WO2023285620A2 - Compositions et procédés de ciblage de protéines virales - Google Patents

Compositions et procédés de ciblage de protéines virales Download PDF

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WO2023285620A2
WO2023285620A2 PCT/EP2022/069796 EP2022069796W WO2023285620A2 WO 2023285620 A2 WO2023285620 A2 WO 2023285620A2 EP 2022069796 W EP2022069796 W EP 2022069796W WO 2023285620 A2 WO2023285620 A2 WO 2023285620A2
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antibody
antibodies
monoclonal antibody
seq
nos
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PCT/EP2022/069796
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WO2023285620A3 (fr
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Jacob Daniel GALSON
Ralph Raymond Minter
Jane Katharine Osbourn
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Alchemab Therapeutics Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1002—Coronaviridae
    • C07K16/1003—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2 or Covid-19]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the present disclosure relates to proteins, polypeptides, antibodies and antibody fragments which bind, neutralize or affect the biological function of a viral protein, including original and/or variant strains of SARS-CoV-2 such as B.1.1.7 (the Alpha variant); B.1.351 (the Beta variant); P.l (the Gamma variant); and/or B.167.2 (the Delta variant).
  • SARS-CoV-2 such as B.1.1.7 (the Alpha variant); B.1.351 (the Beta variant); P.l (the Gamma variant); and/or B.167.2 (the Delta variant).
  • the disclosure also includes polynucleotides encoding said polypeptides, pharmaceutical compositions comprising said polypeptides and the use of said polypeptides in suppressing or treating a disease or disorder mediated by infection with SARS-CoV-2, for providing prophylaxis to a subject at risk of infection of SARS-CoV-2 or for the diagnosis and/or prediction of outcome of SARS-CoV-2 infection.
  • compositions include as immunogens either whole, attenuated vims or whole spike (S) protein - a viral membrane glycoprotein which mediates cell uptake by binding to host angiotensin-converting enzyme 2 (ACE2).
  • S whole spike
  • ACE2 angiotensin-converting enzyme 2
  • J0006J An alternative is to support passive immunity to SARS-CoV-2 by administering one, or a small cocktail of, well-characterized, neutralizing antibodies, which may be isolated from patients recovering from COVID-19.
  • SARS-CoV-2 for example SARS-CoV-2 spike protein or other viral protein relative to a control or other viral protein
  • (ix) activity across a plurality of potential viral epitopes e.g., binding viral epitopes, secreted host epitopes, membrane host epitopes, modulating infected host cells, modulating innate and adaptive immune responses; i.e., “pan-active” functionality,
  • (xi) suitability for administration with other agents in treating COVID-19 (e.g., to enhance anti- viral efficacy or avoid side effects, or where patients are immunocompromised or undergoing treatment for a non- viral related condition),
  • xii suitable for prevention, pre- or post-exposure (prophylaxis or treatment of SARS- CoV-2 infection or reduction in the severity of symptoms), (xiii) suitability for administration by multiple routes (SC, IV, IM, dermal, nasal, oral), and/or
  • one or more polypeptides can be used in the diagnosis or prediction of outcome post SARS-CoV-2 infection.
  • a protein, polypeptide, antibody or antibody fragment comprising any of the antibodies of antibody ID 8-00001 to Antibody ID 8-00055.
  • an antibody or antibody fragment comprising a sequence having at least 80 percent, at least 90 percent, at least 95 percent or at least 99 percent identity to any of any of the antibodies of antibody ID 8-00001 to Antibody ID 8-00055.
  • an antibody or antibody fragment comprising a sequence having at least 80 percent, at least 90 percent, at least 95 percent or at least 99 percent homology to any of any of the antibodies of antibody ID 8-00001 to Antibody ID 8-00055.
  • an antibody or antibody fragment comprising any of the heavy chains of Table 1 (SEQ ID NOs 1-55).
  • an antibody or antibody fragment comprising any of the light chains of Table 2 (SEQ ID NOs 56-110).
  • an antibody or antibody fragment comprising a sequence having at least 80 percent, at least 90 percent, at least 95 percent or at least 99 percent identity to any of the heavy chains of Table 1 (SEQ ID NOs 1-55).
  • an antibody or antibody fragment comprising a sequence having at least 80 percent, at least 90 percent, at least 95 percent or at least 99 percent homology to any of the heavy chains of Table 1 (SEQ ID NOs 1-55).
  • an antibody or antibody fragment comprising a sequence having at least 80 percent, at least 90 percent, at least 95 percent or at least 99 percent identity to any of the light chains of Table 2 (SEQ ID NOs 56-110).
  • an antibody or antibody fragment comprising a sequence having at least 80 percent, at least 90 percent, at least 95 percent or at least 99 percent homology to any of the light chains of Table 2 (SEQ ID NOs 56-110).
  • compositions comprising the polypeptides above and polynucleotides encoding the polypeptides above. Further aspects of the disclosure will be apparent from the detailed description of the disclosure.
