WO2022184659A1 - Antibody domains & multimers - Google Patents

Antibody domains & multimers Download PDF

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Publication number
WO2022184659A1
WO2022184659A1 PCT/EP2022/055020 EP2022055020W WO2022184659A1 WO 2022184659 A1 WO2022184659 A1 WO 2022184659A1 EP 2022055020 W EP2022055020 W EP 2022055020W WO 2022184659 A1 WO2022184659 A1 WO 2022184659A1
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Prior art keywords
multimer
domain
polypeptide
variable domain
amino acid
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PCT/EP2022/055020
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French (fr)
Inventor
Hanif ALI
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Quadrucept Bio Limited
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Priority claimed from GBGB2102896.4A external-priority patent/GB202102896D0/en
Priority claimed from GBGB2103153.9A external-priority patent/GB202103153D0/en
Priority claimed from PCT/EP2021/056576 external-priority patent/WO2021190980A1/en
Priority claimed from GBGB2201282.7A external-priority patent/GB202201282D0/en
Application filed by Quadrucept Bio Limited filed Critical Quadrucept Bio Limited
Publication of WO2022184659A1 publication Critical patent/WO2022184659A1/en

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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
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    • 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]
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    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
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    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • C—CHEMISTRY; METALLURGY
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    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
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    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
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    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/522—CH1 domain
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    • C07K2317/524—CH2 domain
    • C—CHEMISTRY; METALLURGY
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    • C07K2317/526—CH3 domain
    • C—CHEMISTRY; METALLURGY
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    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
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    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
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    • C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
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    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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    • 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
    • C—CHEMISTRY; METALLURGY
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    • C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"
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    • C07K2319/735—Fusion polypeptide containing domain for protein-protein interaction containing a domain for self-assembly, e.g. a viral coat protein (includes phage display)

Definitions

  • the invention relates to novel antibody variable domains that bind to coronavirus virus spike (eg, SARS-CoV-2 spike, SARS-CoV-1 spike or beta-coronavirus spike).
  • coronavirus virus spike eg, SARS-CoV-2 spike, SARS-CoV-1 spike or beta-coronavirus spike.
  • multimers such as multimers comprising 4 copies of such a variable domain.multimers, methods and uses to expand antigen specificity of binding sites, as well as vaccines, methods of vaccination and assay methods and reagents.
  • the invention also relates to multimers such as dimers or tetramers of polypeptides; and tetramers or higher-order multimers (eg, octamers, dodecamers and hexadecamers) of epitopes or effector domains, such as antigen binding sites (eg, antibody or TCR binding sites that specifically bind to antigen or pMHC, or variable domains thereof) or peptides such as incretin, insulin or hormone peptides.
  • multimers such as dimers or tetramers of polypeptides; and tetramers or higher-order multimers (eg, octamers, dodecamers and hexadecamers) of epitopes or effector domains, such as antigen binding sites (eg, antibody or TCR binding sites that specifically bind to antigen or pMHC, or variable domains thereof) or peptides such as incretin, insulin or hormone peptides.
  • antigen binding sites e
  • Multimers of effector domains have recognized utility in medical and non-medical applications for combining and multiplying the activity and presence of effector domains, eg, to provide for higher avidity of antigen binding (for effector domains that are antibody or TCR binding domains, for example) or for enhancing biological or binding activity, such as for providing bi- or multi-specific targeting or interaction with target ligands in vivo or in vitro.
  • Multimerisation domains which cause self-assembly of protein monomers into multimers are known in the art. Examples include domains found in transcription factors such as p53, p63 and p73, as well as domains found in ion channels such as TRP cation channels.
  • the transcription factor p53 can be divided into different functional domains: an N-terminal transactivation domain, a proline-rich domain, a DNA-binding domain, a tetramerisation domain and a C-terminal regulatory region.
  • the tetramerisation domain of human p53 extends from residues 325 to 356, and has a 4-helical bundle fold (Jeffrey et al., Science (New York, N.Y.) 1995, 267(5203):1498-1502).
  • the TRPM tetramerisation domain is a short anti-parallel coiled-coil tetramerisation domain of the transient receptor potential cation channel subfamily M member proteins 1-8.
  • TRP Transient receptor potential
  • T1 cytoplasmic tetramerisation domain
  • Multimeric antibody fragments have been produced using a variety of multimerisation techniques, including biotin, dHLX, ZIP and BAD domains, as well as p53 (Thie et al., Nature Boitech., 2009:26, 314-321). Biotin, which is efficient in production, is a bacterial protein which induces immune reactions in humans.
  • Human p53 (UniProtKB - P04637 (P53_HUMAN) acts as a tumor suppressor in many tumor types, inducing growth arrest or apoptosis depending on the physiological circumstances and cell type. It is involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. Human p53 is found in increased amounts in a wide variety of transformed cells. It is frequently mutated or inactivated in about 60% of cancers. Human p53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium.
  • Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver.
  • Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver.
  • Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast.
  • Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine.
  • Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine.
  • a pharmaceutical composition eg, an inhalable pharmaceutical composition
  • an inhalation device optionally a nebuliser or inhaler
  • a mixture of at least 2 different multimers wherein a first of said multimers comprises 4 copies of an antigen binding site that is capable of binding to a first spike antigen and a second of said multimers comprises 4 copies of an antigen binding site that is capable of binding to a second spike antigen, and the antigens are different; .
  • a method of expanding the antigen binding specificity of a binding site wherein the binding site binds or neutralises (eg, when administered to humans) a first antigen, but not a second antigen when the binding site is comprised in monovalent form by a protein that specifically binds to the first antigen, the method comprising providing a plurality of copies of a polypeptide, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens; .
  • a multimer obtainable by said method of expanding wherein the multimer is for targeting a virus whose antigens evolve through mutation during viral infection of a human subject, optionally for treating a coronavirus infection; . a method of binding multiple copies of an antigen, the method comprising combining the copies with the multimer or composition, wherein the copies are bound by the multimer, and optionally the method comprising isolating the multimer bound to the antigen copies; . a method of detecting the presence of anti-first antigen antibodies in a bodily fluid sample of a human or animal, the method comprising carrying out an ELISA assay; .
  • a method for detecting the presence of an antigen in a sample comprising combining the sample with the multimer, allowing antigen in the sample to bind multimers to form antigen/multimer complexes and detecting antigen/multimer complexes; . a method of expanding a utility of an antigen binding site, the method comprising producing the multimer, wherein the multimer comprises at least 4 copies of the binding site; . a method for the treatment or prevention of a disease or condition in a human or animal subject), the method comprising administering to the subject a plurality of the multimers; .
  • a multimer that is capable of binding to different forms of a virus spike protein for treating, preventing or reducing in a human or animal infection by a virus comprising a first form of spike protein, and for treating, preventing or reducing infection by a virus comprising a second form of the spike protein; . a multimer that is capable of binding to different forms of a virus spike protein for treating or preventing or reducing a seasonal viral infection in a human or animal; and . a medicament for administration to a human or animal subject for treating or preventing a seasonal virus, wherein the medicament comprises a plurality of the multimers, wherein the medicament comprises a pharmaceutically acceptable diluent, carrier or excipient.
  • the invention provides: A polypeptide comprising an antibody Fc region, wherein the Fc region comprises an antibody CH2 and an antibody CH3; and a self-associating multimerisation domain (SAM); wherein the CH2 comprises an antibody hinge sequence and is devoid of a core hinge region.
  • SAM self-associating multimerisation domain
  • the Fc does not directly pair with another Fc, which is useful for producing multimers by multimerization using SAM domains.
  • a benefit may be aiding desired multimer formation and/or enhancing multimer purity formed by such multimerization.
  • the invention also provides: A multimer of a plurality of antibody Fc regions, wherein each Fc is comprised by a respective polypeptide and is unpaired with another Fc region; optionally wherein the multimer is for medical use.
  • the invention also provides:- [0013] In a First Configuration A protein multimer of at least first, second, third and fourth copies of an effector domain (eg, a protein domain or a peptide), wherein the multimer is multimerised by first, second, third and fourth self- associating tetramerisation domains (TDs) which are associated together, wherein each tetramerisation domain is comprised by a respective engineered polypeptide comprising one or more copies of said protein domain or peptide.
  • TDs tetramerisation domain
  • the tetramer or octamer is soluble in aqueous solution (eg, aqueous eukaryotic cell culture medium).
  • aqueous eukaryotic cell culture medium e.g. aqueous eukaryotic cell culture medium.
  • the tetramer or octamer is expressible in a eukaryotic cell. Exemplification is provided below.
  • a tetramer, octamer, dodecamer, hexadecamer or 20-mer eg, a tetramer or octamer of (a) TCR V domains or TCR binding sites, wherein the tetramer or octamer is soluble in aqueous solution (eg, an aqueous eukaryotic cell growth medium or buffer); (b) antibody single variable domains, wherein the tetramer or octamer is soluble in aqueous solution (eg, an aqueous eukaryotic cell growth medium or buffer); (c) TCR V domains or TCR binding sites, wherein the tetramer or octamer is capable of being intracellularly and/or extracellularly expressed by HEK293 cells; or (d) antibody variable domains (eg, antibody single variable domains), wherein the tetramer or octamer
  • An engineered (and optionally isolated) engineered polypeptide (P1) which comprises (in N- to C- terminal direction):- (a) TCR V1 –TCR C1 – antibody CH1 (eg, IgG CH1) – optional linker – TD, wherein (i) V1 is a V ⁇ and C1 is a C ⁇ ; (ii) V1 is a V ⁇ and C1 is a C ⁇ ; (iii) V1 is a V ⁇ and C1 is a C ⁇ ; or (iv) V1 is a V ⁇ and C1 is a C ⁇ ; or (b) TCR V1 – antibody CH1 (eg, IgG CH1) – optional linker – TD, wherein (i) V1 is a V ⁇ ; (ii) V1 is a V ⁇ ; (iii) V1 is a V ⁇ ; or (iv) V1 is a V ⁇ ; or (c) antibody V1 – antibody CH1 (eg, IgG CH
  • nucleic acid encoding an engineered polypeptide or monomer of the invention, optionally wherein the nucleic acid is comprised by an expression vector for expressing the polypeptide.
  • nucleic acid or vector of the invention in a method of manufacture of protein multimers for producing intracellularly expressed and/or secreted multimers, wherein the method comprises expressing the multimers in and/or secreting the multimers from eukaryotic cells comprising the nucleic acid or vector.
  • TCR V domain multimers comprising the soluble and/or intracellular expression of TCR V-TD (eg, NHR2 TD or TCR V- p53 TD) fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers;
  • antibody V domain multimers the method comprising the soluble and/or intracellular expression of antibody V (eg, a single variable domain)-TD (eg, V-NHR2 TD or V- p53 TD) fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers;
  • incretin peptide eg, GLP-1, GIP or insulin
  • incretin peptide-TD eg, incretin peptide-NHR2 TD or incretin peptide-p53 TD
  • TD self-associating tetramerisation domains
  • an engineered polypeptide in a method of the manufacture of a tetramer of a polypeptide comprising multiple copies of a protein domain or peptide, for producing a higher yield of tetramers versus monomer and/or dimer polypeptides, wherein the engineered polypeptide comprises one or more copies of said protein domain or peptide and further comprises a self-associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue).
  • TD self-associating tetramerisation domains
  • TD self-associating tetramerisation domains
  • a eukaryotic host cell comprising the nucleic acid or vector for intracellular and/or secreted expression of the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer, octamer), engineered polypeptide or monomer of the invention.
  • an engineered polypeptide in a method of the manufacture of a tetramer of a polypeptide comprising multiple copies of a protein domain or peptide, for producing a plurality of tetramers that are not in mixture with monomers, dimers or trimers, wherein the engineered polypeptide comprises one or more copies of said protein domain or peptide and further comprises a self-associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue).
  • TD self-associating tetramerisation domains
  • a multivalent heterodimeric soluble T cell receptor capable of binding pMHC complex comprising: (i) TCR extracellular domains; (ii) immunoglobulin constant domains; and (iii) an NHR2 multimerisation domain of ETO.
  • a multimeric immunoglobulin comprising (i) immunoglobulin variable domains; and (ii) an NHR2 multimerisation domain of ETO.
  • a seventeenth Configuration A method for assembling a soluble, multimeric polypeptide, comprising: (a) providing a monomer of the said multimeric polypeptide, fused to an NHR2 domain of ETO; (b) causing multiple copies of said monomer to associate, thereby obtaining a multimeric, soluble polypeptide.
  • a cell line eg, a eukaryotic, mammalian cell line, eg, a HEK293, CHO or Cos cell line
  • a cell line eg, a eukaryotic, mammalian cell line, eg, a HEK293, CHO or Cos cell line
  • a method for enhancing the yield of tetramers of an protein effector domain comprising expressing from a cell line (eg, a mammalian cell, CHO, HEK293 or Cos cell line) tetramers of a polypeptide, wherein the polypeptide is a polypeptide of the invention and comprises one or more effector domains; and optionally isolating said expressed tetramers.
  • a cell line eg, a mammalian cell, CHO, HEK293 or Cos cell line
  • a polypeptide comprising (in N- to C-terminal direction; or in C- to N-terminal direction) (i) An immunoglobulin superfamily domain; (ii) An optional linker; and (iii) A self-associating multimerisation domain (SAM) (optionally a self-associating tetramerisation domain (TD)).
  • SAM self-associating multimerisation domain
  • TD self-associating tetramerisation domain
  • a method of expanding the antigen binding specificity of a binding site, wherein the binding site binds a first antigen, but not a second antigen (eg, when administered to humans) when the binding site is comprised in monovalent or bivalent form by a protein that specifically binds to the first antigen comprising providing a plurality of copies of a polypeptide of the invention, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens.
  • a polyepeptide of the invention in a method of manufacturing a multimer for expanding the antigen binding specificity of a binding site, wherein the binding site binds a first antigen, but not a second antigen (eg, when administered to humans) when the binding site is comprised in monovalent or bivalent form by a protein that specifically binds to the first antigen, wherein the method comprises providing a plurality of copies of a polypeptide of the invention, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens.
