Multivalent Anti-Spike Protein Binding Molecules and Their Uses

Abstract

The present disclosure provides multivalent anti-spike protein binding molecules, comprising multimerization moieties linked to anti-spike protein antigen-binding domains, that specifically bind to RBD regions of SARS-CoV and / or SARS-CoV-2. The present disclosure further relates to the methods of producing the multivalent anti-spike protein binding molecules, pharmaceutical compositions comprising of the multivalent anti-spike protein binding molecules, and methods of use of the multivalent anti-spike protein binding molecules to treat conditions associated with SARS-CoV and SARS-CoV-2 infections, such as COVID-19.

Description

"Multivalent Anti-Spike Protein Binding Molecules and Their Uses" 1. CROSS-REFERENCE TO RELATED ORDERS

[001] This application claims the priority benefit of Interim Application No. U.S. 63 / 487,408, filed February 28, 2023, the contents of which are incorporated herein in their entirety by reference. 2. LISTING OF SEQUENCES

[002] This application contains a Sequence Listing that was submitted electronically in XML format and is incorporated herein by reference in its entirety. Said XML Sequence Listing, created on February 27, 2024, is named RGN-028WO_SL.xml and is 643,930 bytes in size. 3. BACKGROUND

[003] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded, enveloped, positive-sense RNA virus of the genus Betacoronavirus, which also includes SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus (HCoV)-OC43, and HCoV-HKU1 (Jackson et al., 2022, Nat Rev Mol Cell Biol. 23(1): 3-20). SARS-CoV-2 causes COVID-19, a potentially fatal disease that was first characterized in late 2019 and became a global pandemic in early 2020.

[004] SARS-CoV-2 shares approximately 80% identity with SARS-CoV and both viruses depend on their interaction with angiotensin-converting enzyme 2 (ACE2) for cellular entry, an enzyme expressed on the extracellular surface of many cell types.

[005] Currently, several vaccines against SARS-CoV-2 are used to prevent the manifestation of severe disease. However, the ta Petition 870250096939, dated 10 / 23 / 2025, page 16 / 154 2 / 129 vaccination rates vary among populations, and even in areas with high vaccination rates, breakthrough infections leading to COVID-19 have been observed in individuals who were immunized against SARS-CoV-2. Prior SARS-CoV-2 infections also do not appear to provide complete immunity against future infections, as some individuals have been diagnosed with COVID-19 multiple times. Furthermore, SARS-CoV-2 infection in some individuals leads to prolonged illness associated with the persistence of one or more COVID-19 symptoms for weeks or months after the infection has cleared. These observations underscore the serious threat to public health posed by COVID-19 and the need to combat SARS-CoV-2 infections with effective treatments.

[006] Treatments with small molecules, such as Paxlovid – a combination of the oral antiviral drugs nirmatrelvir and ritonavir – can prevent hospitalization, but are associated with a “Paxlovid rebound” effect, in which the virus reappears (Callaway, Nature (News), August 11, 2022). On the other hand, biological treatments, such as monoclonal antibodies, can directly reduce viral spread, leading to robust and long-lasting therapeutic effects. However, due to the rapid emergence of new SARS-CoV-2 variants, antibodies isolated from patients are generally specific to each strain, making them ineffective against certain SARS-CoV-2 variants. Therefore, there is still a need to develop neutralizing treatments that are effective against SARS-CoV-2. 4. SUMMARY

[007] This disclosure relates to multivalent antigen-binding molecules that bind to a coronavirus spike protein, generally referred to herein as “multivalent anti-spike protein-binding molecules”, to inhibit the interaction between Petition 870250096939, dated 10 / 23 / 2025, p. 17 / 154 3 / 129 between coronaviruses and host cells. Multivalent anti-spike protein-binding disclosure molecules typically comprise a plurality of antigen-binding domains of the anti-spike protein (ABDs) operationally linked by one or more multimerization moieties. Multivalent anti-spike protein-binding disclosure molecules are described in Section 6.2 and in embodiments numbered 1 to 96.

[008] Multivalent disclosure anti-spike protein binding molecules are typically tetravalent and comprise four spike protein ABDs, for example, in the form of a Fab or an scFv. The spike protein ABDs of a multivalent disclosure anti-spike protein binding molecule can be monospecific (e.g., all ABDs bind to the same region of the spike protein and optionally all have the same sequence) or multispecific (e.g., at least two of the ABDs bind to different regions or variants of the spike protein and differ in sequence). Spike protein ABDs and spike protein ABD formats that are suitable for incorporation into multivalent disclosure anti-spike protein binding molecules are described in Sections 6.3 and 6.4, and in embodiments numbered 3 to 15 and 48 to 61.

[009] Multivalent disclosure anti-spike protein-binding molecules include one or more multimerization moieties, for example, one or more multimerization moieties comprising or consisting of an Fc domain. Suitable multimerization moieties for incorporation into multivalent disclosure anti-spike protein-binding molecules are described in Section 6.5 and in embodiments numbered 28 to 32 and 36 to 39.

[0010] Two or more components of multivalent molecules binding to the anti-spike protein of the disclosure can be connected to each other by a ligand, for example, a peptide ligand. A Petition 870250096939, dated 10 / 23 / 2025, page 18 / 154 4 / 129 by way of example and without limitation, linkers can be used to connect a spike protein ABD to a multimerization moiety. Suitable linkers for incorporation into the multivalent anti-spike binding protein molecules of disclosure are described in Section 6.6 and in embodiments numbered 44 to 47.

[0011] Disclosure multivalent anti-spike protein-binding molecules may include a linker that is a hinge region. Suitable hinge sequences for incorporation into disclosure multivalent anti-spike protein-binding molecules are described in Section 6.6.1 and in embodiments numbered 40 to 43.

[0012] This disclosure further provides nucleic acids encoding disclosure multivalent anti-spike protein-binding molecules, host cells designed to express disclosure multivalent anti-spike protein-binding molecules, and recombinant methods for producing disclosure multivalent anti-spike protein-binding molecules. These nucleic acids, host cells, and production methods are described in Section 6.7 and in embodiments numbered 97 to 99.

[0013] This disclosure also provides pharmaceutical compositions comprising the multivalent anti-spike protein-binding molecules of the disclosure, as well as therapeutic indications and methods of use. The pharmaceutical compositions are described in Section 6.8 and in embodiment numbered 100. The methods of use of the multivalent anti-spike protein-binding molecules are described in Section 6.9 and in embodiments numbered 101 to 113.

[0014] Other features and advantages of the multivalent anti-spike protein binding molecules of the present disclosure will be evident in the more detailed description that follows, together with the accompanying drawings. 5. BRIEF DESCRIPTION OF THE FIGURES Petition 870250096939, dated 10 / 23 / 2025, p. 19 / 154 5 / 129

[0015] FIGURES 1A to 1D show examples of multivalent anti-spike protein-binding molecules from the disclosure. Figure 1A represents a tetravalent 2x2 N-Fab (“AF”) monospecific antibody construct with identical Fab arms, each comprising two serially linked Fab portions connected to the N-terminal end of an Fc portion. Figure 1B represents a tetravalent 2x2 N-Fab AF bispecific construct with different Fab arms, each comprising two serially linked Fab portions connected to the N-terminal end of an Fc portion. Figure 1C represents a tetravalent 2x2 C-Fab AF monospecific construct with identical Fab arms comprising Fab molecules connected to the N-terminal ends of Fc molecules, which are also linked to Fab molecules at their C-terminal ends.Figure 1D represents a tetravalent bispecific 2x2 C-Fab AF construct with different Fab arms, comprising Fab molecules connected to the N-terminal ends of Fc molecules, which are also connected to Fab molecules at their C-terminal ends. Figures 2A-2B show the neutralization activities of different 2x2 N-Fab AF constructs against SARS-CoV-2 pseudovirus variants. An individual Fab arm from REGN10987, 14315, 10933, 14256, and 10985 was used to form pairs with itself or with others. Figure 2A shows the IC50 values ​​of pseudovirus neutralization of constructs grouped by Fab arms against the D614G variant, while Figure 2B shows the IC50 values ​​of neutralization against the BA.2 variant. Closed circles represent 2x2 N-Fab AF constructs that have identical Fab arms and are therefore monospecific. Open circles represent 2x2 N-Fab AF constructs that have different Fab arms and are therefore bispecific. The closed triangle in each Fab group represents parental IgG control. Petition 870250096939, dated 10 / 23 / 2025, page 20 / 154 6 / 129 with that Fab.

[0016] Figures 3A-3B show the neutralization activities of different 2x2 C-Fab AF constructs against SARS-CoV-2 pseudovirus variants. Figure 3A shows the IC50 neutralization values ​​of the constructs against the D614G variant, while Figure 3B shows the IC50 neutralization values ​​of the same constructs against the BA.2 variant, grouped by Fab arms. Closed circles represent 2x2 C-Fab AF constructs that have identical Fab arms and are therefore monospecific. Open circles represent 2x2 C-Fab AF constructs that have different Fab arms and are therefore bispecific. The closed triangle in each Fab group represents parental IgG control with that Fab.

[0017] Figures 4A-4B show the dose-dependent neutralization activities of tetravalent AF molecules based on REGN14287 against the BQ.1 variant of the SARS-CoV-2 Omicron pseudovirus. Figure 4A shows the neutralization activity in percentage neutralization against BQ.1 at a dose titration of COVAF46-51 in 2x2 N-Fab with the REGN14287 bivalent parental IgG control and the combination cocktail of REGN10933 / REGN10987. Figure 4B shows the neutralization activity in percentage of neutralization against BQ.1 in the dose titration of COVAF-52-57 in C-Fab 2x2 with the bivalent parental IgG control REGN14287 and the REGN10933 / REGN10987 cocktail combination. 6. DETAILED DESCRIPTION 6.1. DEFINITIONS

[0018] As used in this document, the following terms shall have the following meanings:

[0019] About, Approximately: The terms “about”, Petition 870250096939, dated 10 / 23 / 2025, page 21 / 154 7 / 129 “approximately” and similar expressions are used throughout the descriptive report in front of a number to show that the number is not necessarily exact (e.g., to account for fractions, variations in the accuracy and / or precision of the measurement, time, etc.). It should be understood that a disclosure of “about X” or “approximately X”, where X is a number, is also a disclosure of “X”. Thus, for example, the disclosure of an embodiment in which a sequence has “about X% sequence identity” with another sequence is also the disclosure of an embodiment in which the sequence has “X% sequence identity” with the other sequence.

[0020] And, or: Unless otherwise indicated, an “or” conjunction should be used in its correct sense as a Boolean logical operator, encompassing both feature selection in the alternative (A or B, where the selection of A is mutually exclusive of B) and feature selection together (A or B, where A and B are selected). In some parts of the text, the term “and / or” is used for the same purpose, which should not be interpreted as implying that “or” is used with reference to mutually exclusive alternatives.

[0021] Antibody: The term “antibody,” as used in this document, refers to a polypeptide (or set of polypeptides) of the immunoglobulin family that has the ability to bind to an antigen in a non-covalent, reversible, and specific manner. For example, a naturally occurring IgG “antibody” is a tetramer comprising at least two heavy chains (H) and two light chains (L) interconnected by disulfide bonds. Each heavy chain comprises a variable heavy chain region (abbreviated here as VH) and a constant heavy chain region. The constant heavy chain region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a variable light chain region (abbreviated in this document as VL) and a constant light chain region. Petition 870250096939, dated 10 / 23 / 2025, page 22 / 154 8 / 129 light chain. The constant region of the light chain is composed of a domain (abbreviated in this document as CL). The VH and VL regions can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), interspersed with more conserved regions, called structure regions (RFs). Each VH and VL is composed of three CDRs and four RFs, arranged from the amino terminal to the carboxy terminal in the following order: RF1, CDR1, RF2, CDR2, RF3, CDR3, RF4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of antibodies can mediate the binding of immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.The term “antibody” includes, without limitation, monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, bispecific or multispecific antibodies, and anti-idiotypic (anti-id) antibodies. Antibodies can be of any isotype / class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). Both light and heavy chains are divided into regions of structural and functional homology. The terms “constant” and “variable” are used functionally. In this sense, it will be appreciated that the variable domains of the light (VL) and heavy (VH) chain portions determine antigen recognition and specificity. On the other hand, the constant domains of the light chain (LC) and heavy chain (CH1, CH2 or CH3) confer important biological properties, such as secretion, transplacental mobility, binding to the Fc receptor, binding to complement and the like.By convention, the numbering of the constant region domains increases as they become further away from the antigen-binding domain or amino group. Petition 870250096939, dated 10 / 23 / 2025, page 23 / 154 9 / 129 antibody terminal. The N-terminal is a variable region and the C-terminal is a constant region; the CH3 and CL domains represent the carboxy-terminal of the heavy and light chains, respectively, of natural antibodies. For convenience, and unless the context dictates otherwise, reference to an antibody also refers to antibody fragments, as well as to manipulated antibodies that include antigen-binding domains that do not occur naturally and / or antigen-binding domains with non-native configurations.

[0022] Antigen-Binding Molecule or ABM: The term “antigen-binding molecule” or “ABM,” as used in this document, refers to a molecule (e.g., an assembly of several polypeptide chains) comprising two antibody media. Typically, each antibody media comprises at least one antigen-binding domain. In some embodiments, the antigen is a coronavirus spike protein; therefore, disclosure ABMs are generally referred to as “anti-spike protein-binding molecules.” Disclosure ABMs can be monospecific or multispecific (e.g., bispecific). The antigen-binding domain in monospecific binding molecules binds to the same epitope, while multispecific binding molecules have at least two antigen-binding sites that bind to different epitopes, which may be on the same molecule or on different molecules (e.g., different variants of the spike protein).

[0023] Antigen-Binding Domain: The term “antigen-binding domain” or “ABD,” as used in this document, refers to a portion of an antibody or antibody fragment that has the ability to bind to an antigen in a non-covalent, reversible, and specific manner. Examples of an antibody fragment that may contain an ABD include, without limitation, a single-chain Fv (scFv), a Fab fragment, a monovalent fragment consisting of Petition 870250096939, dated 10 / 23 / 2025, page 24 / 154 10 / 129 in the VL, VH, CL, and CH1 domains; an F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; an Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al., 1989, Nature 341:544-546), consisting of a VH domain; and an isolated complementarity-determining region (CDR). Thus, the term “antibody fragment” encompasses both proteolytic antibody fragments (e.g., Fab and F(ab)2 fragments) and engineered proteins comprising one or more portions of an antibody (e.g., an scFv). Antibody fragments can also be incorporated into single-domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, vNAR and bis-scFv (see, for example, Hollinger and Hudson, 2005, Nature Biotechnology 23: 1126-1136).

[0024] Associate: The term “associate” in the context of a multivalent anti-spike protein-binding molecule refers to a functional relationship between two or more polypeptide chains. In particular, the term “associate” means that two or more polypeptides are associated with each other, for example, non-covalently through molecular interactions or covalently through one or more disulfide bridges or chemical cross-links, so as to produce a functional multivalent anti-spike protein-binding molecule. Examples of associations that may be present in a disclosure multivalent anti-spike protein-binding molecule include (without limitation) associations between Fc domains to form an Fc region (e.g., as described in Section 6.5.1).

[0025] Bivalent: The term “bivalent”, as used in this document, refers to a bonding molecule comprising two Petition 870250096939, dated 10 / 23 / 2025, page 25 / 154 11 / 129 antigen-binding domains, either on the same polypeptide chain or on different polypeptide chains.

[0026] Complementarity-Determining Region: The terms “complementarity-determining region” or “CDR,” as used in this document, refer to the amino acid sequences within antibody variable regions that confer antigen specificity and binding affinity. For example, there are generally three CDRs in each variable region of the heavy chain (e.g., CDRH1, CDR-H2, and CDR-H3) and three CDRs in each variable region of the light chain (CDR-L1, CDR-L2, and CDR-L3). The precise amino acid sequence boundaries of a given CDR can be determined using any of several known schemes, including those described by Kabat et al., 1991, “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (Kabat numbering scheme), Al-Lazikani et al., 1997, JMB 273:927-948 (Chothia numbering scheme) and ImMunoGenTics (IMGT) numbering (Lefranc, 1999, The Immunologist 7:132-136; Lefranc et al., 2003, Dev. Comp. Immunol. 27:55-77 (IMGT numbering scheme)). For example, for classical formats, according to Kabat, CDR amino acid residues in the variable domain of the heavy chain (VH) are numbered as 31-35 (CDR-H1), 50-65 (CDR-H2), and 95-102 (CDR-H3); and CDR amino acid residues in the variable domain of the light chain (VL) are numbered as 24-34 (CDR-L1), 50-56 (CDR-L2), and 89-97 (CDR-L3). According to Chothia, the CDR amino acids in VH are numbered 26 to 32 (CDR-H1), 52 to 56 (CDR-H2), and 95 to 102 (CDR-H3); and the amino acid residues in VL are numbered 26 to 32 (CDR-L1), 50 to 52 (CDR-L2), and 91 to 96 (CDR-L3). Combining the definitions of CDR from Kabat and Chothia, the CDRs consist of amino acid residues 26-35 (CDR-H1), 50-65 (CDR-H2), and 95-102 (CDR-H3) in human VH and... Petition 870250096939, dated 10 / 23 / 2025, page 26 / 154 12 / 129 in amino acid residues 24-34 (CDR-L1), 50-56 (CDR-L2), and 89-97 (CDR-L3) in human VL. According to IMGT, CDR amino acid residues in VH are numbered approximately 26 to 35 (CDR-H1), 51 to 57 (CDR-H2), and 93 to 102 (CDR-H3), and CDR amino acid residues in VL are numbered approximately 27 to 32 (CDR-L1), 50 to 52 (CDR-L2), and 89 to 97 (CDR-L3) (numbering according to “Kabat”). According to IMGT, the CDR regions of an antibody can be determined using the IMGT / DomainGap Align program.

[0027] Constant domain: The term “constant domain” refers to a CH1, CH2, CH3 or CL domain of an immunoglobulin.

[0028] The term “CH1 domain” refers to the constant region of the heavy chain that links the variable domain to the hinge in a constant heavy chain domain. In some embodiments, the term “CH1 domain” refers to the region of an immunoglobulin molecule spanning amino acids 118 to 215 (EU numbering). The term “CH1 domain” encompasses wild-type CH1 domains as well as variants thereof (e.g., unnaturally occurring CH1 domains or modified CH1 domains). For example, the term “CH1 domain” includes wild-type IgG1, IgG2, IgG3, and IgG4 CH1 domains and variants thereof with 1, 2, 3, 4, 5, 1-3, 1-5, 3-5, and / or a maximum of 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions, and / or additions. Exemplary CH1 domains include CH1 domains with mutations that modify the biological activity of an antibody, such as ADCC, CDC, or half-life.

[0029] The term “CH2 domain” refers to the constant region of the heavy chain that links the hinge to the CH3 domain in a constant heavy chain domain. In some embodiments, the term “CH2 domain” refers to the region of an immunoglobulin molecule spanning amino acids 238 to 340 (EU numbering). The term “CH2 domain” encompasses wild-type CH2 domains as well as their variations. Petition 870250096939, dated 10 / 23 / 2025, page 27 / 154 13 / 129 before (e.g., unnaturally occurring CH2 domains or modified CH2 domains). For example, the term “CH2 domain” includes wild-type IgG1, IgG2, IgG3, and IgG4 CH2 domains and variants thereof with 1, 2, 3, 4, 5, 1-3, 1-5, 3-5, and / or a maximum of 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions, and / or additions. Exemplary CH2 domains include CH2 domains with mutations that modify the biological activity of an antibody, such as ADCC, CDC, purification, dimerization, and half-life.

[0030] The term “CH3 domain” refers to the constant region of the heavy chain that is the C-terminus of the CH2 domain in a constant heavy chain domain. In some embodiments, the term “CH3 domain” refers to the region of an immunoglobulin molecule spanning amino acids 341 to 447 (EU numbering). The term “CH3 domain” encompasses wild-type CH3 domains as well as their variants (e.g., unnaturally occurring CH3 domains or modified CH3 domains). For example, the term “CH3 domain” includes wild-type IgG1, IgG2, IgG3, and IgG4 CH3 domains and variants thereof with 1, 2, 3, 4, 5, 1-3, 1-5, 3-5, and / or a maximum of 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions, and / or additions. Exemplary CH3 domains include CH3 domains with mutations that modify the biological activity of an antibody, such as ADCC, CDC, purification, dimerization, and half-life.

[0031] The term “CL domain” refers to the constant region of an immunoglobulin light chain. The term “CL domain” encompasses wild-type CL domains (e.g., constant regions of the kappa or lambda light chain) as well as variants thereof (e.g., unnaturally occurring CL domains or modified CL domains). For example, the term “CL domain” includes wild-type kappa and lambda constant domains and variants thereof with 1, 2, 3, 4, 5, 1-3, 1-5, 3-5 and / or a maximum of 5, 4, 3, 2 or 1 mutations, for example. Petition 870250096939, dated 10 / 23 / 2025, page 28 / 154 14 / 129 plo, substitutions, deletions and / or additions.

[0032] COVID-19: The term “COVID-19” is an abbreviation for “Coronavirus Disease 2019” and refers to the infectious disease caused by SARS-CoV-2 infection. Patients with COVID-19 may experience a wide range of symptoms, from mild to severe, which may include, but are not limited to, fever, chills, cough, shortness of breath, difficulty breathing, fatigue, muscle aches, body aches, headache, loss of smell, loss of taste, sore throat, congestion, runny nose, nausea, and diarrhea.

[0033] EC50: The term “EC50” refers to half the maximum effective concentration of a molecule (such as a multivalent anti-spike protein-binding molecule) that induces a response halfway between baseline and maximal after a specified exposure time. EC50 essentially represents the concentration of a multivalent anti-spike protein-binding molecule at which 50% of its maximum effect is observed. In certain embodiments, the EC50 value is equal to the concentration of a multivalent anti-spike protein-binding molecule that provides semi-maximal neutralization of the virus or pseudovirus in an assay, as described in Section 8.1.2.

[0034] Epitope: An epitope, or antigenic determinant, is a part of an antigen recognized by an antibody or a fragment thereof, for example, an antigen-binding domain. An epitope can be linear or conformational.

[0035] Fab: The term “Fab” refers to a pair of polypeptide chains, wherein the first comprises a variable heavy (VH) domain of an antibody operationally linked (typically N-terminal) to a first constant domain (herein referred to as C1), and the second comprises a variable light (VL) domain of an N-terminal antibody operationally linked (typically N-terminal) to a second constant domain (herein referred to as C1). Petition 870250096939, dated 10 / 23 / 2025, page 29 / 154 15 / 129 second constant domain (referred to in this document as C2) with the ability to pair with the first constant domain. In a native antibody, VH is N-terminal to the first constant domain (CH1) of the heavy chain and VL is N-terminal to the constant domain of the light chain (CL). Disclosure Fabs can be arranged according to the native orientation or include domain substitutions or exchanges that facilitate correct VH and VL pairing. For example, it is possible to replace the CH1 and CL domain pair in a Fab with a CH3 domain pair to facilitate correct pairing of the modified Fab chain in heterodimeric molecules. It is also possible to invert CH1 and CL, so that CH1 is attached to VL and CL is attached to VH, a configuration generally known as Crossmab. The term “Fab” encompasses single-chain Fabs.

[0036] Fc Domain and Fc Region: The term “Fc domain” refers to a portion of the heavy chain that joins to the corresponding portion of another heavy chain. In some embodiments, an Fc domain comprises a CH2 domain followed by a CH3 domain, with or without an N-terminal hinge region for the CH2 domain. The term “Fc region” refers to the region formed by the association of two heavy chain Fc domains. The two Fc domains within the Fc region may be identical or different from each other. In a native antibody, the Fc domains are normally identical, but one or both Fc domains may be modified to allow heterodimerization, for example, through a knob-in-hole interaction.

[0037] Fv: The term “Fv” refers to the minimal antibody fragment derived from an immunoglobulin that contains a complete recognition and target binding site. This region consists of a heavy chain dimer and a variable light chain domain in strong non-covalent association. It is in this configuration that the three CDRs of Petition 870250096939, dated 10 / 23 / 2025, page 30 / 154 16 / 129 Each variable domain interacts to define a target binding site on the surface of the VH-VL dimer. In general, the six CDRs confer antibody target binding specificity. However, in some cases, even a single variable domain (or half of an Fv comprising only three target-specific CDRs) may have the ability to recognize and bind to the target. Reference to a VH-VL dimer in this document is not intended to indicate any specific configuration. When present in a single polypeptide chain (e.g., an scFv), the VH may be N-terminal or C-terminal to the VL.

[0038] Antibody Half: The term “antibody half” refers to a molecule comprising at least the Fc domain and capable of associating with another molecule comprising an Fc domain by means of, for example, a disulfide bridge or molecular interactions (e.g., knob-in-hole interactions between Fc heterodimers). An antibody half may be composed of one polypeptide chain or more than one polypeptide chain (e.g., a heavy chain and a light chain).

[0039] Hinge: The term “hinge,” as used in this document, is intended to include the region of consecutive amino acid residues that connect the C-terminus of CH1 to the N-terminus of the CH2 domain of an immunoglobulin. Several amino acids from the N-terminus of the CH2 domain, which are encoded by the CH2 exon, are also considered part of the “lower hinge.” Without being tied to any theory, the amino acids of the hinge region of IgG1, IgG2, and IgG4 have been characterized as comprising 12–15 consecutive amino acids encoded by a distinct hinge exon and several N-terminal amino acids of the CH2 domain (encoded by the CH2 exon) (Brekke et al., 1995, Immunology Today 16(2):85–90). On the other hand, IgG3 comprises a hinge region composed of four sec Petition 870250096939, dated 10 / 23 / 2025, page 31 / 154 17 / 129 mentos: an upper segment similar to the hinge region of IgG1 and 3 segments that are identical amino acid repeats unique to IgG3.