  • the antibodies of the present disclosure may be of any isotype including, but not limited to IgM, IgD, IgA, and IgE.
  • Fig. 1 is plot of the binding affinities (defined as the Delta F(luorescence)) of the antibodies of the disclosure for the Covid-19 Alpha variant spike protein as determined by the HTRF assay of the present disclosure.
  • Fig. 2 is plot of the binding affinities (defined as the Delta F(luorescence)) of the antibodies of the disclosure for the Covid-19 Beta variant spike protein as determined by the HTRF assay of the present disclosure.
  • Fig. 3 is a comparison plot of the binding affinities of the antibodies of the disclosure for the Covid-19 Alpha and Beta variant spike proteins as determined by the HTRF assay of the present disclosure.
  • the present disclosure provides proteins, polypeptides, antibodies, and antibody fragments which are useful in the diagnosis, prophylaxis (pre- and post-exposure) and treatment of Covid-19.
  • Such proteins, polypeptides, antibodies, and antibody fragments may interact, bind or interfere with one or more SARS-CoV-2 proteins.
  • the present disclosure provides antibodies (e.g., anti-spike protein or anti- viral antibodies).
  • antibody e.g., anti-spike protein or anti- viral antibodies.
  • antibody is used in the broadest sense and specifically covers numerous embodiments, including, but not limited to, polyclonal antibodies, monoclonal antibodies, multispecific antibodies (e.g., bispecific antibodies or trispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, single chain antibodies, single chain Fv (scFv) formats, diabodies, intrabodies, unibodies, maxibodies, chimeric antigen receptors (CARs), and antibody fragments.
  • antibody fragment refers to a portion of a whole antibody or a fusion protein that includes such a portion.
  • Antibody fragments may include antigen binding regions.
  • antibody fragments include, but are not limited to Fab fragments, Fab’ fragments, F(ab’)2 fragments, Fv fragments, Fc fragments, variable domains, constant domains, heavy chains, and light chains.
  • antibody fragments may be prepared by enzymatic digestion. Fab fragments may be prepared by papain digestion of whole antibodies. F(ab’)2 fragments may be prepared by pepsin treatment of whole antibodies.
  • “Native antibodies” refer to heterotetrametric proteins having two identical light (L) chains and two identical heavy (H) chains. Genes encoding antibody heavy and light chains have been well characterized (see Matsuda, F. et al., 1998. The Journal of Experimental Medicine. 188(11); 2151-62 and Li, A. et al., 2004. Blood. 103(12): 4602-9, the content of each of which are herein incorporated by reference in their entirety).
  • Light chains are linked to heavy chains by a covalent disulfide bond, while the number of disulfide linkages between heavy chains differs among immunoglobulin isotypes. Each heavy chain includes a variable domain (VH) followed by a number of constant domains.
  • Light chains include a variable domain (VL) at one end and a constant domain at the other.
  • variable domain refers to specific antibody domains found on both the antibody heavy and light chains that differ extensively in sequence among antibodies and determine antibody specificity for particular antigens.
  • Variable domains include hypervariable regions that include amino acid residues responsible for antigen binding. Amino acids present within hypervariable regions determine the structure of complementarity determining regions (CDRs) that become part of the antigen-binding site of the antibody.
  • CDR complementarity determining regions
  • the term “CDR” refers to an antibody region having a structure that is complimentary to its target antigen or epitope. Other portions of variable domains, not interacting with antigen, are referred to as “framework regions” (FRs).
  • Antigen-binding sites include amino acid residues necessary for interacting with particular antigens. Residues making up antigen-binding sites may be determined by CDR analysis.
  • CDR analysis refers to a process for determining which antibody variable domain amino acids form CDRs. Various methods of determining CDR sequences are known in the art and may be applied to known antibody sequences (Strohl, W.R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p47-54, the contents of which are herein incorporated by reference in their entirety). CDR analysis may be carried out by co- crystallography with bound antigen.
  • CDR analysis includes computational assessments based on alignment with other antibodies (Strohl, W.R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p47-54, the contents of which are herein incorporated by reference in their entirety).
  • CDR analysis may utilize numbering schemes including, but not limited to, those described by Rabat [Wu, T.T. et al., 1970, JEM, 132(2):211-50 and Johnson, G. et al., 2000, Nucleic Acids Res. 28(1): 214-8, the contents of each of which are herein incorporated by reference in their entirety], Chothia [Chothia and Lesk, J. Mol. Biol.
  • VH and VL domains each include three CDRs.
  • VL CDRs are referred to herein as CDRL1, CDRL2 and CDRL3, in order of occurrence along the VL from N- to C- terminus.
  • VH CDRs are referred to herein as CDRH1, CDRH2 and CDRH3, in order of occurrence along the VH from N- to C- terminus.