  • the polypeptide comprises aspects useful for treating or preventing a viral infection or cancer wherein the polypeptide comprises A: one or more epitope binding sites, optionally wherein the binding site binds to (i) a SARS- Cov-2 antigen (eg, a SARS-Cov-1 antigen and a SARS-Cov-2 antigen); (ii) BCMA (B-cell maturation antigen) and TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor); (iii) first and second Coronovirus antigens; (iv) first and second HIV antigens; (v) first and second P falciparum antigens; (vi) first and second Salmonella antigens; (vii) a TMPRSS protein (eg, a TMPRSS2 antigen); or (viii) a ACE2 antigen; or B: one, two or more copies of an ACE2 peptide (eg, an ACE2 extracellular
  • the invention also provides: A protein multimer comprising more than 2 copies of a binding site, wherein the binding site is capable of binding to a first antigen, optionally wherein the multimer is capable of binding to the first antigen and a second antigen, wherein the antigens are different.
  • the multimer comprises from 4 to 32 (eg, from 4 to 24, or from 4 to 20, or from 4 to 16) copies of the binding site, ie, this means that the multimer does not comprise any more or less than said number.
  • the multimer comprises, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 copies of the binding site.
  • the multimer contains from 4 to 32 (eg, from 4 to 24, or from 4 to 20, or from 4 to 16) copies of the binding site, ie, this means that the multimer does not contain any more or less than said number.
  • the multimer contains, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 copies of the binding site.
  • a control protein multimer comprising 1 or 2 (but no more than 1 or 2 respectively) of said binding sites is not capable of binding to the first antigen; or is capable of binding to the first antigen, but not to the second antigen.
  • Binding may be determined by an ELISA assay, such as by determining OD 450 , for example in an ELISA assay described herein.
  • An aspect provides: A protein multimer comprising more than 2 copies of a binding site, wherein the binding site is capable of binding to a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different. This is exemplified herein for 2 different viruses.
  • An aspect provides:- A method for detecting the presence of an antigen in a sample, the method comprising combining the sample with a multimer of the invention, allowing antigen in the sample to bind multimers to form antigen/multimer complexes and detecting antigen/multimer complexes.
  • a method of expanding a utility of an antigen (eg, a protein) binding site comprising producing a multimer of the invention, wherein the multimer comprises a plurality of copies (eg, at least 4 or 8 copies) of the binding site.
  • the invention also provides a pharmaceutical composition, cosmetic, foodstuff, beverage, cleaning product, detergent comprising the multimer(s), tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer(s) or octamer(s)) of the invention.
  • a multimer herein is, eg, a dimer, trimer, tetramer, octamer, dodecamer, hexadecamer or 20- mer.
  • dodecamer and hexadecamer multimers surprisingly display a very high functional affinity for antigen binding due to the increasing avidity effect.
  • the functional affinity for these going from 8 to 12 binding sites (compare Tables 15 and 16) or from 8 to 16 binding sites is much more than additive; a synergistic increase is seen as a result of enhanced avidity.
  • a multimer which is 12-valent for an antigen ie, a dodecamer as described herein
  • a multimer which is 16-valent for an antigen ie, hexadecamer as described herein
  • a protein multimer comprising or containing 4 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different).
  • a protein multimer comprising or containing 8 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different).
  • a protein multimer comprising or containing 12 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different).
  • a protein multimer comprising or containing 16 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different).
  • a protein multimer comprising or containing 20 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different).
  • a protein multimer comprising or containing 24 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different).
  • multimers comprising 4 copies of an antigen binding site of REGN10987, REGN10933 or CB6 surprisingly display much improved neutralization potency of the Quad formats over the parental IgG format ( Figure 61-J), with a a 600-fold improvement in neutralization potency over the parental mAb being surprisingly achieved.
  • multimers comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of REGN10933, (iv) 4 copies of an antigen binding site of CB6, or (v) 4 copies of an antigen binding site of regdanvimab are able to neturalise the omicron strain of SARS-CoV-2.
  • the multimer is according to option (i). In one preferred embodiment, the multimer is according to option (ii). In one preferred embodiment, the multimer is according to option (iii).
  • the multimer is according to option (iv).
  • such multimer is able to neturalise a virus comprising the SARS-CoV-2 spike protein in a virus (eg, pseudovirus) assay.
  • virus eg, pseudovirus
  • such multimers are useful for neturalising one or more strains of SARS-CovV-2 wherein the strain(s) comprise omicron.
  • such multimers are useful for use as a medicament for treating or preventing SARS-CovV-2 omicron infection in a human or animal subject.
  • such multimers are useful for use as an assay reagent in a method for detecting SARS-CovV-2 omicron in a biological sample (eg, sputum, urine, faeces or blood sample), wherein the method comprises contacting the sample with the reagent and detecting SARS-CoV-2 omicron (or spike thereof) that is bound by the reagent.
  • a biological sample eg, sputum, urine, faeces or blood sample
  • the present configuration provides: A protein multimer comprising 4 copies of an antigen binding site of an antibody, wherein the antibody is selected from regdanvimab or REGKINORATM, REGN10987, REGN10933REGN10987, REGN10933 and CB6.
  • a protein multimer comprising 4 copies of an antigen binding site of an antibody wherein the multimer comprises a dimer of an antibody or a fragment thereof (eg, a Fab), wherein the antibody is selected from regdanvimab OR REGKINORATM, REGN10987, REGN10933 and CB6.
  • the multimer may comprise mammalian cell glycosylation.
  • the multimer may, for example, comprise 8, 12, 16, 20 or 24 copies of said binding site in certain aspects of the configuration.
  • multimers comprising 4 copies of antigen binding domain Nb-112 (a VHH domain comprising the amino acid sequence of SEQ ID: 1*288) surprisingly display much improved neutralization potency of the Quad formats over the parental VHH format ( Figures 62D & 62E), with a substantial improvement in neutralization potency over the parental VHH being surprisingly achieved.
  • such multimers also surprisingly show substantially higher binding to protein A, which aids purification.
  • the present configuration provides: A protein multimer comprising 4 (and optionally no more than 4) copies of Nb-112 (SEQ ID: 1*288).
  • the multimer may comprise mammalian cell glycosylation.
  • a method of purifying a multimer of the invention from a composition comprising the multimer comprising contacting the composition with an antigen (eg, a supergantigen) and binding the multimer to the antigen, and optionally isolating antigen/multimer complexes.
  • the multimer may be obtained from the complexes.
  • the multimer comprises at least 4 copies (eg, 4, 8, 12, 16, 20, 24 or 28 copies) of a VH3 family domain and the superantigen is Protein A.
  • the multimer comprises at least 4 copies (eg, 4, 8, 12, 16, 20, 24 or 28 copies) of a V ⁇ domain and the superantigen is Protein L.
  • the polypeptide described herein may, for example, comprise binding domain QB-GB or a binding domain (eg, an antibody single variable domain) that competes with QB-GB for binding to SARS- CoV-2 spike in an in vitro competition assay.
  • the polypeptide described herein may, for example, comprise binding domain QB-GB or a binding domain (eg, an antibody single variable domain) that binds to the same SARS-CoV-2 spike epitope (or an overlapping epitope) as QB-GB.
  • the polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike.
  • the polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state.
  • the multimer herein may comprise copies of such a binding domain.
  • the multimer described herein may, for example, bind to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike.
  • the multimer described herein may, for example, bind to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state.
  • An antibody variable domain for use as a medicament for treating humans against multiple different strains of SARS-CoV-2 wherein the variable domain is capable of binding and neutralising SARS- CoV-2 omicron and the variable domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V, or an amino acid sequence that is identical to a said selected sequence except for 1- 25 amino acid differences; wherein said strains comprise SARS-CoV-2 omicron.
  • An antibody variable domain that binds to coronavirus virus spike (eg, SARS-CoV-2 spike, SARS- CoV-1 spike or beta-coronavirus spike) and comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L, S and T or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences.
  • coronavirus virus spike eg, SARS-CoV-2 spike, SARS- CoV-1 spike or beta-coronavirus spike
  • An isolated nucleic acid encoding the antibody variable domain optionally wherein the nucleic acid is comprised by an expression vector for expressing the variable domain or a polypeptide comprising the variable domain.
  • a method of treating a human for a SARS-CoV-2 virus infection wherein the infection is an infection of SARS-CoV-2 delta or omicron; or a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron, wherein the method comprises administering (optionally by injection or inhalation) a medicament comprising a multimer of the variable domain.
  • a method of treating a human for a SARS-CoV-2 virus infection wherein the infection is an infection of SARS-CoV-2 delta or omicron; or a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron, wherein the method comprises administering (optionally by injection or inhalation) a medicament comprising a multimer comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of REGN10933, (iv) 4 copies of an antigen binding site of CB6, or (v) 4 copies of an antigen binding site of regdanvimab.
  • An antibody variable domain that binds to coronavirus virus spike (eg, SARS-CoV-2 spike, SARS- CoV-1 spike or beta-coronavirus spike) and comprises an amino acid sequence selected from SEQ IDs: A-L, S and T, or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences.
  • a polypeptide comprising the amino acid sequence of the antibody variable domain and one or more further amino acid sequences, optionally wherein the polypeptide comprises a self-assembly multimerization domain (SAM domain), eg, a p53 domain.
  • SAM domain self-assembly multimerization domain
  • a tetramer of the polypeptide is also provided.
  • a multimer comprising a plurality (optionally comprising 4) copies of the variable domain.
  • a pharmaceutical composition comprising the variable domain, polypeptide, multimer or tetramer and a pharmaceutically acceptable excipient, diluent or carrier, optionally wherein the composition comprises an anti-inflammatory agent (eg, an anti-IL6R antibody), anti-viral agent (eg, an anti- caronavirus antibody (such as an anti-SARS-CoV-2 antibody) or vaccine), immunosuppressant and/or an ACE2 peptide (eg, ACE2 extracellular domain or a part thereof) or ACE2 peptide mutimer.
  • an anti-inflammatory agent eg, an anti-IL6R antibody
  • anti-viral agent eg, an anti- caronavirus antibody (such as an anti-SARS-CoV-2 antibody) or vaccine
  • immunosuppressant eg, an ACE2 extracellular domain or a part thereof
  • ACE2 peptide mutimer e.g, ACE2 extracellular domain or a part thereof
  • a method of treating or preventing a coronavirus virus eg, SARS-CoV-2, SARS-CoV-1 or beta- coronavirus
  • a coronavirus virus eg, SARS-CoV-2, SARS-CoV-1 or beta- coronavirus
  • the method comprising administering the composition to the subject.
  • a coronavirus virus eg, SARS-CoV-2, SARS-CoV-1 or beta- coronavirus
  • a multimer of this Configuration may have any of the formats disclosed herein or comprise any of the variable domains disclosed herein.
  • a multimer of this Configuration may have any of the formats disclosed herein or comprise any of the variable domains disclosed herein.
  • the invention also provides polypeptide dimers, as well as tetramers of dimers.
  • BRIEF DESCRIPTION OF THE DRAWINGS Drawing 1 New VH Single Variable Domains & Quad Formats. A human IGHV3-23.
  • D In vitro neutralization ELISA comparing neutralization potency of the VHs. Drawing 2: Optimization of Q195.
  • the invention relates to multimers such as tetramers of polypeptides and tetramers, octamers, dodecamers, hexadecamers or 20-mers (eg, tetramers and octamers) of epitopes or effector domains (such as antigen binding sites (eg, antibody or TCR binding sites that specifically bind to antigen or pMHC, or variable domains thereof)) or peptides such as incretin, insulin or hormone peptides.
  • multimers such as tetramers of polypeptides and tetramers, octamers, dodecamers, hexadecamers or 20-mers (eg, tetramers and octamers) of epitopes or effector domains (such as antigen binding sites (eg, antibody or TCR binding sites that specifically bind to antigen or pMHC, or variable domains thereof)) or peptides such as incretin, insulin
  • multimers of the invention are usefully producible in eurkaryotic systems and can be secreted from eukaryotic cells in soluble form, which is useful for various industrial applications, such as producing pharmaceuticals, diagnostics, as imaging agents, detergents etc.
  • Higher order multimers such as tetramers or octamers of effector domains or peptides are useful for enhancing antigen or pMHC binding avidity. This may be useful for producing an efficacious medicine or for enhancing the sensitivity of a diagnostic reagent comprising the multimer, such as tetramer or octamer.
  • an additional or alternative benefit is enhanced half-life in vivo when the multimers of the invention are administered to a human or animal subject, eg, for treating or preventing a disease or condition in the subject.
  • the invention can also provide for multi-specific (eg, bi- or tri-specific) multivalent binding proteins. Specificity may related to specificity of antigen or pMHC binding.
  • the invention in certain examples usefully provides a means for producing multivalent (eg, bi-specific) proteins at high purity.
  • the invention also relates to methods and uses to expand antigen specificity of binding sites, as well as vaccines, methods of vaccination and assay methods and reagents.
  • the invention provides the following Clauses, Aspects, Paragraphs and Concepts (which are not intended to represent “Claims”; Claims are presented towards the end of this disclosure after the Examples and Tables). Any Clause herein can be combined with any Aspect or Concept herein. Any Aspect herein can be combined with any Concept herein.
  • ASPECTS The following Aspects are not to be interpreted as Claims. The Claims start after the Examples section. 1. A protein multimer of at least first, second, third and fourth copies of an effector domain (eg, a protein domain) or a peptide, wherein the multimer is multimerised by first, second, third and fourth self-associating tetramerisation domains (TDs) which are associated together, wherein each tetramerisation domain is comprised by a respective engineered polypeptide comprising one or more copies of said protein domain or peptide.
  • each TD is a TD of any one of proteins 1 to 119 listed in Table 2.
  • each TD is a p53 TD or a homologue or orthologue thereof.
  • each TD is a NHR2 TD or a homologue or orthologue thereof.
  • each TD is a p63 TD or a homologue or orthologue thereof.
  • each TD is a p73 TD or a homologue or orthologue thereof.
  • each TD is not a NHR2 TD.
  • each TD is not a p53 TD.
