; Lee et al., 2020).”

“The removal of this glycosylation site by mutagenesis resulted in impaired RBD folding, decreased expression, and reduced infectivity (Li et al., 2020; Starr et al., 2020, 2021a), most likely explaining its strict conservation.”

“Ib/class 2 Chen et al., 2021a; Gottlieb et al., 2021; ACTIV-3/TICO LY-CoV555 Study Group et al., 2021; Jones et al., 2021 2 NCT04701658 (early treatment) 12 years and older IV BLAZE-5 2/3 NCT04518410 (early treatment) adults IV ACTIV-2 4 NCT04656691 (early treatment, at-home infusion) older adults…”

“In this regard, the most advanced program is represented by VIR-2482, a half-lifeextended version of the previously identified MEDI8852 mAb, which recognizes a conserved epitope on the HA stem shared by all 18 IAV subtypes (Kallewaard et al., 2016).”

“…of anti-RBD mAbs to exert Fc-dependent effector function: (1) epitope specificities of the mAbs, as previously shown for mAbs against IAV HA and NA (DiLillo et al., 2014, 2016); (2) orientation and distance of the Fc fragment relative to the plasma membrane (Dilillo et al., 2016; Pinto et al.,…”

“…NTD is also a target of neutralizing mAbs (Cerutti et al., 2021; Chi et al., 2020; McCallum et al., 2021b; Suryadevara et al., 2021; Voss et al., 2020; Wu et al., 2021) that were shown to be potent in vitro and were all directed toward the same antigenic site of vulnerability (designated site i).”

“The NTD is also a target of neutralizing mAbs (Cerutti et al., 2021; Chi et al., 2020; McCallum et al., 2021b; Suryadevara et al., 2021; Voss et al., 2020; Wu et al., 2021) that were shown to be potent in vitro and were all directed toward the same antigenic site of vulnerability (designated site i).”

“…were defined according to 5 Å distance from ACE2- or mAbs are labeled using both their original and generic (nonproprietary) names. t al., 2020a, Cohen et al. (2021), and Piccoli et al. (2020) and colored as in (A). mAb footprints are highlighted in blue and light green, respectively, as in…”

“However, two recent studies did not confirm that the B.1.1.7 variant is associated with more severe disease (Frampton et al., 2021; Graham et al., 2021).”

“The use of half-life-extending mutations such as LS or YTE may also contribute to an improved biodistribution in mucosal tissues, such as lungs, as previously observed in non-human primates (Ko et al., 2014).”

“…Cell 184, June 10, 2021 bodies, possibly reducing vaccine effectiveness and the duration of protection (Cele et al., 2021; Chen et al., 2021c; Collier et al., 2021; Kustin et al., 2021; Liu et al., 2021a; McCallum et al., 2021a; Muik et al., 2021; Wang et al., 2021b, 2021c; Wu et al., 2021).”

“, 2019); YTE, M252Y/S254T/T256E (Dall’Acqua et al., 2002); LS: M42 (Oganesyan et al.”

“In particular, mAbs with wild-type Fc were shown to reduce SARS-CoV-2 burden and lung disease in animals more efficiently than mAbs with Fc mutated to abrogate binding to FcgRs and required monocyte intervention for therapeutic efficacy (Winkler et al., 2021).”

“Another highly potent RSV mAb (nirsevimab) harboring an Fc fragment engineered for half-life extension recently showed a 78% reduction in hospitalization in pre-term infants in a phase 2b study (Griffin et al., 2020; Zhu et al., 2017).”

“…the recent emergence of several SARS-CoV-2 variants of concern (VOCs) has shown limitation in the coverage by some of these mAbs that target epitopes mutating rapidly (Chen et al., 2021c; Collier et al., 2021; Davies et al., 2021a; McCallum et al., 2021a; Tegally et al., 2021; Wibmer et al., 2021).”