[0040] Host Cells: The term “host cell,” as used in this document, refers to cells into which a nucleic acid of disclosure has been introduced. The terms “host cell” and “recombinant host cell” are used interchangeably in this document. It is understood that these terms refer to the specific cell in question and to the progeny or potential progeny of that cell. As certain modifications may occur in subsequent generations due to mutations or environmental influences, such progeny may, in fact, not be identical to the parent cell, but is still included within the scope of the term as used in this document. Typical host cells are eukaryotic host cells, such as mammalian host cells. Exemplary eukaryotic host cells include yeast and mammalian cells, for example, vertebrate cells such as mice, rats, monkeys, or human cell lines, for example, HKB11 cells, PER cells.C6 cells, HEK cells, or CHO cells.

[0041] Immunoglobulin: The term “immunoglobulin” (Ig) refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light chains (L) and one pair of heavy chains (H), which may be interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, for example, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)). Each heavy chain typically comprises a variable region of the heavy chain (abbreviated in this document as VH or VH) and a constant region of the heavy chain (CH or CH). The constant region of the heavy chain comprises three domains, CH1, CH2, and CH3. The CH1 and CH2 domains Petition 870250096939, dated 10 / 23 / 2025, page 32 / 154 18 / 129 The CH2 groups are linked by a hinge. The Fc portion comprises at least the CH2 and CH3 domains.

[0042] Typically, the numbering of amino acid residues of immunoglobulins is in accordance with IMGT, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), or by the Kabat EU numbering system (also known as “EU numbering” or “EU index”), for example, as in Kabat et al. Sequences of Proteins of Immunological Interest. 5th edition. U.S. Department of Health and Human Services, NIH publication no. 91-3242 (1991).

[0043] Ligand: The term “ligand,” as used in this document, refers to a connecting peptide between two halves. For example, a ligand can connect a spike protein ABD to an Fc domain.

[0044] Multivalent: The term “multivalent”, as used in this document, refers to an antigen-binding molecule comprising two or more ABDs in one, two or more polypeptide chains.

[0045] Neutralization, Blocking: A “neutralizing” or “blocking” spike protein ABD refers to an ABD whose binding to the spike protein inhibits an activity of the spike protein to any detectable degree, for example, it inhibits the ability of the spike protein to bind to a receptor, such as ACE2, to be cleaved by a protease, such as TMPRSS2, or to mediate viral entry into a host cell or viral replication in a host cell.

[0046] Operationally linked: The term “operationally linked” refers to a functional relationship between two or more peptide or polypeptide domains or nucleic acid segments (e.g., DNA). In the context of a fusion protein or other polypeptide, the term “operationally linked” means that two or more Petition 870250096939, dated 10 / 23 / 2025, page 33 / 154 19 / 129 amino acid segments are linked to produce a functional polypeptide. For example, in the context of a multivalent anti-spike protein-binding molecule, the separate components (e.g., an ABD of the anti-spike protein and an Fc domain) can be operationally linked directly or via peptide linkage sequences. In the context of a nucleic acid encoding a fusion protein, such as a multivalent anti-spike protein-binding molecule, “operationally linked” means that the two nucleic acids are joined in such a way that the amino acid sequences encoded by the two nucleic acids remain within the structure.

[0047] Polypeptide, Peptide and Protein: The terms “polypeptide”, “peptide” and “protein” are used interchangeably in this document to refer to a polymer of amino acid residues.

[0048] Recognize: The term “recognize,” as used in this document, refers to an antibody or antibody fragment (e.g., a spike protein ABD) that encounters and interacts (e.g., binds) with its epitope.

[0049] Single-Chain Fab or scFab: The term “single-chain Fab” or “scFab”, as used in this document, refers to a polypeptide chain comprising the VH, CH1, VL, and CL domains of the antibody, when these domains are present in a single polypeptide chain.

[0050] Single-Chain Fv or scFv: The term “single-chain Fv” or “scFv,” as used in this document, refers to ABDs comprising the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. Preferably, the Fv polypeptide additionally comprises a polypeptide linker between the VH and VL domains that allows the scFv to form the desired structure for antigen binding. For a review of Petition 870250096939, dated 10 / 23 / 2025, page 34 / 154 20 / 129 scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. (1994), Springer-Verlag, New York, pages 269-315. The VH and VL can be arranged in the N- to C-terminal order VH-VL or VL-VH, normally separated by a ligand.

[0051] Individual: The term “individual” includes human and non-human animals. Non-human animals include all vertebrates, for example, mammals and non-mammals such as non-human primates, sheep, dogs, cows, chickens, amphibians, and reptiles. Except where indicated, the terms “patient” and “individual” are used interchangeably in this document.

[0052] Tetravalent: The term “tetravalent,” as used in this document in relation to an antigen-binding molecule, refers to an antigen-binding molecule with four ABDs. In some embodiments, a tetravalent anti-spike protein-binding molecule refers to an anti-spike protein-binding molecule comprising four spike protein ABDs. The four spike protein ABDs may be the same or different. In some embodiments, a tetravalent spike protein-binding molecule has the configuration described in either of Figures 1A-1D.

[0053] Treat, Treatment, Treating: As used in this document, the terms “treat”, “treatment” and “treating” refer to the reduction or improvement of the progression, severity and / or duration of a disease or condition and / or the improvement of one or more symptoms (preferably one or more discernible symptoms) of a disease or condition resulting from the administration of one or more multivalent anti-spike protein-binding molecules.

[0054] In some modalities, the disease or condition is caused by a coronavirus infection, for example, SARS-CoV or SARS-CoV-2, for example, COVID-19. In some modalities, the disease or condition is any other illness associated with the infection. Petition 870250096939, dated 10 / 23 / 2025, p. 35 / 154 21 / 129 infection by SARS-CoV or SARS-CoV-2, or similar infections. With respect to these diseases and conditions, the terms “treat,” “treatment,” and “treating” refer to the reduction or improvement of the progression, severity, and / or duration of the disease or the improvement of one or more symptoms (preferably one or more noticeable symptoms) of a disease resulting from the administration of one or more multivalent anti-spike protein-binding molecules. In specific embodiments, the terms “treat,” “treatment,” and “treating” refer to the improvement of at least one measurable physical parameter of COVID-19, such as blood oxygen saturation levels, not necessarily noticeable to the patient. In other embodiments, the terms “treat,” “treatment,” and “treating” refer to the inhibition of COVID-19 progression, either physically, for example, by stabilizing a noticeable symptom, physiologically, for example, by stabilizing a physical parameter, or both.In other contexts, the terms "treat," "treatment," and "being treated" refer to the reduction or elimination of the infection. 6.2. Multivalent Anti-Spike Protein Binding Molecules

[0055] Multivalent antigen-binding molecules that bind to a coronavirus spike protein are disclosed in this document, generally referred to in this document as “anti-spike protein-binding multivalent molecules”.

[0056] Disclosure anti-spike protein binding molecules typically have a valence greater than two. In some embodiments, anti-spike protein binding molecules include at least four antigen-binding domains (ABDs) that bind to the spike protein. In some embodiments, anti-spike protein binding molecules are tetravalent.

[0057] Anti-spike protein binding molecules can be monospecific or multispecific. Petition 870250096939, dated 10 / 23 / 2025, p. 36 / 154 22 / 129

[0058] In some embodiments, the anti-spike protein binding molecules are monospecific, where all ABDs bind to the same epitope and, optionally, all have the same binding sequences.

[0059] In other embodiments, the anti-spike protein binding molecules are multispecific, in which the ABDs bind to two or more different epitopes. In some embodiments, the anti-spike protein binding molecules are bispecific, with antigen-binding domains that bind to two different epitopes. In some embodiments, the two different epitopes are epitopes of the spike protein, whether they are two different epitopes on the same spike protein, two different epitopes present in two variants of the spike protein, or a combination thereof.

[0060] In some respects, a tetravalent anti-spike protein binding molecule comprises four spike protein ABDs, for example, in the form of a Fab or an scFv, as described in Section 6.4.1 or Section 6.4.2, respectively.

[0061] The ABDs of a multivalent anti-spike disclosure protein-binding molecule are operationally linked by one or more multimerization moieties and may be present in one or more polypeptide chains. Exemplary multimerization moieties are described in Section 6.5.

[0062] In some embodiments, one or more multimerization moieties are a pair of Fc domains that associate to form an Fc dimer. The Fc dimer may be a homodimer, for example, as illustrated in Figure 1A or 1C, or a heterodimer, for example, as illustrated in Figure 1B or 1D. Each polypeptide chain comprising an Fc domain and associated polypeptide chains (e.g., light chain polypeptide chains) is referred to in this document as an “antibody moiety”. Petition 870250096939, dated 10 / 23 / 2025, page 37 / 154 23 / 129

[0063] Thus, the present disclosure provides a multivalent spike protein-binding molecule comprising two antibody halves. In some embodiments, each antibody half comprises at least two ABDs.

[0064] In certain respects, the present disclosure provides a tetravalent multivalent spike protein-binding molecule comprising two antibody half-masks. In some embodiments, each antibody half-mask comprises at least two ABDs.

[0065] In some embodiments, the present disclosure provides a multivalent spike protein binding molecule, sometimes referred to in this document as a Type 1 multivalent spike protein binding molecule or Type 1 ABM, comprising two antibody media: a) a first antibody medium comprising: i) a first ABD, which typically comprises a first VH and a first VL; ii) an optional binder; iii) a second ABD, which typically comprises a second VH and a second VL; iv) an optional linker (for example, a hinge domain); and v) a first Fc domain; and b) a second antibody medium comprising: i) a third ABD, which typically comprises a third VH and a third VL; ii) an optional binder; iii) an ABD room, which typically comprises a VH room and a VL room; iv) an optional linker (for example, a hinge domain); and Petition 870250096939, dated 10 / 23 / 2025, page 38 / 154 24 / 129 v) a second Fc domain.

[0066] In other embodiments, the present disclosure provides a multivalent spike protein-binding molecule, sometimes referred to in this document as Type 2 multivalent spike protein-binding molecule or Type 2 ABM, comprising two antibody media: a) a first antibody medium comprising: i) a first ABD, which typically comprises a first VH and a first VL; ii) an optional linker (e.g., a hinge domain); iii) a first Fc domain; iv) an optional linker; and (v) a second ABD, which typically comprises a second VH and a second VL; and b) a second antibody medium comprising: i) a third ABD, which typically comprises a third VH and a third VL; ii) an optional linker (e.g., a hinge domain); iii) a second Fc domain; iv) an optional linker; and (v) an ABD room, which typically comprises a VH room and a VL room.

[0067] In Type 1 and Type 2 ABMs, the first, second, third, and fourth ABDs may be the same or different. In some modalities, the first, second, third, and fourth ABDs are the same. In other modalities, the first and second ABDs are the same, and the third and fourth ABDs are the same (but different from the first and second ABDs). In other modalities, the first and third ABDs are the same, and the second and fourth ABDs are the same (but different from the first and second ABDs). Petition 870250096939, dated 10 / 23 / 2025, p. 39 / 154 25 / 129 different from the first and third ABDs).

[0068] In some embodiments, two of the ABDs or all four ABDs are scFvs and therefore the VH and VLs of such ABDs are on the same polypeptide chain. Exemplary scFv structures are described in Section 6.4.2.

[0069] In some embodiments, two of the ABDs or all four ABDs are Fabs. Optionally, the Fabs are not single-chain Fabs and therefore the VH and VLs of such ABDs are on separate polypeptide chains. In some embodiments, the VH of an ABD is on the same polypeptide chain as the Fc domain of the antibody medium comprising the ABD, and the VL is on a separate polypeptide chain. In some embodiments, the VL of an ABD is on the same polypeptide chain as the Fc domain of the antibody medium comprising the ABD, and the VH is on a separate polypeptide chain. Fab may be in the native immunoglobulin conformation, and the polypeptide chain comprising VH may also include the CH1 domain of Fab, or it may be domain-switched, and therefore the polypeptide chain comprising VH may also include the CL domain of Fab. Exemplary Fab structures (including domain-switched structures) are described in Section 6.4.1.

[0070] Exemplary ligands for the disclosure multivalent spike protein binding molecules, including the ligands for disclosure Type 1 and Type 2 multivalent spike protein binding molecules, are described in Section 6.6.

[0071] In some embodiments, the multivalent spike protein-binding molecule is monospecific, in which all ABDs bind to the same epitope. The ABDs in a monospecific multivalent spike protein-binding molecule may include the same CDR sequences or the same VH and VL sequences. In some embodiments, the ABDs of a monospecific multivalent molecule Petition 870250096939, dated 10 / 23 / 2025, p. 40 / 154 26 / 129 of the spike protein binding sites are configured as shown in Figure 1A or 1C. Figure 1A shows a Type 1 monospecific ABM, and Figure 1C shows a Type 2 monospecific ABM. In Figure 1A, the Fab comprising VH3-VL3 represents the first ABD of a Type 1 ABM, the Fab comprising VH1-VL1 represents the second ABD of a Type 1 ABM, the Fab comprising VH4-VL4 represents the third ABD of a Type 1 ABM, and the Fab comprising VH2-VL2 represents the fourth ABD of a Type 1 ABM. In Figure 1B, the Fab comprising VH1-VL1 represents the first ABD of a Type 2 ABM, the Fab comprising VH3-VL3 represents the second ABD of a Type 2 ABM, the Fab comprising VH2-VL2 represents the third ABD of a Type 2 ABM, and the Fab comprising VH4-VL4 represents the fourth ABD of a Type 2 ABM. Monospecific Type 1 and Type 2 ABMs may include two identical half antibodies, and therefore the association of the two half antibodies forms an Fc homodimer.Appropriate Fc domains are described in Section 6.5.1. Fc domains may include mutations that reduce effector function compared to wild-type Fc domains, for example, as described in Section 6.5.1.1.

[0072] In some embodiments, the multivalent spike protein-binding molecule is multispecific, in which at least two ABDs bind to different epitopes. At least two ABDs in a multispecific multivalent spike protein-binding molecule comprise different CDR sequences. In some embodiments, the multispecific multivalent spike protein-binding molecule is tetravalent, with a first pair of ABDs sharing the same CDR sequences or the same VH and VL sequences and a second pair of ABDs sharing the CDR sequences or the same VH and VL sequences (which differ from the CDR sequences of the first pair of ABDs). In some embodiments, the ABDs of a multivalent molecule Petition 870250096939, dated 10 / 23 / 2025, p. 41 / 154 27 / 129 multi-valent spike protein-binding receptors are configured as shown in Figure 1B or 1D. Figure 1B shows a Type 1 multispecific ABM, and Figure 1D shows a Type 2 multispecific ABM. In Figure 1B, the Fab comprising VH3-VL3 represents the first ABD of a Type 1 ABM, the Fab comprising VH1-VL1 represents the second ABD of a Type 1 ABM, the Fab comprising VH4-VL4 represents the third ABD of a Type 1 ABM, and the Fab comprising VH2-VL2 represents the fourth ABD of a Type 1 ABM. In Figure 1D, the Fab comprising VH1-VL1 represents the first ABD of a Type 2 ABM, the Fab comprising VH3-VL3 represents the second ABD of a Type 2 ABM, the Fab comprising VH2-VL2 represents the third ABD of a Type 2 ABM, and the Fab comprising VH4-VL4 represents the fourth ABD of a Type 2 ABM.Type 1 and Type 2 multispecific ABMs may include two identical half antibodies or two different antibodies, and therefore the association of the two half antibodies may form an Fc homodimer or an Fc heterodimer. Suitable Fc domains are described in Section 6.5.1, and appropriate approaches to heterodimerization are described in Section 6.5.1.2. Fc domains may include mutations that reduce effector function compared to wild-type Fc domains, for example, as described in Section 6.5.1.1.

[0073] Exemplary structures of spike protein ABD (e.g., CDR or VH / VL sequences) are disclosed in Section 6.3. 6.3. Antigen-Binding Domain of the Spike Protein

[0074] This disclosure relates to multivalent anti-spike protein binding molecules comprising a plurality of antigen-binding domains (ABDs) of the spike protein.

[0075] In some embodiments, a multivalent anti-spike protein-binding molecule comprises two or more Petition 870250096939, dated 10 / 23 / 2025, p. 42 / 154 28 / 129 Spike protein ABDs.

[0076] In some embodiments, the multivalent anti-spike protein-binding molecules of the disclosure are monospecific, that is, they bind to the same epitope on the spike protein. In some of these embodiments, the ABDs of the spike protein are identical.

[0077] In other embodiments, the multivalent anti-spike protein-binding molecules of the disclosure are multispecific, that is, they bind to different epitopes. In some embodiments, the multispecific anti-spike protein-binding molecules bind to different epitopes on the same spike protein. In other embodiments, the multispecific anti-spike protein-binding molecules bind to different epitopes on different variants of the spike protein. The different epitopes may correspond to sequence variants of the same region in a spike protein or to completely different regions.

[0078] In other embodiments, a plurality or all of the ABDs in the multivalent anti-spike protein-binding molecules of the disclosure bind to the receptor-binding domain (RBD) of a spike protein and / or have the ability to block or neutralize the spike protein, for example, inhibiting the ability of the spike protein to bind to a receptor, such as ACE2, to be cleaved by a protease, such as TMPRSS2, or to mediate viral entry into a host cell or viral replication in a host cell.

[0079] Suitable formats for spike protein ABDs are described in Section 6.4. The spike protein ABD may be, for example, an antibody or an antigen-binding portion of an antibody, for example, a Fab, as described in Section 6.4.1, or an scFv, as described in Section 6.4.2.