  • each TD is not a p63 TD.
  • each TD is not a p73 TD.
  • each TD is not a p53, 63 or 73 TD.
  • each TD is not a NHR2, p53, 63 or 73 TD.
  • the TDs in Aspect 1 multimerise first, second, third and fourth copies of the engineered polypeptide to provide a multimer protein, for example, a multimer that can be expressed intracellulary in a eukaryotic or mammalian cell (eg, a HEK293 cell) and/or which can be extracellularly secreted from a eukaryotic or mammalian cell (eg, a HEK293 cell) and/or which is soluble in an aqueous medium (eg, a eukaryotic or mammalian cell (eg, a HEK293 cell) culture medium).
  • a eukaryotic or mammalian cell eg, a HEK293 cell
  • an aqueous medium eg, a eukaryotic or mammalian cell (eg, a HEK293 cell) culture medium.
  • NHR TD, p53 TD, p63 TD and p73 TD examples are NHR TD, p53 TD, p63 TD and p73 TD (eg, human NHR TD, p53 TD, p63 TD and p73 TD) or an orthologue or homologue thereof.
  • the TD is not a p53 TD (or homologue or orthologue thereof), eg, it is not a human p53 TD (or homologue or orthologue thereof).
  • the TD is a NHR2 TD or a homologue or orthologue thereof, but excluding a p53 TD or a homologue or orthologue thereof.
  • the TD is a human NHR2 TD or a homologue or orthologue thereof, but excluding a human p53 TD or a homologue or orthologue thereof.
  • the TD is human NHR2.
  • the amino acid sequence of the TD is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to the sequence of human NHR2.
  • the domain or peptide is not naturally comprised by a polypeptide that also comprise a NHR2 TD. [0059] In an example, all of the domains of the polypeptide are human.
  • the engineered polypeptide may comprise one or more copies of said domain or peptide N- terminal to a copy of said TD.
  • the engineered polypeptide may comprise one or more copies of said domain or peptide C- terminal to a copy of said TD.
  • the engineered polypeptide comprises a first said domain or peptide and a TD, wherein the first domain or peptide is spaced by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 contiguous amino acids from the TD, wherein there is no further said domain or peptide between the first domain or peptide and the TD.
  • the multimer (eg, tetramer of said engineered polypeptide) comprises 4 (but no more than 4) TDs (eg, identical TDs) and 4, 8, 12 or 16 (but no more than said 4, 8, 12 or 16 respectively) copies of said domain or peptide.
  • each TD and each said domain or peptide is human.
  • the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises first, second, third and fourth identical copies of an engineered polypeptide, the polypeptide comprising a TD and one (but no more than one), two (but no more than two), or more copies of the said protein domain or peptide.
  • a tetramer of the epitope or effector domain has 4 identical copies of the polypeptide comprising a TD and each polypeptide has 1 such epitope or effector domain.
  • an octamer of the epitope or effector domain has 4 identical copies of the polypeptide comprising a TD and each polypeptide has 2 such epitope or effector domain.
  • a dodecamer of the epitope or effector domain has 4 identical copies of the polypeptide comprising a TD and each polypeptide has 3 such epitope or effector domain.
  • a hexadecamer of the epitope or effector domain has 4 identical copies of the polypeptide comprising a TD and each polypeptide has 4 such epitope or effector domain.
  • a 20-mer of the epitope or effector domain has 4 identical copies of the polypeptide comprising a TD and each polypeptide has 5 such epitope or effector domain.
  • the invention advantageously provides a format that can be readily isolated in pure (or highly pure, ie >90, 95, 96, 97, 98 or 99% purity) format, as well as a method for producing such a format in pure (or highly pure) form.
  • the multimer of the invention not being in mixture in a composition with any other multimer or polypeptide monomer, or wherein the multimer of the invention comprises >90, 95, 96, 97, 98 or 99% of species in a composition comprising the multimer of the invention and other multimers and/or polypeptide monomers which comprise the engineered polyeptide.
  • the multimer of the invention comprises >90, 95, 96, 97, 98 or 99% of species in a composition comprising the multimer of the invention and other multimers and/or polypeptide monomers which comprise the engineered polyeptide.
  • multimers eg, a plurality of tetramers or octamers or dodecamers or hexadecamers
  • the multimers are monospecific (but multivalent) for antigen binding, or alternatively bi- or multi-specific for antigen binding.
  • the invention provides a plurality of multimers (eg, a plurality of tetramers or octamers or dodecamers or hexadecamers, each polypeptide being at least tetra-valent for antigen binding and (i) bi-specific (ie, capable of specifically binding to 2 different antigens) or (ii) mono-specific and at least tetravalent for antigen binding.
  • a plurality of multimers eg, a plurality of tetramers or octamers or dodecamers or hexadecamers, each polypeptide being at least tetra-valent for antigen binding and (i) bi-specific (ie, capable of specifically binding to 2 different antigens) or (ii) mono-specific and at least tetravalent for antigen binding.
  • antigen binding is mentioned this can instead be pMHC binding when the domain is a TCR V domain.
  • the plurality is in pure form (ie, not mixed with multimers (eg, tetramers or octamers or dodecamers or hexadecamers) that comprise more than one type of polypeptide monomer.
  • the multimer comprises at least 2 different types of antigen binding site.
  • the multimer is bi-specific, tri-specific or tetra-specific.
  • the multimer has an antigen binding site or pMHC binding site valency of 4, 6, 8, 10 or 12, preferably 4 or 8.
  • a peptide MHC is a class I or class II pMHC.
  • KD specifically binds
  • SPR surface plasmon resonance
  • the surface plasmon resonance (SPR) is carried out at 25° C. In another embodiment, the SPR is carried out at 37° C. In one embodiment, the SPR is carried out at physiological pH, such as about pH7 or at pH7.6 (eg, using Hepes buffered saline at pH7.6 (also referred to as HBS-EP)). In one embodiment, the SPR is carried out at a physiological salt level, eg, 150 mM NaCl. In one embodiment, the SPR is carried out at a detergent level of no greater than 0.05% by volume, eg, in the presence of P20 (polysorbate 20; eg, Tween-20TM) at 0.05% and EDTA at 3 mM.
  • P20 polysorbate 20
  • Tween-20TM eg, Tween-20TM
  • the SPR is carried out at 25° C. or 37° C. in a buffer at pH7.6, 150 mM NaCl, 0.05% detergent (eg, P20) and 3 mM EDTA.
  • the buffer can contain 10 mM Hepes.
  • the SPR is carried out at 25° C. or 37° C. in HBS-EP.
  • HBS-EP is available from Teknova Inc (California; catalogue number H8022).
  • the affinity eg, of a VH/VL binding site
  • the affinity is determined using SPR by using any standard SPR apparatus, such as by BiacoreTM or using the ProteOn XPR36TM (Bio-Rad®).
  • a multimer, tetramer or octamer or dodecamer or hexadecamer or 20-mer of the invention is an isolated multimer, tetramer or octamer or dodecamer or hexadecamer or 20-mer.
  • a multimer, tetramer or octamer of the invention consists of copies of said engineered polypeptide.
  • the multimer, tetramer or octamer or dodecamer or hexadecamer or 20-mer of the invention comprises 4 or 8 or 12 or 16 or 20 but not more than 4 or 8 or 12 or 16 or 20 copies respectively of the engineered polypeptide.
  • engineered is meant that the polypeptide is not naturally-occurring, for example the protein domain or peptide is not naturally comprised by a polypeptide that also comprises said TD.
  • Each said protein domain or peptide may be a biologically active domain or peptide (eg, biologically active in humans or animals), such as a domain that specifically binds to an antigen or peptide-MHC (pMHC), or wherein the domain is comprised by an antigen or pMHC binding site.
  • the domain or peptide is a carbohydrate, glucose or sugar-regulating agent, such as an incretin or an insulin peptide.
  • the domain or peptide is an inhibitor or an enzyme or an inhibitor of a biological function or pathway in humans or animals.
  • the domain or peptide is an iron-regulating agent.
  • each protein domain or peptide is selected from an antigen or pMHC binding domain or peptide; a hormone; a carbohydrate, glucose or sugar- regulating agent; an iron-regulating agent; and an enzyme inhibitor.
  • the multimer of any Aspect 1 or 2 comprising a tetramer, octamer, 12-mer, 16-mer or 20- mer (eg, a tetramer, octamer, 12-mer or 16-mer) of an immunoglobulin superfamily binding site (eg, an antibody or TCR binding site, such as a scFv or scTCR).
  • an immunoglobulin superfamily binding site eg, an antibody or TCR binding site, such as a scFv or scTCR.
  • T-cell receptor (TCR) domains can be V ⁇ (eg. paired with a V ⁇ ), V ⁇ (eg.
  • the binding site comprises a first variable domain paired with a second variable domain.
  • the first and second variable domains are comprised by the engineered polypeptide.
  • the first domain is comprised by the engineered polypeptide and the second domain is comprised a by a further polypeptide that is different from the engineered polypeptide (and optionally comprises a TD or is devoid of a TD).
  • the domains are constant region domains.
  • the domains are FcAbs.
  • the domains are non-Ig antigen binding sites or comprises by a non-Ig antigen binding site, eg, an affibody.
  • ANTIGEN BINDING SITES & EFFECTOR DOMAINS [0074]
  • the or each antigen binding site (or effector domain) is selected from the group consisting of an antibody variable domain (eg, a VL or a VH, an antibody single variable domain (domain antibody or dAb), a camelid VHH antibody single variable domain, a shark immunoglobulin single variable domain (NA V), a NanobodyTM or a camelised VH single variable domain); a T-cell receptor binding domain; an immunoglobulin superfamily domain; an agnathan variable lymphocyte receptor (J Immunol; 2010 Aug l;185(3):1367-74; "Alternative adaptive immunity in jawless vertebrates; Herrin BR & Cooper M D.); a fibronectin domain (eg, an AdnectinTM); an scFv;
  • variable domains and VH/VL pairs of antibodies disclosed in WO2007024715 at page 40, line 23 to page 43, line 23.
  • This specific disclosure is incorporated herein by reference as though explicitly written herein to provide basis for epitope binding moieties for use in the present invention and for possible inclusion in claims herein.
  • a "domain” is a folded protein structure which has tertiary structure independent of the rest of the protein. Generally, domains are responsible for discrete functional properties of proteins and in many cases may be added, removed or transferred to other proteins without loss of function of the remainder of the protein and/or of the domain.
  • a "single antibody variable domain” is a folded polypeptide domain comprising sequences characteristic of antibody variable domains.
  • immunoglobulin single variable domain or "antibody single variable domain” refers to an antibody variable domain (VH, VHH, VL) that specifically binds an antigen or epitope independently of a different V region or domain.
  • An immunoglobulin single variable domain can be present in a format (e.g., homo- or hetero-multimer) with other, different variable regions or variable domains where the other regions or domains are not required for antigen binding by the single immunoglobulin variable domain (i.e., where the immunoglobulin single variable domain binds antigen independently of the additional variable domains).
  • a “domain antibody” or “dAb” is the same as an "immunoglobulin single variable domain" which is capable of binding to an antigen as the term is used herein.
  • An immunoglobulin single variable domain may be a human antibody variable domain, but also includes single antibody variable domains from other species such as rodent (for example, as disclosed in WO 00/29004), nurse shark and Camelid VHH immunoglobulin single variable domains.
  • Such VHH domains may be humanised according to standard techniques available in the art, and such domains are still considered to be "domain antibodies" according to the invention.
  • VH includes camelid VHH domains.
  • NA V are another type of immunoglobulin single variable domain which were identified in cartilaginous fish including the nurse shark. These domains are also known as Novel Antigen Receptor variable region (commonly abbreviated to V(NAR) or NARV).
  • V(NAR) Novel Antigen Receptor variable region
  • CTLA-4 Cytotoxic T Lymphocyte-associated Antigen 4
  • CTLA-4 molecules engineered to have different binding specificities are also known as Evibodies.
  • Lipocalins are a family of extracellular proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids and lipids. They have a rigid ⁇ -sheet secondary structure with a numer of loops at the open end of the conical structure which can be engineered to bind to different target antigens. Anticalins are between 160-180 amino acids in size, and are derived from lipocalins. For further details see Biochim Biophys Acta 1482: 337-350 (2000), US7250297B1 and US20070224633.
  • An affibody is a scaffold derived from Protein A of Staphylococcus aureus which can be engineered to bind to antigen.
  • the domain consists of a three- helical bundle of approximately 58 amino acids. Libraries have been generated by randomisation of surface residues. For further details see Protein Eng. Des. Sel.17, 455-462 (2004) and EP1641818A1.
  • AvimersTM are multidomain proteins derived from the A-domain scaffold family. The native domains of approximately 35 amino acids adopt a defined disulphide bonded structure. Diversity is generated by shuffling of the natural variation exhibited by the family of A-domains. For further details see Nature Biotechnology 23(12), 1556 - 1561 (2005) and Expert Opinion on Investigational Drugs 16(6), 909-917 (June 2007).
  • a transferrin is a monomeric serum transport glycoprotein. Transferrins can be engineered to bind different target antigens by insertion of peptide sequences in a permissive surface loop. Examples of engineered transferrin scaffolds include the Trans-body. For further details see J. Biol. Chem 274, 24066-24073 (1999). Designed Ankyrin Repeat Proteins (DARPinsTM) are derived from ankyrin which is a family of proteins that mediate attachment of integral membrane proteins to the cytoskeleton. A single ankyrin repeat is a 33 residue motif consisting of two a-helices and a ⁇ - turn.
  • Fibronectin is a scaffold which can be engineered to bind to antigen.
  • AdnectinsTM consist of a backbone of the natural amino acid sequence of the 10th domain of the 15 repeating units of human fibronectin type III (FN3).
  • Peptide aptamers are combinatorial recognition molecules that consist of a constant scaffold protein, typically thioredoxin (TrxA) which contains a constrained variable peptide loop inserted at the active site.
  • TrxA thioredoxin
  • Microbodies are derived from naturally occurring microproteins of 25-50 amino acids in length which contain 3-4 cysteine bridges - examples of microproteins include KalataBI and conotoxin and knottins.