“3102 Cell 184, June 10, 2021 cate a high potential for mAb-based immune prophylaxis of COVID-19 and support the hypothesis that protection from infection and disease can be mediated by neutralizing mAbs, furthermore indicating that vaccine-elicited antibodies are likely the major correlate of protection, as observed i…”

“It was hypothesized that this control was mediated by T cell immunity (Barouch et al., 2013; Schoofs et al., 2016) and boosted by viral antigen presentation through immune complexes formed between HIV-1 envelope glycoprotein and the infused mAbs, through the so-called antibody vaccinal effect.”

“Similarly, in a mouse model of COVID-19, the elimination of effector functions through the introduction of GRLR mutations (G236R/L328R) in the Fc fragment that abrogates binding to FcgRs and complement resulted in a reduced antiviral efficacy in terms of viral load in lungs of infected mice (Schäfer et al., 2021).”

“Only the ADG2 mAb has been affinity matured in vitro (Rappazzo et al., 2021), while all others were developed in their native or semi-native forms.”

“However, two recent studies did not confirm that the B.1.1.7 variant is associated with more severe disease (Frampton et al., 2021; Graham et al., 2021).”

“N297-bound A (Hezareh et al., 2001; Xu et al., 2000); GAALIE, G236A/A330L/I332E (Weit8L/N434S (Zalevsky et al., 2010); TM, triple mutant in Fc, L234F/L235E/P331S Cell 184, June 10, 2021 3091 Side (left) and top (right) views of a structural model of SARS-CoV-2 S trimer (gray) with two RBDs in the…”

“Three major studies (REMACCAP, COVACTA, and RECOVERY) have published the validity of this approach in COVID-19 hospitalized patients, with contrasting results (Horby et al., 2021; REMAP-CAP Investigators et al., 2021; Rosas et al., 2021).”

“…regdanvimab) are sensitive to one ormore of themutations found in RBD residues at positions 417, 452, or 484 that are carried by multiple circulating VOCs, including the recently emerging B.1.617 (Hoffmann et al., 2021; McCallum et al., 2021a; Starr et al., 2021b; Wang et al., 2021b) (Figure 5C).”

“N297-bound A (Hezareh et al., 2001; Xu et al., 2000); GAALIE, G236A/A330L/I332E (Weit8L/N434S (Zalevsky et al., 2010); TM, triple mutant in Fc, L234F/L235E/P331S Cell 184, June 10, 2021 3091 Side (left) and top (right) views of a structural model of SARS-CoV-2 S trimer (gray) with two RBDs in the…”

“This process is the basis for antigenic drift and the continuous requirement to update influenza vaccines (Doud et al., 2018; Kirkpatrick et al., 2018).”

“A comprehensive and updated overview is provided by Nussenzweig and Barouch to reflect recent progress in the field (Caskey et al., 2019; Julg and Barouch, 2021).”

“In the following years after palivizumab was approved, two additional RSV mAbs (motavizumab and suptavumab) were evaluated in phase 3 clinical trials but safety and resistance concerns halted further development in 2010 and 2018, respectively (Carbonell-Estrany et al., 2010; Simões et al., 2020).”

“Several mutations found in these VOCs/VOIs are found to reduce or abolish the neutralizing activity of several mAbs, including those already approved or in late stages of development (Figure 5).”

“However, this may not necessarily apply to acute viral infections and be a consideration in the treatment of prolonged infections in immunocompromised individuals, such as has been observed with COVID-19 (Avanzato et al., 2020; Choi et al., 2020; Kemp et al., 2021; McCarthy et al., 2021).”

“This study will assess VIR-2482 for immune prophylaxis in outpatients and could be pivotal for the field to investigate if stem-directed HA mAbs can be effective in prophylaxis, as indirectly suggested by a serological study in humans (Ng et al., 2019).”

“List of Fc abbreviations: LALA, L234A/L235 zenfeld et al., 2019); YTE, M252Y/S254T/T256E (Dall’Acqua et al., 2002); LS: M42 (Oganesyan et al., 2008). by blocking binding to the ACE2 entry receptor but also by inactivating S by acting as receptor mimics before viral encounter of a host cell.”