[0080] In some modalities, a spike protein ABD competes with an exemplary antibody or an antibody with the sequence Petition 870250096939, dated 10 / 23 / 2025, p. 43 / 154 29 / 129 defined in Table 1 below for binding to spike protein and / or comprises binding moieties of an exemplary antibody or an antibody with an antibody sequence defined in Table 1. In some aspects, the spike protein ABD competes with an antibody established in Table 1 to bind to a spike protein. In other aspects, the spike protein ABD comprises CDRs with CDR sequences of an antibody established in Table 1. In some embodiments, the spike protein ABD comprises all 6 antibody CDR sequences established in Table 1. In other embodiments, the spike protein ABD comprises at least the heavy chain CDR sequences (CDR-H1, CDR-H2, CDR-H3) and the light chain CDR sequences of a universal light chain. In other aspects, a spike protein ABD comprises a VH with the amino acid sequence of the VH of an antibody established in Table 1.In some embodiments, the spike protein ABD further comprises a VL with the amino acid sequence of the antibody VL established in Table 1. In other embodiments, the spike protein ABD also includes a universal light chain VL sequence. TABLE 1 Spike Protein Antibodies and Antigen-Binding Domains Target Samples / Epitope Antibody Name and / or Binding Sequences ACE2 Binding Blockage / Non-blockage SARS-CoV-2 P5-22 Spike Protein VH: SEQ ID NO: 2 of publication PCT no: WO 2022 / 052968 A1 VL: SEQ ID NO: 4 of publication PCT no: WO 2022 / 052968 A1 Blockage Petition 870250096939, dated 10 / 23 / 2025, p. 44 / 154 30 / 129 TABLE 1 Spike Protein Antibodies and Antigen-Binding Domains Target Samples / Epitope Antibody Name and / or Binding Sequences ACE2 Binding Blockage / Non-blockage SARS-CoV-2 Spike Protein P14-44 VH: SEQ ID NO: 6 from publication PCT No: WO 2022 / 052968 A1 VL: SEQ ID NO: 8 from publication PCT No: WO 2022 / 052968 A1 Blockage SARS-CoV-2 Spike Protein P15-16 VH: SEQ ID NO: 10 from publication PCT No: WO 2022 / 052968 A1 VL: SEQ ID NO: 12 from publication PCT No: WO 2022 / 052968 A1 Blockage SARS-CoV-2 Spike Protein P10-20 VH: SEQ ID NO: 14 of publication PCT no: WO 2022 / 052968 A1 VL: SEQ ID NO: 16 of publication PCT no: WO 2022 / 052968 A1 Blocking of SARS-CoV-2 Spike Protein P14-37 VH: SEQ ID NO: 18 of publication PCT no: WO 2022 / 052968 A1 VL: SEQ ID NO: 20 of publication PCT no: WO 2022 / 052968 A1 Blocking of SARS-CoV-2 Spike Protein P23-29 VH: SEQ ID NO: 22 of publication PCT no: WO 2022 / 052968 A1 VL: SEQ ID NO: 24 of publication PCT no: WO 2022 / 052968 A1 Blocking Petition 870250096939, dated 10 / 23 / 2025, p. 45 / 154 31 / 129 TABLE 1 Spike Protein Antibodies and Antigen-Binding Domains Target Samples / Epitope Antibody Name and / or Binding Sequences ACE2 Binding Blockage / Non-blockage SARS-CoV-2 Spike Protein P3-11 VH: SEQ ID NO: 26 of publication PCT no: WO 2022 / 052968 A1 VL: SEQ ID NO: 28 of publication PCT no: WO 2022 / 052968 A1 Blockage of aa 319-532 of the RBD domain of the S protein P16-A3 VH: SEQ ID NO: 17 of publication PCT no: WO 2021 / 196268 A1 VL: SEQ ID NO: 18 of publication PCT no: WO 2021 / 196268 A1 Blockage of aa 319-532 of the S protein RBD domain P17-A11 VH: SEQ ID NO: 19 of publication PCT no: WO 2021 / 196268 A1 VL: SEQ ID NO: 20 of publication PCT no: WO 2021 / 196268 A1 Blocking of aa 319-532 of the S protein RBD domain R15-F7 VH: SEQ ID NO: 1 of publication PCT no: WO 2022 / 104918 A1 VL: SEQ ID NO: 2 of publication PCT no: WO 2022 / 104918 A1 Blocking of the S protein RBD domain DH1041 VH: SEQ ID NO: 1100 of publication PCT no: WO 2022 / 060906 A1 VL: SEQ ID NO: 1102 of publication PCT No.: WO2022 / 060906 A1 Blockage Petition 870250096939, dated 10 / 23 / 2025, page 46 / 154 32 / 129 TABLE 1 Spike Protein Antibodies and Antigen-Binding Domains Target Samples / Epitope Antibody Name and / or Binding Sequences ACE2 Binding Blockage / Non-blockage aa 481-491 of the S protein RBD domain DH1042 VH: SEQ ID NO: 1104 from publication PCT no: WO 2022 / 060906 A1 VL: SEQ ID NO: 1106 from publication PCT no: WO 2022 / 060906 A1 Blockage of the S protein RBD domain DH1043 VH: SEQ ID NO: 1108 from publication PCT no: WO 2022 / 060906 A1 VL: SEQ ID NO: 1110 from publication PCT no: WO 2022 / 060906 A1 Blockage of the domain RBD of S protein DH1044 VH: SEQ ID NO: 1112 from publication PCT no: WO 2022 / 060906 A1 VL: SEQ ID NO: 1114 from publication PCT no: WO 2022 / 060906 A1 No blocking RBD domain of S protein DH1221 VH: SEQ ID NO: 1214 from publication PCT no: WO 2022 / 060906 A1 VL: SEQ ID NO: 1226 from publication PCT no: WO 2022 / 060906 A1 Blocking RBD domain of S protein DH1222 VH: SEQ ID NO: 1216 from publication PCT no: WO 2022 / 060906 A1 VL: SEQ ID NO: 1228 from publication PCT no: WO 2022 / 060906A1 Block Petition 870250096939, dated 10 / 23 / 2025, page 47 / 154 33 / 129 TABLE 1 Spike Protein Antibodies and Antigen-Binding Domains Target Samples / Epitope Antibody Name and / or Binding Sequences ACE2 Binding Blockage / Non-blockage S protein RBD domain DH1223 VH: SEQ ID NO: 1218 from publication PCT no: WO 2022 / 060906 A1 VL: SEQ ID NO: 1230 from publication PCT no: WO 2022 / 060906 A1 Blockage S protein RBD domain DH1224 VH: SEQ ID NO: 1220 from publication PCT no: WO 2022 / 060906 A1 VL: SEQ ID NO: 1232 from publication PCT no: WO 2022 / 060906 A1 Blockage S protein RBD domain DH1225 VH: SEQ ID NO: 1222 from publication PCT no: WO 2022 / 060906 A1 VL: SEQ ID NO: 1234 from publication PCT no: WO 2022 / 060906 A1 RBD Domain Blockade of S protein DH1226 VH: SEQ ID NO: 1224 from publication PCT no: WO 2022 / 060906 A1 VL: SEQ ID NO: 1236 from publication PCT no: WO 2022 / 060906 A1 RBD Domain Blockade of S protein SEQ ID NO: 5 from PCT WO 2022 / 032139 A1 mAb S1D2 VH: SEQ ID NO: 6 from publication PCT no: WO 2022 / 032139 A1 VL: SEQ ID NO: 7 from publication PCT no:WO 2022 / 032139 A1 Blockade Petition 870250096939, dated 10 / 23 / 2025, page 48 / 154 34 / 129 TABLE 1 Spike Protein Antibodies and Antigen-Binding Domains Target Samples / Epitope Antibody Name and / or Binding Sequences ACE2 Binding Blockage / Non-blockage S protein RBD domain SEQ ID NO: 5 from PCT WO 2022 / 032139 A1 mAb S1D7270 VH: SEQ ID NO: 28 from publication PCT no: WO 2022 / 032139 A1 VL: SEQ ID NO: 29 from publication PCT no: WO 2022 / 032139 A1 S protein RBD domain aa 331-524 Blockage SEQ ID NO: 61 413-2 VH: SEQ ID NO: 15 from publication PCT no: WO 2021 / 248279 A1 VL: SEQ ID NO: 43 from publication PCT No.: WO 2021 / 248279 A1 aa 331-524 of the RBD domain of protein S SEQ ID NO: 61 413-3 VH: SEQ ID NO: 16 from publication PCT No.: WO 2021 / 248279 A1 VL: SEQ ID NO: 44 from publication PCT No.: WO 2021 / 248279 A1 aa 331-524 of the RBD domain of protein S SEQ ID NO: 61 505-1 VH: SEQ ID NO: 17 from publication PCT No.: WO 2021 / 248279 A1 VL: SEQ ID NO: 45 from publication PCT No.: WO 2021 / 248279 A1 aa 331-524 of the RBD domain of protein S SEQ ID NO: 61 505-3 VH: SEQ ID NO: 18 daPCT publication no.: WO 2021 / 248279 A1 VL: SEQ ID NO: 46 of PCT publication no.: WO 2021 / 248279 A1 Petition 870250096939, dated 10 / 23 / 2025, p. 49 / 154 35 / 129 TABLE 1 Spike Protein Antibodies and Antigen-Binding Domains Target Samples / Epitope Antibody Name and / or Binding Sequences ACE2 Binding Blockage / Non-blockage S protein RBD domain aa 331-524 SEQ ID NO: 61 505-5 VH: SEQ ID NO: 19 PCT publication no: WO 2021 / 248279 A1 VL: SEQ ID NO: 47 PCT publication no: WO 2021 / 248279 A1 S protein RBD domain aa 331-524 SEQ ID NO: 61 515-5 VH: SEQ ID NO: 20 PCT publication no: WO 2021 / 248279 A1 VL: SEQ ID NO: 48 PCT publication no: WO 2021 / 248279 A1 aa 331-524 of the S protein RBD domain SEQ ID NO: 61 553-13 VH: SEQ ID NO: 21 of publication PCT no: WO 2021 / 248279 A1 VL: SEQ ID NO: 49 of publication PCT no: WO 2021 / 248279 A1 aa 331-524 of the S protein RBD domain SEQ ID NO: 61 553-15 VH: SEQ ID NO: 22 of publication PCT no: WO 2021 / 248279 A1 VL: SEQ ID NO: 50 of publication PCT no: WO 2021 / 248279 A1 aa 331-524 of the S protein RBD domain SEQ ID NO: 61 553-17 VH: SEQ ID NO: 23 of publication PCT n°: WO2021 / 248279 A1 VL: SEQ ID NO: 51 of publication PCT No: WO 2021 / 248279 A1 Petition 870250096939, dated 10 / 23 / 2025, p. 50 / 154 36 / 129 TABLE 1 Spike Protein Antibodies and Antigen-Binding Domains Target Samples / Epitope Antibody Name and / or Binding Sequences ACE2 Binding Blockage / Non-blockage S protein RBD domain aa 331-524 SEQ ID NO: 61 553-18 VH: SEQ ID NO: 24 PCT publication no: WO 2021 / 248279 A1 VL: SEQ ID NO: 52 PCT publication no: WO 2021 / 248279 A1 S protein RBD domain aa 331-524 SEQ ID NO: 61 553-20 VH: SEQ ID NO: 25 PCT publication no: WO 2021 / 248279 A1 VL: SEQ ID NO: 53 PCT publication no: WO 2021 / 248279 A1 aa 331-524 of the RBD domain of protein S SEQ ID NO: 61 553-27 VH: SEQ ID NO: 26 of publication PCT no: WO 2021 / 248279 A1 VL: SEQ ID NO: 54 of publication PCT no: WO 2021 / 248279 A1 aa 331-524 of the RBD domain of protein S SEQ ID NO: 61 553-60 VH: SEQ ID NO: 27 of publication PCT no: WO 2021 / 248279 A1 VL: SEQ ID NO: 55 of publication PCT no: WO 2021 / 248279 A1 aa 331-524 of the RBD domain of protein S SEQ ID NO: 61 553-63 VH: SEQ ID NO: 28 of publication PCT No: WO2021 / 248279 A1 VL: SEQ ID NO: 56 of publication PCT No: WO 2021 / 248279 A1 Petition 870250096939, dated 10 / 23 / 2025, p. 51 / 154 37 / 129 TABLE 1 Spike Protein Antibodies and Antigen-Binding Domains Target Samples / Epitope Antibody Name and / or Binding Sequences ACE2 Binding Blockage / Non-blockage SARS-CoV-2 N3-1 Spike Protein RBD VH: SEQ ID NO: 1 from publication PCT No: WO 2022 / 192661 A1 VL: SEQ ID NO: 2 from publication PCT No: WO 2022 / 192661 A1 SARS-CoV-2 N3-3 Spike Protein RBD VH: SEQ ID NO: 1 from publication PCT No: WO 2022 / 192661 A1 VL: SEQ ID NO: 15 from publication PCT No: WO 2022 / 192661 A1 SARS-CoV-2 1D4 Spike Protein RBD VH: SEQ Publication ID No: 18 PCT No: WO 2022 / 192661 A1 VL: SEQ Publication ID No: 19 PCT No: WO 2022 / 192661 A1 SARS-CoV-2 N3-7 Spike Protein RBD VH: SEQ Publication ID No: 1 PCT No: WO 2022 / 192661 A1 VL: SEQ Publication ID No: 10 PCT No: WO 2022 / 192661 A1 SARS-CoV-2 N3-63A Spike Protein RBD VH: SEQ Publication ID No: 1 PCT No: WO 2022 / 192661 A1 VL: SEQ Publication ID No: 21 PCT No: WO 2022 / 192661 A1 Petition 870250096939, dated 10 / 23 / 2025, p. 52 / 154 38 / 129 TABLE 1 Spike Protein Antibodies and Antigen-Binding Domains Target Samples / Epitope Antibody Name and / or Binding Sequences ACE2 Binding Blocking / Non-blocking SARS-CoV-2 N3-63B Spike Protein RBD VH: SEQ ID NO: 1 from publication PCT No: WO 2022 / 192661 A1 VL: SEQ ID NO: 27 from publication PCT No: WO 2022 / 192661 A1 SARS-CoV-2 N3-63C Spike Protein RBD VH: SEQ ID NO: 1 from publication PCT No: WO 2022 / 192661 A1 VL: SEQ ID NO: 37 from publication PCT No: WO 2022 / 192661 A1 SARS-CoV-2 8B5 Spike Protein RBD VH: SEQ ID NO: 22 from PCT publication no: WO 2022 / 192661 A1 VL: SEQ ID NO: 23 from PCT publication no: WO 2022 / 192661 A1 SARS-CoV-2 Spike Protein RBD 4A5 VH: SEQ ID NO: 24 from PCT publication no: WO 2022 / 192661 A1 VL: SEQ ID NO: 23 from PCT publication no: WO 2022 / 192661 A1 SARS-CoV-2 Spike Protein RBD 1D1 VH: SEQ ID NO: 18 from PCT publication no: WO 2022 / 192661 A1 VL: SEQ ID NO: 2 from PCT publication no: WO 2022 / 192661 A1 Petition 870250096939, dated 10 / 23 / 2025, p. 53 / 154 39 / 129 TABLE 1 Spike Protein Antibodies and Antigen-Binding Domains Target Samples / Epitope Antibody Name and / or Binding Sequences ACE2 Binding Blockage / Non-blockage SARS-CoV-2 Spike Protein RBD 1D9 VH: SEQ ID NO: 18 from publication PCT no: WO 2022 / 192661 A1 VL: SEQ ID NO: 26 from publication PCT no: WO 2022 / 192661 A1 SARS-CoV-2 Spike Protein RBD 4A7 VH: SEQ ID NO: 24 from publication PCT no: WO 2022 / 192661 A1 VL: SEQ ID NO: 10 from publication PCT no: WO 2022 / 192661 A1 SARS-CoV-2 Spike Protein RBD 1D5 VH: SEQ ID NO: 18 of publication PCT No: WO 2022 / 192661 A1 VL: SEQ ID NO: 23 of publication PCT No: WO 2022 / 192661 A1

[0081] In some embodiments, the spike protein ABDs comprise an amino acid sequence or are encoded by a nucleotide sequence defined in Table 2 below. In specific aspects, the spike protein ABD comprises heavy and light chain CDRs of an antibody established in Table 2 below. In other embodiments, the spike protein ABD comprises at least the heavy chain CDR sequences and the light chain CDR sequences of a universal light chain. In other aspects, the spike protein ABD comprises a VH with the amino acid sequence of the VH of an antibody established in Table 2 and a VL with the amino acid sequence of the VL of the same antibody, as established in Table 2. In other aspects, the spike protein ABD with Petition 870250096939, dated 10 / 23 / 2025, page 54 / 154 40 / 129 binds a VH with the amino acid sequence of the VH of an antibody established in Table 2 and a universal light chain VL sequence. Tabela 2 Antibody design Part of the component Sequência mAb10933 Aminoácidos VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYITYSGSTIYYADSVKGRFTISRDNAKSSLYLQMNSLRAEDTAVYYCARDRGTTMVPFFDYWGQGTLVTVSS (SEQ ID) NO:1) CDR-H1 GFTFSDYY (SEQ ID NO:2) CDR-H2 ITYSGSTI (SEQ ID NO:3) CDR-H3 ARDRGTTMVPFDY (SEQ ID NO:4) VL DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNWYQQKPGKAPKLLIYAASNLETGVPSRFSGSGTDFTFTISGLQPEDIATYYCQQYDNLPLTFGGGTKVEIK (SEQ ID NO:5) CDR-L1 QDITNY (SEQ ID NO:6) CDR-L2 AAS CDR-L3 QQYDNLPLT (SEQ ID NO:7) HC QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYITYSGSTIY- YADSVKGRFTISRDNAKSSLYLQMNSLRAEDTAVYYCARDRGTTMVPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS- TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN- Petition 870250096939, dated 10 / 23 / 2025, page 55 / 154 41 / 129 Table 2 Designation of Antibody Part of Component Sequence VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:8) LC DIQMTQSPSSLSASVGDRVTITCQASQDITNYLNWYQQKPGKAPKLLIAASNLETGVPSRFSGSGSGTDFTFTISGLQPEDIATYYCQQYDNLPLTFGGG TKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLSKADYEKHKVYACEVTHQGLSS PVTKSFNRGEC (SEQ ID NO:9) VH CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGGGGGGGTI ICATACATTACTTATAGTGGTAGTACCATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCCAGGGACAACG- CCAAGAGCTCACTGTATCTGCAAATGAACAGCCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGATCGCGGTACAACTATGGTCCCdUGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCCA (SEQ ID NO:10) CDR-H1 GGATTCACCTTCAGTCAGTCAGTCAGTCAGTCACTACQ NO:12:1 ATTACTTATAGTGGTAGTACCATA (SEQ ID NO:12) CDR-H3 GCGAGAGATCGCGGTACAACTATGGTCCCdHGACTAC (SEQ ID NO:13) VL GACATCCAGATGACCCAG-TCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTACCAACTAmAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTACG- CTGCATCCAAmGGAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGA- Petition 870250096939, dated 10 / 23 / 2025, page 56 / 154 42 / 129 Table 2 Designation of Antibody Part of Component Sequence TCTGGGACAGAIIIIACIIICACCATCAGCGGCCTGCAGCCTGAAGATATTGCAACATATTACTGTCAACAGTATGATAATCTCCCTCTCAACIII CGGCGGAGGGACCAAGGTGGAGATCCAAA (SEQ ID:14 CGAGGAGGACCATCAAGGTGGAGATCAA) (SEQ ID NO:15) CDR-L2 GCTGCATCC CDR-L3 CAACAGTATGATAATCTCCCTCTCACT (SEQ ID NO:16) HC CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCCTGGAGGGTCCCTGACTCTTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCT GGAGTGGGIIICATACATTACTTATAGTGGTAGTACCATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCCAGGGACAACGCCAAGCTCACTGTATCTGAACAGCCCTGAGAGCCGAGGACACGGCCGTTACTTACTGTGCG AGAGATCGCGGTACAACTATGGTCCCCIIIGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGCCCTGGGCTGCCTGGTCAAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACCCCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACCCTCAGCAGCGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACCTGCAACGTGAATCACAAGCCCAAGCCAGCAGCAAGCAAGCAAGTT Petition 870250096939, dated 10 / 23 / 2025, p. 57 / 154 43 / 129 Tabela 2 Designação de Anticorpo Parte de Componente Sequência GAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGA CACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGT GGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCC AAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGG TAAATGA (SEQ ID NO:17) LC GACATCCAGATGACCCAG- TCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTACCAACTAIIIAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTACG- Petição 870250096939, de 23 / 10 / 2025, pág. 58 / 154 44 / 129 Tabela 2 Design of Anticorpo Part of Componente Sequence CTGCATCCAAIIIGGAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAGAIIIIACIIICACCATCAGCGGCCTGCAGCCTGAAGATATTGCAACATATTACTGTCAACAGTATGATAATCTTCCCTCTCACIII CGGCGGAGGGA- CCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAAGAGGCCAAAGTACAGTG GAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTG- CGAAGTCACCCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO:19) mAb10934 VH CDR-H2 IKSKTDGGTT ID NO: 22) CDR-H3 TTARWDWYFDL (SEQ ID NO: 23) (SEQ ID NO:25) CDR-L2 DAS CDR-L3QQHDDLPPT (SEQ ID NO:26) HC EVQLVESGGGLVKPGGSLRLSCAASGITFSNAWMSWVR- Petition 870250096939, dated 10 / 23 / 2025, p. 59 / 154 45 / 129 Table 2 Antibody Designation Component Part Sequence QAPGKGLEWVGRIKSKTDGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTARWDWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:27) LC DIQMTQSPSSLSASVGDRVTITCQASQDIWNYINWYQQKPGKAPKLLIYDASNLKTGVPSRFSGSGTDFTISSLQPEDIATYYCQHDDLPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSS PVTKSNRGEC (SEQ ID NO:28) VH GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGGGGGTCCCTTAGACTCTCCTGTGCAGCCTCTGGAATCACI- Petition 870250096939, dated 10 / 23 / 2025, page 60 / 154 46 / 129 Table 2 Antibody Part Component Designation Sequence CGATCTCTGGGGCCGTGGCACCCTGGTCACTGTCTCCTCA (SEQ ID NO:29) CDR-H1 GGAATCACIIICAGTAACGCCTGG (SEQ ID NO:30) CDR-H2 ATTAAAAGCAACTGACTGACTGAGGAGGA NO:31) CDR-H3 ACCACAGCGAGGTGGGACTGGTACTTCGATCTC (SEQ ID NO:32) VL GACATCCAGATGACCCAG- TCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACAmGGAATTATAAATTGAGGAGGAGTCAGTC GAAGGCCCCTAAGCTCCTGATCTACGATGCATCCAAmGAAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAGAIIACIIICACCATCAGCCTGCAGCCTGAAGATA- TTGCAACATATTACTGTCAACAGCATGATGATCTCCCTGACCTACCAGGAGGAGAGGAGGAQGAGATGATCTCCCTGAAGATA- NO:33) CDR-L1 CAGGACAmGGAATTAT (SEQ ID NO:34) CDR-L2 GATGCATCC CDR-L3 CAACAGCATGATGATCTCCCTCCGACC (SEQ ID NO:35) HC GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCTGGGGGGTCCCTTAGACTCTCCTGTGCAGCCTCTGGAATCAdUCAGTAACGCCTGGATGAGTTGGGTCCGCCAGGCTCCAGGGAAGGGGGGCTGGAGTGGGTTGGCCGTATTAAAAGCAAAACTGATGGTGGGACAACAGACTACGCCGCACCCGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCAAAAAACACGCTGTATCTACAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTACCACAGCGAGGTGGGACTGG- Petition 870250096939, dated 10 / 23 / 2025, page 61 / 154 47 / 129 Tabela 2 Designação de Anticorpo Parte de Componente Sequência TACTTCGATCTCTGGGGCCGTGGCACCCTGGTCACTGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGA CACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGT GGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCC AAAGCCAAAGGGCAGCCCCGAGAACCACAGGTG- TACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC- Petição 870250096939, de 23 / 10 / 2025, pág. 62 / 154 48 / 129 Tabela 2 Designação de Anticorpo Parte de Componente Sequência TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGG TAAATGA (SEQ ID NO:36) LC GACATCCAGATGACCCAG- TCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACAIIIGGAATTATATAAATTGGTATCAGCAGAAACCAGGGAAGGCCCCTAAGCTCCTGATCTACGATGCATCCAAmGAAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAGAIIIIACIIICACCATCAGCAGCCTGCAGCCTGAAGATA- TTGCAACATATTACTGTCAACAGCATGATGATCTCCCTCCGACCTTCGG- CCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCA- GGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT- TAG (SEQ ID NO:37) mAb10987 VHQVQLVESGGGVVQPGRSLRLSCAASGFTFSNYAMYWVRQAPGKGLEWVA- Petition 870250096939, dated 10 / 23 / 2025, page 63 / 154 49 / 129 Table 2 Antibody Design Component Sequence VISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRTEDTAVYYCASGSDYGDYLLVYWGQGTLVTVSS (SEQ ID NO:38) CDR-H1 GFTFSNYA (SEQ ID NO:39) CDR-H2 ISYDGSNK (SEQ ID NO:40) CDR-H3 ASGSDYGDYLLVY (SEQ ID NO:41) VL QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVSNRFSGSKSGNTASLTISGLQSEDEADYYCNSLTSISTWVFGGGTKLTVL (SEQ ID NO:42) CDR-L1 SSDVGGYNY (SEQ ID NO:43) CDR-L2 DVS CDR-L3 NSLTSISTWV (SEQ ID NO:44) HC QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYAMYWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTIS- RDNSKNTLYLQMNSLRTEDTAVYYCASGSDYGDYLLVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD- KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN- VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:45) LCQSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSKRPSGVSNRFSGSKSGNTASLTISGLQSEDEADYYCNSLTSISTWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVE IIIPSKQSNNKYAAS- Petition 870250096939, dated 10 / 23 / 2025, page 64 / 154 50 / 129 Table 2 Designação de Anticorpo Parte de Componente Sequência SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:46) VH CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAACTATGCTATGTACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAACTGAGGACACGGCTGTGTATTACTGTGCGAGTGGCTCCGACTACGGTGACTACTTATTGGI IIACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO:47) CDR-H1 GGATTCACCTTCAGTAACTATGCT (SEQ ID NO:48) CDR-H2 ATATCATATGATGGAAGTAATAAA (SEQ ID NO:409) CDR-H3 GCGAGTGGCTCCGACTACGGTGACTACTTATTGGmAC (SEQ ID NO:50) VL CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCATGAmATGATGTCAGTAAGCGGCCCTCAGGGGmCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGTCTGAGGACGAGGCTGATTATTACTGCAACTdHGACAAGCATCAGCACTTGGGTGTTCGGCGGAGGGACCAAGCTGACCG- TCCTA (SEQ ID NO:51) CDR-L1AGCAGTGACGTTGGTGGTTATAACTAT (SEQ ID NO:52) Petition 870250096939, dated 10 / 23 / 2025, p. 65 / 154 51 / 129 Table 2 Antibody Designation Component Part Sequence CDR-L2 GATGTCAGT CDR-L3 AACTCIIIGACAAGCATCAGCACTTGGGTG (SEQ ID NO:53) HC CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCCTGGGAGGTCCCTGAGACTCTTCCTGTGCAGCCTCTGGATTCACCTTCAGTAACTATGTACTGGGTCCGCCAGGCTCCAGG CAAGGGGCTGGAGTGGGTGGCAGTTATATCATGATGGATAGGAGGGACTGACTGGCAGCC TCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAACTGAGGACACGGCTGTGTATTACTGTGCGAGTGGCTCCGACTACGGTGACTTATTGGmACTGGGGCCAGGGAA CCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGGCACCCAGACCTA CATCTGCAACGTGAATCACAAGCCCAAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTTGTGAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTCCCCCAAAACCCAAAGGA CACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGT Petition 870250096939, of 23 / 10 / 2025, p. 66 / 154 52 / 129 Tabela 2 Designação de Anticorpo Parte de Componente Sequência GGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCC AAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGG TAAATGA (SEQ ID NO:54) LC CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCATGAIIIATGATGTCAGTAAGCGGCCCTCAGGGGmCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGTCTGAGGA- CGAGGCTGATTATTACTGCAACTCmGACAAGCATCAGCACTTGGGTGTTCGGCGGAGGGACCAAGCTGACCG- Petition 870250096939, dated 10 / 23 / 2025, p. 67 / 154 53 / 129 Tabela 2 Design of Anticorpo Part of Componente Sequência TCCTAGGCCAGCCCAAGGCCGCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTGGAAGGCCGACTCCTCCCCCGTGAAGGCCGGCGT GGAGACCACCACCCCCTCCAAGCAGTCCAACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCGAGCAGTGGAAGTCCCACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCGTGGAGAAAGACCGTGGCCCCCACCGAGTGCTCCTGA (SEQ ID NO:55) mAb10989 VH QVQLVQSGAEVKKPGASVKVSCKASGYIFTGYYMHWVRQAPGQGLEWMGWINPNSGGANYAQKFQGRVTLTRDTSITTVYMELSRLRFDDTAVYYCARGSRYDWNQNNWFDPWGQGTLVTVSS (SEQ ID NO:56) CDR-H1 GYIFTGYY (SEQ ID NO:57) CDR-H2 INPNSGGA (SEQ ID NO:58) CDR-H3 ARGSRYDWNQNNWFDP (SEQ ID NO:59) VL QSALTQPASVSGSPGQSITISCTGTSSDVGTYNYVSWYQQHPGKAPKLMIFDVSNRPSGVSDRFSGSKSGNTASLTISGLQAEDEADYYCSSFTTSSTVVFGGGT- KLTVL (SEQ ID NO:60) CDR-L1 SSDVGTYNY (SEQ ID NO:61) CDR-L2 DVS CDR-L3 SSFTTSSTVV (SEQ ID NO:62) HCQVQLVQSGAEVKKPGASVKVSCKASGYIFTGYYMHWVRQAPGQGLEWMGWINPNSGGANYAQKFQGRVTLTRDTSITTVYMELSRLRFDDTAVYYCARGSRYDWNQNNWFDPWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD- Petition 870250096939, dated 10 / 23 / 2025, page 68 / 154 54 / 129 Tabela 2 Designação de Anticorpo Parte de Componente Sequência KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN- VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:63) LC QSALTQPASVSGSPGQSITISCTGTSSDVGTYNYVSWYQQHPGKAPKLMIFDVSNRPSGVSDRFSGSKSGNTASLTISGLQAEDEADYYCSSFTTSSTVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVE IIIPSKQSNNKYAASSYLSLTPEQW- KSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:64) VH CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACATCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAGGGGCTTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCGCAAACTATGCACAGAAGm CAGGGCAGGGTCACCCTGACCAGGGACACGTCCATCACCACAGTCTACATGGAACTGAGCAGGCTGAGATUGACGACACGGCCGTGTATTACTGTGCGAGAGGATCCCGGTATGACTGGAACCAGAACAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO:65) CDR-H1 GGATACATCTTCACCGGCTACTAT (SEQ ID NO:66) CDR-H2ATCAACCCTAACAGTGGTGGCGCA (SEQ ID NO:67) CDR-H3 GCGAGAGGATCCCGGTATGACTGGA- Petition 870250096939, of 23 / 10 / 2025, p. 69 / 154 55 / 129 Table 2 Antibody Designation Component Part Sequence ACCAGAACAACTGGTTCGACCCC (SEQ ID NO:68) VL CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTACTTATAACTATGTCTCCTGGTACCAACAACCCAGGCAAAGCCCCAAACTCATGAIIIIIIGTCAGTAATCGGGCCTCAGGGGGIII CTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCAIIIACAACCAGCAGCACTGTGGIIIICGGCGGAGGGACCAAG- CTGACCGTCCTA (SEQ ID NO:69) CDR-LCGGAGGAGGACCAGGTTATTA (SEQ ID NO:69) NO:70) CDR-L2 GATGTCAGT CDR-L3 AGCTCAIIIACAACCAGCAGCACTGTGGTT (SEQ ID NO:71) HC CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACATCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAGGGGCTTGAGTGGATGGGGATGGATCAACCTAGAGGGGGGGG GCAAACTATGCACAGAAGIIICAGGGCAGGGTCACCCTGACCAGGGACACGTCCATCACCACAGTCTACATGGAACTGAGCAGGCTGAGAIIIGACGACACGGCCGTGTATTACTGTGCGAGAGGATCCCGGTATGACTGGAACCAGAACAACTGGTTCGACCCTGGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCAC- Petition 870250096939, dated 10 / 23 / 2025, page 70 / 154 56 / 129 Table 2 Antibody Designation Component Part Sequence CTCTGGGGG- CACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG- CAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTT- GTGACAAAACTCACACATGCCCACCGTGCCCAGCAC- CTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGA CACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGT GGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAA ACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGAC- CTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGG- Petition 870250096939, dated 10 / 23 / 2025, page 71 / 154 57 / 129 Table 2 Antibody Part Designation Component Sequence CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGGGG TAAATGA (SEQ ID NO:72) LC CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTACTTATAACTATGTCTCCTGGTACCAACAACCCAGGCAAAGCCCCAAACTCATGAIIIIGTCAGTAATCGCCAGGGGGIII ^GAICGCHCICIGGCICCAAGICIGGCAACACGGCCTCCCTGACCATCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAGCICAIIIACAACCAGCAGCACIGIGGIIIICGGCGGAGGGACCAAGCIGACCGICCIAGGCCAGCCCAAGG- CCGCCCCCICCGIGACCCIGIICCCCCCCCCGAGGAGCIGCAGGCCAACAGGCCACCCIGGIGCCTGATCTCCGACTTACCCCG CACCCCCICCAAGCAGTCCAACAACAAGTACGCCGCCTCCTCCIACCIGICCGACCCCCGAGCAGIGGAAGTCCCACCGGTCCTACTCCTGCCAGGIGACCCACGAGGCICCACCGIGGAGAAGACCGIGGCCCCCACCGAGGCCCGA (SEQ ID NO:73)