  • the microproteins have a loop which can be engineered to include upto 25 amino acids without affecting the overall fold of the microprotein.
  • engineered knottin domains see WO2008098796.
  • epitope binding moieties and domains include proteins which have been used as a scaffold to engineer different target antigen binding properties include human ⁇ -crystallin and human ubiquitin (affilins), kunitz type domains of human protease inhibitors, PDZ- domains of the Ras-binding protein AF-6, scorpion toxins (charybdotoxin), C-type lectin domain (tetranectins) are reviewed in Chapter 7 - Non- Antibody Scaffolds from Handbook of Therapeutic Antibodies (2007, edited by Stefan Dubel) and Protein Science 15:14-27 (2006).
  • the or each antigen binding site comprises a non-Ig scaffoled, eg, is selected from the group consisting of Affibodies, Affilins, Anticalins, Atrimers, Avimers, Bicycle Peptides, Cys-knots, DARpins, Fibronectin type III, Fyomers, Kunitz Domain, OBodies, Aptamers, Adnectins, Armadillo Repeat Domain, Beta-Hairpin mimetics and Lipocalins. 5.
  • Affibodies eg, is selected from the group consisting of Affibodies, Affilins, Anticalins, Atrimers, Avimers, Bicycle Peptides, Cys-knots, DARpins, Fibronectin type III, Fyomers, Kunitz Domain, OBodies, Aptamers, Adnectins, Armadillo Repeat Domain, Beta-Hairpin mimetics and Lipocalins. 5.
  • each polypeptide comprises first and second copies of said protein domain or peptide, wherein the polypeptide comprises in (N- to C-terminal direction) (i) a first of said copies – TD – the second of said copies; (ii) TD – and the first and second copies; or (iii) said first and second copies – TD. 6.
  • the TDs are NHR2 TDs and the domain or peptide is not a NHR2 domain or peptide; or wherein the TDs are p53 TDs and the domain or peptide is not a p53 domain or peptide. 7.
  • the engineered polypeptide comprises one or more copies of a second type of protein domain or peptide, wherein the second type of protein domain or peptide is different from the first protein domain or peptide.
  • the domains are immunoglobulin superfamily domains. 9.
  • the domain or peptide is an antibody variable or constant domain (eg, an antibody single variable domain), a TCR variable or constant domain, an incretin, an insulin peptide, or a hormone peptide.
  • the multimer comprises first, second, third and fourth identical copies of a said engineered polypeptide, the polypeptide comprising a TD and one (but no more than one), two (but no more than two) or more copies of the said protein domain or peptide.
  • the engineered polypeptide comprises an antibody or TCR variable domain (V1) and a NHR2 TD. 12.
  • each engineered polypeptide comprises (in N- to C- terminal direction) V1-an optional linker-NHR2 TD, wherein V1 is an antibody or TCR variable domain and each engineered polypeptide is paired with a respective second engineered polypeptide that comprises V2, wherein V2 is a an antibody or TCR variable domain respectively that pairs with V1 to form an antigen or pMHC binding site, and optionally one polypeptide comprises an antibody Fc, or comprises antibody CH1 and the other polypeptide comprises an antibody CL that pairs with the CH1.
  • the TD comprises (i) an amino acid sequence identical to SEQ ID: 1*10 or 1*126 or at least 80% identical thereto; or (ii) an amino acid sequence identical to SEQ ID: 1*120 or 1*123 or at least 80% identical thereto. 16.
  • the multimer comprises a tetramer, octamer, 12-mer, 16-mer or 20-mer (eg, a tetramer, octamer, 12-mer or 16-mer; or a tetramer or octamer) of an antigen binding site of an antibody selected from the group consisting of ReoProTM; Abciximab; RituxanTM; Rituximab; ZenapaxTM; Daclizumab; SimulectTM; Basiliximab; SynagisTM; Palivizumab; RemicadeTM; Infliximab; HerceptinTM; MylotargTM; Gemtuzumab; CampathTM; Alemtuzumab; ZevalinTM; Ibritumomab; HumiraTM; Adalimumab; XolairTM; Omalizumab; BexxarTM; Tositumomab; RaptivaTM; E
  • the binding site of the polypeptide of the multimer comprises a VH of the binding site of the antibody and also the CH1 of the antibody (ie, in N- to C-terminal direction the VH-CH1 and SAM).
  • the polypeptide may be paired with a further polypeptide comprising (in N- to C-terminal direction a VL-CL, eg, wherein the CL is the CL of the antibody).
  • a said protein domain of the engineered polypeptide is a V domain (a VH or VL) of an antibody binding site of an antibody selected from said group, wherein the multimer comprises a further V domain (a VL or VH respectively) that pairs with the V domain of the engineered polypeptide to form the antigen binding site of the selected antibody.
  • the invention provides tetramer, octamer, 12-mer, 16-mer or 20-mer (eg, a tetramer, octamer, 12-mer or 16-mer; or tetramer or octamer)of a binding site of said selected antibody, which beneficially may have improved affinity, avidity and/or efficacy for binding its cognate antigen or for treating or preventing a disease or condition in a human or animal wherein the multimer is administered thereto to bind the cognate antigen in vivo.
  • tetramer, octamer, 12-mer, 16-mer or 20-mer eg, a tetramer, octamer, 12-mer or 16-mer; or tetramer or octamer
  • the multimer, tetramer, octamer, 12-mer, 16-mer or 20-mer comprises 4 (or said X/4 as described above) copies of an antigen binding site of an antibody, wherein the antibody is adalimumab, sarilumab, dupilumab, bevacizumab (eg, AVASTINTM), cetuximab (eg, ERBITUXTM), tocilizumab (eg, ACTEMRATM) or trastuzumab (HERCEPTINTM).
  • the antibody is an anti-CD38 antibody, an anti-TNFa antibody, an anti-TNFR antibody, an anti-IL-4Ra antibody, an anti-IL-6R antibody, an anti-IL-6 antibody, an anti-VEGF antibody, an anti-EGFR antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, an anti-PCSK9 antibody, an anti-CD3 antibody, an anti-CD20 antibody, an anti-CD138 antibody, an anti-IL-1 antibody.
  • the antibody is selected from the antibodies disclosed in WO2007024715 at page 40, line 23 to page 43, line 23, the disclosure of which is incorporated herein by reference.
  • a binding site herein may, for example, be a ligand (eg, cytokine or growth factor, eg, VEGF or EGFR) binding site of a receptor (eg, KDR or Flt).
  • a binding site herein may, for example, be a binding site of EyeleaTM , AvastinTM or LucentisTM, eg, for ocular or oncological medical use in a human or animal.
  • the mutlimer, tetramer or octamer may be for treatment or prevention of a caner or ocular condition (eg, wet or dry AMD or diabetic retinopathy) or as an inhibitor of neovascularisation in a human or animal subject.
  • a caner or ocular condition eg, wet or dry AMD or diabetic retinopathy
  • an inhibitor of neovascularisation in a human or animal subject 17.
  • prolactin which acts on the mammary gland
  • adrenocorticotropic hormone (ACTH)
  • glucocorticoids which acts on the adrenal cortex to regulate the secretion of glucocorticoids
  • growth hormone which acts on bone, muscle, and the liver.
  • Peptide hormones are produced by many different organs and tissues, however, including the heart (atrial-natriuretic peptide (ANP) or atrial natriuretic factor (ANF)) and pancreas (glucagon, insulin and somatostatin), the gastrointestinal tract (cholecystokinin, gastrin), and adipose tissue stores (leptin).
  • the peptide hormone of the invention is selected from prolactin, ACTH, growth hormone (somatotropin), vasopressin, oxytocin, glucagon, insulin, somatostatin, cholecystokinin, gastrin and leptin (eg, selected from human prolactin, ACTH, growth hormone, vasopressin, oxytocin, glucagon, insulin, somatostatin, cholecystokinin, gastrin and leptin).
  • the incretin is a GLP-1, GIP or exendin-4 peptide.
  • the invention provides, in embodiments, the following engineered multimers:- An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an incretin. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an insulin peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a GLP-1 (glucagon-like peptide-1 (GLP-1) peptide.
  • GLP-1 glucagon-like peptide-1
  • An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an antibody binding site eg, a scFv or Fab.
  • An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a TCR binding site eg, a scTCR.
  • An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a TCR V ⁇ /V ⁇ binding site etramer, octamer, dodecamer, hexadecamer or 20-mer of a TCR V ⁇ /V ⁇ binding site.
  • an isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an antibody single variable domain binding site An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an FcAb binding site. [0086] In an example of any of these tetramer, octamer, dodecamer, hexadecamer or 20-mers, the domain or peptide is human.
  • the tetramer, octamer, dodecamer, hexadecamer or 20-mers comprises a NHR2 TD (eg, a human NHR2).
  • the tetramer, octamer, dodecamer, hexadecamer or 20-mers comprises a p53 TD (eg, a human p53 TD).
  • the tetramer, octamer, dodecamer, hexadecamer or 20-mers comprises a p63 TD (eg, a human p63 TD).
  • the tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises a p73 TD (eg, a human p73 TD).
  • the tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises a tetramer of TDs (eg, human NHR2 TDs), whereby the domains or peptides form a multimer of 4 or 8 domains or peptides.
  • TDs eg, human NHR2 TDs
  • the plurality is pure, eg, is not in mixture with multimers of said binding site or peptide wherein the multimers comprise more than one type of polypeptide monomer. 18.
  • aqueous solution eg, an aqueous eukaryotic cell growth medium or buffer
  • the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer is secretable from a HEK293T (or other eukaryotic, mammalian, CHO or Cos) cell in stable form as indicated by a single band at the molecular weight expected for said multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer on a PAGE gel using a sample of supernatant from such cells and detected using Western Blot. 19.
  • HEK293T or other eukaryotic, mammalian, CHO or Cos
  • a tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, atetramer or octamer) of (a) TCR V domains or TCR binding sites, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is soluble in aqueous solution (eg, an aqueous eukaryotic cell growth medium or buffer); (b) antibody single variable domains, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is soluble in aqueous solution (eg, an aqueous eukaryotic cell growth medium or buffer); (c) TCR V domains or TCR binding sites, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is capable of being intracellularly and/or extracellularly expressed by
  • the medium is SFMII growth medium supplemented with L-glutamine (eg, complete SFMII growth medium supplemented with 4 mM L-glutamine).
  • the medium is serum-free HEK293 cell culture medium.
  • the medium is serum-free CHO cell culture medium.
  • a cell herein is a human cell, eg, a HEK293 cell (such as a HEK293T cell). 20.
  • the glycosylation is CHO cell glycosylation.
  • the glycosylation is HEK (eg, HEK293, such as HEK293T) cell glycosylation.
  • the glycosylation is Cos cell glycosylation.
  • the glycosylation is Picchia cell glycosylation.
  • the glycosylation is Sacchaaromyces cell glycosylation.
  • 23 The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of Aspect 22, wherein the cell is a HEK293 cell.
  • 24 A plurality of multimers, tetramer, octamer, dodecamer, hexadecamer or 20-mer of any preceding Aspect. 25.
  • a pharmaceutical composition comprising the multimer(s), tetramer(s), octamer(s), dodecamer(s), hexadecamer(s) or 20-mer(s) of any preceding Aspect and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier diluent or excipient.
  • the monomer is an engineered polypeptide as disclosed herein, comprising a said protein domain or peptide and further comprising a TD.
  • the engineered polypeptide comprises (in N- to C-terminal direction) a variable domain (V1) – a constant domain (C) (eg, a CH1 or Fc) – optional linker – TD. 28.
  • An engineered (and optionally isolated) engineered polypeptide (P1) which comprises (in N- to C-terminal direction):- (a) TCR V1 –TCR C1 – antibody C (eg, CH, CH1 (such as IgG CH1) or CL (such as C ⁇ or a C ⁇ )) – optional linker – TD, wherein (i) V1 is a V ⁇ and C1 is a C ⁇ ; (ii) V1 is a V ⁇ and C1 is a C ⁇ ; (iii) V1 is a V ⁇ and C1 is a C ⁇ ; or (iv) V1 is a V ⁇ and C1 is a C ⁇ ; or (b) TCR V1 – antibody C (eg, CH, CH1 (such as IgG CH1) or CL (such as C ⁇ or a C ⁇ )) – optional linker – TD, wherein (i) V1 is a V ⁇ ; (ii) V1 is a V ⁇ ; (iii)
  • the TCR V is comprised by an single chain TCR binding site (scTCR) that specifically binds to a pMHC , wherein the binding site comprises TCR V-linker - TCRV.
  • the engineered polypeptide comprises (in N- to C-terminal direction) (i) V1 – linker – V - optional C - optional linker – TD, or (ii) Va – linker – V1 - optional C - optional linker – TD, wherein Va is a TCR V domain and C is an antibody C domain (eg, a CH1 or CL) or a TCR C.
  • the antibody C is CH1 (eg, IgG CH1).
  • the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer has a size of no more than 155 kDa, eg, wherein said protein domain is an antibody variable domain comprising a CDR3 of at least 16, 17, 18, 19, 20, 21 or 22 amino acids, such as a Camelid CDR3 or bovine CDR3.
  • the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises TCR binding sites and antibody binding sites.
  • each polypeptide comprises a TCR V (eg, comprised by a scTCR that specifically binds a pMHC) and an antibody V (eg, comprised by a scFv or paired with a second V domain comprised by a said second polypeptide to form a V/V paired binding site that specifically binds to an antigen).
  • the pMHC comprises a RAS peptide.
  • the antigen is selected from the group consisting of PD-1, PD-L1 or any other antigen disclosed herein.
  • the antigen is PD-1 and the pMHC comprises a RAS peptide. 29.