“AbbVie is also testing ABBV-47D11 and ABBV-2B04 mAbs (Alsoussi et al., 2020; Wang et al., 2020) alone and in combination for treating adults hospitalized with COVID-19 in a phase 1 study.”

“In the following years after palivizumab was approved, two additional RSV mAbs (motavizumab and suptavumab) were evaluated in phase 3 clinical trials but safety and resistance concerns halted further development in 2010 and 2018, respectively (Carbonell-Estrany et al., 2010; Simões et al., 2020).”

“This process is the basis for antigenic drift and the continuous requirement to update influenza vaccines (Doud et al., 2018; Kirkpatrick et al., 2018).”

“…if the global demand of mAbs exceeds the current production capacity of individual companies in the near future, then a cooperation between multiple private and public sectors will be needed for the simultaneous access to multiple very-large-scale bioreactors (Kelley, 2020; Kelley et al., 2021).”

“…et al., 2014, 2016); (2) orientation and distance of the Fc fragment relative to the plasma membrane (Dilillo et al., 2016; Pinto et al., 2020; Tang et al., 2019); (3) steric hindrance of effector cells; (4) high-density binding of mAbs for efficient Fcg receptor (FcgR) cross-linking and…”

“The breadth Cell 184, June 10, 2021 3087 ll Review of reactivity of HA stem mAbs toward all IAVs represents an opportunity to develop an off-the-shelf approach to prepare for future influenza A pandemics.”

“…infected with IAV (the so-called human challenge model), while no signs of efficacy were observed when trials were run in outpatient settings with uncomplicated influenza A infection or in hospitalized patients (Ali et al., 2018; Corti et al., 2017; Hershberger et al., 2019; Lim et al., 2020).”

“Three major studies (REMACCAP, COVACTA, and RECOVERY) have published the validity of this approach in COVID-19 hospitalized patients, with contrasting results (Horby et al., 2021; REMAP-CAP Investigators et al., 2021; Rosas et al., 2021).”

“…infected with IAV (the so-called human challenge model), while no signs of efficacy were observed when trials were run in outpatient settings with uncomplicated influenza A infection or in hospitalized patients (Ali et al., 2018; Corti et al., 2017; Hershberger et al., 2019; Lim et al., 2020).”

“Whether occupancy is relevant to viral neutralization is unclear, but it might affect the ability of mAbs to trigger effector functions, since the density of mAbs on virions or infected cells can influence the ability to engage and activate low-affinity Fcg-receptors (Ortiz et al., 2016).”

“Palivizumab was developed as monotherapy and has been proven to work for more than 20 years despite the fact that viral escape is readily observed in vitro (Zhao et al., 2004; Zhu et al., 2011).”

“…infected with IAV (the so-called human challenge model), while no signs of efficacy were observed when trials were run in outpatient settings with uncomplicated influenza A infection or in hospitalized patients (Ali et al., 2018; Corti et al., 2017; Hershberger et al., 2019; Lim et al., 2020).”

“The NTD is also a target of neutralizing mAbs (Cerutti et al., 2021; Chi et al., 2020; McCallum et al., 2021b; Suryadevara et al., 2021; Voss et al., 2020; Wu et al., 2021) that were shown to be potent in vitro and were all directed toward the same antigenic site of vulnerability (designated site i).”

“However, some clinical mAbs are not sensitive in vitro and in vivo to themutations present in the current VOCs/VOIs due to targeting of highly conserved epitopes, as is the case for VIR-7831, COV22196, and other mAbs (Chen et al., 2021b; Dong et al., 2021; McCallum et al., 2021a; Pinto et al., 2020; Starr et al., 2021…”

“IV/class 3 Cathcart et al., 2021; Gupta et al., 2021; Lempp et al., 2021; Pinto et al., 2020; Tortorici et al., 2021 2 NCT04634409, VIR-7831+ bamlanivimab (early treatment) adults IV 0.5 + 0.7 BLAZE-4 LS 3 NCT04501978 (late treatment) hospitalized IV 0.5 ACTIV-3 LS 1b/2a (UK) (1b–2a) (early…”

“Indeed, the B.1.1.7 variant was found to be more transmissible and cause more severe infections compared to the parental virus (Davies et al., 2021a, 2021b; Munitz et al., 2021).”