[0082] In other embodiments, the spike protein ABDs comprise an amino acid sequence defined in Table 3 below. In specific aspects, the spike protein ABD comprises light and heavy chain CDRs of an antibody defined in Table 3 below. In other embodiments, the spike protein ABD comprises at least the heavy chain CDR sequences and the CDR sequences. Petition 870250096939, dated 10 / 23 / 2025, page 72 / 154 58 / 129 of the light chain of a universal light chain. In other aspects, the spike protein ABD comprises a VH with the amino acid sequence of the VH of an antibody established in Table 3 and a VL with the amino acid sequence of the VL of the same antibody, as established in Table 3. In other aspects, the spike protein ABD comprises a VH with the amino acid sequence of the VH of an antibody established in Table 3 and a universal light chain VL sequence. The initial sequence identifiers in Table 3 are related to the sequence listing in document WO 2021 / 045836A1, whose sequence identifiers are incorporated by reference herein, while the sequence identifiers presented in parentheses are those of the disclosure. Table 3 SEQ ID NO in document WO2021 / 045836A1 (SEQ ID NO of disclosure) Antibody Designation VH CDRH1 CDRH2 CDRH3 VL CDRL1 CDRL2 CDRL3 mAb10913 2 (88) 4 (89) 6 (90) 8 (91) 10 (92) 12 (93) 14 (94) 16 (95) mAb10915 22 (96) 24 (97) 26 (98) 28 (99) 30 (100) 32 (101) 34 (102) 36 (103) mAb10916 2 (88) 4 (89) 6 (90) 8 (91) 10 (92) 12 (93) 14 (94) 16 (95) mAb10917 44 (104) 46 (105) 26 (98) 49 (106) 51 (107) 53 (108) 55 (109) 57 (110) mAb10918 22 (96) 24 (97) 26 (98) 28 (99) 30 (100) 32 (101) 34 (102) 36 (103) mAb10920 65 (111) 67 (112) 69 (113) 71 (114) 73 (115) 75 (116) 55 (109) 77 (117) mAb10921 83 (118) 85 (119) 26 (98) 87 (120) 89 (121) 91 (122) 55 (109) 93 (123) mAb10922 119 (132) 121 (133) 123 (134) 125 (135) 127 (136) 129 (137) 55 (109) 131 (138) mAb10924 137 (139) 139 (140) 141 (141) 143 (142) 145 (143) 147 (144) 149 (145) 151 (146) mAb10925 65 (111) 67 (112) 69 (113) 71 (114) 73 (115) 75 (116)55 (109) 77 (117) Petition 870250096939, dated 10 / 23 / 2025, p. 73 / 154 59 / 129 Table 3 SEQ ID NO in document WO2021 / 045836A1 (SEQ ID NO from disclosure) mAb10926 83 (118) 85 (119) 26 (98) 87 (120) 89 (121) 91 (122) 55 (109) 93 (123) mAb10927 99 (124) 101 (125) 103 (126) 105 (127) 107 (128) 109 (129) 111 (130) 113 (131) mAb10928 119 (132) 121 (133) 123 (134) 125 (135) 127 (136) 129 (137) 55 (109) 131 (138) mAb10929 137 (139) 139 (140) 141 (141) 143 (142) 145 (143) 147 (144) 149 (145) 151 (146) mAb10930 167 (147) 169 (148) 171 (149) 173 (150) 175 (151) 129 (137) 55 (109) 177 (152) mAb10931 167 (147) 169 (148) 171 (149) 173 (150) 175 (151) 129 (137) 55 (109) 177 (152) mAb10932 185 (153) 187 (154) 26 (98) 189 (155) 191 (156) 75 (116) 194 (157) 196 (158) mAb10933 202 (1) 204 (2) 206 (3) 208 (4) 210 (5) 212 (6) 55 (109) 214 (7) mAb10934 220 (20) 222 (21) 224 (22) 226 (23) 228 (24) 230 (25) 194 (157) 232 (26) mAb10935 238 (173) 24 (97) 26 (98) 240 (174) 242 (175) 244 (176) 194 (157) 246 (177) mAb10936 252 (178) 254 (179) 256 (180) 258 (181) 260 (182) 129 (137) 55 (109)262 (183) mAb10937 268 (184) 270 (185) 272 (186) 274 (187) 276 (188) 129 (137) 55 (109) 278 (189) mAb10940 284 (190) 169 (148) 286 (191) 288 (192) 290 (193) 292 (194) 294 (195) 296 (196) mAb10938 302 (197) 24 (97) 26 (98) 304 (198) 306 (199) 308 (200) 194 (157) 310 (201) mAb10939 316 (202) 187 (154) 319 (203) 321 (204) 323 (205) 325 (206) 55 (109) 327 (207) mAb10941 333 (208) 85 (119) 26 (98) 336 (209) 338 (210) 340 (211) 294 (195) 296 (196) mAb10942 185 (153) 187 (154) 26 (98) 189 (155) 191 (156) 75 (116) 194 (157) 196 (158) mAb10943 202 (1) 204 (2) 206 (3) 208 (4) 210 (5) 212 (6) 55 (109) 214 (7) mAb10944 220 (20) 222 (21) 224 (22) 226 (23) 228 (24) 230 (25) 194 (157) 232 (26) mAb10945 238 (173) 24 (97) 26 (98) 240 (174) 242 (175) 244 (176) 194 (157) 246 (177) mAb10946 252 (178) 254 (179) 256 (180) 258 (181) 260 (182) 129 (137) 55 (109) 262 (183) Petition 870250096939, dated 10 / 23 / 2025, page 74 / 154 60 / 129 Table 3 SEQ ID NO in document WO2021 / 045836A1 (SEQ ID NO from disclosure) mAb10947 268 (184) 270 (185) 272 (186) 274 (187) 276 (188) 129 (137) 55 (109) 278 (189) mAb10948 302 (197) 24 (97) 26 (98) 304 (198) 306 (199) 308 (200) 194 (157) 310 (201) mAb10949 316 (202) 187 (154) 319 (203) 321 (204) 323 (205) 325 (206) 55 (109) 327 (207) mAb10951 333 (208) 85 (119) 26 (98) 336 (209) 338 (210) 340 (211) 294 (195) 296 (196) mAb10950 284 (190) 169 (148) 286 (191) 288 (192) 290 (193) 292 (194) 294 (195) 296 (196) mAb10954 366 (212) 85 (119) 26 (98) 370 (213) 372 (214) 244 (176) 194 (157) 375 (215) mAb10955 381 (216) 383 (217) 26 (98) 385 (218) 387 (219) 389 (220) 194 (157) 310 (201) mAb10956 396 (221) 187 (154) 26 (98) 399 (222) 401 (223) 389 (220) 194 (157) 403 (224) mAb10957 409 (225) 411 (226) 26 (98) 414 (227) 416 (228) 53 (108) 55 (109) 418 (229) mAb10958 366 (212) 85 (119) 26 (98) 370 (213) 372 (214) 244 (176) 194 (157) 375 (215) mAb10959 381 (216) 383 (217) 26 (98) 385 (218) 387 (219)389 (220) 194 (157) 310 (201) mAb10960 396 (221) 187 (154) 26 (98) 399 (222) 401 (223) 389 (220) 194 (157) 403 (224) mAb10961 409 (225) 411 (226) 26 (98) 414 (227) 416 (228) 53 (108) 55 (109) 418 (229) mAb10964 432 (230) 434 (231) 436 (232) 438 (233) 440 (234) 442 (235) 55 (109) 445 (236) mAb10965 451 (237) 453 (238) 26 (98) 455 (239) 457 (240) 459 (241) 34 (102) 462 (242) mAb10966 468 (243) 187 (154) 26 (98) 470 (244) 472 (245) 389 (220) 194 (157) 474 (246) mAb10967 480 (247) 24 (97) 483 (248) 485 (249) 487 (250) 389 (220) 194 (157) 489 (251) mAb10969 495 (252) 497 (253) 499 (254) 501 (255) 503 (256) 389 (220) 194 (157) 214 (165) mAb10970 510 (257) 24 (97) 26 (98) 512 (258) 514 (259) 516 (260) 194 (157) 518 (261) mAb10971 524 (262) 411 (226) 26 (98) 528 (263) 530 (264) 532 (265) 55 (109) 534 (266) mAb10973 432 (230) 434 (231) 436 (232) 438 (233) 440 (234) 442 (235) 55 (109) 445 (236) Petition 870250096939, dated 10 / 23 / 2025, page 75 / 154 61 / 129 Table 3 SEQ ID NO in document WO2021 / 045836A1 (SEQ ID NO from disclosure) mAb10974 451 (237) 453 (238) 26 (98) 455 (239) 457 (240) 459 (241) 34 (102) 462 (242) mAb10975 468 (243) 187 (154) 26 (98) 470 (244) 472 (245) 389 (220) 194 (157) 474 (246) mAb10976 480 (247) 24 (97) 483 (248) 485 (249) 487 (250) 389 (220) 194 (157) 489 (251) mAb10977 548 (267) 550 (268) 552 (269) 554 (270) 556 (271) 558 (272) 294 (195) 560 (273) mAb10978 495 (252) 497 (253) 499 (254) 501 (255) 503 (256) 389 (220) 194 (157) 214 (165) mAb10979 510 (257) 24 (97) 26 (98) 512 (258) 514 (259) 516 (260) 194 (157) 518 (261) mAb10980 524 (262) 411 (226) 26 (98) 528 (263) 530 (264) 532 (265) 55 (109) 534 (266) mAb10981 548 (267) 550 (268) 552 (269) 554 (270) 556 (271) 558 (272) 294 (195) 560 (273) mAb10982 574 (274) 187 (154) 576 (275) 578 (276) 580 (277) 582 (278) 584 (279) 586 (280) mAb10983 574 (274) 187 (154) 576 (275) 578 (276) 580 (277) 582 (278) 584 (279) 586 (280) mAb10984 594 (281) 596 (282) 26 (98) 598 (283) 600(284)12 (93)14 (94)602 (285)mAb10985 624 (292) 626 (293) 26 (98) 628 (294) 630 (295) 582 (278) 632 (296) 634 (297) mAb10987 640 (38) 642 (39) 499 (40) 644 (41) 646 (42) 648 (43) 650 (303) 652 (44) mAb10988 658 (305) 660 (306) 662 (307) 664 (308) 666 (309) 668 (310) 670 (311) 672 (312) mAb10989 678 (56) 680 57 682 (58) 684 (59) 686 (60) 688 (61) 650 (303) 690 (62) mAb10990 594 (281) 596 (282) 26 (98) 598 (283) 600 (284) 12 (93) 14 (94) 602 (285) mAb10991 608 (286) 169 (148) 610 (287) 612 (288) 614 (289) 616 (290) 584 (279) 618 (291) mAb10992 624 (292) 626 (293) 26 (98) 628 (294) 630 (295) 582 (278) 632 (296) 634 (297) mAb10993 640 (38) 642 (39) 499 (40) 644 (41) 646 (42) 648 (43) 650 (303) 652 (44) mAb10994 658 (305) 660 (306) 662 (307) 664 (308) 666 (309) 668 (310) 670 (311) 672 (312) Petition 870250096939, dated 10 / 23 / 2025, page 76 / 154 62 / 129 Table 3 SEQ ID NO in document WO2021 / 045836A1 (SEQ ID NO from disclosure) mAb10995 678 (313) 680 (314) 682 (315) 684 (316) 686 (317) 688 (318) 650 (303) 690 (319) mAb10996 708 (320) 24 (97) 26 (98) 711 (321) 713 (322) 129 (137) 55 (109) 715 (323) mAb10997 708 (320) 24 (97) 26 (98) 711 (321) 713 (322) 129 (137) 55 (109) 715 (323) mAb10998 723 (324) 187 (154) 26 (98) 725 (325) 727 (326) 129 (137) 55 (109) 729 (327) mAb10999 723 (324) 187 (154) 26 (98) 725 (325) 727 (326) 129 (137) 55 (109) 729 (327) mAb11000 737 (328) 24 (97) 26 (98) 739 (329) 741 (340) 743 (341) 55 (109) 745 (342) mAb11001 737 (328) 24 (97) 26 (98) 739 (329) 741 (340) 743 (341) 55 (109) 745 (342) mAb11002 753 (343) 24 (97) 26 (98) 755 (344) 713 (322) 129 (137) 55 (109) 715 (323) mAb11003 753 (343) 24 (97) 26 (98) 755 (344) 713 (322) 129 (137) 55 (109) 715 (323) mAb10914 44 (104) 46 (105) 26 (98) 49 (106) 51 (107) 53 (108) 55 (109) 57 (110) mAb11004 764 (345) 766 (346) 499 (254) 768 (347) 770 (348) 91 (122) 55 (109) 772(349) mAb11005 764 (345) 766 (346) 499 (254) 768 (347) 770 (348) 91 (122) 55 (109) 772 (349) mAb11006 780 (350) 782 (351) 26 (98) 784 (352) 786 (353) 53 (108) 55 (109) 788 (354) mAb11007 780 (350) 782 (351) 26 (98) 784 (352) 786 (353) 53 (108) 55 (109) 788 (354) mAb11008 796 (355) 24 (97) 26 (98) 798 (356) 800 (357) 53 (108) 55 (109) 802 (358) mAb11009 796 (355) 24 (97) 26 (98) 798 (356) 800 (357) 53 (108) 55 (109) 802 (358) mAb11010 810 (359) 812 (360) 814 (361) 816 (362) 818 (363) 129 (137) 820 (364) 822 (365) mAb11011 810 (359) 812 (360) 814 (361) 816 362 818 363 129 (137) 820 364 822 (365)

[0083] In some embodiments, the spike protein ABDs comprise an amino acid sequence defined in Table 4 below. In some aspects, the spike protein ABD comprises heavy and light chain CDRs of an antibody defined in Table 4 below. In Petition 870250096939, dated 10 / 23 / 2025, page 77 / 154 63 / 129 In certain aspects, the spike protein ABD comprises a VH with the amino acid sequence of the VH of an antibody as set out in Table 4 and a VL with the amino acid sequence of the VL of the same antibody as set out in Table 4. In other aspects, the spike protein ABD comprises a VH with the amino acid sequence of the VH of an antibody as set out in Table 4 and a universal light chain VL sequence. The initial sequence identifiers in Table 4 relate to the sequence listing in WO 2023 / 287875A1, whose sequence identifiers are incorporated by reference herein, while the sequence identifiers shown in parentheses are those of the disclosure. Table 4 SEQ ID NO in document WO2023 / 287875A1 Antibody Designation VH CDRH1 CDRH2 CDRH3 VL CDRL1 CDRL2 CDRL3 mAb15163 2 (366) 4 (367) 6 (368) 8 (369) 10 (370) 12 (371) 14 (372) 16 (373) mAb15164 22 (374) 24 (375) 26 (376) 28 (377) 30 (378) 32 (379) 34 (380) 36 (381) mAb15165 42 (382) 44 (383) 26 (376) 47 (384) 49 (385) 51 (386) 34 (380) 36 (381) mAb15166 58 (387) 60 (388) 62 (389) 64 (390) 66 (391) 51 (386) 68 (392) 36 (381) mAb15167 74 (393) 76 (394) 78 (395) 80 (396) 82 (397) 84 (398) 86 (399) 88 (400) mAb15170 94 (401) 96 (402) 98 (403) 100 (404) 102 (405) 104 (406) 106 (407) 108 (408) mAb14296 114 (409) 116 (410) 118 (411) 120 (412) 122 (413) 124 (414) 126 (415) 128 (417) mAb14297 134 (418) 136 (419) 138 (420) 140 (421) 142 (422)144 (423)126 (415)146 (424)mAb14312 172 (433) 174 (434) 176 (435) 178 (436) 180 (437) 182 (438) 184 (439) 186 (440) mAb14314 192 (441) 194 (442) 196 (443) 198(444) 200 (445) 202 (446) 204 (447) 206 (448) Petition 870250096939, dated 10 / 23 / 2025, p. 78 / 154 64 / 129 Table 4 SEQ ID NO in document WO2023 / 287875A1 Antibody Designation VH CDRH1 CDRH2 CDRH3 VL CDRL1 CDRL2 CDRL3 mAb14315 212 (449) 214 (450) 216 (451) 218 ​​(452) 220 (453) 222 (454) 126 (415) 224 (455) mAb14316 230 (456) 232 (457) 234 (458) 236 (459) 238 (460) 240 (461) 242 (462) 244 (463) mAb15150 250 (464) 252 (465) 254 (466) 256 (467) 258 (468) 260 (469) 262 (470) 264 (471) mAb15151 270 (472) 272 (473) 274 (474) 276 (475) 278 (476) 280 (477) 106 (407) 282 (478) mAb15156 288 (479) 290 (480) 292 (481) 294 (482) 296 (483) 298 (484) 300 (485) 302 (486) mAb15157 308 (487) 310 (488) 312 (489) 314 (490) 316 (491) 318 (492) 320 (493) 322 (494) mAb15158 328 (495) 330 (496) 332 (497) 334 (498) 336 (499) 338 (500) 106 (407) 340 (501) mAb15159 346 (752) 96 (402) 98 (403) 350 (502) 352 (503) 354 (504) 106 (407) 356 (505) mAb15160 362 (506) 364 (507) 366 (508) 368 (509) 370 (510) 372 (511) 106 (407) 374 (512) mAb15161 380 (513) 382 (514) 384 (515) 386 (516) 388 (517) 390 (518) 392 (519) 394(520) mAb15162 400 (521) 402 (522) 98 (403) 405 (523) 407 (524) 409 (525) 242 (462) 411 (526) mAb14280 417 (527) 419 (528) 421 (529) 423 (530) 425 (531) 427 (532) 14 (372) 429 (533) mAb14281 435 (534) 437 (535) 138 (420) 440 (536) 442 (537) 444 (538) 446 (539) 448 (540) mAb14282 454 (541) 456 (542) 458 (543) 460 (544) 462 (545) 84 (398) 465 (546) 467 (547) mAb14283 473 (548) 475 (549) 477 (550) 479 (551) 481 (552) 483 (553) 485 (554) 487 (555) mAb14284 493 (556) 495 (557) 497 (558) 499 (559) 501 (560) 503 (561) 505 (562) 507 (563) mAb14285 513 (564) 515 (565) 517 (566) 519 (567) 521 (568) 523 (569) 525 (570) 36 (381) mAb14286 531 (571) 533 (572) 535 (573) 537 (574) 539 (575) 483 (553) 542 (576) 544 (577) mAb14287 550 (578) 552 (579) 554 (580) 556 (581) 558 (582) 84 (398) 14 (372) 560 (583) mAb14288 566 (584) 568 (585) 570 (586) 572 (587) 574 (588) 576 (589) 578 (590) 580 (591) Petition 870250096939, dated 10 / 23 / 2025, page 79 / 154 65 / 129 Table 4 SEQ ID NO in document WO2023 / 287875A1 Antibody Designation VH CDRH1 CDRH2 CDRH3 VL CDRL1 CDRL2 CDRL3 mAb14289 586 (592) 588 (593) 590 (594) 592 (595) 594 (596) 596 (597) 126 (415) 598 (598) mAb14290 604 (599) 606 (600) 608 (601) 610 (602) 612 (603) 614 (604) 126 (415) 616 (605) mAb14291 622 (606) 624 (607) 626 (608) 628 (609) 630 (610) 632 (611) 634 (612) 636 (613) mAb14292 642 (614) 644 (615) 646 (616) 648 (617) 650 (618) 652 (619) 634 (612) 655 (620) mAb14293 661 (621) 663 (622) 665 (623) 667 (624) 669 (625) 124 (414) 126 (415) 671 (626) mAb14295 677 (627) 679 (628) 78 (395) 682 (629) 684 (630) 686 (631) 126 (415) 688 (632) mAb13459 694 (633) 696 (634) 698 (635) 700 (636) 702 (637) 704 (638) 706 (639) 708 (640) mAb14230 714 (641) 696 (634) 716 (642) 718 (643) 720 (644) 722 (645) 126 (415) 724 (646) mAb14231 730 (647) 732 (648) 734 (649) 736 (650) 738 (651) 740 (652) 106 (407) 742 (653) mAb14232 748 (654) 750 (655) 497 (558) 752 (656) 754 (657) 756 (658) 505 (562) 758(659) mAb14233 764 (660) 766 (661) 768 (662) 770 (663) 772 (664) 774 (665) 776 (666) 778 (667) mAb14234 784 (668) 786 (669) 788 (670) 790 (671) 792 (672) 794 (673) 796 (674) 798 (675) mAb14235 804 (676) 806 (677) 497 (558) 808 (678) 810 (679) 812 (680) 505 (562) 814 (681) mAb14247 820 (682) 822 (683) 497 (558) 825 (684) 827 (685) 756 (658) 14 (372) 829 (686) mAb14248 835 (687) 837 (688) 839 (689) 841 (690) 843 (691) 845 (692) 847 (693) 849 (694) mAb14249 855 (695) 857 (696) 859 (697) 861 (698) 863 (699) 865 (700) 106 (407) 867 (701) mAb14255 873 (702) 76 (394) 876 (703) 878 (704) 880 (705) 84 (398) 86 (399) 36 (381) mAb14256 887 (706) 889 (707) 891 (708) 893 (709) 895 (710)897 (711)164 (431)899 (712)mAb14257 922 (719) 924 (720) 926 (721) 928 (722) 930 (723) 576 (589) 933 (724) 935 (725) Petition 870250096939, dated 10 / 23 / 2025, page 80 / 154 66 / 129 Table 4 SEQ ID NO in document WO2023 / 287875A1 Antibody Designation VH CDRH1 CDRH2 CDRH3 VL CDRL1 CDRL2 CDRL3 mAb14259 941 943 945 947 949 951 634 655 (726) (727) (728) (729) (730) (731) (612) (620) mAb14260 957 959 961 963 965 967 969 971 (732) (733) (734) (735) (736) (737) (738) (739) mAb13457 694 696 698 700 977 704 706 979 (633) (634) (635) (636) (740) (638) (639) (741) mAb13458 694 696 698 700 983 704 706 985 (633) (634) (635) (636) (742) (638) (639) (743) mAb14294 989 991 993 995 997 999 1001 1003 (744) (745) (746) (747) (748) (749) (750) (751) mAb17090 493 495 497 499 501 503 505 507 (556) (557) (558) (559) (560) (561) (562) (563) mAb15160 362 364 366 368 370 372 106 374 _2 (506) (507) (508) (509) (510) (511) (407) (512)

[0084] In some embodiments, a spike protein ABD of a multivalent anti-spike protein binding molecule comprises the heavy and light chain CDRs of the antibody “mAb14287”, as set forth in Table 4. Thus, in some embodiments, the spike protein ABD comprises a VH with CDR-H1, CDR-H2, and CDR-H3 with amino acid sequences of SEQ ID NO: 579, 580, and 581, respectively, and a VL with CDR-L1, CDRL2, and CDR-L3 with amino acid sequences of SEQ ID NO: 398, 372, and 583, respectively. In some embodiments, the ABD protein peak comprises a VH with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO:578 and a VL with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO:582.In some forms, the spike protein ABD comprises a VH with the amino acid sequence. Petition 870250096939, dated 10 / 23 / 2025, p. 81 / 154 67 / 129 of those from SEQ ID NO:578 and a VL with the amino acid sequence from SEQ ID NO:582.

[0085] In some embodiments, a spike protein ABD of a multivalent anti-spike protein binding molecule comprises the heavy and light chain CDRs of the antibody “mAb15160”, as set forth in Table 4. Thus, in some embodiments, the spike protein ABD comprises a VH with CDR-H1, CDR-H2, and CDR-H3 with amino acid sequences of SEQ ID NO: 507, 508, and 509, respectively, and a VL with CDR-L1, CDRL2, and CDR-L3 with amino acid sequences of SEQ ID NO: 511, 407, and 512, respectively. In some embodiments, the ABD protein peak comprises a VH with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO:506 and a VL with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO:510.In some embodiments, the spike protein ABD comprises a VH with the amino acid sequence SEQ ID NO:506 and a VL with the amino acid sequence SEQ ID NO:510.