  • Most CDRs have favored canonical structures except CDRH3, which includes amino acid sequences with high variability in sequence and length among antibodies resulting in varying three-dimensional antigen-binding domain structures (Nikoloudis, D. et al., 2014. PeerJ. 2:e456).
  • VH and VL domains have four framework regions (FRs) each positioned before, after, and between CDR regions.
  • VH framework regions are referred to herein as FRH1, FRH2, FRH3, and FRH4 and VL framework regions are referred to herein as FRL1, FRL2, FRL3, and FRL4.
  • FRs and CDRs of VH domains are typically in the order of FRH1-CDRH1-FRH2-CDRH2- FRH3-CDRH3-FRH4, from N- to C-terminus.
  • FRs and CDRs of VL domains are typically in the order of FRL 1 -CDRL 1 -FRL2-CDRL2-FRL3 -CDRL3 -FRL4, from N- to C-terminus.
  • Fv antibody fragments include the minimum antibody fragment needed to form a complete antigen-binding site. These regions include a heavy chain and light chain variable domain dimer in tight, non-covalent association. Stable Fv fragments may be synthesized recombinantly through incorporation of a flexible linker between light and heavy chain variable domains to form single chain Fv (scFv) formats. Other Fv formats may include a disulfide bridge between heavy and light chain variable domains (Strohl, W.R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p46-47, the contents of which are herein incorporated by reference in their entirety).
  • Vertebrate antibody light chains typically fall into one of two distinct types, kappa and lambda based on constant domain amino acid sequence. Additional antibody classes depend on heavy chain constant domain amino acid sequences.
  • ScFvs may be utilized in conjunction with phage display, yeast display or other display technologies to create scFv libraries expressed in association with cell or coat surfaces (e.g., in association with phage coat proteins) for identification of peptides with high antigen affinity.
  • Antibodies may be prepared as scFvFc antibodies which include fusions of scFvs with antibody Fc domains.
  • Chimeric antibodies refer to antibodies with portions derived from two or more sources, e.g., from different species. Chimeric antibodies may include mouse variable domains and human constant domains. Examples of chimeric antibodies and related methods of synthesis are described in United States Patent Numbers 5,807,715; 4,816,567; and 4,816,397, the contents of each of which are incorporated herein by reference in their entirety.
  • CARs Chimeric antigen receptors
  • CARs refer to artificial receptors engineered for expression on immune effector cell surfaces facilitating specific targeting of such immune effector cells to cells expressing CAR target antigens.
  • CARs may be designed to include one or more antibody segments, e.g., antibody variable domains and/or antibody CDRs, to direct immune effector cells to antigens recognized by such antibody segments.
  • CARs are designed to specifically target cancer cells, leading to immune-mediated clearance of the cancer cells.
  • the term "monoclonal antibody” refers to an antibody obtained from a substantially homogeneous cell population producing substantially identical antibodies binding to the same epitope of a specific target antigen. “Polyclonal” antibody preparations typically include a heterogeneous group of antibodies directed against different epitopes of a specific target.
  • Monoclonal antibodies may be prepared using a number of different methods. Monoclonal antibodies may be chimeric with portions derived from two or more species. For example, chimeric monoclonal antibodies may include antibody variable domains corresponding with human variable domain sequences and antibody constant domains corresponding with mouse constant domain sequences. (0035] Antibodies of the present disclosure may be derived from or correspond with antibodies of different animal origins including mammals, birds, reptiles, and insects.
  • Mammalian antibodies may be, for example, of murine (e.g., mouse or rat), rabbit, donkey, sheep, goat, guinea pig, camel, bovine, horse, or human origin.
  • murine e.g., mouse or rat
  • rabbit donkey
  • sheep goat
  • guinea pig camel
  • bovine bovine
  • horse or human origin.
  • antibody variant refers to a biomolecule resembling an antibody in structure, sequence and/or function, but including some differences in their amino acid sequence, composition or structure as compared to another antibody or a native antibody.
  • J0037J Antibodies of the present disclosure may include a conjugate.
  • conjugate refers to any agent, cargo, or chemical moiety attached to a recipient compound or the process of attaching such an agent, cargo, or chemical moiety.
  • antibody conjugate refers to an antibody having an attached agent, cargo, or chemical moiety. Conjugates may include therapeutic agents. Therapeutic agents may include drugs.
  • Antibody conjugates that include conjugated drugs are referred to herein as “antibody drug conjugates.”
  • Antibody drug conjugates may be used to deliver conjugated drugs to specific targets based on antibody affinity for specific proteins or epitopes.
  • Antibody drug conjugates may be used to focus biological activity of conjugated drugs to targeted cells, tissues, organs, etc.
  • antibody conjugates include detectable labels.
  • Detectable labels may be used to detect antibody binding.
  • detectable labels include, but are not limited to, radioisotopes, fluorophores, chromophores, chemiluminescent compounds, enzymes, enzyme co-factors, dyes, metal ions, ligands, biotin, avidin, streptavidin, haptens, quantum dots, or any other detectable labels known in the art or described herein.