“Indeed, a three-times-higher frequency of transitions over transversions was observed in the SARS-CoV2 genome (Roy et al., 2020; Sarkar et al., 2021).”

“A comprehensive and updated overview is provided by Nussenzweig and Barouch to reflect recent progress in the field (Caskey et al., 2019; Julg and Barouch, 2021).”

“Indeed, a three-times-higher frequency of transitions over transversions was observed in the SARS-CoV2 genome (Roy et al., 2020; Sarkar et al., 2021).”

“…infected with IAV (the so-called human challenge model), while no signs of efficacy were observed when trials were run in outpatient settings with uncomplicated influenza A infection or in hospitalized patients (Ali et al., 2018; Corti et al., 2017; Hershberger et al., 2019; Lim et al., 2020).”

“…if the global demand of mAbs exceeds the current production capacity of individual companies in the near future, then a cooperation between multiple private and public sectors will be needed for the simultaneous access to multiple very-large-scale bioreactors (Kelley, 2020; Kelley et al., 2021).”

“Ib/class 2 Chen et al., 2021a; Gottlieb et al., 2021; ACTIV-3/TICO LY-CoV555 Study Group et al., 2021; Jones et al., 2021 2 NCT04701658 (early treatment) 12 years and older IV BLAZE-5 2/3 NCT04518410 (early treatment) adults IV ACTIV-2 4 NCT04656691 (early treatment, at-home infusion) older adults…”

“The removal of this glycosylation site by mutagenesis resulted in impaired RBD folding, decreased expression, and reduced infectivity (Li et al., 2020; Starr et al., 2020, 2021a), most likely explaining its strict conservation.”

“…for efficient Fcg receptor (FcgR) cross-linking and engagement of the hexameric C1q; and (5) the ability of some RBD-specific mAbs to trigger shedding of the S1 subunit and S conformational change, which limit their ability to trigger effector functions (Lempp et al., 2021; Tortorici et al., 2021).”

“…for efficient Fcg receptor (FcgR) cross-linking and engagement of the hexameric C1q; and (5) the ability of some RBD-specific mAbs to trigger shedding of the S1 subunit and S conformational change, which limit their ability to trigger effector functions (Lempp et al., 2021; Tortorici et al., 2021).”

“Twenty years after the first use of antitoxin, convalescent serum from survivors of the 1918 Spanish flu was used to treat pneumonia, showing a modest level of efficacy when administered early after symptom onset (Redden, 1919).”

“Indeed, in two other recent studies, convalescent plasma was shown to be a valuable treatment option for hospitalized patients if provided early in the course of disease before patients require ventilation or are admitted to the intensive care unit (ICU) (Ma et al., 2021; Tworek et al., 2021).”

“The epitope ofmAb 47D11 resides in a conserved hydrophobic pocket nearby glycan N343 (structural data not publicly available; Fedry et al., 2020).”

“…VOCs/VOIs were already previously identified as resistant variants in vitro by using mAbs and convalescent or vaccine-elicited serum antibodies (Andreano et al., 2020; Baum et al., 2020b; Liu et al., 2021b; Weisblum et al., 2020), suggesting that the emergence of these VOCs/VOIs may result…”

“…(Arunachalam et al., 2021; Case et al., 2020a; Corbett et al., 2021; Hassan et al., 2021; Khoury et al., 2021; McMahan et al., 2021; Winkler et al., 2020), and multiple clinical trials have shown the benefits of therapeutic administration of monoclonal antibodies in humans (Corti et al., 2021).”