  • polypeptide of Aspect 28 wherein the engineered polypeptide P1 is paired with a further polypeptide (P2), wherein P2 comprises (in N- to C-terminal direction):- (g) TCR V2 –TCR C2 – antibody CL (eg, a C ⁇ or a C ⁇ ), wherein P1 is according to (a) recited in Aspect 28 and (i) V2 is a V ⁇ and C2 is a C ⁇ when P1 is according to (a)(ii); (ii) V2 is a V ⁇ and C2 is a C ⁇ when P1 is according to (a)(i); (iii) V2 is a V ⁇ and C2 is a C ⁇ when P1 is according to (a)(iv); or (iv) V2 is a V ⁇ and C2 is a C ⁇ when P1 is according to (a)(iii); or (h) TCR V2 – antibody CL (eg, a C ⁇ or a C ⁇ ), where
  • V1 and V2 form a paired variable domain binding site that is capable of specifically binding to an antigen or pMHC.
  • V1 and V2 are variable domains of an antibody, eg, selected from the group consisting of ReoProTM; Abciximab; RituxanTM; Rituximab; ZenapaxTM; Daclizumab; SimulectTM; Basiliximab; SynagisTM; Palivizumab; RemicadeTM; Infliximab; HerceptinTM; MylotargTM; Gemtuzumab; CampathTM; Alemtuzumab; ZevalinTM; Ibritumomab; HumiraTM; Adalimumab; XolairTM; Omalizumab; BexxarTM; Tositumomab; RaptivaTM; Efalizumab; ErbituxTM; Cetuximab; AvastinTM; Bevacizumab; TysabriTM
  • the binding site of the polypeptide of the multimer comprises a VH of the binding site of the antibody and also the CH1 of the antibody (ie, in N- to C-terminal direction the VH-CH1 and SAM).
  • the polypeptide may be paired with a further polypeptide comprising (in N- to C-terminal direction a VL-CL, eg, wherein the CL is the CL of the antibody).
  • the antibody is Avastin.
  • the antibody is Actemra.
  • the antibody is Erbitux.
  • the antibody is Lucentis.
  • the antibody is sarilumab.
  • the antibody is dupilumab. [00105] In one embodiment, the antibody is alirocumab. [00106] In one embodiment, the antibody is bococizumab. [00107] In one embodiment, the antibody is evolocumab. [00108] In one embodiment, the antibody is pembrolizumab. [00109] In one embodiment, the antibody is nivolumab. [00110] In one embodiment, the antibody is ipilimumab. [00111] In one embodiment, the antibody is remicade. [00112] In one embodiment, the antibody is golimumab. [00113] In one embodiment, the antibody is ofatumumab.
  • the antibody is Benlysta. [00115] In one embodiment, the antibody is Campath. [00116] In one embodiment, the antibody is rituximab. [00117] In one embodiment, the antibody is Herceptin. [00118] In one embodiment, the antibody is durvalumab. [00119] In one embodiment, the antibody is daratumumab.
  • any binding domain herein eg, a dAb or scFv or Fab
  • V1 is capable (itself when a single variable domain, or when paired with V2) of specifically binding to an antigen selected from the group consisting of ABCF1; ACVR1; ACVR1B; ACVR2; ACVR2B; ACVRL1; ADORA2A; Aggrecan; AGR2; AICDA; AWI; AIG1; AKAP1; AKAP2; AIYIH; AMHR2; ANGPT1; ANGPT2; ANGPTL3; ANGPTL4; ANPEP; APC; APOC1; AR; AZGP1 (zinc-a-glycoprotein); B7.1; B7.2; BAD; BAFF; BAG1; BAI1; BCL2; BCL6; BDNF; BLNK; BLRl (MDR15); BlyS; BM Pl; BMP2; BMP3B (GDFIO);
  • an antigen selected from
  • the multimer, octamer, dodecamer, hexadecamer or 20-mer specifically binds to first and second (eg, for an octamer, dodecamer, hexadecamer or 20-mer); optionally, first, second and third (eg, for a dodecamer, hexadecamer or 20- mer); or optionally, first, second, third and fourth (eg, for a hexadecamer or 20-mer); or optionally, first, second, third, fourth and fifth (eg, for a 20-mer) epitopes or antigens, each of which is selected from the group consisting of EpCAM and CD3; CD19 and CD3; VEGF and VEGFR2; VEGF and EGFR; CD138 and CD20; CD138 and CD40; CD20 and CD3; CD38 and CD138; CD38 and CD20; CD38 and CD40; CD40 and CD20
  • any binding domain herein eg, a dAb or scFv or Fab
  • V1 is capable (itself when a single variable domain, or when paired with V2) of specifically binding to an antigen selected from the group consisting of human IL-1A, IL-1 ⁇ , IL-1RN, IL-6, BLys, APRIL, activin A, TNF alpha, a BMP, BMP2, BMP7, BMP9, BMP10, GDF8, GDF11, RANKL, TRAIL, VEGFA, VEGFB or PGF; optionally the multimer comprises a cytokine amino acid sequence (eg, C-terminal to a TD), such as IL-2 or an IL2-peptide; and the multimer, octamer, dodecamer, hexadecamer or 20-mer is for treating or preventing a cancer in a human subject.
  • an antigen selected from the group consisting of human IL-1A, IL-1 ⁇ ,
  • the said effector or protein domain is capable of binding to such an antigen;
  • the multimer comprises a cytokine amino acid sequence (eg, C-terminal to a TD), such as IL-2 or an IL2-peptide; and the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer is for treating or preventing a cancer in a human subject.
  • a multimer (eg, a dimer, trimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer) of P1 as defined in Aspect 28; or of P1 paired with P2 as defined in Aspect 29; or a plurality of said multimers, optionally wherein the multimer is according to any one of aspects 1 to 24.
  • the multimer is a tetramer of the engineered polypeptide and/or effector domain.
  • the plurality of tetramers are not in mixture with monomers, dimers or trimers of the polypeptide,
  • the multimer eg, tetramer
  • the multimer is a capable of specifically binding to two different pMHC. 31.
  • the nucleic acid is a DNA, optionally operably connected to or comprising a promoter for expression of the polypeptide or monomer.
  • the nucleic acid is a RNA (eg, mRNA). 32.
  • a eukaryotic host cell comprising the nucleic acid or vector of Aspect 31 for intracellular and/or secreted expression of the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer, engineered polypeptide or monomer of any one of Aspects 1 to 24.
  • a nucleic acid or vector according to aspect 31 in a method of manufacture of protein multimers for producing intracellularly expressed and/or secreted multimers, wherein the method comprises expressing the multimers in and/or secreting the multimers from eukaryotic cells comprising the nucleic acid or vector.
  • nucleic acid or vector according to aspect 31 Use of a nucleic acid or vector according to aspect 31 in a method of manufacture of protein multimers for producing glycosylated multimers in eukaryotic cells comprising the nucleic acid or vector.
  • Mammalian glycosylation of the invention is useful for producing medicines comprising or consisting of the multimers, tetramer, octamer, dodecamer, hexadecamer or 20-merof the invention for medical treatment or prevention of a disease or condition in a mammal, eg, a human.
  • the invention thus provides such a method of use as well as the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-merof the invention for this purpose.
  • the invention comprises a detergent or personal healthcare product comprising a multimer, tetramer, octamer, dodecamer, hexadecamer or 20-merof the invention.
  • the invention comprises a foodstuff or beverage comprising a multimer, tetramer, octamer, dodecamer, hexadecamer or 20-merof the invention.
  • the multimer, monomer, dimer, trimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer, polypeptide, composition, mixture, use or method of the present invention is for an industrial or domestic use, or is used in a method for such use.
  • a mixture comprising (i) a eukaryotic cell line encoding an engineered polypeptide according to any one of Aspects 27 to 29; and (ii) multimers, tetramers, octamers, dodecamers, hexadecamers or 20-mersas defined in any one of Aspects 1 to 24.
  • 36. The mixture of Aspect 35, wherein the cell line is in a medium comprising secretion products of the cells, wherein the secretion products comprise said multimers, tetramers, octamers, dodecamers, hexadecamers or 20-mers.
  • a method producing (a) TCR V domain multimers, the method comprising the soluble and/or intracellular expression of TCR V-NHR2 TD or TCR V- p53 TD fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers; (b) antibody V domain multimers, the method comprising the soluble and/or intracellular expression of antibody V (eg, a single variable domain)-NHR2 TD or V- p53 TD fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers; (c) incretin peptide (eg, GLP-1, GIP or insulin) multimers, the method comprising the soluble and/or intracellular expression of incretin peptide-NHR2 TD
  • TD self-associating tetramerisation domains
  • an engineered polypeptide in a method of the manufacture of a tetramer of a polypeptide comprising multiple copies of a protein domain or peptide, for producing a higher yield of tetramers versus monomer and/or dimer polypeptides, wherein the engineered polypeptide comprises one or more copies of said protein domain or peptide and further comprises a self- associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue).
  • TD self- associating tetramerisation domains
  • TD self-associating tetramerisation domains
  • an engineered polypeptide in a method of the manufacture of a tetramer of a polypeptide comprising multiple copies of a protein domain or peptide, for producing a plurality of tetramers that are not in mixture with monomers, dimers or trimers, wherein the engineered polypeptide comprises one or more copies of said protein domain or peptide and further comprises a self-associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue).
  • TD self-associating tetramerisation domains
  • any one of Aspects 39 to 42 wherein the yield of tetramers is at least 10, 20, 30, 40 or 50x the yield of monomers and/or dimers.
  • 44. The use of any one of Aspects 39 to 43, wherein the ratio of tetramers produced : monomers and/or dimers produced in the method is at least 90:10 (eg, at least 95:5 or 98:2, or 99:1).
  • 45. The use of any one of Aspects 39 to 44, wherein each monomer has a size of no more than 40, 35, 30, 25 or 20 kDa.
  • 46. The use of any one of Aspects 39 to 45, wherein each tetramer has a size of no more than 200, 160, 155 or 150 kDa.
  • a multivalent heterodimeric soluble T cell receptor capable of binding pMHC complex comprising: (i) TCR extracellular domains; (ii) immunoglobulin constant domains; and (iii) an NHR2 multimerisation domain of ETO.
  • a multimeric immunoglobulin comprising (i) immunoglobulin variable domains; and (ii) an NHR2 multimerisation domain of ETO. 50.
  • a method for assembling a soluble, multimeric polypeptide comprising: (a) providing a monomer of the said multimeric polypeptide, fused to an NHR2 domain of ETO; (b) causing multiple copies of said monomer to associate, thereby obtaining a multimeric, soluble polypeptide.
  • the invention further provides (i) A monomer as shown in Fig 1; (ii) A homodimer as shown in Fig 1; (iii) A homotetramer as shown in Fig 1; (iv) A monomer 2 as shown in Fig 2; (v) A homodimer 2 as shown in Fig 2; (vi) A homotetramer 2 as shown in Fig 2; (vii) A monomer as shown in Fig 11a; (viii) A homodimer as shown in Fig 11a; (ix) A homotetramer as shown in Fig 11a; (x) A monomer as shown in Fig 12a; (xi) A homodimer as shown in Fig 12a; (xii) A homotetramer as shown in Fig 12a; (xiii) A monomer 2 as shown in Fig 13a; (xiv) A homodimer 2 as shown in Fig 13a; (xv) A homotetramer 2 as shown in Fig 13a; (
  • the invention also provides (i) A tetravalent or octavalent antibody V molecule; (ii) A tetravalent or octavalent antibody Fab molecule; (iii) A tetravalent or octavalent antibody dAb molecule; (iv) A tetravalent or octavalent antibody scFv molecule; (v) A tetravalent or octavalent antibody TCR V molecule; or (vi) A tetravalent or octavalent antibody scFv molecule; Wherein the molecule is (a) soluble in aqueous solution (eg, a solution or cell culture medium disclosed herein) and/or; (b) capable of being intracellularly and/or extracellularly expressed by HEK293 cells.
  • aqueous solution eg, a solution or cell culture medium disclosed herein
  • the invention provides a claim multimer (eg, tetramer) of NHR2 or p53 (or another TD disclosed herein) fused at its N- and/or C-terminus to an amino acid sequence (eg, a peptide, protein domain or protein) that is not an NHR2 sequence.
  • a claim multimer eg, tetramer
  • NHR2 or p53 or another TD disclosed herein
  • amino acid sequence eg, a peptide, protein domain or protein
  • sequence is selected from a TCR (eg, TCR ⁇ , TCR ⁇ , C ⁇ or C ⁇ ), cytokine (eg, interleukin, eg, IL-2, IL-12, IL-12 and IFN), antibody fragments (eg, scFv, dAb or Fab) and a antibody domain (eg, V or C domain, eg, VH, VL, V ⁇ , V ⁇ , CH, CH1, CH2, CH3, hinge, C ⁇ or C ⁇ domain).
  • TCR eg, TCR ⁇ , TCR ⁇ , C ⁇ or C ⁇
  • cytokine eg, interleukin, eg, IL-2, IL-12, IL-12 and IFN
  • antibody fragments eg, scFv, dAb or Fab
  • V or C domain eg, VH, VL, V ⁇ , V ⁇ , CH, CH1, CH2, CH3, hinge, C ⁇ or C ⁇ domain.
  • the multimer is the molecule is a) soluble in aqueous solution (eg, a solution or cell culture medium disclosed herein) and/or; b) capable of being intracellularly and/or extracellularly expressed by HEK293 cells.
  • aqueous solution eg, a solution or cell culture medium disclosed herein
  • the invention provides:- (i) Use of NHR2 or p53 (or another TD disclosed herein) for the manufacture of a polypeptide for soluble expression of a multimer of the polypeptide from a cell, eg, a eukaryotic cell, eg, a mammalian, HEK293, CHO or Cos cell.
  • NHR2 or p53 (or another TD disclosed herein) for the manufacture of a polypeptide for intracellular expression of a multimer of the polypeptide in a cell, eg, a eukaryotic cell, eg, a mammalian, HEK293, CHO or Cos cell.
  • a cell comprising an intracelllular expression product, wherein the product comprises a multimer of a polypeptide comprising NHR2 or p53 (or another TD disclosed herein) fused at its N- and/or C-terminus to an amino acid sequence (eg, a peptide, protein domain or protein) that is not an NHR2 sequence.
  • NHR2 as a promiscuous tetramerisation domain for tetramerising peptides, protein domains, polypeptides or proteins in tha manufacture of multimers that are intracellularly and/or solubly expressed from host cell.