  • Conjugates may be attached directly or via a linker. Direct attachment may involve covalent bonding or non-covalent associations (e.g., ionic bonds, hydrostatic bonds, hydrophobic bonds, hydrogen bonds, hybridization, etc.).
  • Linkers used for conjugation may include any chemical structures capable of joining antibodies with conjugates.
  • linkers may include polymeric molecules (e.g., nucleic acids, polypeptides, polyethylene glycols, carbohydrates, lipids, or combinations thereof).
  • Antibody conjugate linkers may be cleavable (e.g., through contact with an enzyme, change in pH, or change in temperature).
  • Heavy and Light chain sequences junctions of the present disclosure include those in Tables 3 A and 4.
  • the heavy chain CDR3 sequences of the Heavy chain junction sequences (Table 3A) are provided in Table 3B.
  • the light chain CDR3 sequences of the Light chain junction sequences (Table 4A) are provided in Table 4B.
  • Antibodies may be developed (e.g., through immunization) or selected (e.g., from pool of candidates such as patients who are or have been infected with a viral pathogen), for example, using antigens.
  • An “antigen,” as referred to herein, is any entity that induces an immune response in an organism or may simply refer to an antibody binding partner.
  • Immune responses are reactions of cells, tissues and/or organs of an organism to a foreign entity. Immune responses typically lead to the production of one or more antibodies against a foreign entity by an organism.
  • antigens of the present disclosure include viral proteins or portions thereof, referred to herein as “viral antigens.”
  • target antigen refers to an entity, protein, or epitope to which an antibody binds or for which an antibody is desired, designed, or developed to have affinity for such as for example a viral protein, e.g., S, N, or other.
  • SARS-CoV-2 is a member of the large coronavims family of viruses. Multiple variants (sometimes referred to as “strains” or “lineages”) of SARS-CoV-2 have been identified globally. The nomenclature for SARS-CoV-2 variants used in this description is consistent with the PANGO nomenclature for new virus lineages (Rambaut, Andrew, et al. "A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology.” Nature microbiology 5.11 (2020): 1403-1407, the contents of which are incorporated herein by reference in their entirety).
  • PANGO lineage variants of SARS-CoV-2 have been identified, including the following (number in parentheses represents number of cases per each submitted PANGO lineage: A (37); A.l (8); A.ll (2); A.12 (1); A.19 (5); A.2 (6); A.2.2 (9); A.2.4 (5); A.2.5 (12); A.21 (8); A.22 (1); A.23 (2); A.23.1 (40); A.24 (2); A.25 (1); A.28 (4); A.3 (3); A.5 (5); A.6 (1); AD.2 (1); AE.l (1); AE.2 (2); AE.4 (1); AE.5 (1); AE.7 (1); AE.8 (1); AG.l (1); B (47); B.l (374); B.E1 (237); B.EE1 (40); B.EE10 (2); B.l.1.111 (2); B.l.1.121 (1); B.l.1.133 (2);
  • B.l.1.214 (22); B.l.1.216 (9); B.l.1.219 (1); B.l.1.222 (32); B.l.1.226 (1); B.l.1.230 (1);
  • B.l.160.28 (1); B.l.160.8 (1); B.l.160.9 (1); B.l.164 (2); B.l.170 (2); B.l.177 (71); B.l.177.11 (1); B.l.177.12 (1); B.l.177.15 (1); B.l.177.18 (1); B.l.177.21 (7); B.l.177.32 (4); B.l.177.35 (1); B.l.177.4 (1); B.l.177.40 (2); B.l.177.42 (1); B.l.177.43 (1); B.l.177.44 (2); B.l.177.46 (3); B.l.177.49 (1); B.l.177.51 (1); B.l.177.52 (3); B.l.177.53 (1); B.l.177.54 (2); B.l.177.59
  • B.l.177.6 (1); B.l.177.60 (23); B.l.177.68 (1); B.l.177.73 (6); B.l.177.76 (1); B.l.177.77
  • B.1.369 (12); B.1.369.1 (1); B.1.370 (1); B.1.371 (1); B.1.375 (1); B.1.379 (1); B.1.380 (9);
  • SARS-CoV-2 encodes four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N).
  • S spike
  • E envelope
  • M membrane
  • N nucleocapsid
  • the spike protein is generally the leading mediator for viral entry and is a protective antigen that elicits neutralizing antibodies, nonstructural proteins (named nspl to nspl6) and accessory proteins.
  • spike protein of SARS- CoV-2 also has a functional furin cleavage site at the S1-S2 boundary (SI is the receptor binding unit and S2 is the membrane fusion unit).
  • SI is the receptor binding unit
  • S2 is the membrane fusion unit.
  • the membrane protein and the envelope protein are for viral assembly.