[0086] In some embodiments, a spike protein ABD of a multivalent anti-spike protein-binding molecule comprises the heavy and light chain CDRs of the antibody “mAb14315”, as set forth in Table 4. Thus, in some embodiments, the spike protein ABD comprises a VH with CDR-H1, CDR-H2, and CDR-H3 with amino acid sequences of SEQ ID NO: 450, 451, and 452, respectively, and a VL with CDR-L1, CDRL2, and CDR-L3 with amino acid sequences of SEQ ID NO: 454, 415, and 455, respectively. In some embodiments, the ABD of Petition 870250096939, 10 / 23 / 2025, p. 82 / 154 68 / 129 spike protein comprises a VH with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO:449 and a VL with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO:453. In some embodiments, the spike protein ABD comprises a VH with the amino acid sequence of SEQ ID NO:449 and a VL with the amino acid sequence of SEQ ID NO:453.

[0087] Exemplary formats of spike protein ABDs are disclosed in Section 6.4, and include Fabs (e.g., as described in Section 6.4.1) and scFvs (e.g., as described in Section 6.4.2).

[0088] In some forms, the spike protein ABD is in the form of a Fab or an scFv.

[0089] In other embodiments, all spike protein ABDs in a multivalent disclosure spike protein binding molecule (e.g., a tetravalent disclosure spike protein binding molecule) are Fabs.

[0090] In some embodiments, the multivalent spike protein-binding molecule is monospecific, in which all ABDs bind to the same epitope. The ABDs in a monospecific multivalent spike protein-binding molecule may include the same CDR sequences or the same VH and VL sequences. In some embodiments, the ABDs of a multivalent multispecific spike protein-binding molecule are configured as shown in Figure 1A or 1C.

[0091] In some embodiments, the multivalent spike protein-binding molecule is multispecific, in which at least two ABDs Petition 870250096939, dated 10 / 23 / 2025, p. 83 / 154 69 / 129 bind to different epitopes. At least two ABDs in a multivalent multispecific spike protein-binding molecule comprise different CDR sequences. In some embodiments, the multivalent multispecific spike protein-binding molecule is tetravalent, with a first pair of ABDs sharing the same CDR sequences or the same VH and VL sequences and a second pair of ABDs sharing the CDR sequences or the same VH and VL sequences (which differ from the CDR sequences of the first pair of ABDs). In some embodiments, the ABDs of a multivalent multispecific spike protein-binding molecule are configured as shown in Figure 1B or 1D. Table S Sequences from Tables 3 and 4 Excluded from the Sequence Listing in ST.26 Format SEQ ID NO Sequence 94 DNN 102 KAS 109 AAS 130 WAS 145 GVS 157 DAS 195 GAS 279 GNS 296 GNT 303 DVS 311 SNN 364 TAS 372 EVS 380 EGN 392 EGT 399 EDS 407 AAS 415 GAS 431 GNS 439 SND 447 DND 462 DAS 470 GAT 485 SDN Petition 870250096939, dated 10 / 23 / 2025, page 84 / 154 70 / 129 Table S Sequences from Tables 3 and 4 Excluded from the Sequence Listing in ST.26 Format 493 VNN 519 KAS 539 DKN 546 ELT 554 DVT 562 EVT 570 EGS 576 DVS 590 ENN 612 LGS 639 SAS 666 KDS 674 GNT 693 KIS 718 GHT 724 RNN 738 WAS 750 GAS 6.4. Spike Protein Antigen-Binding Domain Formats

[0092] In certain respects, multivalent anti-spike protein-binding disclosure molecules comprise an ABD of an anti-spike protein antibody that maintains specific binding to an antigenic determinant. In one embodiment, the spike protein ABD is a fragment of an immunoglobulin that occurs naturally (e.g., by protease cleavage) or that has been manipulated. Antibody fragments include, without limitation, VH (or VH fragments), VL (or VL fragments), Fab fragments, F(ab')2 fragments, scFv fragments, Fv fragments, minibodies, diabobodies, triabodies, and tetrabodies. 6.4.1. Fab

[0093] Fab domains were traditionally produced by proteolytic cleavage of immunoglobulin molecules using enzymes such as papain. Fab domains can include constant domain and variable region sequences of any suitable species and, Petition 870250096939, dated 10 / 23 / 2025, page 85 / 154 71 / 129 therefore, they can be murine, chimeric, human or humanized.

[0094] Fab domains typically comprise a domain CH1 is linked to a VH domain which binds to a CL domain linked to a VL domain. In a wild-type immunoglobulin, the VH domain is paired with the VL domain to form the Fv region, and the CH1 domain is paired with the CL domain to further stabilize the binding site. A disulfide bond between the two constant domains can further stabilize the Fab domain.

[0095] For non-homodimeric anti-spike protein-binding antibodies, especially when the anti-spike protein antibody light chains are not common or universal light chains, it is advantageous to use Fab heterodimerization strategies to allow the correct association of Fab domains belonging to the same antigen-binding domain and to minimize aberrant pairing of Fab domains belonging to different antigen-binding domains. For example, the Fab heterodimerization strategies shown in Table 5 below can be used: TABLE 5 Fab Heterodimerization Strategies STRATEGY VH CH1 VL CL REFERENCE CrossMabCH1-CL WT CL Domain WT CH1 Domain Schaefer et al., 2011, Cancer Cell 2011; 20:472-86; PMID:22014573. fab VHVRD1C H1CRD2VLVRD1C ÀCRD2 orthogonal 39K, 62E H172A, F174G 1R, 38D, 36F. L135Y, S176W Lewis et al., 2014, Nat Biotechnol 32:191-8 Petition 870250096939, dated 10 / 23 / 2025, page 86 / 154 72 / 129 TABLE 5 Fab Heterodimerization Strategies STRATEGY VH CH1 VL CL REFERENCE Fab VHVRD2C H1wt VLVRD2C Àwt orthogonal 39Y WT 38R WT Lewis et al., 2014, Nat Biotechnol 32:191-8 TCR CaCe 39K TCR Ca 38D TCR Ce Wu et al., 2015, MABD 7:364-76 CR3 WT T192E WT N137K, S114A Golay et al., 2016, J Immunol 196:3199-211. MUT4 WT L143Q, S188V WT V133T, S176V Golay et al., 2016, J Immunol 196:3199-211. DuetMab WT F126C WT S121C Mazor et al., 2015, MABD 7:377-89; Mazor et al., 2015, MABD 7:461669. Switched domain WT CH3 + knob or hole mutation WT CH3 + knob or hole mutation Wozniak-Knopp et al., 2018, PloS ONE13(4):e0195 442

[0096] Thus, in certain modalities, the association Correct interaction between the two polypeptides of a Fab is promoted by the exchange of the VL and VH domains of the Fab with each other or by the exchange of the CH1 and CL domains with each other, for example, as described in document WO 2009 / 080251.

[0097] Correct Fab pairing can also be promoted by introducing one or more amino acid modifications in the CH1 domain and one or more amino acid modifications in the CL domain of Fab and / or one or more amino acid modifications in the VH domain and one or more amino acid modifications in the VL domain. The modified amino acids are usually part of the interface. Petition 870250096939, dated 10 / 23 / 2025, page 87 / 154 73 / 129 VH:VL and CH1:CL, so that Fab components preferentially pair with each other and not with components from other Fabs.

[0098] In one embodiment, modifications of one or more amino acids are limited to the conserved residues of the variable (VH, VL) and constant (CH1, CL) domain structures, as indicated by the Kabat numbering of the residues. Almagro, 2008, Frontiers In Bioscience 13:1619-1633 provides a definition of the structure residues based on the Kabat, Chothia, and IMGT numbering schemes.

[0099] In one embodiment, the modifications introduced in the VH and CH1 and / or VL and CL domains are complementary to each other. Complementarity at the interface of the light and heavy chains can be achieved based on steric and hydrophobic contacts, electrostatic / charge interactions, or a combination of several interactions. Complementarity between protein surfaces is widely described in the literature in terms of lock-and-key fit, knob-into-hole, protrusion and cavity, donor and acceptor, etc., all implying the nature of the structural and chemical correspondence between the two interacting surfaces.

[00100] In one embodiment, one or more introduced modifications create a new hydrogen bond at the interface of the Fab components. In another embodiment, the introduced modifications introduce a new salt bridge at the interface of the Fab components. Exemplary substitutions are described in documents WO 2014 / 150973 and WO 2014 / 082179, the content of which is incorporated by reference herein.

[00101] In some embodiments, the Fab domain comprises a 192E substitution in the CH1 domain and 114A and 137K substitutions in the CL domain, which introduces a salt bridge between the CH1 and CL domains (see, for example, Golay et al., 2016, J Immunol 196: 3199-211).

[00102] In some modalities, the Fab domain comprises Petition 870250096939, dated 10 / 23 / 2025, p. 88 / 154 74 / 129 143Q and 188V substitutions in the CH1 domain and 113T and 176V substitutions in the CL domain, which serve to exchange hydrophobic and polar contact regions between the CH1 and CL domains (see, for example, Golay et al., 2016, J Immunol 196:3199-211).

[00103] In some embodiments, the Fab domain may include modifications in some or all of the VH, CH1, VL, and CL domains to introduce orthogonal Fab interfaces that promote the correct assembly of the Fab domains (Lewis et al., 2014, Nature Biotechnology 32:191-198). In one embodiment, modifications 39K, 62E are introduced in the VH domain, modifications H172A, F174G are introduced in the CH1 domain, modifications 1R, 38D, (36F) are introduced in the VL domain, and modifications L135Y, S176W are introduced in the CL domain. In another embodiment, a 39Y modification is introduced in the VH domain and a 38R modification is introduced in the VL domain.

[00104] Fab domains can also be modified to replace the native CH1:CL disulfide bond with a designed disulfide bond, thereby increasing the pairing efficiency of Fab components. For example, a designed disulfide bond can be introduced by introducing a 126C in the CH1 domain and a 121C in the CL domain (see, for example, Mazor et al., 2015, MABD 7:377-89).

[00105] Fab domains can also be modified by replacing the CH1 and CL domains with alternative domains that promote correct assembly. For example, Wu et al., 2015, MABD 7:364-76, describes replacing the CH1 domain with the constant domain of the T cell receptor and replacing the CL domain with the b domain of the T cell receptor, and pairing these domain substitutions with an additional charge-charge interaction between the VL and VH domains, introducing a 38D modification in the VL domain and a 39K modification in the VH domain. Petition 870250096939, dated 10 / 23 / 2025, page 89 / 154 75 / 129 6.4.2. scFv

[00106] Single-chain Fv antibody fragments or “scFv” comprise the VH and VL domains of an antibody in a single polypeptide chain, can be expressed as a single-chain polypeptide, and retain the specificity of the antibodies from which they are derived. In general, the scFv polypeptide also includes a linking polypeptide between the VH and VL domains that allows the scFv to form the desired structure for target binding. Examples of suitable ligands for connecting the VH and VL chains of an scFv are the ligands identified in Section 6.6.

[00107] Unless specified, as used in this document, an scFv may have the variable regions VL and VH in any order, for example, with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or it may comprise VH-linker-VL.

[00108] The scFv may include VH and VL sequences from any suitable species, such as murine, human, or humanized VH and VL sequences.

[00109] To create a nucleic acid encoding scFv, the DNA fragments encoding VH and VL are operationally ligated to another fragment encoding a ligand, for example, encoding any of the ligands described in Section 6.6 (typically a repetition of a sequence containing the amino acids glycine and serine, such as the amino acid sequence (Gly4~Ser)3 (SEQ ID NO: 74)), so that the VH and VL sequences can be expressed as a contiguous single-stranded protein, with the VL and VH regions joined by the flexible ligand (see, for example, Bird et al., 1988, Science 242:423-426; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., 1990, Nature 348:552-554). 6.5. Multimerization Portion Petition 870250096939, dated 10 / 23 / 2025, page 90 / 154 76 / 129

[00110] In some embodiments, the ABDs of the multivalent anti-spike disclosure protein-binding molecules include and / or are operationally linked by one or more multimerization moieties, for example, one or more multimerization moieties comprising or consisting of an Fc domain.

[00111] In certain embodiments, a multivalent anti-spike protein-binding molecule of the disclosure comprises a single multimerization moiety (e.g., a single Fc domain), but generally comprises two or more multimerization moieties (e.g., two or more Fc domains that can associate to form an Fc region). In some embodiments, the multivalent anti-spike protein-binding molecule is a dimer, and the Fc region comprises two IgG-derived Fc domains, for example, as described in Section 6.5.1. 6.5.1. FC Domain

[00112] Multivalent anti-spike protein-binding molecules may include an Fc domain or a pair of Fc domains that associate to form an Fc region, derived from any suitable species operationally linked to a spike protein ABD. In one embodiment, the Fc domain is derived from a human Fc domain. In preferred embodiments, the spike protein ABD is fused to an IgG Fc domain.

[00113] Fc domains that can be incorporated into multivalent anti-spike protein-binding molecules can be derived from any suitable antibody class, including IgA (including subclasses lgA1 and lgA2), IgD, IgE, IgG (including subclasses lgG1, lgG2, lgG3, and lgG4), and IgM. In one embodiment, the Fc domain is derived from lgG1, lgG2, lgG3, or lgG4. In another embodiment, the Fc domain is derived from lgG1. In another embodiment, the Fc domain is derived from IgG4.

[00114] In native antibodies, the Fc heavy chain domain of Petition 870250096939, dated 10 / 23 / 2025, page 91 / 154 77 / 129 IgA, IgD, and IgG are composed of two constant heavy chain domains (CH2 and CH3), while IgE and IgM are composed of three constant heavy chain domains (CH2, CH3, and CH4). They dimerize to create an Fc region.

[00115] In the multivalent antispike protein-binding molecules of the present disclosure, the Fc region and / or the Fc domains within it may include heavy chain constant domains from one or more different antibody classes, for example, one, two or three different classes.

[00116] In one embodiment, the Fc region comprises the CH2 and CH3 domains derived from lgG1.

[00117] In one embodiment, the Fc region comprises the CH2 and CH3 domains derived from lgG2.

[00118] In one embodiment, the Fc region comprises the CH2 and CH3 domains derived from IgG3.

[00119] In one embodiment, the Fc region comprises the CH2 and CH3 domains derived from IgG4.

[00120] The heavy chain constant domains for use in producing an Fc region for the multivalent anti-spike protein-binding molecules of the present disclosure may include variants of the naturally occurring constant domains described above. These variants may include one or more amino acid variations compared to the wild-type constant domains. In one example, the Fc region of the present disclosure comprises at least one constant domain that varies in sequence from the wild-type constant domain. It will be appreciated that the variant constant domains may be longer or shorter than the wild-type constant domain.

[00121] The Fc domains incorporated into the multivalent anti-spike protein-binding molecules of this disclosure may include a Petition 870250096939, dated 10 / 23 / 2025, page 92 / 154 78 / 129 or more modifications that alter the functional properties of proteins, for example, binding to Fc receptors, such as FcRn or leukocyte receptors, complement binding, modified disulfide bond architecture, or altered glycosylation patterns. Exemplary Fc modifications that alter effector function are described in Section 6.5.1.1.

[00122] Fc domains can also be altered to include modifications that improve the ability to manufacture multivalent asymmetric anti-spike protein-binding molecules, for example, by enabling heterodimerization, which is the preferential pairing of non-identical Fc domains over identical Fc domains. Heterodimerization allows the production of multivalent anti-spike protein-binding molecules in which different polypeptide components are connected to each other by an Fc region containing sequence-differentiating Fc domains. Examples of heterodimerization strategies are exemplified in Section 6.5.1.2.

[00123] It is important to emphasize that any of the modifications mentioned above can be combined in any suitable way to obtain the desired functional properties and / or combined with other modifications to alter the properties of the multivalent anti-spike protein binding molecules. 6.5.1.1. Fc Domains with Altered Effector Function

[00124] In some embodiments, the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor and / or effector function.

[00125] In a specific embodiment, the Fc receptor is an Fcy receptor. In one embodiment, the Fc receptor is a human Fc receptor. In one embodiment, the Fc receptor is an activating Fc receptor. In a specific embodiment, the Fc receptor is a human activating Fcy receptor, more specifically human FcYRIIIa, FcyRI or FcYRlla, Petition 870250096939, dated 10 / 23 / 2025, p. 93 / 154 79 / 129 more specifically human FcYRllla. In one embodiment, the effector function is one or more selected from the complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and cytokine secretion groups. In one specific embodiment, the effector function is ADCC.

[00126] In one embodiment, the Fc domain (e.g., an Fc domain of a multivalent antispike protein-binding molecule polypeptide chain) or the Fc region (e.g., one or both Fc domains of a multivalent antispike protein-binding construct that can associate to form an Fc region) comprises an amino acid substitution at a selected position in the E233, L234, L235, N297, P331, and P329 group (numbering according to the EU Kabat index). In a more specific embodiment, the Fc domain or the Fc region comprises an amino acid substitution at a selected position in the L234, L235, and P329 group (numbering according to the EU Kabat index). In some embodiments, the Fc domain or the Fc region comprises the amino acid substitutions L234A and L235A (numbering according to the EU Kabat index). In one of these embodiments, the The Fc domain or region is an IgD Fc domain or region, specifically a human IgD Fc domain or region.In one embodiment, the Fc domain or Fc region comprises an amino acid substitution at position P329. In a more specific embodiment, the amino acid substitution is P329A or P329G, especially P329G (numbering according to the EU Kabat index). In another embodiment, the Fc domain or Fc region comprises an amino acid substitution at position P329 and an additional amino acid substitution at a position selected from E233, L234, L235, N297, and P331 (numbering according to the EU Kabat index). In a more specific embodiment, the substitution... (Petition 870250096939, dated 10 / 23 / 2025, page 94 / 154.) 80 / 129 additional amino acid composition is E233P, L234A, L235A, L235E, N297A, N297D, or P331S. In certain embodiments, the Fc domain or Fc region comprises amino acid substitutions at positions P329, L234, and L235 (numbering according to the EU Kabat index). In other specific embodiments, the Fc domain comprises amino acid mutations L234A, L235A, and P329G (“P329G LALA”, “PGLALA”, or “LALAPG”).

[00127] Typically, the same substitution of one or more amino acids is present in each of the two Fc domains of an Fc region. Thus, in a given embodiment, each Fc domain of the Fc region comprises the amino acid substitutions L234A, L235A and P329G (Kabat EU index numbering), that is, in each of the first and second Fc domains in the Fc region, the leucine residue at position 234 is substituted by an alanine residue (L234A), the leucine residue at position 235 is substituted by an alanine residue (L235A) and the proline residue at position 329 is substituted by a glycine residue (P329G) (Kabat EU index numbering).

[00128] In one embodiment, the Fc domain is an IgG1 Fc domain, specifically a human IgG1 Fc domain. In some embodiments, the IgG1 Fc domain is an IgG1 variant that includes the D265A and N297A mutations (EU numbering) to reduce effector function.

[00129] In another embodiment, the Fc domain is an IgG4 Fc domain with reduced binding to Fc receptors. Exemplary IgG4 Fc domains with reduced binding to Fc receptors may include an amino acid sequence selected from Table 6 below: In some embodiments, the Fc domain includes only the bold portion of the sequences shown below: TABLE 6 Domain Fc Sequence Petition 870250096939, dated 10 / 23 / 2025, page 95 / 154 81 / 129 TABLE 6 Domain Fc Sequence SEQ ID NO:1 of WO2014 / 121087 Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys (SEQ ID NO: 75)SEQ ID NO:2 of WO2014 / 121087 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Petition 870250096939, dated 10 / 23 / 2025, page 96 / 154 82 / 129 TABLE 6 Domain Fc Sequence Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys (SEQ ID NO: 18) SEQ ID NO:30 of WO2014 / 121087 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu TyrLys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys (SEQ ID NO: 76) SEQ ID NO:31 de WO2014 / 121087 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Petition 870250096939, dated 10 / 23 / 2025, page 97 / 154 83 / 129 TABLE 6 Domain Fc Sequence Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys SerArg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys (SEQ ID NO: 77) SEQ ID NO:37 of WO2014 / 121087 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Be Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Petition 870250096939, dated 10 / 23 / 2025, page 98 / 154 84 / 129 TABLE 6 Domain Fc Sequence Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys (SEQ ID NO: 78) SEQ ID NO:38 of WO2014 / 121087 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr PhePro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Petition 870250096939, dated 10 / 23 / 2025, page 99 / 154 85 / 129 TABLE 6 Domain Fc Sequence Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys (SEQ ID NO: 79)

[00130] In a specific embodiment, IgG4 with reduced effector function comprises the bold part of the amino acid sequence of SEQ ID NO:31 of WO2014 / 121087, sometimes referred to in this document as IgG4s or hIgG4s.

[00131] For heterodimeric Fc regions, it is possible to incorporate a combination of the IgG4 Fc variant sequences established above, for example, an Fc region comprising an Fc domain comprising the amino acid sequence of SEQ ID NO:30 of WO2014 / 121087 (or the bold part) and an Fc domain comprising the amino acid sequence of SEQ ID NO:37 of WO2014 / 121087 (or the bold part thereof) or an Fc region comprising an Fc domain comprising the amino acid sequence SEQ ID NO:31 of WO2014 / 121087 (or the bold part thereof) and an Fc domain comprising the amino acid sequence SEQ ID NO:38 of WO2014 / 121087 (or the bold part thereof). 6.5.1.2. Fc Heterodimerization Variants

[00132] Certain multivalent antispike protein-binding molecules involve dimerization between two Fc domains that, unlike a native immunoglobulin, are operationally linked to non-identical N-terminal regions, for example, an Fc domain connected to a Fab that binds to a first spike protein epitope. Petition 870250096939, dated 10 / 23 / 2025, pp. 100 / 154 86 / 129 and the other Fc domain connected to a different Fab that binds to a second spike protein epitope. Inadequate heterodimerization of two Fc domains to form an Fc region can be an obstacle to increasing the yield of desired heterodimeric molecules and presents challenges for purification. Several approaches available in the art can be used to increase the dimerization of Fc domains that may be present in the disclosure ACE2 fusion proteins, for example, as disclosed in document EP 1870459A1; US ​​Patent No. 5,582,996; US Patent No. 5,731,168; US Patent No. 5,910,573; US Patent No. 5,932,448; US Patent No. 6,833,441; US ​​Patent No. 7,183,076; Publication of Patent Application No. US 2006204493A1; and Publication No. PCT WO 2009 / 089004A1.

[00133] This disclosure provides multivalent anti-spike protein-binding molecules comprising Fc heterodimers, i.e., Fc regions comprising heterologous and non-identical Fc domains. Typically, each Fc domain in the Fc heterodimer comprises a CH3 domain of an antibody. The CH3 domains are derived from the constant region of an antibody of any isotype, class, or subclass, and preferably of the IgG class (IgG1, IgG2, IgG3, and IgG4), as described in the previous section.

[00134] Heterodimerization of the two different heavy chains in the CH3 domains gives rise to the desired multivalent anti-spike protein-binding molecule, while homodimerization of identical heavy chains will reduce the yield of the desired multivalent anti-spike protein-binding molecule. Thus, in a preferred embodiment, the polypeptides that associate to form a multivalent anti-spike protein-binding molecule of the disclosure will contain CH3 domains with modifications that favor heterodimeric association over unmodified Fc domains.

[00135] In a specific modality, this modification that Petition 870250096939, dated 10 / 23 / 2025, pp. 101 / 154 The 87 / 129 modification that promotes the formation of Fc heterodimers is called a “knob-into-hole” or “knob-in-hole” modification, which comprises a “knob” modification in one of the Fc domains and a “hole” modification in the other Fc domain. The knob-into-hole technology is described, for example, in US Patent No. 5,731,168; US 7,695,936; Ridgway et al., 1996, Prot Eng 9:617-621 and Carter, 2001, Immunol Meth 248:7-15. In general, the method involves introducing a protrusion (“knob”) at the interface of a first polypeptide and a corresponding cavity (“hole”) at the interface of a second polypeptide, so that the protrusion can be positioned in the cavity to promote the formation of heterodimers and prevent the formation of homodimers. The bumps are constructed by replacing small amino acid side chains at the interface of the first polypeptide with larger side chains (e.g., tyrosine or tryptophan).Compensatory cavities of identical or similar size to the protrusions are created at the interface of the second polypeptide by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine).

[00136] Thus, in some embodiments, an amino acid residue in the CH3 domain of the first subunit of the Fc domain is replaced by an amino acid residue with a larger side chain volume, thus generating a protrusion in the CH3 domain of the first subunit that can be positioned in a cavity in the CH3 domain of the second subunit, and an amino acid residue in the CH3 domain of the second subunit of the Fc domain is replaced by an amino acid residue with a smaller side chain volume, thus generating a cavity in the CH3 domain of the second subunit in which the protrusion in the CH3 domain of the first subunit can be positioned. Preferably, the amino acid residue with the larger side chain volume is selected from the group consisting of arginine (R), Petition 870250096939, dated 10 / 23 / 2025, pp. 102 / 154 88 / 129 phenylalanine (F), tyrosine (Y), and tryptophan (W). Preferably, the amino acid residue with the smallest side chain volume is selected from the group consisting of alanine (A), serine (S), threonine (T), and valine (V). The bulge and cavity can be achieved by altering the nucleic acid encoding the polypeptides, for example, by site-specific mutagenesis or peptide synthesis. An exemplary substitution is Y470T.