“The WHO labeling of clades is marked besides. b Sequential frequency of major clades of SARS-CoV-2 variants from April 2021 to February 2022. c Linear genome architecture of encoded viral protein and structural overview of SARS-CoV-2.”

“…spike (S) glycoprotein ( 1 ) have been an effective treatment for improving outcomes for patients with coronavirus disease 2019 (COVID-19) ( 2 – 5 ), but many are sensitive to viral escape through point mutations in their epitopes on the S trimer ( 6 , 7 ), and producing mAbs in sufficient…”

“Since the coronavirus S glycoprotein is the target of neutralizing antibodies, it is the main focus of therapeutics and vaccine development, including monoclonal antibody therapies and vaccines (Baum et al., 2020; Corbett et al., 2020; Corti et al., 2021; Hansen et al., 2020; McCallum et al., 2021a; Piccoli et al., 20…”

“Immunotherapies based on SARS-CoV-2–neutralizing antibodies have been rapidly explored, and this led to the clinical use of several mAbs alone or in bi-therapies (Corti et al., 2021).”

“…(i) rapid and high-throughput antibody discovery platforms and (ii) identifying high-af fi nity antibodies targeting conserved 9,10 or non-overlapping epitopes 11,12 to resist viral escape and increase the ability to neutralize viral variants 6,13 ; both of whichrequireintensivescreeningcampaigns.”

“This approach is feasible because many Spike-antibody complexes have been solved in the last two years (17, 18, 21), enabling structural modeling of mutational effects (22, 23).”

“Although a number of neutralizing monoclonal antibodies (nmAbs) have been found to target the NTD, especially the NTD supersite,(7) the majority of the nmAbs, particularly the most potent broadly reactive, target the RBD,(8,9) including all those in clinical use.(10) The RBD is thus under intense selective pressure, a…”

“Numerous neutralizing epitopes have been identified on spike, including epitopes on RBD, NTD, and S2, and their modes of antibody recognition characterized at the molecular level (Castro Dopico et al., 2022; Corti et al., 2021; Yuan et al., 2021).”

“In case of virus diseases, FcγR interaction also has a risk of antibody-dependent enhancement (ADE) of virus infection to FcγRpositive immune cells, which has been, in fact, observed during secondary infection with dengue virus [63].”

“35 Casirivimab and im‑ devimab are recombinant human immunoglobu‑ lin G1 (IgG1) monoclonal antibodies approved by the Food and Drug Administration for the treat‑ ment of adult and pediatric patients with mild‑ ‑to ‑moderate COVID ‑19, as well as individuals at high risk of progression to severe…”

“Immunotherapeutics represent an important class of medical countermeasures against viruses, including poliovirus 71 , orthopoxviruses 72 , rabies virus 73 , Ebola virus 74 , Junin virus 75 , and SARS-CoV-2 76 .”

“2.(8,16,37,38) The mechanisms underlying the nanomolar broad neutralization by 35B5 at least involve three aspects: (1) broad interface and extensive interactions between 35B5 and RBD endow 35B5 as a potent cross-epitope mAb; (2) proactive dissociation of the spike trimer by structural clashes between 35B5 Fab FRH1 an…”

“Other clinical antibodies, however, were developed as wild-type IgG1 (casirivimab/imdevimab, bamlanivimab) (10).”

“…and presentation of viral antigen to T cells is also important for the antiviral activity of non-neutralizing antibodies (not shown in the figure), a phenomenon that is illustrated by the boosting of adaptive immune responses by pre-existing antibodies (known as the antibody vaccinal effect) 198 .”

“…of factors, including the limited access or resistance to vaccination in some areas of the world, as well as the continuous viral evolution, which leads to the emergence of new variants of concern (VOC) that escape from the control of current vaccines and therapeutic neutralizing antibodies (5–7).”