  • the nucleocapsid protein packages the viral genome into a helical ribonucleocapsid (RNP) and has a role in viral self-assembly (Chang et al.; The SARS coronavirus nucleocapsid protein – Forms and functions; Antiviral Res.2014; the contents of which are herein incorporated by reference in their entirety).
  • SARS-CoV-2 structural proteins include (a) spike protein (NCBI Ref.: YP_009724390.1) (“S protein”), (b) spike protein with D614G mutation (c) envelope protein (NCBI Ref.: YP_009724392.1), (d) membrane protein (NCBI Ref.: YP_009724393.1), (e) nucleocapsid phosphoprotein (NCBI Ref.: YP_009724397.2) and (f) B.1.351 (South African) Variant Spike protein.
  • variants are typically categorized as Variants of Interest (VOIs), Variants of Concern (VOCs), and Variants of High Consequence (VOHCs).
  • VOIs Variants of Interest
  • VOCs Variants of Concern
  • VOHCs Variants of High Consequence
  • VOIs may have certain genetic markers associated with changes to receptor binding, reduced neutralization by antibodies generated against previous infection or vaccination, reduced efficacy of treatments, potential diagnostic impact, or predicted increase in transmissibility or disease severity.
  • VOIs have specific genetic markers that are predicted to affect transmission, diagnostics, therapeutics, or immune escape, or cause an increased proportion of cases or unique outbreak clusters.
  • SARS-CoV-2 VOIs include, for example, PANGO lineage B.1.526, B.1.525, and P.2.
  • VOCs may include variants for which there is evidence of an increase in transmissibility, more severe disease (increased hospitalizations or deaths), significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnostic detection failures.
  • VOCs have evidence of impact on diagnostics, treatments, and vaccines, widespread interference with diagnostic test targets, evidence of substantially increased resistance to one or more class of therapies, evidence of significant decreased neutralization by antibodies generated during previous infection or vaccination, evidence of reduced vaccine-induced protection from severe disease, evidence of increased transmissibility, or evidence of increased disease severity.
  • SARS- CoV-2 VOCs may include, for example, PANGO lineage B.1.17, P.1, B.1.351, B.1.427, and B.1.429.
  • VOHCs may have clear evidence that prevention measures or medical countermeasures (MCMs) have significantly reduced effectiveness relative to previously circulating variants.
  • VOHCs have impact on Medical Countermeasures (MCM), demonstrated failure of diagnostics, evidence to suggest a significant reduction in vaccine effectiveness, a disproportionately high number of vaccine breakthrough cases, very low vaccine-induced protection against severe disease, significantly reduced susceptibility to multiple Emergency Use Authorization (EUA) or approved therapeutics, more severe clinical disease and increased hospitalizations.
  • MCM Medical Countermeasures
  • EUA Emergency Use Authorization
  • Covid-19 Antibodies It is envisaged that the proposed heavy chains be paired with suitable light chains to enable production of monoclonal antibodies, for example in IgG1 format.
  • Cognate light chains can be identified by various methods, including computational prediction (e.g., Mason et al bioRxiv 617860 (2019)), the use of promiscuous or ‘common light chains’ (e.g., Xue et al. Biochem Biophys Res Commun.515(3):481 ⁇ 486, (2019)), high-throughput paired heavy and light chain sequencing to identify native pairings (e.g., Wang et al Nat Biotechnol.36(2):152-155 (2016)) and antibody display-based methods to find and optimize heavy and light chain pairings (e.g., Guo-Qiang et al. Methods Mol Biol.562:133 ⁇ 1422009).
  • computational prediction e.g., Mason et al bioRxiv 617860 (2019)
  • the use of promiscuous or ‘common light chains’ e.g., Xue et al. Biochem Biophys Res Commun.515(3):481 ⁇ 486,
  • the polypeptide is an antibody, such as an antibody which belongs to the isotype subclass IgG1.
  • the polypeptide is an antibody fragment, such as a F(ab') 2 , an Fd, an Fv, an scFv, a VH, or a VHH.
  • the antibodies may be any of single-chain, canonical (2H+2L chains), fusion proteins, and the like.
  • the antibodies of the disclosure may be delivered as any isotype or class and may be delivered as proteins, protein fragments, separate H and L chains, or encoded in a polynucleotide.
  • Such encoding polynucleotides include, but are not limited to, plasmids, vectors, vector genomes (such as those of a viral vector, e.g., lentivirus, adenovirus, adeno-associated virus, and the like), or mRNA sequences (one or more with heavy and light chains in any orientation (H-L or L-H, whether contiguous or separated).
  • the polypeptide of the disclosure is isolated.
  • An "isolated" polypeptide is one that is removed from its original environment. For example, a naturally occurring polypeptide of the disclosure is isolated if it is separated from some or all of the coexisting materials in the natural system.
  • a pharmaceutical composition comprising the polypeptide and one or more pharmaceutically acceptable diluents or carriers.