[00137] In one of these specific embodiments, in the first Fc domain, the threonine residue at position 366 is replaced by a tryptophan residue (T366W), and in the Fc domain, the tyrosine residue at position 407 is replaced by a valine residue (Y407V) and, optionally, the threonine residue at position 366 is replaced by a serine residue (T366S) and the leucine residue at position 368 is replaced by an alanine residue (L368A) (numbering according to the EU Kabat index).In another embodiment, in the first Fc domain, in addition, the serine residue at position 354 is replaced by a cysteine ​​residue (S354C) or the glutamic acid residue at position 356 is replaced by a cysteine ​​residue (E356C) (particularly the serine residue at position 354 is replaced by a cysteine ​​residue), and in the second Fc domain, in addition, the tyrosine residue at position 349 is replaced by a cysteine ​​residue (Y349C) (numbering according to the EU Kabat index). In a specific embodiment, the first Fc domain comprises the amino acid substitutions S354C and T366W, and the second Fc domain comprises the amino acid substitutions Y349C, T366S,. L368A and Y407V (numbering according to the EU Kabat index).

[00138] In some embodiments, the electrostatic direction (e.g., as described in Gunasekaran et al., 2010, J Biol Chem 285(25):19637-46) can be used to promote the association of the first and second Fc domains of the Fc region. Petition 870250096939, dated 10 / 23 / 2025, pp. 103 / 154 89 / 129

[00139] Alternatively, or in addition to the use of modified Fc domains to promote heterodimerization, an Fc domain can be modified to allow a purification strategy that enables the selection of Fc heterodimers. In one such embodiment, a polypeptide comprises a modified Fc domain that abolishes its binding to protein A, thus allowing a purification method that yields a heterodimeric protein. See, for example, US Patent No. 8,586,713. In this way, IL12 receptor agonists comprise a first CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from each other by at least one amino acid, and wherein at least one amino acid difference reduces the binding of the IL12 receptor agonist to protein A compared with a corresponding IL12 receptor agonist without the amino acid difference.In one embodiment, the first CH3 domain binds to Protein A and the second CH3 domain contains a mutation / modification that reduces or eliminates binding to Protein A, such as an H95R modification (by exon numbering IMGT; H435R by exon numbering EU). The second CH3 may also comprise a Y96F modification (by IMGT; Y436F by EU). This class of modifications is referred to in this document as “star” mutations.

[00140] In some embodiments, the Fc may contain one or more mutations (e.g., knob and hole mutations) to facilitate heterodimerization, as well as star mutations to facilitate purification. 6.6. Ligands

[00141] In certain respects, the present disclosure provides multivalent anti-spike protein binding molecules in which two or more components are connected to each other by a peptide linker. By way of example and without limitation, the linkers can be used to connect a spike protein ABD to a multi-portion Petition 870250096939, dated 10 / 23 / 2025, pp. 104 / 154 90 / 129 merization.

[00142] A peptide linker can range from 1 amino acid to 60 or more amino acids and, in certain aspects, the peptide linker ranges from 3 amino acids to 50 amino acids, from 4 to 30 amino acids, from 5 to 25 amino acids, from 10 to 25 amino acids, from 10 amino acids to 60 amino acids, from 12 amino acids to 20 amino acids, from 20 amino acids to 50 amino acids, or from 25 amino acids to 35 amino acids in length.

[00143] In specific aspects, a peptide linker has at least 1 amino acid, at least 2 amino acids, at least 3 amino acids, at least 4 amino acids, at least 5 amino acids, at least 6 amino acids, or at least 7 amino acids in length and, optionally, has up to 30 amino acids, up to 40 amino acids, up to 50 amino acids, or up to 60 amino acids in length.

[00144] In some specific embodiments, a peptide linker varies from 1 amino acid to 50 amino acids in length, for example, it varies from 1 to 50, from 1 to 45, from 1 to 40, from 1 to 35, from 1 to 30, from 1 to 25, or from 1 to 20 amino acids in length. In other specific embodiments, a peptide linker varies from 2 amino acids to 50 amino acids in length, for example, it varies from 2 to 50, from 2 to 45, from 2 to 40, from 2 to 35, from 2 to 30, from 2 to 25, or from 2 to 20 amino acids in length. In some other specific embodiments, a peptide linker varies from 3 amino acids to 50 amino acids in length, for example, it varies from 3 to 50, from 3 to 45, from 3 to 40, from 3 to 35, from 3 to 30, from 3 to 25, or from 3 to 20 amino acids in length. In some other specific embodiments, a peptide linker varies from 4 amino acids to 50 amino acids in length, for example, it varies from 4 to 50, from 4 to 45, from 4 to 40, from 4 to 35, from 4 to 30, from 4 to 25, or from 4 to 20 amino acids in length.In some other specific forms, a peptide linker varies from 5 to 50 amino acids in length, for example, it varies from 5 to 50, from 5 to 45, from 5 to 40, from 5 to 35. Petition 870250096939, dated 10 / 23 / 2025, pp. 105 / 154 91 / 129 from 5 to 30, from 5 to 25, or from 5 to 20 amino acids in length. In other specific embodiments, a peptide ligand varies from 6 amino acids to 50 amino acids in length, for example, it varies from 6 to 50, from 6 to 45, from 6 to 40, from 6 to 35, from 6 to 30, from 6 to 25, or from 6 to 20 amino acids in length. In other specific embodiments, a peptide ligand varies from 7 amino acids to 50 amino acids in length, for example, it varies from 7 to 50, from 7 to 45, from 7 to 40, from 7 to 35, from 7 to 30, from 7 to 25, or from 7 to 20 amino acids in length.

[00145] In some embodiments, the linker is a G4S linker (SEQ ID NO:80). In some embodiments, the linker comprises two consecutive G4S sequences (SEQ ID NO:81), three consecutive G4S sequences (SEQ ID NO:74), four consecutive G4S sequences (SEQ ID NO:82), five consecutive G4S sequences (SEQ ID NO:83), or six consecutive G4S sequences (SEQ ID NO:84). 6.6.1. Hinge Sequences

[00146] In other embodiments, multivalent anti-spike protein-binding disclosure molecules include a linker that is a hinge region. The hinge region may be a native or modified region. Hinge regions are typically found at the N-terminus of Fc regions. The term “hinge region,” unless the context states otherwise, refers to a naturally occurring or unnatural hinge sequence that, in the context of a single or monomeric polypeptide chain, is a monomeric hinge domain and, in the context of a dimeric polypeptide (e.g., homodimeric or heterodimeric multivalent anti-spike protein-binding molecules formed by the association of two IgG Fc domains), may comprise two hinge sequences associated on separate polypeptide chains.

[00147] A native hinge region is the hinge region that would normally be found between the Fab and Fc domains in a Petition 870250096939, dated 10 / 23 / 2025, pp. 106 / 154 92 / 129 naturally occurring antibody. A modified hinge region is any hinge that differs in length and / or composition from the native hinge region. These hinges may include hinge regions from other species, such as hinge regions from humans, mice, rats, rabbits, sharks, pigs, hamsters, camels, llamas, or goats. Other modified hinge regions may comprise a complete hinge region derived from an antibody of a class or subclass different from that of the heavy chain Fc domain or Fc region. Alternatively, the modified hinge region may comprise part of a natural hinge or a repeat unit in which each unit in the repeat is derived from a natural hinge region.Alternatively, the natural hinge region can be altered by converting one or more cysteine ​​residues or other residues into neutral residues, such as serine or alanine, or by converting suitably positioned residues into cysteine ​​residues. In this way, the number of cysteine ​​residues in the hinge region can be increased or decreased. Other modified hinge regions can be entirely synthetic and can be engineered to have desired properties such as length, cysteine ​​composition, and flexibility.

[00148] Several modified hinge regions have already been described, for example, in US Patent No. 5,677,425, WO 99 / 15549, WO 2005 / 003170, WO 2005 / 003169, WO 2005 / 003170, WO 98 / 25971 and WO 2005 / 003171 and are incorporated herein by reference.

[00149] In some embodiments, a multivalent anti-spike disclosure protein-binding molecule comprises an Fc region in which one or both Fc domains have an intact hinge region at their N-terminus.

[00150] In several modalities, positions 233-236 in a regi Petition 870250096939, dated 10 / 23 / 2025, pp. 107 / 154 93 / 129 hinge positions can be G, G, G and unoccupied; G, G, unoccupied and unoccupied; G, unoccupied, unoccupied and unoccupied; or all unoccupied, with positions numbered according to EU numbering.

[00151] In some embodiments, the multivalent anti-spike protein-binding molecules of the disclosure comprise a modified hinge region that reduces the binding affinity for an Fcy receptor relative to a wild-type hinge region of the same isotype (e.g., human IgG1 or human IgG4).

[00152] In one embodiment, the multivalent anti-spike protein-binding molecules of the disclosure comprise an Fc region in which each Fc domain has an intact hinge region at its N-terminus, wherein each Fc domain and hinge region are derived from lgG4, and each hinge region comprises the modified CPPC sequence (SEQ ID NO:85). The central hinge region of human lgG4 contains the CPSC sequence (SEQ ID NO:86) compared to lgG1, which contains the CPPC sequence (SEQ ID NO:85). The serine residue present in the lgG4 sequence leads to greater flexibility in this region and, therefore, a proportion of molecules form disulfide bonds within the same protein chain (an intrachain disulfide) instead of bridging with the other heavy chain in the IgG molecule to form the interchain disulfide. (Angel et al., 1993, Mol Immunol 30(1):105-108).Replacing the serine residue with a proline to give the same core sequence as lgG1 allows for the complete formation of disulfide bonds between the chains in the lgG4 hinge region, thus reducing heterogeneity in the purified product. This altered isotype is called lgG4P. 6.7. Nucleic Acids and Host Cells

[00153] In another aspect, disclosure provides nucleic acids that encode multivalent molecules that bind to the disclosure anti-spike protein. In some embodiments, multivalent molecules Petition 870250096939, dated 10 / 23 / 2025, pp. 108 / 154 94 / 129 anti-spike protein binding molecules are encoded by a single nucleic acid. In other embodiments, multivalent anti-spike protein binding molecules may be encoded by a plurality (e.g., two, three, four, or more) of nucleic acids.

[00154] A single nucleic acid may encode a multivalent antispike protein-binding molecule comprising a single polypeptide chain, a multivalent antispike protein-binding molecule comprising two or more polypeptide chains, or a portion of a multivalent antispike protein-binding molecule comprising more than two polypeptide chains (e.g., a single nucleic acid may encode two polypeptide chains of a multivalent antispike protein-binding molecule comprising three, four, or more polypeptide chains, or three polypeptide chains of a multivalent antispike protein-binding molecule comprising four or more polypeptide chains). For separate control of expression, open reading frames encoding two or more polypeptide chains may be under the control of separate transcription regulatory elements (e.g., promoters and / or enhancers).Open reading frames encoding two or more polypeptides can also be controlled by the same transcription regulatory elements and separated by internal ribosome entry site (IRES) sequences, allowing translation into separate polypeptides.

[00155] In some embodiments, a multivalent anti-spike protein-binding molecule comprising two or more polypeptide chains is encoded by two or more nucleic acids. The number of nucleic acids encoding a multivalent anti-spike protein-binding molecule may be equal to or less than the number of polypeptide chains in the multivalent anti-spike protein-binding molecule (for example, when two or more polypeptide chains Petition 870250096939, dated 10 / 23 / 2025, pp. 109 / 154 95 / 129 are encoded by a single nucleic acid.

[00156] The nucleic acids in the disclosure can be DNA or RNA (e.g., mRNA).

[00157] In another aspect, disclosure provides host cells and vectors containing the disclosure nucleic acids. The nucleic acids may be present in a single vector or in separate vectors present in the same host cell or in a separate host cell, as described in more detail below. 6.7.1. Vectors

[00158] The disclosure provides vectors comprising nucleotide sequences encoding a multivalent anti-spike protein-binding molecule or a component thereof described in this document, for example, one or two of the polypeptide chains of a multivalent anti-spike protein-binding molecule. Vectors include, without limitation, a virus, plasmid, cosmid, lambda phage, or yeast artificial chromosome (YAC).

[00159] Several vector systems can be employed. For example, one class of vectors uses DNA elements that are derived from animal viruses, such as bovine papillomavirus, polyomavirus, adenovirus, vaccinia virus, baculovirus, retroviruses (Rous sarcoma virus, MMTV or MOMLV) or SV40 virus. Another class of vectors uses RNA elements derived from RNA viruses, such as Semliki Forest virus, Eastern Equine Encephalitis virus and Flavivirus.

[00160] Furthermore, cells that have stably integrated DNA into their chromosomes can be selected by introducing one or more markers that allow the selection of transfected host cells. The marker can provide, for example, prototropy to an auxotrophic host, resistance to biocides (e.g., antibiotics), or resistance to heavy metals such as copper or similar. The Petition 870250096939, dated 10 / 23 / 2025, pp. 110 / 154 96 / 129 selectable marker genes can be directly ligated to DNA sequences to be expressed or introduced into the same cell by cotransformation. Additional elements may also be required for optimal mRNA synthesis. These elements may include splicing signals, as well as transcriptional promoters, enhancers, and termination signals.

[00161] Once the expression vector or DNA sequence containing the constructs has been prepared for expression, the expression vectors can be transfected or introduced into an appropriate host cell. Several techniques can be used to achieve this, such as, for example, protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene gun, lipid-based transfection, or other conventional techniques. Methods and conditions for culturing the resulting transfected cells and for recovering the expressed polypeptides are known to those skilled in the art and can be varied or optimized depending on the specific expression vector and mammalian host cell used, based on the present description. 6.7.2. Cells

[00162] The disclosure also provides host cells that comprise a nucleic acid from the disclosure.

[00163] In one embodiment, the host cells are genetically modified to include one or more nucleic acids described in this document.

[00164] In one embodiment, host cells are genetically modified using an expression cassette. The term "expression cassette" refers to nucleotide sequences that have the ability to affect the expression of a gene in hosts compatible with such sequences. These cassettes may include a promoter, an open reading frame with or without introns, and a signal. Petition 870250096939, dated 10 / 23 / 2025, pp. 111 / 154 97 / 129 termination. Additional factors necessary or useful for effecting expression may also be used, such as, for example, an inducible promoter.

[00165] The disclosure also provides host cells comprising the vectors described in this document.

[00166] The cell may be, without limitation, a eukaryotic cell, a bacterial cell, an insect cell, or a human cell. Suitable eukaryotic cells include, without limitation, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells, and MDCKII cells. Suitable insect cells include, without limitation, Sf9 cells. 6.8. Pharmaceutical Compositions

[00167] Multivalent anti-spike protein-binding molecules may be in the form of compositions comprising the multivalent anti-spike protein-binding molecule and one or more carriers, excipients, and / or diluents. Compositions may be formulated for specific uses, such as for veterinary or pharmaceutical uses in humans. The form of the composition (e.g., dry powder, liquid formulation, etc.) and the excipients, diluents, and / or carriers used will depend on the intended uses of the multivalent anti-spike protein-binding molecules and, for therapeutic uses, on the route of administration.

[00168] For therapeutic uses, the compositions may be supplied as part of a sterile pharmaceutical composition that includes a pharmaceutically acceptable carrier. This composition may be in any suitable form (depending on the desired method of administration to a patient). The pharmaceutical composition may be administered to a patient by a variety of routes, such as oral, transdermal, subcutaneous, intranasal, intravenous, intramuscular, intratumoral, intrathecal, topical, or local. The most suitable route of administration Petition 870250096939, dated 10 / 23 / 2025, pp. 112 / 154 98 / 129 The dosage in a given case will depend on the specific antibody, the individual, the nature and severity of the disease, and the individual's physical condition. Typically, the pharmaceutical composition will be administered intravenously or subcutaneously.

[00169] Pharmaceutical compositions may be conveniently presented in unit dosage forms containing a predetermined amount of a multivalent anti-spike protein-binding molecule per dose. The amount of a multivalent anti-spike protein-binding molecule included in a unit dose will depend on the disease being treated, as well as other factors well known in the art. These unit dosages may be in the form of a lyophilized dry powder containing an amount of multivalent anti-spike protein-binding molecule suitable for a single administration or in the form of a liquid. Dry powder unit dosage forms may be packaged in a kit with a syringe, an appropriate amount of diluent and / or other components useful for administration.Unit doses in liquid form can be conveniently supplied in the form of a pre-filled syringe containing an amount of multivalent anti-spike protein-binding molecule suitable for a single administration.

[00170] Pharmaceutical compositions may also be supplied in bulk, containing quantities of multivalent anti-spike protein-binding molecules suitable for multiple administrations.

[00171] Pharmaceutical compositions can be prepared for storage as lyophilized formulations or aqueous solutions by mixing a multivalent anti-spike protein-binding molecule of the desired degree of purity with pharmaceutically acceptable carriers, excipients or optional stabilizers commonly employed in the art (all of which are mentioned Petition 870250096939, dated 10 / 23 / 2025, pp. 113 / 154 99 / 129 of these are referred to here as “carriers”), that is, buffering agents, stabilizing agents, preservatives, isotonic agents, non-ionic detergents, antioxidants, and other miscellaneous additives. See Remington's Pharmaceutical Sciences, 16th edition (Osol, ed. 1980). These additives must not be toxic to receptors at the dosages and concentrations used.

[00172] Buffering agents help maintain pH in a range that approximates physiological conditions. They can be present in a wide variety of concentrations, but are typically found in concentrations ranging from about 2 mM to about 50 mM. Suitable buffering agents for use with the present disclosure include organic and inorganic acids and salts thereof, such as citrate buffers (e.g., monosodium citrate-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture, etc.), succinate buffers (e.g., succinic acid-monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture, etc.), tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaric acid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.).), fumarate buffers (e.g., mixture of fumaric acid-monosodium fumarate, mixture of fumaric acid-disodium fumarate, mixture of monosodium fumarate-disodium fumarate, etc.), gluconate buffers (e.g., gluconic acid-sodium gluconate mixture, mixture of gluconic acid-sodium hydroxide, mixture of gluconic acid-potassium gluconate, etc.), oxalate buffers (e.g., mixture of oxalic acid-sodium oxalate, mixture of oxalic acid-sodium hydroxide, mixture of oxalic acid-potassium oxalate, etc.), lactate buffers (e.g., mixture of lactic acid-sodium lactate, mixture of lactic acid-sodium hydroxide, Petition 870250096939, dated 10 / 23 / 2025, page. 114 / 154. 100 / 129 Lactic acid-potassium lactate mixture, etc.) and acetate buffers (e.g., acetic acid-sodium acetate mixture, acetic acid-sodium hydroxide mixture, etc.). In addition, phosphate buffers, histidine buffers, and trimethylamine salts, such as Tris, may be used.

[00173] Preservatives may be added to retard microbial growth and may be added in amounts ranging from 0.2% to 1% (by weight / volume). Suitable preservatives for use with this disclosure include phenol, benzyl alcohol, metacresol, methylparaben, propylparaben, octadecyldimethylbenzylammonium chloride, benzalkonium halides (e.g., chloride, bromide and iodide), hexamethonium chloride and alkylparabens such as methylparaben or propylparaben, catechol, resorcinol, cyclohexanol and 3-pentanol. Isotonic agents, sometimes known as "stabilizers," may be added to ensure the isotonicity of the liquid compositions of the present disclosure and include polyhydric sugar alcohols, for example, trihydric or higher sugar alcohols such as glycerin, erythritol, arabitol, xylitol, sorbitol, and mannitol.Stabilizers refer to a broad category of excipients that can vary in function, from a bulking agent to an additive that solubilizes the therapeutic agent or helps prevent denaturation or adhesion to the container wall. Typical stabilizers may be polyhydric sugar alcohols (listed above); amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc., organic sugars or sugar alcohols such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol and the like, including cyclitols such as inositol; polyethylene glycol; amino acid polymers; Reducing agents containing sulfur, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, etc. Petition 870250096939, dated 10 / 23 / 2025, pp. 115 / 154 101 / 129 monothioglycerol and sodium thiosulfate; low molecular weight polypeptides (e.g., peptides of 10 residues or less); proteins such as human serum albumin, bovine serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; monosaccharides such as xylose, mannose, fructose, glucose; disaccharides such as lactose, maltose, sucrose, and trehalose; and trisaccharides such as raffinose; and polysaccharides such as dextran. Stabilizers may be present in amounts ranging from 0.5 to 10% by weight per multivalent molecule of anti-spike protein binding.

[00174] Non-ionic surfactants or detergents (also known as “wetting agents”) can be added to help solubilize the glycoprotein, as well as to protect the glycoprotein against agitation-induced aggregation, which also allows the formulation to be exposed to shear surface tension without causing protein denaturation. Suitable non-ionic surfactants include polysorbates (20, 80, etc.), polyoxamers (184, 188, etc.) and pluronic polyols. Non-ionic surfactants can be present in a range of about 0.05 mg / ml to about 1.0 mg / ml, for example, about 0.07 mg / ml to about 0.2 mg / ml.

[00175] Other miscellaneous excipients include bulking agents (e.g., starch), chelating agents (e.g., EDTA), antioxidants (e.g., ascorbic acid, methionine, vitamin E) and cosolvents.

[00176] The multivalent anti-spike protein-binding molecules of the disclosure can be formulated as pharmaceutical compositions comprising the multivalent anti-spike protein-binding molecules, for example, containing one or more pharmaceutically acceptable excipients or carriers. To prepare pharmaceutical or sterile compositions that include the multivalent anti-spike protein-binding molecules of the present disclosure, a preparation Petition 870250096939, dated 10 / 23 / 2025, pp. 116 / 154 102 / 129 multivalent anti-spike protein-binding molecule can be combined with one or more pharmaceutically acceptable excipients or carriers.

[00177] For example, formulations of multivalent anti-spike protein-binding molecules can be prepared by mixing multivalent anti-spike protein-binding molecules with physiologically acceptable carriers, excipients, or stabilizers in the form of, for example, lyophilized powders, pastes, aqueous solutions, lotions, or suspensions (see, for example, Hardman et al., 2001, Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro, 2000, Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al. Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.), 1990, Pharmaceutical Dosage Forms: Dispersal Systems, Marcel Dekker, NY; 6.9. Therapeutic Indications and Treatment Methods

[00178] This disclosure provides methods for the use and applications of multivalent anti-spike protein binding molecules.

[00179] In certain respects, disclosure provides a method of preventing or treating a disease or condition in which an interaction between a coronavirus RBD and cellular ACE2 is implicated. In some embodiments, the disease or condition is prevented or treated by neutralizing the spike protein. In several embodiments, neutralization of spike proteins comprises (a) inhibiting the ability of the spike protein to bind to a receptor such as ACE2, (b) inhibiting the cleavage of the spike protein by a protease such as Petition 870250096939, dated 10 / 23 / 2025, pp. 117 / 154 103 / 129 TMPRSS2, (c) inhibit the spike protein from mediating (i) viral entry into a host cell or (ii) viral replication in a host cell, or (d) any combination of two, three, or all four items from (a), (b), (c)(i), and (c)(ii).

[00180] Thus, in some embodiments, multivalent anti-spike protein-binding molecules and pharmaceutical compositions of the disclosure can be used to inhibit an interaction between a coronavirus RBD and cellular ACE2. In some embodiments, the disclosure provides methods to inhibit the interaction between the SARS-CoV RBD. In other embodiments, the disclosure provides methods to inhibit the interaction between the SARS-CoV-2 RBD. Thus, in some embodiments, the disclosure provides methods to inhibit an interaction between a coronavirus RBD and cellular ACE2, including administering to an individual in need of the same a multivalent pharmaceutical composition of anti-spike protein-binding molecule, as described in this document.

[00181] In some embodiments, the disclosure provides methods of administering a multivalent pharmaceutical composition of an anti-spike protein-binding molecule, as described in this document, to an individual who has been exposed to a coronavirus but has not been diagnosed with an infection. In other embodiments, the subject has tested positive for a coronavirus but is asymptomatic. In other embodiments, the individual has tested positive for coronavirus and is pre-symptomatic. In other embodiments, the subject has tested positive for a coronavirus and is symptomatic. In other embodiments, the individual has developed COVID-19 or another coronavirus-mediated disease or condition.

[00182] In some modalities, the disclosure provides a method for reducing the severity of coronavirus infection, which comprises administering to an individual in need the same composition Petition 870250096939, dated 10 / 23 / 2025, pp. 118 / 154 104 / 129 multivalent pharmaceutical application of the antispike protein-binding molecule, as described in this document.

[00183] In some other embodiments, the disclosure provides a method of reducing the viral load of a coronavirus, which comprises administering to an individual in need thereof the multivalent pharmaceutical composition of the antispike protein binding molecule, as described in this document.

[00184] In other embodiments, the disclosure provides a method of preventing disease progression in an individual with coronavirus infection, comprising administering to an individual in need the pharmaceutical composition of the multivalent anti-spike protein-binding molecule, as described in this document.

[00185] In some embodiments, the disclosure provides a method for reducing the duration of a coronavirus infection, comprising administering to an individual in need thereof the multivalent pharmaceutical composition of anti-spike protein binding molecule, as described in this document.

[00186] In other embodiments, the disclosure provides a method for reducing the risk of serious illness or death in an individual with coronavirus infection, comprising administering to an individual in need the pharmaceutical composition of the multivalent anti-spike protein-binding molecule, as described in this document. 7. Numbered Modalities

[00187] Although several specific embodiments have been illustrated and described, it will be appreciated that various changes may be made without departing from the spirit and scope of the disclosure(s). The present disclosure is exemplified by the numbered embodiments presented below. Unless otherwise specified, Petition 870250096939, dated 10 / 23 / 2025, pp. 119 / 154 105 / 129 The characteristics of any of the concepts, aspects and / or modalities described in the detailed description above are applicable mutatis mutandis to any of the modalities numbered below.