  • the amino acid is an amino acid sequence of a human peptide, protein domain or protein,eg, a TCR (eg, TCR ⁇ , TCR ⁇ , C ⁇ or C ⁇ ), cytokine (eg, interleukin, eg, IL-2, IL-12, IL-12 and IFN), antibody fragments (eg, scFv, dAb or Fab), or an antibody domain (eg, V or C domain, eg, VH, VL, V ⁇ , V ⁇ , CH, CH1, CH2, CH3, hnige, C ⁇ or C ⁇ domain).
  • a TCR eg, TCR ⁇ , TCR ⁇ , C ⁇ or C ⁇
  • cytokine eg, interleukin, eg, IL-2, IL-12, IL-12 and IFN
  • antibody fragments eg, scFv, dAb or Fab
  • an antibody domain eg, V or C domain, eg, VH, VL, V ⁇ , V ⁇ ,
  • the or each polypeptide comprises a polypeptide selected from the group consisting of Quad 1-46 (ie, a polypeptide as shown in Figure 21 but excluding any leader or tag sequence).
  • the invention provides a multimer (eg, a dimer, trimer, tetramer, pentamer, hexamer, septamer or octamer, preferably a tetramer or octamer) of a polypeptide selected from the group consisting of such Quad 1-46 (ie, 2, 3, 4, 5, 6, 7 or 8 copies of such a polypeptide), eg, for medical or diagnostic use, eg, medical use for treating or preventing a disease or condition in a human or animal (eg, a human).
  • the or each polypeptide comprises a polypeptide (excluding any leader or tag sequence) that is encoded by a nucleotide sequence selected from the group consisting of SEQ IDs: 1*13-1*50.
  • the or each polypeptide comprises a polypeptide (excluding any leader or tag sequence) that comprises an amino acid sequence selected from the group consisting of SEQ IDs: 1*83-1*115.
  • the invention provides a multimer (eg, a dimer, trimer, tetramer, pentamer, hexamer, septamer or octamer, preferably a tetramer or octamer) of such a polypeptide, eg, for medical or diagnostic use, eg, medical use for treating or preventing a disease or condition in a human or animal (eg, a human).
  • the TD is a TD comprised by any one of SEQ IDs: 1*1-1*9.
  • the TD is a TD comprising SEQ ID: 1*10 or 1*126.
  • the TD is encoded by SEQ ID: 1*124 or 1*125.
  • the amino acid sequence of each TD is SEQ ID: 1*10 or 1*126 or is at least 80, 85, 90, 95, 96m 97, 98 or 99% identical to SEQ ID: 1*10 or 1*126.
  • the TD is a TD comprising SEQ ID: 1*120 or 123.
  • the TD is encoded by SEQ ID: 1*116 or 1*119.
  • the amino acid sequence of each TD is SEQ ID: 1*120 or 1*123 or is at least 80, 85, 90, 95, 96m 97, 98 or 99% identical to the SEQ ID: 1*120 or 1*123.
  • the domain or peptide comprised by the engineered polypeptide or monomer comprises an amino acid selected from SEQ ID NOs: 1*51-1*82.
  • the invention in one configuration is based on the surprising realization that tetramerisation domains (TD), eg, p53 tetramerisation domain (p53 TD), can be used to preferentially produce tetramers of effector domains over the production of lower-order structures such as dimers and monomers.
  • TD tetramerisation domains
  • p53 TD p53 tetramerisation domain
  • This is particularly useful for secretion of tetramers is desirable yields from mammalian expression cell lines, such as CHO, HEK293 and Cos cell lines.
  • the invention is also particularly useful for the production of tetramers no more than 200, 160, 155 or 150 kDa in size.
  • the invention provides the following Concepts:- CONCEPTS
  • the following Concepts are not to be interpreted as Claims.
  • the Claims start after the Examples section. 1.
  • a tetramerisation domain eg, p53 tetramerisation domain (p53 TD) or NHR2 TD
  • a homologue or orthologue thereof in a method of the manufacture of a tetramer of polypeptides, for producing a higher yield of tetramers versus monomer and/or dimer polypeptides.
  • the monomers and dimers comprise one or two copies of the TD, homologue or orthologue respectively
  • the TD, orthologue or homologue is a human domain.
  • the TD is a human TD or a homologue, eg, a TD selected from any of the p53 TD sequences disclosed in UniProt (www.uniprot.org), for example the p53 TD is a TD disclosed in Table 13.
  • the homologue is a p53TD of a non-human animal species, eg, a mouse, rat, horse cat or dog p53TD. See Figure 32, which shows the high level of conservation between p53 TDs of different species, which supports the use of non-human p53 TDs as an alternative to human p53 TDs.
  • the homologue is a p53TD of a non-human mammalian species.
  • the homologue is identical to human p53 TD with the exception of up to 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid change(s).
  • the yield of tetramers is higher than the yield of monomers; In an example, the yield of tetramers is higher than the yield of dimers; In an example, the yield of tetramers is higher than the yield of trimers; In an example, the yield of tetramers is higher than the yield of monomers and dimers; In an example, the yield of tetramers is higher than the yield of monomers and trimers; In an example, the yield of tetramers is higher than the yield of monomers, dimers and trimers [00146]
  • the TD is the TD of p53 isoform 1.
  • the TD comprises or consists of an amino acid sequence that is identical to positions 325 to 356 (or 319-360; or 321-359) of human p53 (eg, isoform 1).
  • the TD, orthologue or homologue comprises or consists of an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*10, 1*126, 1*11 or 1*12.
  • the sequence is identical to said selected sequence.
  • the TD, orthologue or homologue comprises or consists of an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*120, 1*121, 1*122 or 1*123.
  • the sequence is identical to said selected sequence.
  • the TD is an orthologue or homologue of a p53 TD, eg, a human p53 TD. 4.
  • the yield of tetramers is at least 10x the yield of monomers and/or dimers.
  • the yield is at least 2x 3x, 4x, 5x, 6x, 7x, 8x, 9x, or 10x the yield of monomers and/or dimers.
  • the ratio of tetramers produced : monomers and/or dimers is at least 90:10, eg, at least 95:5; or 96:4; or 97:3; or 98:2; or 99:1.
  • only tetramers are produced.
  • each domain comprised by each monomer, dimer or tetramer is a human domain; and optionally the monomer, dimer or tetramer does not comprise non-human amino acid sequences or linkers. 5.
  • the ratio of tetramers produced : monomers and/or dimers produced in the method is at least 90:10 (ie, 9x the amount of monomers; 9x the amount of dimers; or 9x the amount of the combination of monomers and dimers). 6.
  • Amounts of tetramers, monomers, dimers and trimers can be determined, for example, using Western Blot analysis of a gel described herein, eg, a native gel, ie, a gel not under denatured conditions, such as in the absence of SDS. 7.
  • each monomer has a size of no more than 40 kDa.
  • the monomer has a size of no more than 35, 30, 25, 24, 23, 22, 21 or 20 kDa 11.
  • each tetramer has a size of no more than 150 kDa.
  • the tetramer has a size of no more than 80, 90, 100, 110, 120, 130 or 140 kDa.
  • the method comprises expressing the tetramers from a mammalian cell line, eg, a HEK293, CHO or Cos cell line.
  • the cell line is a HEK293 (eg, HEK293T) cell line.
  • the cell line is a yeast (eg, Saccharomyces or Pichia, eg, P pastoris) or bacterial cell line. 13.
  • the method comprises secreting the tetramers from a mammalian cell line, eg, a HEK293, CHO or Cos cell line.
  • the use or tetramer is for expression from a mammalian cell line (eg, a HEK293, CHO or Cos cell line) or a eukaryotic cell line.
  • the cell line is a HEK293 (eg, HEK293T) cell line.
  • the cell line is a yeast (eg, Saccharomyces or Pichia, eg, P pastoris) or bacterial cell line.
  • yeast eg, Saccharomyces or Pichia, eg, P pastoris
  • bacterial cell line e.g, bacterial cell line.
  • the polypeptide comprises one or more of (i) an antibody single variable domain (dAb or VHH or NanobodyTM) that is capable of specifically binding an antigen; (ii) an scFv that is capable of binding an antigen or an scTCR that is capable of binding pMHC; (iii) a Fab that is capable of binding an antigen; or (iv) a TCR variable domain or pMHC binding site.
  • dAb or VHH or NanobodyTM an antibody single variable domain
  • an scFv that is capable of binding an antigen or an scTCR that is capable of binding pMHC
  • a Fab that is capable of binding an antigen
  • TCR variable domain or pMHC binding site a TCR variable domain or pMHC binding site.
  • each polypeptide or monomer comprises a said TD, homologue or orthologue; and first and second antigen binding sites.
  • each binding site is provided by (i) an antibody single variable domain (dAb or VHH or NanobodyTM) that is capable of specifically binding an antigen; (ii) an scFv that is capable of binding an antigen or an scTCR that is capable of binding pMHC; (iii) a Fab that is capable of binding an antigen; or (iv) a TCR variable domain or pMHC binding site. 19.
  • each binding site is provided by an antibody single variable domain. 20.
  • each polypeptide comprises (i) a tetramerisation domain (TD) (eg, a p53 TD or a NHR2 TD) or a homologue or orthologue thereof; (ii) one or more protein effector domains; and (iii) optionally a linker linking (i) to (ii) (eg, linking the C-terminus of (ii) to the N-terminus of (i)); wherein optionally each tetramer has a size of no more than 150 or 200 kDa.
  • the tetramer has a size of no more than 80, 90, 100, 110, 120, 130 or 140 kDa.
  • any multimer, dimer, trimer, tetramer, octamer, dodecamer, hexadecamer or 20- merherein has a size of at least 60 or 80 kDa; this may be useful for example to increase half -life in a human or animal subject administered with the multimer, dimer, trimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, to treat or prevent a disease or condition in the subject). Sizes in these ranges may be above the renal filtration size.
  • each polypeptide comprises one or more of (i) an antibody single variable domain (dAb or VHH or NanobodyTM) that is capable of specifically binding an antigen; (ii) an scFv that is capable of binding an antigen or an scTCR that is capable of binding pMHC; (iii) a Fab that is capable of binding an antigen; or (iv) a TCR variable domain or pMHC binding site.
  • dAb or VHH or NanobodyTM an antibody single variable domain
  • scFv that is capable of binding an antigen or an scTCR that is capable of binding pMHC
  • a Fab that is capable of binding an antigen
  • a TCR variable domain or pMHC binding site a TCR variable domain or pMHC binding site.
  • each polypeptide comprises a said TD, homologue or orthologue and one or more incretin, insulin, GLP-1 or Exendin-4 domains.
  • each polypeptide comprises a said TD, homologue or orthologue; and first and second antigen binding sites.
  • each binding site is provided by (i) an antibody single variable domain (dAb or VHH or NanobodyTM) that is capable of specifically binding an antigen; (ii) an scFv that is capable of binding an antigen or an scTCR that is capable of binding pMHC; (iii) a Fab that is capable of binding an antigen; or (iv) a TCR variable domain or pMHC binding site.
  • dAb or VHH or NanobodyTM an antibody single variable domain
  • an scFv that is capable of binding an antigen or an scTCR that is capable of binding pMHC
  • a Fab that is capable of binding an antigen
  • TCR variable domain or pMHC binding site a TCR variable domain or pMHC binding site.
  • each polypeptide comprises the TD, homologue or orthologue fused directly or via a peptide linker to the C-terminal of a said effector domain.
  • each polypeptide comprises only 2 (ie, only a first and a second, but not a third) effector domains or only 2 dAbs, VHH, scFvs, scTCRs, Fabs or antigen binding sites.
  • a pharmaceutical composition comprising a tetramer of any one of Concepts 22 to 29 and a pharmaceutically acceptable carrier, diluent or excipient.
  • the composition is comprised by a sterile medical container or device, eg, a syringe, vial, inhaler or injection device.
  • a cosmetic, foodstuff, beverage, cleaning product, detergent comprising a tetramer of any one of Concepts 22 to 29.
  • 32. A mixture comprising a cell line (eg, a mammalian cell line, eg, a HEK293, CHO or Cos cell line) encoding a polypeptide as recited in any preceding Concept; and tetramers as defined in any preceding Concept.
  • the mixture is comprised by a sterile container. 33.
  • the mixture of Concept 32 wherein the cell line is in a medium comprising secretion products of the cells, wherein the secretion products comprise said tetramers.
  • 34. The mixture of Concept 33, wherein the secretion products do not comprise monomers and/or dimers as defined in any one of Concepts 1 to 31.
  • 35. The mixture of Concept 33, wherein the secretion products comprise said tetramers in an amount of at least 10x the amount of monomers and/or dimers.
  • 36 The mixture of Concept 33, wherein the secretion products comprise said tetramers in a ratio of tetramers : monomers and/or dimers of at least 90:10. 37.
  • a method for enhancing the yield of tetramers of an protein effector domain comprising expressing from a cell line (eg, a mammalian cell, CHO, HEK293 or Cos cell line) tetramers of a polypeptide, wherein the polypeptide is as defined in any preceding Concept and comprises one or more effector domains; and optionally isolating said expressed tetramers.
  • a cell line eg, a mammalian cell, CHO, HEK293 or Cos cell line
  • the homologue, orthologue or equivalent has multimerisation or tetramerisation function.
  • Homologue A gene, nucleotide or protein sequence related to a second gene, nucleotide or protein sequence by descent from a common ancestral DNA or protein sequence.
  • orthologue may apply to the relationship between genes separated by the event of or to the relationship between genes separated by the event of genetic duplication.
  • Orthologue are genes, nucleotide or protein sequences in different species that evolved from a common ancestral gene, nucleotide or protein sequence by speciation. Normally, orthologues retain the same function in the course of evolution.
  • the TD, orthologue or homologue is a TD of any one of proteins 1 to 119 listed in Table 2.
  • the orthologue or homologue is an orthologue or homologue of a TD of any one of proteins 1 to 119 listed in Table 2.