  • the composition may comprises at least one further, different polypeptide and/or at least one further active agent.
  • the polypeptide or pharmaceutical composition is for use in suppressing or treating a disease or disorder mediated by infection of SARS-CoV-2, such as COVID-19, or for providing prophylaxis to a subject at risk of infection of SARS-CoV-2, such as COVID-19.
  • a method of suppressing or treating a disease or disorder mediated by infection of SARS-CoV-2, such as COVID-19 or for providing prophylaxis to a subject at risk of infection of SARS-CoV-2, such as COVID-19 comprising administering to a person in need thereof a therapeutically effective amount of the polypeptide or pharmaceutical composition.
  • a polynucleotide encoding any of the proteins, polypeptides, antibodies or antibody fragments of the disclosure will now be further described by means of the following non- limiting examples.
  • association means that the entities are physically associated or connected with one another, either directly or via one or more moieties that serve as linking agents, to form a structure that is sufficiently stable so that the entities remain physically associated, e.g., under working conditions, e.g., under physiological conditions.
  • An “association” need not be through covalent chemical bonding and may include other forms of association or bonding sufficiently stable such that the “associated” entities remain physically associated, e.g., ionic or hydrogen bonding or a hybridization-based connectivity.
  • an “epitope” refers to a surface or region on one or more entities that is capable of interacting with an antibody or other binding biomolecule.
  • a protein epitope may contain one or more amino acids and/or post-translational modifications (e.g., phosphorylated residues) which interact with an antibody.
  • an epitope may be a “conformational epitope,” which refers to an epitope involving a specific three-dimensional arrangement of the entity(ies) having or forming the epitope.
  • conformational epitopes of proteins may include combinations of amino acids and/or post-translational modifications from folded, non-linear stretches of amino acid chains.
  • expression of a nucleic acid sequence refers to one or more of the following events: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5' cap formation, and/or 3' end processing); (3) translation of an RNA into a polypeptide or protein; and (4) post- translational modification of a polypeptide or protein.
  • HTRF is “homogeneous time resolved fluorescence,” an assay technology used to measure analytes in a homogeneous format. This format is used in high throughput screening in drug target studies. This technology combines fluorescence resonance energy transfer technology (FRET) with time -resolved measurement (TR). In TR-FRET assays, a signal is generated through fluorescent resonance energy transfer between a donor and an acceptor molecule when in close proximity to each other. Buffer and media interference is dramatically reduced by dual-wavelength detection, and the final signal is proportional to the extent of product formation.
  • FRET fluorescence resonance energy transfer technology
  • TR time -resolved measurement
  • Identity refers to the overall relatedness between polymeric molecules, e.g., between polynucleotide molecules (e.g., DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of the percent identity of two polynucleotide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes).
  • the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence.
  • the nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position.
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • the percent identity between two nucleotide sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; and Sequence Analysis Primer, Gribskov, M.
  • the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4:11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H.
  • sample refers to a subset of its tissues, cells or component parts (e.g., body fluids, including but not limited to blood, serum, plasma, mucus, lymphatic fluid, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, and urine).
  • body fluids including but not limited to blood, serum, plasma, mucus, lymphatic fluid, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, and urine).
  • Samples may further include a homogenate, lysate, or extract prepared from a whole organism or a subset of its tissues, cells or component parts, or a fraction or portion thereof, including but not limited to, for example, plasma, serum, spinal fluid, lymph fluid, the external sections of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, milk, blood cells, tumors, and organs. Samples may further refer to a medium, such as a nutrient broth or gel, which may contain cellular components or other biological materials, such as proteins (e.g., antibodies) or nucleic acid molecules.
  • a medium such as a nutrient broth or gel, which may contain cellular components or other biological materials, such as proteins (e.g., antibodies) or nucleic acid molecules.
  • SPR refers to “surface plasmon resonance,” a biosensor-based technique which measures resonant oscillation of conduction electrons at the interface between negative and positive permittivity materials stimulated by incident light. This technique measures adsorption of material onto planar metal such as gold or silver. In context of the experiments described herein, SPR is used to determine kinetics parameters of ligand binding to biomolecules.
  • Subject refers to any organism to which a composition in accordance with the disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes.
  • Target refers to an entity of interest or attention, which may include a subject, an organ, a tissue, a cell, a protein, a nucleic acid, biomolecule, or a group, complex, or portion of any of the foregoing.
  • a target may be a protein or epitope thereof for which an antibody has affinity or for which an antibody is desired, designed, or developed to have affinity for.
  • target may also be used to refer to an activity of an agent that is directed to a particular object.
  • an antibody that has affinity for a specific protein “X” may be said to target protein X or may be referred to as an antibody targeting protein X or referred to as a protein X-targeting antibody.
  • an object that is the subject of an agent’s activity may be referred to as a “targeted” object.