[00188] In the embodiments numbered below, the multimerization moieties are preferably derived from a mammalian multimerization moiety (e.g., a human Fc domain), the antigen-binding domains are preferably from a human or humanized antibody, and the subjects are preferably mammals (e.g., humans).

[00189] 1. A multivalent antispike protein-binding molecule comprising at least 4 antispike protein antigen-binding domains (ABDs) operationally linked by one or more multimerization moieties.

[00190] 2. The multivalent anti-spike protein binding molecule of modality 1, which is tetravalent.

[00191] 3. The multivalent anti-spike protein-binding molecule of modality 1 or modality 2, in which the antigen-binding domains (ABDs) are human or humanized.

[00192] 4. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 3, wherein one or more (or all) ABDs comprise CDR sequences set out in any of Tables 1 to 3.

[00193] 5. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 3, wherein one or more (or all) ABDs comprise CDR sequences set out in any of Tables 1 to 4.

[00194] 6. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) of the ABDs comprise the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences of an antibody established in Ta Petition 870250096939, dated 10 / 23 / 2025, pp. 120 / 154 106 / 129 beautiful 1.

[00195] 7. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) of the ABDs comprise the CDR-H1, CDR-H2, CDRH3, CDR-L1, CDR-L2 and CDR-L3 sequences of an antibody established in Table 2.

[00196] 8. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) of the ABDs comprise the CDR-H1, CDR-H2, CDRH3, CDR-L1, CDR-L2 and CDR-L3 sequences of an antibody established in Table 3.

[00197] 9. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) of the ABDs comprise the CDR-H1, CDR-H2, CDRH3, CDR-L1, CDR-L2, and CDR-L3 sequences of an antibody established in Table 4.

[00198] 10. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) ABDs comprise: (a) a VH comprising CDR-H1, CDR-H2 and CDR-H3 with amino acid sequences of SEQ ID NO: 579, 580 and 581, respectively; and (b) a VL comprising CDR-L1, CDR-L2 and CDR-L3 with amino acid sequences of SEQ ID NO: 398, 372 and 583, respectively.

[00199] 11. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) ABDs comprise: (a) a VH comprising CDR-H1, CDR-H2 and CDR-H3 with amino acid sequences of SEQ ID NO: 507, 508 and 509, Petition 870250096939, dated 10 / 23 / 2025, pp. 121 / 154 107 / 129 respectively; and (b) a VL comprising CDR-L1, CDR-L2 and CDR-L3 with amino acid sequences of SEQ ID NO: 511, 407 and 512, respectively.

[00200] 12. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) ABDs comprise: (a) a VH comprising CDR-H1, CDR-H2 and CDR-H3 with amino acid sequences of SEQ ID NO: 450, 451 and 452, respectively; and (b) a VL comprising CDR-L1, CDR-L2 and CDR-L3 with amino acid sequences of SEQ ID NO: 454, 415 and 455, respectively.

[00201] 13. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 3, wherein one or more (or all) ABDs comprise VH and VL sequences set out in any of Tables 1 to 3.

[00202] 14. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 3, wherein one or more (or all) ABDs comprise VH and VL sequences set out in any of Tables 1 to 4.

[00203] 15. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) ABDs comprise VH and VL sequences of an antibody established in Table 1.

[00204] 16. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) of the ABDs comprise VH and VL sequences of an antibody established in Table 2.

[00205] 17. The multivalent anti-spike protein binding molecule Petition 870250096939, dated 10 / 23 / 2025, pp. 122 / 154 108 / 129 of any of the embodiments 1 to 5, in which one or more (or all) of the ABDs comprise VH and VL sequences of an antibody established in Table 3.

[00206] 18. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) ABDs comprise VH and VL sequences of an antibody established in Table 4.

[00207] 19. The multivalent anti-spike protein binding molecule of any of embodiments 1 to 5, wherein one or more (or all) ABDs comprise (a) a VH with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:578 and (b) a VL with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:582.

[00208] 20. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) ABDs comprise (a) a VH comprising the amino acid sequence of SEQ ID NO:578 and (b) a VL comprising the amino acid sequence of SEQ ID NO:582.

[00209] 21. The multivalent anti-spike protein binding molecule of any of embodiments 1 to 5, wherein one or more (or all) ABDs comprise (a) a VH with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:506 and (b) a VL with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:510. Petition 870250096939, dated 10 / 23 / 2025, pp. 123 / 154 109 / 129

[00210] 22. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) ABDs comprise (a) a VH comprising the amino acid sequence of SEQ ID NO:506 and (b) a VL comprising the amino acid sequence of SEQ ID NO:510.

[00211] 23. The multivalent anti-spike protein binding molecule of any of embodiments 1 to 5, wherein one or more (or all) ABDs comprise (a) a VH with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:449 and (b) a VL with at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:453.

[00212] 24. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 5, wherein one or more (or all) ABDs comprise (a) a VH comprising the amino acid sequence of SEQ ID NO:449 and (b) a VL comprising the amino acid sequence of SEQ ID NO:453.

[00213] 25. The multivalent anti-spike protein-binding molecule of any of the embodiments 1 to 24, in which one or more (or all) ABDs are neutralizing.

[00214] 26. The multivalent anti-spike protein-binding molecule of any of the embodiments 1 to 25, which is capable of neutralizing the BA.1 variant of SARS-CoV-2.

[00215] 27. The multivalent anti-spike protein-binding molecule of any of the embodiments 1 to 25, which is capable of neutralizing the BA.2 variant of SARS-CoV-2.

[00216] 28. The multivalent anti-spike protein-binding molecule of any of the embodiments 1 to 27, where one or more meta Petition 870250096939, dated 10 / 23 / 2025, pp. 124 / 154 110 / 129 des de multimerização são domínios Fc.

[00217] 29. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 28, comprising two antibody halves, each comprising an Fc domain.

[00218] 30. The multivalent anti-spike protein-binding molecule of mode 28 or mode 29, in which the Fc domains are IgG domains.

[00219] 31. The multivalent anti-spike protein-binding molecule of modality 30, in which the IgG domains are IgG1 domains.

[00220] 32. The multivalent anti-spike protein-binding molecule of modality 30, in which the IgG domains are IgG4 domains.

[00221] 33. The multivalent anti-spike protein-binding molecule of any of the embodiments 29 to 32, wherein each half antibody comprises two ABDs.

[00222] 34. The multivalent anti-spike protein binding molecule of any of embodiments 1 to 33, comprising: (a) a first antibody medium comprising: (i) a first ABD, which typically comprises a first VH and a first VL; (ii) an optional first linker; (iii) a second ABD, which typically comprises a second VH and a second VL; (iv) an optional first hinge domain; and (v) a first Fc domain; and (b) a second antibody half comprising: (i) a third ABD, which typically comprises a third VH and a third VL; (ii) an optional second linker; (iii) an ABD room, which typically comprises a VH room and a VL room; Petition 870250096939, dated 10 / 23 / 2025, pp. 125 / 154 111 / 129 (iv) an optional second hinge domain; and (v) a second Fc domain.

[00223] 35. The multivalent anti-spike protein binding molecule of any of the embodiments 1 to 33: (a) a first antibody medium comprising: (i) a first ABD, which typically comprises a first VH and a first VL; (ii) an optional first hinge domain; (iii) a first Fc domain; (iv) an optional first linker; and (v) a second ABD, which typically comprises a second VH and a second VL; and (b) a second antibody half comprising: (i) a third ABD, which typically comprises a third VH and a third VL; (ii) an optional second hinge domain; (iii) a second Fc domain; (iv) an optional second linker; and (v) an ABD quarter, which typically comprises a VH quarter and a VL quarter.

[00224] 36. The multivalent anti-spike protein binding molecule of embodiment 34 or embodiment 35, in which the first Fc domain and the second Fc domain form an Fc homodimer.

[00225] 37. The multivalent anti-spike protein-binding molecule of embodiment 34 or embodiment 35, in which the first Fc domain and the second Fc domain form an Fc heterodimer.

[00226] 38. The multivalent anti-spike protein-binding molecule of modality 37, wherein the first Fc domain or the second Fc domain comprises knob mutations and the other Fc domain comprises hole mutations. Petition 870250096939, dated 10 / 23 / 2025, pp. 126 / 154 112 / 129

[00227] 39. The multivalent anti-spike protein-binding molecule of either embodiment 34 to 38, in which the first Fc domain or the second Fc domain comprises a star mutation.

[00228] 40. The multivalent anti-spike protein-binding molecule of any of the embodiments 34 to 39, comprising a first hinge domain and a second hinge domain.

[00229] 41. The multivalent anti-spike protein-binding molecule of modality 40, wherein the first hinge domain and the second hinge domain are IgG1 hinge domains.

[00230] 42. The multivalent anti-spike protein-binding molecule of modality 40, wherein the first hinge domain and the second hinge domain are IgG4 hinge domains.

[00231] 43. The multivalent anti-spike protein-binding molecule of modality 40, in which the first hinge domain and the second hinge domain are chimeric hinge domains.

[00232] 44. A multivalent anti-spike protein binding molecule according to any one of claims 34 to 43, which does not have the first linker and the second linker.

[00233] 45. The multivalent anti-spike protein binding molecule of any of the embodiments 34 to 43, comprising the first ligand and the second ligand.

[00234] 46. The multivalent anti-spike protein binding molecule of embodiment 45, wherein the first ligand and the second ligand are independently selected from (a) 1 to 60 amino acids in length, or (b) 1 to 40 amino acids in length, or (c) any range or value of ligand length set forth in Section 6.6.

[00235] 47. The multivalent anti-spike protein binding molecule of embodiment 45 or embodiment 46, wherein the first ligand and the second ligand comprise a glycine-serine sequence, opci Petition 870250096939, dated 10 / 23 / 2025, pp. 127 / 154 113 / 129 respectively where the glycine-serine sequence is (GnS)x (SEQ ID NO:87), where n= 0-5 and x= 1-6.

[00236] 48. The multivalent anti-spike protein binding molecule of any of the embodiments 34 to 47, wherein the first, second, third and fourth ABDs are the same.

[00237] 49. The multivalent anti-spike protein binding molecule of any of the embodiments 34 to 48, where the first and second ABDs are the same.

[00238] 50. The multivalent anti-spike protein binding molecule of modality 49, where the third and fourth ABDs are the same.

[00239] 51. The multivalent anti-spike protein binding molecule of modality 50, where the third and fourth ABDs are different from the first and second ABDs.

[00240] 52. The multivalent anti-spike protein binding molecule of any of the embodiments 34 to 47, wherein the first and third ABDs are the same.

[00241] 53. The multivalent anti-spike protein binding molecule of modality 52, where the second and fourth ABDs are the same.

[00242] 54. The multivalent anti-spike protein binding molecule of modality 53, where the second and fourth ABDs are different from the first and third ABDs.

[00243] 55. The multivalent anti-spike protein-binding molecule of any of embodiments 1 to 54, wherein at least two of the ABDs are Fab domains, optionally wherein the Fab domains are not single-stranded Fab domains.

[00244] 56. The multivalent anti-spike protein-binding molecule of any of the embodiments 1 to 54, where all ABDs are Fab domains, optionally where the Fab domains are not single-stranded Fab domains.

[00245] 57. The multivalent anti-spike protein binding molecule Petition 870250096939, dated 10 / 23 / 2025, pp. 128 / 154 114 / 129 of any of the modalities 1 to 54, in which at least two of the ABDs are scFvs.

[00246] 58. The multivalent anti-spike protein-binding molecule of any of the embodiments 1 to 54, where all ABDs are scFvs.

[00247] 59. The multivalent anti-spike protein binding molecule of any of the embodiments 1 to 58, which is monospecific.

[00248] 60. The multivalent anti-spike protein binding molecule of any of the embodiments 1 to 58, which is multispecific.

[00249] 61. The multivalent anti-spike protein binding molecule of modality 60, which is bispecific.

[00250] 62. A multivalent antispike protein binding molecule comprising at least 4 spike protein binding means operationally linked by one or more multimerization moieties.

[00251] 63. The multivalent anti-spike protein binding molecule of modality 62, which is tetravalent for spike protein binding media.

[00252] 64. The multivalent anti-spike protein-binding molecule of modality 62 or 63, which has the capacity to neutralize the BA.1 variant of SARS-CoV-2.

[00253] 65. The multivalent anti-spike protein-binding molecule of modality 62 or 63, which has the capacity to neutralize the BA.2 variant of SARS-CoV-2.

[00254] 66. The multivalent anti-spike protein-binding molecule of any of the embodiments 62 to 65, in which one or more multimerization moieties are Fc domains.

[00255] 67. The multivalent anti-spike protein-binding molecule of any of the embodiments 62 to 65, comprising two antibody halves, each comprising an Fc domain. Petition 870250096939, dated 10 / 23 / 2025, pp. 129 / 154 115 / 129

[00256] 68. The multivalent anti-spike protein binding molecule of modality 66 or modality 67, in which the Fc domains are IgG domains.

[00257] 69. The multivalent anti-spike protein-binding molecule of modality 68, in which the IgG domains are IgG1 domains.

[00258] 70. The multivalent anti-spike protein-binding molecule of modality 68, in which the IgG domains are IgG4 domains.

[00259] 71. The multivalent spike protein-binding molecule of any of the embodiments 67 to 70, wherein each antibody half comprises two spike protein-binding means.

[00260] 72. The multivalent anti-spike protein binding molecule of any of embodiments 1 to 71, comprising: (a) a first antibody medium comprising: (i) a first means of binding to the spike protein; (ii) an optional first linker; (iii) a second means of binding to the spike protein; (iv) an optional first hinge domain; and (v) a first Fc domain; and (b) a second antibody half comprising: (i) a third means of binding to the spike protein; (ii) an optional second linker; (iii) a fourth means of binding to the spike protein; (iv) an optional second hinge domain; and (v) a second Fc domain.

[00261] 73. The multivalent anti-spike protein binding molecule of any of the embodiments 1 to 71: (a) a first antibody medium comprising: (i) a first means of binding to the spike protein; (ii) an optional first hinge domain; (iii) a first Fc domain; Petition 870250096939, dated 10 / 23 / 2025, pp. 130 / 154 116 / 129 (iv) an optional first linker; and (v) a second spike protein binding medium; and (b) a second antibody medium comprising: (i) a third means of binding to the spike protein; (ii) an optional second hinge domain; (iii) a second Fc domain; (iv) an optional second linker; and (v) a fourth medium for binding the spike protein.

[00262] 74. The multivalent anti-spike protein-binding molecule of embodiment 72 or embodiment 73, in which the first Fc domain and the second Fc domain form an Fc homodimer.

[00263] 75. The multivalent anti-spike protein-binding molecule of embodiment 72 or embodiment 73, in which the first Fc domain and the second Fc domain form an Fc heterodimer.

[00264] 76. The multivalent anti-spike protein-binding molecule of modality 75, wherein the first Fc domain or the second Fc domain comprises knob mutations and the other Fc domain comprises hole mutations.

[00265] 77. The multivalent anti-spike protein-binding molecule of either embodiment 72 to 76, in which the first Fc domain or the second Fc domain comprises a star mutation.

[00266] 78. The multivalent anti-spike protein-binding molecule of any of the embodiments 72 to 77, comprising a first hinge domain and a second hinge domain.

[00267] 79. The multivalent anti-spike protein-binding molecule of modality 78, wherein the first hinge domain and the second hinge domain are IgG1 hinge domains.

[00268] 80. The multivalent anti-spike protein-binding molecule of modality 78, in which the first hinge domain and the second hinge domain are IgG4 hinge domains. Petition 870250096939, dated 10 / 23 / 2025, pp. 131 / 154 117 / 129

[00269] 81. The multivalent anti-spike protein-binding molecule of modality 78, in which the first hinge domain and the second hinge domain are chimeric hinge domains.

[00270] 82. A multivalent anti-spike protein binding molecule according to any one of claims 72 to 81, which does not have the first linker and the second linker.

[00271] 83. The multivalent anti-spike protein binding molecule of any of the embodiments 72 to 81, comprising the first ligand and the second ligand.

[00272] 84. The multivalent anti-spike protein-binding molecule of embodiment 83, wherein the first ligand and the second ligand are independently selected from (a) 1 to 60 amino acids in length, or (b) 1 to 40 amino acids in length, or (c) any range or value of ligand length set forth in Section 6.6.

[00273] 85. The multivalent anti-spike protein binding molecule of embodiment 83 or embodiment 84, wherein the first ligand and the second ligand comprise a glycine-serine sequence, optionally wherein the glycine-serine sequence is (GnS)x (SEQ ID NO:87), where n= 0-5 ex = 1-6.

[00274] 86. The multivalent anti-spike protein-binding molecule of any of embodiments 62 to 85, wherein the first half of the antibody comprises a first Fab with the first spike protein-binding medium.

[00275] 87. The multivalent anti-spike protein binding molecule of any of embodiments 62 to 85, wherein the first antibody half comprises a first scFv comprising the first spike protein binding half.

[00276] 88. The multivalent anti-spike protein binding molecule of any of the embodiments 62 to 87, in which the first means Petition 870250096939, dated 10 / 23 / 2025, pp. 132 / 154 118 / 129 antibody comprises a second Fab that comprises the second means of binding to the spike protein.

[00277] 89. The multivalent anti-spike protein-binding molecule of any of embodiments 62 to 87, wherein the first half of the antibody comprises a second scFv comprising the second spike protein-binding medium.

[00278] 90. The multivalent anti-spike protein-binding molecule of any of embodiments 62 to 89, wherein the second half of the antibody comprises a third Fab comprising the third spike protein-binding means.

[00279] 91. The multivalent anti-spike protein binding molecule of any of embodiments 62 to 89, wherein the second antibody medium comprises a third scFv comprising the third spike protein binding medium.

[00280] 92. The multivalent anti-spike protein binding molecule of any of embodiments 62 to 91, wherein the second antibody half comprises a fourth scFv comprising the fourth spike protein binding half.

[00281] 93. The multivalent anti-spike protein binding molecule of any of embodiments 62 to 91, wherein the second antibody half comprises a fourth scFv comprising the fourth spike protein binding half.

[00282] 94. The multivalent anti-spike protein binding molecule of any of the embodiments 62 to 93 that is monospecific.

[00283] 95. The multivalent anti-spike protein binding molecule of any of the embodiments 62 to 93, which is multispecific.

[00284] 96. The multivalent anti-spike protein binding molecule of modality 95, which is bispecific.

[00285] 97. A nucleic acid or a plurality of nucleic acids encoding the multivalent anti-protein-binding molecule Petition 870250096939, dated 10 / 23 / 2025, pp. 133 / 154 119 / 129 spike from any of the modalities 1 to 96.

[00286] 98. A host cell engineered to express the multivalent anti-spike protein-binding molecule of any embodiment 1 to 96 or the nucleic acid(s) of embodiment 97.

[00287] 99. A method for producing the multivalent anti-spike protein-binding molecule of any embodiment 1 to 96, comprising culturing the host cell of embodiment 98 and recovering the multivalent anti-spike protein-binding molecule expressed by it.

[00288] 100. A pharmaceutical composition comprising the multivalent anti-spike protein-binding molecule of any of embodiments 1 to 96 and an excipient.

[00289] 101. A method of treating a disease caused by coronavirus, comprising administering to an individual in need thereof the multivalent anti-spike protein-binding molecule of any of embodiments 1 to 96 or the pharmaceutical composition of embodiment 100.

[00290] 102. A method for inhibiting an interaction between a coronavirus RBD and cellular ACE2, comprising administering to an individual in need thereof the multivalent anti-spike protein binding molecule of any of embodiments 1 to 96 or the pharmaceutical composition of embodiment 100.

[00291] 103. A method for neutralizing the coronavirus spike protein in vivo, comprising administering to an individual in need thereof the multivalent anti-spike protein-binding molecule of any of embodiments 1 to 96 or the pharmaceutical composition of embodiment 100.

[00292] 104. A method for inhibiting protease-mediated cleavage (e.g., TMPRSS2-mediated cleavage) of a coronavirus spike protein in vivo, comprising administering to an individual Petition 870250096939, dated 10 / 23 / 2025, pp. 134 / 154 120 / 129 duo in need of the same multivalent spike protein binding molecule of either embodiment 1 to 96 or the pharmaceutical composition of embodiment 100.

[00293] 105. A method of inhibiting viral entry of a coronavirus into a host cell in an individual, comprising administering to an individual in need thereof the multivalent anti-spike protein-binding molecule of any of embodiments 1 to 96 or the pharmaceutical composition of embodiment 100.

[00294] 106. A method for inhibiting the replication of a coronavirus spike protein in a host cell in an individual comprising administering to an individual in need thereof the multivalent spike protein binding molecule of any of embodiments 1 to 96 or the pharmaceutical composition of embodiment 100.

[00295] 107. A method for reducing the severity of coronavirus infection, comprising administering to an individual in need thereof the multivalent antispike protein-binding molecule of any of embodiments 1 to 96 or the pharmaceutical composition of embodiment 100.

[00296] 108. A method for reducing the viral load of a coronavirus, comprising administering to an individual in need thereof the multivalent anti-spike protein-binding molecule of any of embodiments 1 to 96 or the pharmaceutical composition of embodiment 100.

[00297] 109. A method of preventing disease progression in an individual with coronavirus infection, comprising administering to an individual in need thereof the multivalent anti-spike protein-binding molecule of any of embodiments 1 to 96 or the pharmaceutical composition of embodiment 100.

[00298] 110. A method for reducing the duration of an infection Petition 870250096939, dated 10 / 23 / 2025, pp. 135 / 154 121 / 129 for coronavirus, which comprises administering to an individual in need the multivalent anti-spike protein-binding molecule of any of the embodiments 1 to 96 or the pharmaceutical composition of embodiment 100.

[00299] 111. A method for reducing the risk of serious illness or death in an individual with coronavirus infection, comprising administering to an individual in need thereof the multivalent anti-spike protein-binding molecule of any of embodiments 1 to 96 or the pharmaceutical composition of embodiment 100.

[00300] 112. The method of any of the modalities 101 to 111, where the coronavirus is SARS-CoV.

[00301] 113. The method of any of the modalities 101 to 111, where the coronavirus is SARS-CoV-2. 8. EXAMPLES 8.1. Materials and Methods

[00302] 8.1.1. Construction and Production of Tetravalent Fab-Fc AF Antibodies

[00303] Monospecific and bispecific tetravalent 2x2 N-Fab AF antibodies were constructed by connecting two identical VH-CH1 fragments linked via the (G4S)x3 ligand (SEQ ID NO:74) to the N-terminal end of an Fc fragment via the hinge region (Figures 1A and 1B). 2x2 C-Fab AF antibodies were constructed by connecting a VH-CH1 fragment to the N-terminal end of an Fc fragment, which, in turn, is linked to another identical VH-CH1 fragment at its C-terminal end via a (G4S)x3 ligand (SEQ ID NO:74) (Figures 1C and 1D). To achieve consistency in production, all AF antibodies were incorporated with “knob-in-hole” mutations in the Fc region to promote the formation of the Fc heterodimer, a step subsequent to the assembly of the Red-Ox annealing.

[00304] All antibodies were expressed separately in Petition 870250096939, dated 10 / 23 / 2025, pp. 136 / 154 122 / 129 Expi293™ cells (ThermoFisher) were used as antibody media, designated “knob chains” and “hole chains*” by transient transfection, following the manufacturer's protocol. Antibodies were purified from the supernatant using Hitrap Protein G HP (Cytiva). After single-step elution, the antibodies were neutralized, dialyzed in a final buffer of phosphate-buffered saline (PBS) with 5% glycerol, aliquoted, and stored at -80 °C.

[00305] For the Red-Ox annealing set, a solution containing 0.5 mg / ml of button chains, 0.5 mg / ml of hole chains*, 50 mM Tris pH 8.0, 25 mM 2-MEA, and 50 mM L-arginine was prepared. The reaction was carried out at 37 °C for 5 hours and then at 4 °C overnight. The product was desalted in a final phosphate-buffered saline (PBS) solution with 5% glycerol using Zeba Spin Desalting Columns (ThermoFisher), aliquoted, and stored at -80 °C.

[00306] The elution fraction material was subsequently polished to increase the purity of the species of interest by SEC. Thus, a Superdex 200 10 / 300GL column (Cytiva) was used at a flow rate of 0.75 ml / min, in 1xDPBS running buffer, 5% glycerol, pH 7.4. The fractions of interest were pooled and concentrated. 8.1.2. Pseudovirus / Variant SARS-CoV-2 Neutralization Assay

[00307] Vero cells were cultured in DMEM medium with high glucose sodium pyruvate and without glutamine, supplemented with 10% heat-inactivated FBS and penicillin / streptomycin / glutamine (complete DMEM) and seeded at 20,000 cells / well in 96-well black / clear background cell culture plates. On the day of the assay, antibodies were diluted to a 2X assay concentration and serially diluted 3 times, for a total of 11 concentrations (e.g., 40 nM to 677.4 fM for controls). Petition 870250096939, dated 10 / 23 / 2025, pp. 137 / 154 123 / 129 of IgG and all constructs in Table 10). The concentrations used for the constructs in Table 9 were from 13.3 nM to 225.8 fM). All dilutions were performed using infection media consisting of DMEM medium with high glucose content, without sodium pyruvate / with glutamine, supplemented with sodium pyruvate, 0.2% BSA without IgG and gentamicin.