  • p53-TD p53 tetramerisation domain
  • all aspects of the invention herein can be read to relate to the use or inclusion in a polypeptide, monomer, dimer, trimer or tetramer of aTD of any one of proteins 1 to 119 listed in Table 2 or a homologue or orthologue thereof.
  • the TD may be a NHR2 (eg, a human NHR2) TD or an orthologue or homologue thereof.
  • the TD may be a p63 (eg, a human p63) TD or an orthologue or homologue thereof.
  • the TD may be a p73 (eg, a human p73) TD or an orthologue or homologue thereof.
  • This may have one or more advantages as follows:- - secretion of tetramers from mammalian or other eukaryotic cells, eg, a mammalian cell disclosed herein such as CHO, HEK293 or Cos; - enhanced yield of secreted tetramers versus monomers; - enhanced yield of secreted tetramers versus dimers; - enhanced yield of secreted tetramers versus trimers; - enhanced yield of secreted tetramers versus monomers and dimers combined; - enhanced yield of secreted tetramers versus monomers, dimers and trimers combined; - enhanced affinity or avidity of antigen binding in tetramers comprising antigen binding sites; - enhanced tetramer production and/or expression, wherein the tetramer is no more than 200 or no more than
  • each polypeptide or monomer comprises one or more VH, VL or VH/VL binding sites of an antibody selected from ReoProTM; Abciximab; RituxanTM; Rituximab; ZenapaxTM; Daclizumab; SimulectTM; Basiliximab; SynagisTM; Palivizumab; RemicadeTM; Infliximab; HerceptinTM; Trastuzumab; MylotargTM; Gemtuzumab; CampathTM; Alemtuzumab; ZevalinTM; Ibritumomab; HumiraTM; Adalimumab; XolairTM; Omalizumab; BexxarTM; Tositumomab; RaptivaTM; Efalizumab; ErbituxTM; Cetuximab; AvastinTM; Bevacizumab; TysabriTM; Natalizumab; ActemraTM; Tocilizumab; Vectibi
  • each polypeptide or monomer comprise one or more VH, VL or VH/VL binding sites of an antibody selected from ipilimumab (or YERVOY TM ), tremelimumab, nivolumab (or OPDIVO TM ), pembrolizumab (or KEYTRUDA TM ), pidilizumab, BMS-936559, durvalumab and atezolizumab.
  • an antibody selected from ipilimumab (or YERVOY TM ), tremelimumab, nivolumab (or OPDIVO TM ), pembrolizumab (or KEYTRUDA TM ), pidilizumab, BMS-936559, durvalumab and atezolizumab.
  • the binding site of the polypeptide of the multimer comprises a VH of the binding site of the antibody and also the CH1 of the antibody (ie, in N- to C-terminal direction the VH-CH1 and SAM).
  • the polypeptide may be paired with a further polypeptide comprising (in N- to C-terminal direction a VL-CL, eg, wherein the CL is the CL of the antibody).
  • the tetramer comprises 4 copies of the antigen binding site of a first antibody selected from the group consisting of ipilimumab (or YERVOY TM ), tremelimumab, nivolumab (or OPDIVO TM ), pembrolizumab (or KEYTRUDA TM ), pidilizumab, BMS-936559, durvalumab and atezolizumab and optionally 4 copies of the antigen binding site of a second antibody selected from said group, wherein the first and second antibodies are different.
  • a first antibody selected from the group consisting of ipilimumab (or YERVOY TM ), tremelimumab, nivolumab (or OPDIVO TM ), pembrolizumab (or KEYTRUDA TM ), pidilizumab, BMS-936559, durvalumab and atezolizumab and optionally 4 copies of the
  • the first antibody is ipilimumab (or YERVOY TM ) and optionally the second antibody is nivolumab (or OPDIVO TM ) or pembrolizumab (or KEYTRUDA TM ).
  • the tetramer comprises 4 copies of the antigen binding site of Avastin.
  • the tetramer comprises 4 copies of the antigen binding site of Humira.
  • the tetramer comprises 4 copies of the antigen binding site of Erbitux.
  • the tetramer comprises 4 copies of the antigen binding site of ActemraTM.
  • the tetramer comprises 4 copies of the antigen binding site of sarilumab. In an example, the tetramer comprises 4 copies of the antigen binding site of dupilumab. In an example, the tetramer comprises 4 copies of the antigen binding site of alirocumab or evolocumab. In an example, the tetramer comprises 4 copies of the antigen binding site of In an example, the tetramer comprises 4 copies of the antigen binding site of Remicade. In an example, the tetramer comprises 4 copies of the antigen binding site of Lucentis. In an example, the tetramer comprises 4 copies of the antigen binding site of EyleaTM.
  • Such tetramers are useful for administering to a human to treat or prevent a cancer.
  • Such tetramers are useful for administering to a human to treat or prevent an ocular condition (eg, wet AMD or diabetic retinopathy, eg, when the binding site is an Avastin, Lucentis or Eylea site).
  • Such tetramers are useful for administering to a human to treat or prevent angiogenesis.
  • the tetramer comprises 4 copies of insulin.
  • the tetramer comprises 4 copies of GLP-1.
  • the tetramer comprises 4 copies of GIP.
  • the tetramer comprises 4 copies of Exendin-4.
  • the tetramer comprises 4 copies of insulin and 4 copies of GLP-1. In an example, the tetramer comprises 4 copies of insulin and 4 copies of GIP. In an example, the tetramer comprises 4 copies of insulin and 4 copies of Exendin-4. In an example, the tetramer comprises 4 copies of GLP-1 and 4 copies of Exendin-4.
  • Such tetramers are useful for administering to a human to treat or prevent diabetes (eg, Type II diabetes) or obesity.
  • the polypeptide, multimer may bind to one or more antigens or epitopes, or each of the binding sites herein (eg, dAb or scFv binding sites) herein may bind to an antigen or epitope.
  • an (or each) antigen herein is selected from the following list.
  • an (or each) epitope herein is an epitope of an antigen selected from the following list.
  • Activin type-II receptor Activin type-IIB receptor; ADAM11; ADAM12; ADAM15; ADAM17; ADAM18; ADAM19; ADAM1A; ADAM1B; ADAM2; ADAM20; ADAM21; ADAM22; ADAM23; ADAM24P; ADAM28; ADAM29; ADAM30; ADAM32; ADAM33; ADAM3A; ADAM3B; ADAM5; ADAM6; ADAM7; ADAM8; ADAM9; ADORA2A; AKT; ALK; alpa-4 integrin; alpha synuclein; anthrax protective antigen; BACE1; BCMA; beta amyloid; BRAF; BTLA; BTNL2; CCR4; CCR5; CD126; CD151; CD16; CD160; CD19; CD20; CD22; CD226; CD244; CD27; CD274 (PDL1); CD276; CD28; CD3; CD30; CD300A;
  • an antigen herein is a PCSK9, eg, human PCSK9; optionally the multimer has 4, 8, 12 or 16 copies an anti- PCSK9 binding site (eg, a dAbs).
  • An example antigen is a toxin, such as a snake venom toxin, eg, wherein a multimer of the invention is administered (such as systemically or by IV injection) to a human or animal subject and the antigen binding sites comprised by the multimer specifically bind to the toxin in the subject.
  • each binding site or domain of the multimer is a dAb (eg, a NanobodyTM).
  • each snake venom toxin antigen binding site of the multimer of the invention is a C33 single domain VH as disclosed in Figure 4 of PLoS One.2013 Jul 22;8(7):e69495. doi: 10.1371/journal.pone.0069495; “In vivo neutralization of ⁇ -cobratoxin with high-affinity llama single-domain antibodies (VHHs) and a VHH-Fc antibody”, Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • each snake venom toxin antigen binding site of the multimer of the invention is a C15 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • each snake venom toxin antigen binding site of the multimer of the invention is a C7 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • each snake venom toxin antigen binding site of the multimer of the invention is a C13 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • each snake venom toxin antigen binding site of the multimer of the invention is a C19 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • each snake venom toxin antigen binding site of the multimer of the invention is a C34 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • each snake venom toxin antigen binding site of the multimer of the invention is a C31 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • each snake venom toxin antigen binding site of the multimer of the invention is a C20 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • each snake venom toxin antigen binding site of the multimer of the invention is a C2 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • each snake venom toxin antigen binding site of the multimer of the invention is a C29 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • each snake venom toxin antigen binding site of the multimer of the invention is a C42 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • each snake venom toxin antigen binding site of the multimer of the invention is a C43 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH.
  • An example of a snake venom toxin is 3FTx, dendrotoxin or PLA2 toxin.
  • the toxin is an alpha-neurotoxin, eg, from Cobra.
  • a toxin is a blood toxin, eg, wherein a multimer of the invention is administered (such as systemically or by IV injection) to a human or animal subject and the antigen binding sites comprised by the multimer specifically bind to the toxin in the blood of the subject.
  • the antigen is a viral antigen, each a capsid protein or carbohydrate (eg, a sugar).
  • a multimer of the invention binds to a virus or virus antigen, eg, a virus selected from Table 19 wherein the virus comprises a surface antigen that is bound by the multimer; or the multimer of the invention binds to a cell or virus antigen, eg, selected from an antigen disclosed in Table 20. Binding to the virus may, for example, reduce or inhibit attachment of the virus to its host cell or infection of the cell by the virus.
  • the invention provides a method of treating or preventing (eg, reducing the risk of) a viral or cell infection in a human or animal or plant subject (eg, in a human subject), the method comprising administering a multimer of the invention to the subject wherein the multimer binds to a surface antigen of the virus, thereby inhibiting the virus from attaching to a host cell; inhibiting infection of a host cell by the virus and/or sequestering the virus in the subject (eg, to mark the bound virus for clearance from the systemic circulation or a tissue of the subject).
  • the invention provides a method of treating or preventing (eg, reducing the risk of) a bacterial or archaeal cell infection in a human or animal or plant subject (eg, in a human subject), the method comprising administering a multimer of the invention to the subject wherein the multimer binds to a surface antigen of the cell, thereby inhibiting infection of the subject by the cell and/or sequestering the cell in the subject (eg, to mark the bound cell for clearance from the systemic circulation or a tissue of the subject).
  • the invention provides a method of treating or preventing (eg, reducing the risk of) a cancer in a human or animal subject (eg, in a human subject), the method comprising administering a multimer of the invention to the subject wherein the multimer binds to a surface antigen of a tumour cell, thereby sequestering the cell in the subject (eg, to mark the bound cell for clearance from the systemic circulation or a tissue of the subject) or marking the cell for targeting by the immune sytem or another therapy (eg, immune checkpoint therapy or CAR-T therapy) administered to the subject.
  • a multimer of the invention to the subject wherein the multimer binds to a surface antigen of a tumour cell, thereby sequestering the cell in the subject (eg, to mark the bound cell for clearance from the systemic circulation or a tissue of the subject) or marking the cell for targeting by the immune sytem or another therapy (eg, immune checkpoint therapy or CAR-T therapy) administered to the subject.
  • the antigen is selected from CXCR2, CXCR4, GM-CSF, ICAM-1, IFN-g, IL- 1, IL-10, IL-12, IL-1R1, IL-1R2, IL-1Ra, IL-1 ⁇ , IL-4, IL-6, IL-8, MIF, TGF- ⁇ , TNF- ⁇ , TNFR1, TNFR2 and VCAM-1.
  • Targeting one or more of these antigens may be useful for treating or preventing sepsis in a subject.
  • the multimer of the invention comprises one or more antigen binding sites (eg, each one provided by a dAb), wherein the multimer is for use in a method of treating or preventing sepsis in a human or animal subject, wherein the multimer is administered to the subject (eg, systemically or intravenously).
  • the multimer is monospecific, bispecific, trispecific or tetraspecific for antigen binding.
  • the multimer is bispecific, trispecific or tetraspecific for an antigen selected from CXCR2, CXCR4, GM-CSF, ICAM- 1, IFN-g, IL-1, IL-10, IL-12, IL-1R1, IL-1R2, IL-1Ra, IL-1 ⁇ , IL-4, IL-6, IL-8, MIF, TGF- ⁇ , TNF- ⁇ , TNFR1, TNFR2 and VCAM-1.
  • an antigen selected from CXCR2, CXCR4, GM-CSF, ICAM- 1, IFN-g, IL-1, IL-10, IL-12, IL-1R1, IL-1R2, IL-1Ra, IL-1 ⁇ , IL-4, IL-6, IL-8, MIF, TGF- ⁇ , TNF- ⁇ , TNFR1, TNFR2 and VCAM-1.
  • a pharmaceutical composition comprising such a multimer and a pharmaceutically acceptable diluent, carrier
  • the polypeptide monomer or multimer (eg, dimer, trimer, tetramer or octamer) of the invention can be used in a method for administration to a human or animal subject to treat or prevent a disease or condition in the subject.
  • the disease or condition is selected from (a) A neurodegenerative disease or condition; (b) A brain disease or condition; (c) A CNS disease or condition; (d) Memory loss or impairment; (e) A heart or cardiovascular disease or condition, eg, heart attack, stroke or atrial fibrillation; (f) A liver disease or condition; (g) A kidney disease or condition, eg, chronic kidney disease (CKD); (h) A pancreas disease or condition; (i) A lung disease or condition, eg, cystic fibrosis or COPD; (j) A gastrointestinal disease or condition; (k) A throat or oral cavity disease or condition; (l) An ocular disease or condition; (m) A genital disease or condition, eg, a vaginal, labial, penile or scrotal disease or condition; (n) A sexually-transmissible disease or condition, eg, gonorrhea, HIV infection, syphilis or Chlamydia infection; (o
  • the neurodegenerative or CNS disease or condition is selected from the group consisting of Alzheimer disease , geriopsychosis, Down syndrome, Parkinson's disease, Creutzfeldt- jakob disease, diabetic neuropathy, Parkinson syndrome, Huntington's disease, Machado-Joseph disease, amyotrophic lateral sclerosis, diabetic neuropathy, and Creutzfeldt Creutzfeldt- Jakob disease.
  • the disease is Alzheimer disease.
  • the disease is Parkinson syndrome.