“…development of NAbs has focused on the mechanisms of SARS-CoV-2 entry into host cells, including the binding of the S protein to its receptor ACE2 and subsequent membrane fusion mediated by the S protein, which are also shared by other CoVs (Corti et al., 2021; Li et al., 2022b; Li et al., 2021).”

“Individuals were enrolled in the UWARN: COVID-19 in WA study at the University of Washington in Seattle, WA.”

“Since the interaction between the RBD and the host cell receptor ACE2 is essential for infection, the phenotypic impact of mutations accumulated in the RBD can be avoided by generating an ACE2 based decoy therapeutic.28 As mutational escape of the SARS-CoV-2 from ACE2 binding for viral attachment and host cell entry w…”

“It is noteworthy that NAbs binding to spike S1 subunits outside the RBD motif are no longer evaluated using the method reported above [6,66].”

“Although several antiviral drugs including neutralizing antibodies (Corti et al., 2021) and molnupiravir (Sheahan et al., 2020; Toots et al., 2019), a nucleoside analog that inhibits viral genome replication, have been developed, additional drugs with novel anti-viral mechanisms of action still…”

“Spike protein, specifically the RBD, 60 is the primary target antigen for COVID vaccines in the market and interfering with the interface between RBD and ACE2 is the action mechanism of the majority of existing therapeutic antibodies [16], indicating the importance of RBD and its binding to the cellular receptor for c…”

“It has been suggested that mAbs may act as antiviral neutralizing agents through multiple mechanisms, such as targeting free virus and virally infected cells (28).”

“The NTD is also a target for mAbs, and these antibodies either prevent spike conformational changes or get in the way of the ACE2‐binding site.(10,11) The approval of therapeutic mAbs for COVID‐19 treatment was granted in less than a year and represented exceptional achievements in modern science, technology, and medi…”

“…(Arunachalam et al., 2021; Case et al., 2020a; Corbett et al., 2021; Hassan et al., 2021; Khoury et al., 2021; McMahan et al., 2021; Winkler et al., 2020) and multiple clinical trials have shown the benefits of therapeutic administration of monoclonal antibodies in humans (Corti et al., 2021).”

“Likewise, passive transfer of therapeutic neutralizing monoclonal antibodies (mAb) was initially successful in treating COVID-19 before the arrival of the variants (12), but many neutAbs previously approved for emergency use by the FDA do not retain efficacy against Delta and Omicron strains (13, 14).”

“During the COVID-19 pandemic, monoclonal antibody therapies have also played a vital role (Corti et al. 2021a).”

“Moreover, a multitude of non‐RBM monoclonal antibodies have showcased their capacity to thwart viral infection by impeding the structural rearrangement of the S protein and spatially disrupting ACE2 engagement.(44,49)”

“In the case of SARS-CoV-2, the current monoclonal antibodies mostly target the receptor-binding domain (RBD), a spike glycoprotein subunit essential for viral entry [1].”

“43,44 In addition, RBD barely induces antibody-dependent enhancement (ADE), which is found in full-length spike vaccines and deteriorates the infection.”

“vidual mutations to the host immunity escape of SARS-CoV-2 variants (Corti et al., 2021; Liu et al., 2022; Planas et al., 2021; Wang, Casner, et al., 2021; Wang, Nair, et al., 2021).”

“Later, other mAbs for anthrax, rabies, HIV, and Ebola were marketed or approved for conditional emergency use [1].”

“For these patients, it would be worth to further explore a combination of antiviral therapy (for example, Interferons (IFNs)  and  , remdesivir [23] or convalescent plasma), immune activation therapy (anti-PD-L1 or CTLA-4 antibody), or more recently developed neutralizing antibodies to SARS-CoV-2 [21-26].”

“Functional Fc receptor domain modification has been shown to improve treatment outcomes in SARS-CoV-2-infected mice [58].”

“By contrast, mAbs remain a powerful platform for combating a wide range of pathogens because they can speci fi cally target viral antigens and reduce viral burden, hospitalization, and mortality (34, 35).”