  • protein X may be referred to as being targeted by the antibody.
  • Treatment As used herein the terms “treat,” “treatment,” and the like, refer to any actions taken to offer relief from or alleviation of pathological processes.
  • the terms “treat,” “treatment,” and the like mean to relieve or alleviate at least one symptom associated with such indications, or to slow or reverse the progression or anticipated progression of such indications.
  • articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the disclosure includes embodiments in which exactly one member of a group is present in, employed in, or otherwise relevant to a given product or process.
  • the disclosure includes embodiments in which more than one, or all group members are present in, employed in, or otherwise relevant to a given product or process.
  • Embodiment 1 A monoclonal antibody comprising the heavy and light chain variable regions of any of antibodies (Antibody ID 8-00001 to Antibody ID 8-00055).
  • Embodiment 2. A monoclonal antibody comprising a heavy chain variable region of any of SEQ ID NOs 1-55.
  • Embodiment 3. A monoclonal antibody comprising a light chain variable region of SEQ ID NOs 56-110.
  • Embodiment 4. A monoclonal antibody comprising a heavy chain CDR3 of any of SEQ ID NOs 221-275.
  • Embodiment 5. A monoclonal antibody comprising a light chain CDR3 of any of SEQ ID NOs 276-330.
  • Embodiment 7. A polypeptide comprising the amino acid sequence of any of SEQ ID NOs 56-110.
  • Embodiment 8. A polypeptide comprising the amino acid sequence of any of SEQ ID NOs 221-275.
  • Embodiment 9. A polypeptide comprising the amino acid sequence of any of SEQ ID NOs 276-330.
  • Embodiment 10 A monoclonal antibody fragment comprising all or a portion of any of SEQ ID NOs 1-110 and in the form selected from the group consisting of a F(ab') 2 , an Fd, an Fv, and an scFv.
  • Embodiment 13 A pharmaceutical composition comprising the monoclonal antibody of Embodiments 1-5 and Embodiment 10 and one or more pharmaceutically acceptable diluents or carriers.
  • Embodiment 14 A pharmaceutical composition comprising the monoclonal antibody of Embodiments 1-5 and Embodiment 10 and one or more pharmaceutically acceptable diluents or carriers.
  • Embodiment 13 comprising at least one further active agent such as an anti-viral or anti-inflammatory agent.
  • Embodiment 15 A method of suppressing or treating a disease or disorder mediated by infection of SARS-CoV-2 or any variant thereof or for providing prophylaxis to a subject at risk of infection of SARS-CoV-2 or any variant thereof comprising administering any of the monoclonal antibodies of Embodiments 1-5 and Embodiment 11.
  • Embodiment 16 A polynucleotide encoding one or more of the monoclonal antibodies of Embodiments 1-5 and Embodiment 11.
  • Embodiment 17. A vector, plasmid, or mRNA comprising the polynucleotide according to Embodiment 16.
  • EXAMPLES Example 1 Identification of Covid-19 variant specific targeting antibodies
  • the antibodies of the present disclosure were evaluated for binding to either the Alpha or Beta variant of SARS-CoV2 by an HTRF assay. See Figures 1-3. Briefly, histidine tagged Alpha and Beta variant spike proteins (antigens) were incubated with either control or test antibodies (Antibody IDs 8-00001 to 8-00055). Detection reagents were then added (Donor anti HuIgG Eurporium cryptate (K) and Acceptor anti-His (d2) pAb). The components were incubated at room temperature for 4 hours and fluorescence measured at 665nm and 620nm. [0102] Binding of the antibodies to the spike trimer was detected via FRET whereby an energy transfer occurs from the Emporium cryptate to the d2 pAb when the moieties are in close proximity.
  • the positive control was an anti-spike RNA binding domain monoclonal antibody (Sino Biological #40150-D001) with an eight (8) point titration 1:3 from 27nM.
  • the negative control was an anti-human IgGl isotype control monoclonal antibody (supplied by kymab, Cambridge, UK) with an eight (8) point titration 1:3 from 27nM. Control antibodies were determined to be specific for their targets (data not shown).
  • the data illustrate that the antibodies of the disclosure exhibit effective binding to the Alpha and Beta variants with 9/18 of the convergent candidates (selected by novel light chain pairing) showing positive binding to the Alpha variant spike protein and 5/18 of the convergent candidates showing positive binding to the Beta variant spike protein.
  • a higher percentage of the antibodies having heavy chains suspected to be involved in neutralization of the vims (Beta variant neutralizer VH Candidates) showed binding with 15/17 binding to the Alpha variant spike protein and 13/17 binding to the Beta variant spike protein.
  • antibodies designed as candidates which were considered non-RBD neutralizer candidates also showed some binding the Alpha and Beta variant spike protein, 6/16 and 3/16, respectively.