[00308] The pVSV-Luc-SARS-CoV2-S pseudoviruses used here were non-replicating VSV-DGs, which expressed a dual reporter of GFP / firefly luciferase in place of their native glycoprotein, and pseudotyped with SARS-CoV-2 Spike. The SARS-CoV-2 pseudoviruses or variants were diluted 1:4 in infection medium and then combined 1:1 with antibody dilutions to a final pseudovirus / variant dilution of 1:8 and final test article concentrations of 20 nM to 338.7 fM for all controls and IgG constructs shown in Table 10, or 6.7 nM to 112.9 fM for constructs shown in Table 9, and incubated at room temperature for 30 minutes. Next, the culture medium was removed from the cells and the combined antibodies and pseudoviruses / variants were added at 100 µL / well in duplicate to the wells, which were then incubated at 37°C, 5% CO2 for 24 hours.Twenty-four hours after infection, the media was removed from the wells and the cells were lysed using 100 µl / well of Glo-Lysis buffer (Promega). Immediately before luminescence reading on the Spectramax i3X plate reader, 100 µl of prepared Bright-Glo substrate (Promega) were added to the lysates. The results were exported to Microsoft Excel, where the percentage of neutralization was calculated using the following equation: % neutralization = ((1-(average control well value) / (virus control - average control)) x 100. % neutralization is then plotted on GraphPad Prism and analyzed using nonlinear regression: log(inhibitor) vs. response - Variable slope (four parameters) to calculate the IC50 values. Petition 870250096939, dated 10 / 23 / 2025, pp. 138 / 154 124 / 129 8.2. Example 1: Neutralization Activity of 2x2 N-Fab Tetravalent FAs

[00309] Using five different Fab metamorphoses against the SARS-CoV-2 S protein (REGN10933, 10985, 10987, 14256 and 14315; which comprises the VH and VL domains of mAb10933, mAb10985, mAb10987, mAb14256, and mAb14315, as set out in Tables 3 and 4, respectively), a total of five monospecific and 10 bispecific 2x2 N-Fab AF constructs were generated as described in Section 8.1.1 and are listed in Table 7. Cell cultures and virus neutralization assays were conducted as described in Section 8.1.2. Table 7 Exemplary Constructs of 2x2 N-Fab AF Tetravalents Construct Name Fab Specificity Fab Knob Fab Hole* COVAF-16 Monospecific REGN10933 REGN10933 COVAF-17 Bispecific REGN10933 REGN14256 COVAF-18 Bispecific REGN10987 REGN10933 COVAF-19 Bispecific REGN10933 REGN14315 COVAF-20 Bispecific REGN10985 REGN10933 COVAF-21 Monospecific REGN14256 REGN14256 COVAF-22 Bispecific REGN14256 REGN10987 COVAF-23 Bispecific REGN14315 REGN14256 COVAF-24 Bispecific REGN14256 REGN10985 COVAF-25 Monospecific REGN10987 REGN10987 COVAF-26 Bispecific REGN10987 REGN14315 COVAF-27 Bispecific REGN10985 REGN10987 COVAF-28 Monospecific REGN14315 REGN14315 COVAF-29 Bispecific REGN14315 REGN10985 COVAF-30 Monospecific REGN10985 REGN10985 COVAF-46 Bispecific REGN10933 REGN14287 COVAF-47 Bispecific REGN14287 REGN14256 COVAF-48 Bispecific REGN10987 REGN14287 COVAF-49 Bispecific REGN14287 REGN14315 COVAF-50 Bispecific REGN10985 REGN14287 COVAF-51 MonospecificREGN14287 REGN14287

[00310] The IC50 values ​​for neutralization of the SARS-CoV-2 pseudovirus or the variant of the 2x2 N-Fab AF constructs were compared. Petition 870250096939, dated 10 / 23 / 2025, pp. 139 / 154 125 / 129 to the IC50 values ​​of IgG mAb controls with the same Fab portion. In general, the monospecific 2x2 N-Fab AF constructs were more effective at neutralizing the SARS-CoV-2 pseudovirus, D614G, than the IgG mAb controls (Figure 2A). This observation suggests that an increase in valence may help boost neutralization activities. Most bispecific 2x2 N-Fab AF constructs also performed better than their IgG mAb controls. However, the change in neutralization activity depended on which Fab arms were used to generate the constructs.

[00311] The ability of the monospecific and bispecific anti-SARS-CoV-2 2x2 N-Fab constructs to neutralize the SARS-CoV-2 BA.2 variant depended entirely on which Fab arms were used to generate the constructs. For example, constructs lacking the Fab molecules REGN14315 and REGN10987 failed to neutralize the BA.2 variant.However, the inclusion of REGN14315 or REGN10987 in the construct allowed the constructs to neutralize the BA variant. 2 (Figure 2B). 8.3. Example 2: Neutralization Activity of 2x2 C-Fab Tetravalent FAs

[00312] As performed in Example 1, the same five Fab moieties were used to generate a total of five monospecific and 10 bispecific 2x2 C-Fab AF constructs, as described in Section 8.1.1 and listed in Table 8. Cell cultures and virus neutralization assays were conducted as described in Section 8.1.2. Table 8 2x2 C-Fab AF Tetravalent Constructs Examples Construct Name Fab Specificity Fab Knob Fab Hole* COVAF-31 Monospecific REGN10933 REGN10933 COVAF-32 Bispecific REGN10933 REGN14256 COVAF-33 Bispecific REGN10987 REGN10933 COVAF-34 Bispecific REGN10933 REGN14315 Petition 870250096939, dated 10 / 23 / 2025, pp. 140 / 154 126 / 129 Table 8 2x2 C-Fab AF Tetravalent Constructs Examples Construct Name Fab Specificity Fab Knob Fab Hole* COVAF-35 Bispecific REGN10985 REGN10933 COVAF-36 Monospecific REGN14256 REGN14256 COVAF-37 Bispecific REGN14256 REGN10987 COVAF-38 Bispecific REGN14315 REGN14256 COVAF-39 Bispecific REGN14256 REGN10985 COVAF-40 Monospecific REGN10987 REGN10987 COVAF-41 Bispecific REGN10987 REGN14315 COVAF-42 Bispecific REGN10985 REGN10987 COVAF-43 Monospecific REGN14315 REGN14315 COVAF-44 Bispecific REGN14315 REGN10985 COVAF-45 Monospecific REGN10985 REGN10985 COVAF-52 Bispecific REGN10933 REGN14287 COVAF-53 Bispecific REGN14287 REGN14256 COVAF-54 Bispecific REGN10987 REGN14287 COVAF-55 Bispecific REGN14287 REGN14315 COVAF-56 Bispecific REGN10985 REGN14287 COVAF-57 Monospecific REGN14287 REGN14287

[00313] The IC50 values ​​of neutralization of SARS-CoV-2 pseudovirus or variant 2x2 C-Fab AF constructs were compared to the IC50 values ​​of IgG mAb controls with the same Fab portion. In general, the monospecific 2x2 C-Fab AF constructs were more effective at neutralizing SARS-CoV-2 pseudovirus than the IgG mAb controls, except for COVAF36, which has the REGN14356 Fab portion (Figure 3A). As in Example 1, most of the bispecific 2x2 C-Fab AF constructs also performed better than their IgG mAb controls. Again, the change in neutralization activity depended on which Fab arms were used to generate the constructs.

[00314] The ability of the monospecific and bispecific 2x2 C-Fab constructs to neutralize the SARS-CoV-2 BA.2 variant again depended entirely on which Fab arms were used to generate the constructs. According to the observations from Example 1, the constructs without the Fab molecules REGN14315 and REGN10987 did not achieve Petition 870250096939, dated 10 / 23 / 2025, pp. 141 / 154 127 / 129 guided to neutralize variant BA.2. However, according to the 2x2 N-Fab screening, the inclusion of REGN14315 or REGN10987 in the construct allowed the 2x2 C-Fab AF constructs to neutralize variant BA.2 (Figure 3B).

[00315] Three selected 2x2 C-Fab strains, COVAF-40, 41, and 43, were purified using size exclusion chromatography and tested for potency and breadth coverage in the SARS-CoV-2 pseudovirus neutralization assay using various Omicron variants, including: BA.1, BA.2, BA.2.12.1, BA.4 / BA.5, and BA.4+BA.4.6 (Table 9). Compared to the parental IgG control, 2x2 C-Fab COV-AF40 (10987x10987) demonstrated greater broad neutralization potency against D614G and all tested Omicron variants compared to REGN10987 IgG. However, this improvement is not sufficient to provide protection against the individual variant of Omicron, as a power loss of 18 to 576 times is observed when compared to the neutralization power (IC50) of REGN 10987 against D614G (Table 9). Typist, change the following in the tables below: Table 9 Summary of Neutralization Activity of Pseudovinjs of the Main 2x2 C-Fab AFs against D614G Multiple Variants of Omicron IC50 (M) Fold Change in Relation to RI0M7 against D614G AF10 Format Arms REGN MW (kOa) D614G BA.1 BA.2 BA2.12.1 BA.4 / BA.5 BA.4 + R34&T (BA.4.6) D614G BA.1 BA.2 BA.2.12.1 BA.4 / BA.5 BA.4 + R34&T (BA.4.-S) 2x2 CFab CCVAF-40 10987X 10987 250 2.73E- 12 3 05E09 9.38E- 11 2.01E-10 2.40E- 10 3.17ΕΊ0 0.51 575.53 17.&9 37.88 45.22 59.77 COVAF43 14315x 14315 250 1 05E- 11 3.37E- 11 1.84E10 1 97E-10 Ί.35Ε- 10 2.68E-09 1.98 6.35 34.63 37.21 25.44 502.36 CCVAF-41 10987x 14315 250 848E^ 12 4 34E- 10 6.79E11 5 86E-11 8.82E- 11 1.12E-09 1.60 81.33 12.82 11.06 16.64 211.93 Ctrl rgG REGNT0987 10987 150 NC 1.06E* 09 1.48E-Õ9 9.33E- 10 1.25E-09 NC 199.09 278.92 176.15 236.08 REGN14315 14315 150 1.15E- 12 5.47E- 12 3S9E- 11 6.73E-11 4.97E- 11 1.35E-09 0.22 1.03 6.78 12.70 9.38 254.95 REGN14315+ REGN10987 14315+ 10987 150 3.68E12 1.69B 11 6.99E- 11 1.11E10 1.10E10 5.98E-10 0.70 3.18 13.18 20.97 20.74 131.78. NC. Not calculated 8.1. Example 3: 2x2 AF Separation Activity Based on REGN 14287 Tetravalent

[00316] As REGN14287 (which comprises the VH and VL domains of mAb14287, as set out in Table 4) targets a Petition 870250096939, dated 10 / 23 / 2025, pp. 142 / 154 128 / 129 epitope different from the 5 antibodies previously tested, a second set of 12 AF molecules (COVAF46-57) was generated by pairing REGN10933, 10987, 10985, 14315, and 14256 with the anchoring arm of REGN14287 in 2x2 N and C-Fab formats. Two 14287 x 14287 auto-pairing AF molecules were also made for comparison (Tables 7 and 8). These AFs, the corresponding parental IgGs, and the REGN10933 / 10987 combination were tested in the pseudovirus neutralization assay, as described in Section 8.1.2, using D614G and various Omicron variants. The neutralization power (IC50) and the IC50 doubling change of individual AF relative to the IC50 of REGN10933 / 10987 against D614G were determined.

[00317] Two tetravalent monospecific FAs, 2x2 N-Fab COVAF-51 and 2x2 C-Fab COVAF-57 (14287 x 14287) demonstrated the broadest and strongest potency against all Omicron variants (BA.1, BA.2, BA.2.75, BA.4 / 5 tested, with an IC50 range between 1.2-2.9 E-11 M, which is within 1-2 times the potency for REGN10933 / 10987 against D614G (Table 10). All other tetravalent bispecific FAs showed much lower neutralizing potency (by at least 4 times) against at least one Omicron variant (Table 10).

[00318] The neutralizing activity of COVAF-41-57 against the currently circulating dominant Omicron variant BQ.1 was tested in the pseudovirus assay (Figures 4A and 4B). Both COVAF-51 2x2 N-Fab and COVAF-57 2x2 C-Fab with monospecific tetravalent REGN14287 arms demonstrated superior activity to other bispecific bivalent FAs with an IC50 of 1.3E-11 M (Figures 4A and 4B). The potency for COVAF-51 and 57 is slightly better than the parental control REGN14287 IgG and is similar to that of REGN10933 / 10987 against the D614G variant (IC50 = 1.2E-11 M). However, the neutralization Petition 870250096939, dated 10 / 23 / 2025, pages 143 / 154 129 / 129 The effect of this IgG combination is completely lost against BQ.1 (Figures 4A and 4B). Table 10 Summary of Pseudovirus Neutralization Activity of 2x2 N-Fab and C-Fab Pairing REGN14287 with Proprietary and Other REGN Arms Against D614G and Multiple Variants Omicron IC50 (M) Fold Change Relative to RW&33+R 10987 against D614G AFID Format REGN Arms MW (kDa) D614G BA.1 BA.2 BA.2.75 BA.4 / BA.5 D614G 8A.1 BA.2 BA. 2.75 BA,4 / BA.5 2x2 NFab COVAF-46 10933x14267 250 134E-11 2.71ΕΊ1 2.83ΕΊ1 2.28ΕΊ1 1.10ΕΊ0 0.91 1.85 1.96 1.55 7.47 COVAF-17 14287x14258 250 223E 11 4.49E-11 3.24ΕΊ1 7.Ο8ΕΊ1 1.Ο1ΕΊ0 1.52 3.06 2.21 4.83 6.91 CCVAF-48 10987x14287 250 1.71E-11 7.00E-11 8.24E-12 7 93E-11 2.38E-11 1.16 4.77 0.56 5.41 1.63 GQVAF-49 14287x14315 250 5.156-11 2.71E-11 2.376-11 5.51E-11 6.40E-11 3.52 1.85 1.62 3.76 4.37 COVAF-5Q 10985x14287 250 1.72E-10 3.196-11 5.176-11 8.75E-11 1.156-10 11.73 2.18 3.53 5.97 7.85 COVAF-51 14287x14287 260 5.576-11 2.056-11 1.236-11 1.736-11 2.946-11 3.80 1.40 0.84 1.18 2.01 2x2 CFab COVAF-52 10933x14287 250 2.94E-11 3.39E-11 2.95E-11 3.72E-11 1.43E-10 2,00 2,31 2r01 2,54 9,78 COVAF53 14287x14256 250 3J8E-11 4.2ΘΕ-11 5.3SE-11 8.15E-11 1.80E-10 2,17 2.92 3rS7 5,56 12r31 COVAFS4 10987x14287 250 2r39E-11 6,68E-11 2.17E-11 1.57E-10 3.80E-11 1,63 4,58 1.48 10,72 2,59 CQVAF-55 14287x14315 250 3.3&EH 3.29E-11 4.48E-11 7.47E-11 9.37E-11 2.29 2.24 3.06 5.10 6.39 COVAF-56 10986x14287 260 1,086-10 3,736-11 8,126-11 1,086-10 1,386-10 7,37 2,55 5,54 7,34 9,39 COVAF-57 14287x14287 260 3,426-11 2,506-11 1,446-11 2,296-11 2,466-11 2,33 1,71 0,98 1,56 1,68 IgG de Controle REGN14287 14287 150 9.06E11’ 4Ί81Ε11 2,84E11 5J8E-11* 5,00E11 6,18 3,28 1,94 3,94 3,41 REGN10933 10933 150 2,91 ΕΊ1 NC NC 2.17ΕΌ9 NC 1,98 NC NC 148,02 NC. Table 10 Summary of Neutralization Activity of the 2x2 N-Fab and C-Fab Pairing Pseudovirus REGN142B7 with Self and Other REGN Arms Against D614G and Multiple Omicron Variants IC50 (M) α-Bending Change R10933+R10987 against D614G R6GN14256 14256 150 1.146-11 NC NC NC NC 0.77 NC NC NC NC NC R6GN10987 10987 150 1.316-11 NC 2.186-09 NC 3.466-09 0.89 NC 148.77 NC 235.95 REGN10933 REGN109E7 10933 + 10987 150 1.47E-11 NC 4.77E-Q9 NC 3.37E-09 1.00 NC 325.51 NC 229.67 REGN14315 14315 150 878E.12 4.04E-11 1.68E-10 1.28E-09 1.59E-10 0.60 2.76 1147 87.04 10.83 REGN14287 REGN14315 14287 + 14315 150 1.11E-11 8.96E-11 1.43E-10 3.00E-10 2.196-10 0.76 6.11 9.75 20.48 14.95 * Average value calculated based on two or three independent runs. NC Not calculated 9. Citing references

[00319] All publications, patents, patent applications and other documents cited in this application are incorporated herein by reference in their entirety for all purposes, to the same extent as if each individual publication, patent, patent application or other document were individually indicated for incorporation by reference for all purposes. In the event of any inconsistency between the teachings of one or more of the references incorporated herein and the present disclosure, the teachings of this descriptive report shall be those intended.

Claims

1. Multivalent anti-spike protein binding molecule characterized in that it comprises at least 4 antigen-binding domains (ABDs) of the anti-spike protein operationally linked by one or more multimerization moieties.

2. Multivalent anti-spike protein binding molecule according to claim 1, characterized in that it is tetravalent.

3. Multivalent anti-spike protein binding molecule according to claim 1 or 2, characterized in that it comprises: (a) a first antibody half comprising: (i) a first ABD comprising a first VH and a first VL; (ii) an optional first linker; (iii) a second ABD comprising a second VH and a second VL; (iv) an optional first hinge domain; and (v) a first Fc domain; and (b) a second antibody half comprising: (i) a third ABD comprising a third VH and a third VL; (ii) an optional second linker; (iii) a fourth ABD comprising a fourth VH and a fourth VL; (iv) an optional second hinge domain; and (v) a second Fc domain.

4. Multivalent anti-spike protein binding molecule according to claim 1 or 2, characterized in that it has: (a) a first antibody half comprising: Petition 870250096939, 10 / 23 / 2025, pp. 145 / 154 2 / 8 (i) a first ABD, typically comprising a first VH and a first VL; (ii) an optional first hinge domain; (iii) a first Fc domain; (iv) an optional first linker; and (v) a second ABD, typically comprising a second VH and a second VL; and (b) a second antibody half comprising: (i) a third ABD, typically comprising a third VH and a third VL; (ii) an optional second hinge domain; (iii) a second Fc domain; (iv) an optional second linker; and (v) a fourth ABD, typically comprising a fourth VH and a fourth VL.

5. Multivalent anti-spike protein binding molecule according to claim 3 or 4, characterized in that the first Fc domain and the second Fc domain form an Fc homodimer.

6. Multivalent anti-spike protein binding molecule according to claim 3 or 4, characterized in that the first Fc domain and the second Fc domain form an Fc heterodimer.

7. Multivalent anti-spike protein binding molecule, according to any one of claims 3 to 6, characterized in that the first, second, third and fourth ABDs are the same.

8. Multivalent anti-spike protein binding molecule according to any one of claims 3 to 6, characterized in that the first and second ABDs are the same. Petition 870250096939, dated 10 / 23 / 2025, pp. 146 / 154 3 / 8 9. Multivalent anti-spike protein binding molecule according to claim 8, characterized in that the third and fourth ABDs are the same.

10. Multivalent anti-spike protein binding molecule according to claim 9, characterized in that the third and fourth ABDs are different from the first and second ABDs.

11. Multivalent anti-spike protein binding molecule, according to any one of claims 3 to 10, characterized in that the first and third ABDs are the same.

12. Multivalent anti-spike protein binding molecule according to claim 11, characterized in that the second and fourth ABDs are the same.

13. Multivalent anti-spike protein binding molecule according to claim 12, characterized in that the second and fourth ABDs are different from the first and third ABDs.

14. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 13, characterized in that the antigen-binding domains (ABDs) are human or humanized.

15. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 14, characterized in that one or more (or all) of the ABDs are neutralizing.

16. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 15, characterized in that the Fc domains are IgG domains.

17. Multivalent anti-spike protein binding molecule according to claim 16, characterized in that the IgG domains are IgG1 domains.

18. Multivalent anti-spike protein binding molecule, Petition 870250096939, 10 / 23 / 2025, pp. 147 / 154 4 / 8 according to claim 16, characterized in that the IgG domains are IgG4 domains.

19. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 18, characterized in that it does not possess the first ligand and the second ligand.

20. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 18, characterized in that it comprises the first ligand and the second ligand.

21. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 20, characterized in that one or more of the ABDs comprise the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 sequences of an antibody established in Table 4.

22. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 20, characterized in that one or more of the ABDs comprise VH and VL sequences of an antibody established in Table 4.

23. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 30, characterized in that one or more of the ABDs comprise: (a) a VH comprising CDR-H1, CDR-H2 and CDR-H3 having the amino acid sequences of SEQ ID NOs: 579, 580 and 581, respectively; and (b) a VL comprising CDR-L1, CDR-L2 and CDR-L3 having the amino acid sequences of SEQ ID NOs: 398, 372 and 583, respectively.

24. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 23, characterized in that at least two of the ABDs are Fab domains, optionally in that the Fab domains are not single-strand Fab domains. Petition 870250096939, dated 10 / 23 / 2025, pp. 148 / 154 5 / 8.

25. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 23, characterized in that all ABDs are Fab domains, optionally in that the Fab domains are not single-stranded Fab domains.

26. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 23, characterized in that at least two of the ABDs are scFvs.

27. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 23, characterized in that at least all ABDs are scFvs.

28. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 27, characterized in that it is monospecific.

29. Multivalent anti-spike protein binding molecule, according to any one of claims 1 to 27, characterized in that it is multispecific.

30. Multivalent anti-spike protein binding molecule according to claim 29, characterized in that it is bispecific.

31. Nucleic acid or plurality of nucleic acids characterized in that they encode the multivalent anti-spike protein-binding molecule, as defined in any one of claims 1 to 30.

32. Host cell characterized in that it is designed to express the multivalent anti-spike protein binding molecule, as defined in any one of claims 1 to 30, or the nucleic acid(s), as defined in claim 31.

33. Method for producing the multivalent anti-spike protein binding molecule, as defined in any of claims 1 to 30, characterized in that it comprises cultivating the host cell, as defined in claim 32, and recovering the multivalent anti-spike protein binding molecule expressed by it.

34. Pharmaceutical composition characterized in that it comprises the multivalent anti-spike protein binding molecule, as defined in any one of claims 1 to 30, and an excipient.

35. A method for treating a disease caused by coronavirus, characterized in that it comprises administering to an individual in need thereof the multivalent anti-spike protein binding molecule, as defined in any one of claims 1 to 30, or the pharmaceutical composition, as defined in claim 34.

36. Method for inhibiting an interaction between a coronavirus RBD and cellular ACE2, characterized in that it comprises administering to an individual in need thereof the multivalent anti-spike protein binding molecule, as defined in any one of claims 1 to 30, or the pharmaceutical composition, as defined in claim 34.

37. Method for neutralizing a coronavirus spike protein in vivo, characterized in that it comprises administering to an individual in need thereof the multivalent anti-spike protein binding molecule, as defined in any one of claims 1 to 30, or the pharmaceutical composition, as defined in claim 34.

38. Method for inhibiting protease-mediated cleavage (e.g., TMPRSS2-mediated cleavage) of a coronavirus spike protein in vivo, characterized in that it comprises administering to an individual in need thereof the multivalent anti-spike protein binding molecule, as defined in any one of claims 1 to 30, or the pharmaceutical composition, as defined in claim 34.

39. A method for inhibiting viral entry of a coronavirus into a host cell in an individual, characterized in that it comprises administering to an individual in need thereof the multivalent anti-spike protein binding molecule, as defined in any one of claims 1 to 30, or the pharmaceutical composition, as defined in claim 34.

40. A method for inhibiting the replication of a coronavirus spike protein in a host cell in an individual, characterized in that it comprises administering to an individual in need thereof the multivalent anti-spike protein binding molecule, as defined in any one of claims 1 to 30, or the pharmaceutical composition, as defined in claim 34.

41. A method for reducing the severity of coronavirus infection, characterized in that it comprises administering to an individual in need thereof the multivalent anti-spike protein binding molecule, as defined in any one of claims 1 to 30, or the pharmaceutical composition, as defined in claim 34.

42. A method for reducing the viral load of a coronavirus, characterized in that it comprises administering to an individual in need thereof the multivalent anti-spike protein binding molecule, as defined in any one of claims 1 to 30, or the pharmaceutical composition, as defined in claim 34.

43. Method for preventing disease progression in an individual with coronavirus infection characterized in that it comprises administering to an individual in need thereof the multivalent anti-spike protein binding molecule, as defined in any of claims 1 to 30, or the pharmaceutical composition, as defined in claim 34.

44. Method for reducing the duration of a coronavirus infection characterized in that it comprises administering to an individual in need of the multivalent anti-spike protein binding molecule, as defined in any of claims 1 to 30, or the pharmaceutical composition, as defined in claim 34.

45. Method for reducing the risk of serious illness or death in an individual with coronavirus infection, characterized in that it comprises administering to an individual in need thereof the multivalent anti-spike protein binding molecule, as defined in any one of claims 1 to 30, or the pharmaceutical composition, as defined in claim 34.

46. ​​Method, according to any one of claims 35 to 45, characterized in that the coronavirus is SARS-CoV.

47. Method, according to any one of claims 35 to 45, characterized in that the coronavirus is SARS-CoV-2.

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