  • VH+VL represent a class of antibodies which will serve useful in clinical scenarios where binding of the spike protein is implicated across a broad dose range. It is noted that the Hook effect can be observed in the data of Figure 3 and that this is not an uncommon immunologic phenomenon.
  • Selected anti-spike protein antibodies of Example 1 were investigated to determine kinetics of binding of three different models of spike protein trimers, representing His-tagged spike protein ectodomains of different variants of SARS-CoV-2.
  • the model spike protein trimers are provided with engineered modifications to increase their stability for binding assays.
  • the selected antibodies are the same as the antibodies listed in Table 5, with the exception that antibodies 8-0021, 8-0026, 8-0035, 8-0039 and 8-0043 were not included in this study.
  • “Wuhan Trimer HexaPro” is a prefusion-stabilized spike variant based on the original Wuhan virus, which includes six stabilizing proline substitutions (Schaub et al., Nature Protocols, 2021, 16, 5339-5356, incorporated herein by reference in its entirety).
  • “Kymab Wuhan trimer (PP) PPB-1119” is a model spike protein trimer produced by Kymab Ltd of Cambridge, UK, as a model for the original Wuhan vims.
  • “B.1.351 (SA) Trimer Hexapro” is model spike protein trimer of the B.1.351 variant of SARS-CoV-2 (originating in South Africa) with six stabilizing proline substitutions. These model spike protein trimers were used in an SPR assay to determine binding kinetics parameters for selected antibodies described herein.
  • the SPR assay design included immobilization of an anti-hFc antibody to carboxymethylated dextrans of a CM4 or a CM5 sensor chips (creativebiomart.net). Then a candidate antibody is bound to the anti-hFc antibody to prepare the sensor chip for the assay. Individual trimers were then flowed through the channel of the SPR biosensor instmment. In these experiments, single cycle kinetics were investigated with five different concentrations of spike protein model analytes up to 100 nM. The SPR signal originates from changes in the refractive index at the surface of the sensor chip.
  • the increase in mass associated with a binding event where the spike protein trimer binds to the anti-spike antibody causes a proportional increase in the refractive index, which is observed as a change in response in resonance units (RU).
  • RU resonance angle
  • dq the resonance angle of refracted light
  • the response signal is quantified in resonance units (RU) and represents a shift in the resonance angle, where 1RU is equal to a critical angle shift of 10 4 deg or 10 12 gmm 2 .
  • K a is the association constant
  • K d is the dissociation constant
  • Chi 2 is a statistical parameter indicating goodness of fit of the curve fitted to the sensorgrams of the SPR analysis.
  • the parameter “t c ” is the mass transfer coefficient.
  • HBS is a saline control and RBD is the Receptor Binding Domain.
  • Table 8 1:1 Binding kinetics of binding model spike protein trimers to antibody candidates Wuhan Trimer 8-00032 HexaPro 2.11E+01 5.91E+02 1.43E-03 2.41E-06 0.0 1.00E+08 8 8 7 6 8 8 7 7 7 7 8 8 8 8 7 5 7 7 7 8 9 8
  • the data presented in Table 8 indicate that certain antibodies have RU max values in the same range as those of the benchmark antibodies.
  • Antibody 8-00027 has the highest RU max value determined of all antibodies of 830.0 RU in the case of binding the Wuhan Trimer HexaPro. This antibody also has a relatively high RUmax value of 253.9 for binding B.1.1351 (SA) Trimer HexaPro.
  • Example 1 The HTRF data collected in Example 1 and the SPR data (in terms of binding response) collected in Example 2 are compared with an additional SPR data set obtained for another Wuhan spike protein trimer model is included with the HexaPro Wuhan trimer and the HexaPro (B.1.351) SA trimer.
  • candidate antibodies 8-00019, 8-00022, 8- 00028, 8-00029, and 8-00033 indicate favorable binding responses for the different trimer models representing spike protein of different variants.
  • Candidate antibodies 8-00019, 8-00022, 8-00028, 8-00029, and 8-00033, indicated in previous examples to exhibit favorable binding to the model spike protein trimers were tested for the ability to neutralize SARS-CoV-2 variants.
  • the variant conventionally known as “Victoria” is an early variant of the original Wuhan strain identified in Victoria, Australia.
  • the Alpha, Beta, Gamma and Delta variants are well known variants.
  • the data listed in Table 10 in arbitrary units indicates the extent of neutralization where smaller numbers indicate a greater extent of neutralization.
  • the 253/165 antibody is a benchmark antibody combining the heavy chain of an antibody named 253 and a light chain of an antibody named 165, which has neutralization activity vs. the B.1.351 (beta variant) (Zhou et al., Cell, 2021, 189, 2348-2361, the contents of which is herein incorporated by reference in its entirety).

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Abstract

La présente invention concerne un(e) ou plusieurs polypeptides, protéines, anticorps ou fragments d'anticorps utiles dans le diagnostic, la prophylaxie (pré- ou post-exposition), ou le traitement de la COVID-19.
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