  • the method of the invention causes downregulation of Treg cells in the subject, thereby promoting entry of systemic monocyte-derived macrophages and/or Treg cells across the choroid plexus into the brain of the subject, whereby the disease or condition (eg, Alzheimer’s disease) is treated, prevented or progression thereof is reduced.
  • the method causes an increase of IFN-gamma in the CNS system (eg, in the brain and/or CSF) of the subject.
  • the method restores nerve fibre and//or reduces the progression of nerve fibre damage.
  • the method restores nerve myelin and//or reduces the progression of nerve myelin damage.
  • the method of the invention treats or prevents a disease or condition disclosed in WO2015136541 and/or the method can be used with any method disclosed in WO2015136541 (the disclosure of this document is incorporated by reference herein in its entirety, eg, for providing disclosure of such methods, diseases, conditions and potential therapeutic agents that can be administered to the subject for effecting treatement and/or prevention of CNS and neurodegenerative diseases and conditions, eg, agents such as immune checkpoint inhibitors, eg, anti- PD-1, anti-PD-L1, anti-TIM3 or other antibodies disclosed therein).
  • Cancers that may be treated include tumours that are not vascularized, or not substantially vascularized, as well as vascularized tumours.
  • the cancers may comprise non-solid tumours (such as haematological tumours, for example, leukaemias and lymphomas) or may comprise solid tumours.
  • Types of cancers to be treated with the invention include, but are not limited to, carcinoma, blastoma, and sarcoma, and certain leukaemia or lymphoid malignancies, benign and malignant tumours, and malignancies e.g., sarcomas, carcinomas, and melanomas.
  • sarcomas e.g., sarcomas, carcinomas, and melanomas.
  • Adult tumours/cancers and paediatric tumours/cancers are also included.
  • Haematologic cancers are cancers of the blood or bone marrow.
  • haematological (or haematogenous) cancers include leukaemias, including acute leukaemias (such as acute lymphocytic leukaemia, acute myelocytic leukaemia, acute myelogenous leukaemia and myeloblasts, promyeiocytic, myelomonocytic, monocytic and erythroleukaemia), chronic leukaemias (such as chronic myelocytic (granulocytic) leukaemia, chronic myelogenous leukaemia, and chronic lymphocytic leukaemia), polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (indolent and high grade forms), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myeiodysplastic syndrome, hairy cell leuka
  • Solid tumours are abnormal masses of tissue that usually do not contain cysts or liquid areas. Solid tumours can be benign or malignant. Different types of solid tumours are named for the type of cells that form them (such as sarcomas, carcinomas, and lymphomas).
  • solid tumours such as sarcomas and carcinomas
  • solid tumours include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumour, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer, lung cancers, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous eel!
  • carcinoma basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, pheochromocytomas sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, Wilms' tumour, cervical cancer, testicular tumour, seminoma, bladder carcinoma, melanoma, and CNS tumours (such as a glioma (such as brainstem glioma and mixed gliomas), glioblastoma (also known as glioblastoma multiforme) astrocytoma, CNS lymphoma, germinoma, medu!loblastoma, Schwannoma craniopharyogioma, ependymoma, pineaioma, hemangioblastoma, acoustic
  • Acute Disseminated Encephalomyelitis (ADEM) . Acute necrotizing hemorrhagic leukoencephalitis . Addison’s disease . Agammaglobulinemia . Alopecia areata . Amyloidosis . Ankylosing spondylitis . Anti-GBM/Anti-TBM nephritis . Antiphospholipid syndrome (APS) . Autoimmune angioedema . Autoimmune aplastic anemia . Autoimmune dysautonomia . Autoimmune hepatitis . Autoimmune hyperlipidemia .
  • Autoimmune immunodeficiency Autoimmune inner ear disease (AIED) . Autoimmune myocarditis . Autoimmune oophoritis . Autoimmune pancreatitis . Autoimmune retinopathy . Autoimmune thrombocytopenic purpura (ATP) . Autoimmune thyroid disease . Autoimmune urticaria . Axonal & neuronal neuropathies . Balo disease . Behcet’s disease . Bullous pemphigoid . Cardiomyopathy . Castleman disease . Celiac disease . Chagas disease . Chronic fatigue syndrome . Chronic inflammatory demyelinating polyneuropathy (CIDP) .
  • AIED Autoimmune inner ear disease
  • Autoimmune myocarditis Autoimmune oophoritis . Autoimmune pancreatitis . Autoimmune retinopathy . Autoimmune thrombocytopenic purpura (ATP
  • Chronic recurrent multifocal ostomyelitis CRMO
  • Churg-Strauss syndrome Cicatricial pemphigoid/benign mucosal pemphigoid . Crohn’s disease .
  • Cogans syndrome Cold agglutinin disease .
  • Congenital heart block Coxsackie myocarditis .
  • CREST disease Essential mixed cryoglobulinemia .
  • Demyelinating neuropathies Dermatitis herpetiformis . Dermatomyositis . Devic’s disease (neuromyelitis optica) . Discoid lupus . Dressler’s syndrome . Endometriosis .
  • Eosinophilic esophagitis Eosinophilic fasciitis . Erythema nodosum . Experimental allergic encephalomyelitis . Evans syndrome . Fibromyalgia . Fibrosing alveolitis . Giant cell arteritis (temporal arteritis) . Giant cell myocarditis . Glomerulonephritis . Goodpasture’s syndrome . Granulomatosis with Polyangiitis (GPA) (formerly called Wegener’s Granulomatosis) . Graves’ disease . Guillain-Barre syndrome . Hashimoto’s encephalitis . Hashimoto’s thyroiditis . Hemolytic anemia .
  • Henoch-Schonlein purpura Herpes gestationis . Hypogammaglobulinemia . Idiopathic thrombocytopenic purpura (ITP) . IgA nephropathy . IgG4-related sclerosing disease . Immunoregulatory lipoproteins . Inclusion body myositis . Interstitial cystitis . Juvenile arthritis . Juvenile diabetes (Type 1 diabetes) . Juvenile myositis . Kawasaki syndrome . Lambert-Eaton syndrome . Leukocytoclastic vasculitis . Lichen planus . Lichen sclerosus . Ligneous conjunctivitis .
  • Linear IgA disease LAD
  • Lupus SLE
  • Microscopic polyangiitis .
  • Mixed connective tissue disease MCTD
  • Mucha-Habermann disease Multiple sclerosis .
  • Myasthenia gravis Myositis .
  • Narcolepsy Neuromyelitis optica (Devic’s) .
  • Neutropenia Ocular cicatricial pemphigoid .
  • Optic neuritis Palindromic rheumatism .
  • PANDAS Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus
  • Paroxysmal nocturnal hemoglobinuria PNH
  • Parry Romberg syndrome Parsonnage-Turner syndrome
  • Pars planitis (peripheral uveitis) .
  • Pemphigus Peripheral neuropathy .
  • Perivenous encephalomyelitis .
  • Pernicious anemia POEMS syndrome .
  • Polyarteritis nodosa Type I, II, & III autoimmune polyglandular syndromes .
  • Polymyalgia rheumatica Polymyositis . Postmyocardial infarction syndrome . Postpericardiotomy syndrome . Progesterone dermatitis .
  • Stiff person syndrome Subacute bacterial endocarditis (SBE) . Susac’s syndrome . Sympathetic ophthalmia . Takayasu’s arteritis . Temporal arteritis/Giant cell arteritis . Thrombocytopenic purpura (TTP) . Tolosa-Hunt syndrome . Transverse myelitis . Type 1 diabetes . Ulcerative colitis . Undifferentiated connective tissue disease (UCTD) . Uveitis . Vasculitis . Vesiculobullous dermatosis . Vitiligo . Wegener’s granulomatosis (now termed Granulomatosis with Polyangiitis (GPA).
  • INFLAMMATORY DISEASES FOR TREATMENT OR PREVENTION Alzheimer's . ankylosing spondylitis . arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis) . asthma . atherosclerosis . Crohn's disease . colitis . dermatitis . diverticulitis . fibromyalgia . hepatitis . irritable bowel syndrome (IBS) . systemic lupus erythematous (SLE) . nephritis . Parkinson's disease . ulcerative colitis.
  • IBS systemic lupus erythematous
  • the present configuration relates to a multivalent soluble TCR protein.
  • the invention relates to tetravalent and octavalent soluble TCR analogues.
  • the TCR proteins of the invention are capable of self-assembly from monomers and are entirely of human origin.
  • the proteins are multimers which comprise an ETO NHR2 multimerisation domain.
  • the invention also relates to methods of constructing multimeric soluble TCRs, and methods of using such proteins. [00183] Attempts to exploit alternative soluble TCR formats as therapeutic molecules have lagged far behind compared to the plethora of antibody formats.
  • the present configuration of the invention provides a TCR protein which is both multivalent and soluble. Multivalency increases the avidity of the TCR for cognate pMHC, and solubility allows the TCR to be used outside of a transmembrane environment.
  • a multivalent heterodimeric soluble T cell receptor capable of binding pMHC complex comprising: (i) TCR extracellular domains; (ii) (ii) immunoglobulin constant domains; and (iii) (iii) an NHR2 multimerisation domain of ETO.
  • Ig constant domains provides the TCR extracellular domains with stability and solubility; multimerisation via the NHR2 domains provides multivalency and increased avidity.
  • all of the domains are of human origin or conform to human protein sequences.
  • Using the Ig constant domain to stabilise and render soluble the TCR avoids the use of non- native disulphide bonds.
  • the TCR of the invention does not comprise a non-native disulphide bond.
  • said complex comprises a heavy chain and a light chain, and each light chain comprises a TCR V ⁇ domain and an immunoglobulin C ⁇ domain, and each heavy chain comprises a TCR V ⁇ domain and an immunoglobulin C H 1 domain.
  • each light chain additionally comprises a TCR C ⁇ domain, and each heavy chain additionally comprises a TCR C ⁇ domain.
  • the TCR and immunoglobulin domains can be separated by a flexible linker.
  • the NHR2 multimerisation domain is advantageously attached to the C-terminus of an immunoglobulin domain.
  • each dimer of heavy and light chains will be attached to one multimerisation domain, so that the heavy chain-light chain dimers associate into multivalent oligomers.
  • the multimerisation domain and the immunoglobulin domain are separated by a flexible linker. In certain embodiments, this allows the multimerisation domain to multimerise without hindrance from the immunoglobulin domain(s).
  • the TCR protein may further comprise an immunoglobulin hinge domain. Hinge domains allow dimerization of heavy chain-light chain dimers; this allows further multimerisation of the TCR proteins.
  • a multimerisation domain which forms polypeptide tetramers can, using an immunoglobulin hinge domain, form multimers up to polypeptide octamers.
  • a dimerising multimerisation domain can form tetramers in the presence of a hinge domain.
  • the TCR protein of the invention is tetravalent.
  • the TCR protein of the invention is octavalent [00195]
  • the present invention provides a soluble TCR where it is stably assembled in a tetravalent heterodimeric format using the nervy homology region 2 (NHR2) domain found in the ETO family protein in humans (Liu et al.2006).
  • the NHR2 domain is found naturally to form homotetramer, which is formed from pairing of two NHR2 homodimers.
  • NHR2 linked operably to the extracellular TCR ⁇ or TCR ⁇ chain will preferentially form tetravalent heterodimeric soluble TCR protein molecules sequentially self-assembled from a monomer followed by a homodimer ( Figure 1).
  • TCR proteins assembling into octamers can be created using the NHR2 domain, by employing immunoglobulin hinge domains.
  • the TCR proteins of the invention can be coupled to biologically active polypeptides/effector molecules.
  • polypeptides can include immunologically active moieties such as cytokines, binding proteins such as antibodies or targeted polypeptides, and the like.
  • the invention further relates to methods for making tetravalent and octavalent heterodimeric soluble TCR, the DNA vectors encoding the proteins used for transfecting host cells of interests and the use of these novel highly sensitive multivalent soluble TCR protein molecules. Applications for use could include but not limited to, therapeutics, diagnostics and drug discovery.
  • the invention provides a method for constructing multivalent immunoglobulin molecules in an efficient manner, without employing non-human construct components.
  • a multimeric immunoglobulin comprising (i) immunoglobulin variable domains; and (ii) an NHR2 multimerisation domain of ETO.
  • the immunoglobulin variable domains are preferably antibody variable domains. Such domains are fused to the ETO NHR2 multimerisation domain, which provides means for forming tetramers of the immunoglobulin variable domains.
  • the ETO NHR2 domain is more efficient than p53 and similar multimerisation domains in the production of immunoglobulin multimers, and permits the production of multimeric immunoglobulin molecules without the use of non-human components in the construct.
  • the immunoglobulin variable domains are attached to one or more immunoglobulin constant domains.
  • the immunoglobulin domains are antibody domains.
  • the variable domains can be V H and V L antibody domains.
  • the constant domains are antibody CH1 domains.
  • the multimeric immunoglobulin molecules according to the invention, both TCR and non-TCR immunoglobulins are produced for screening by phage display or another display technology.
  • the multivalent immunoglobulins are produced as fusions with a phage coat protein.
  • other immunoglobulin molecules are produced without a coat protein, such that they can assemble on the phage surface as a result of NHR2 multimerisation.
  • the present configuration of the invention as detailed above relates to the nucleic acid sequences and methods for producing novel multivalent, for example tetravalent and octavalent, soluble proteins.
  • the soluble protein is a TCR assembled into a tetravalent heterodimeric format that can bind four pMHC with high sensitivity, affinity and specificity.
  • the soluble tetravalent heterodimeric TCR is a unique protein molecule composed from either the entire or in part the extracellular TCR ⁇ / ⁇ chains.
  • the extracellular TCR ⁇ / ⁇ chains are linked to immunoglobulin C H 1 and C L (either C ⁇ or C ⁇ ) domains. This linkage allows stable formation of heterodimeric TCR ⁇ / ⁇ .
  • the unique feature is the NHR2 homotetramer domain of the ETO family of proteins, which is operably linked to the C-terminus of C H 1 or the C-terminus of C L .
  • TCR Extracellular domains are composed of variable and constant regions. These domains are present in T-cell receptors in the same way as they are present in antibodies and other immunoglobulin domains.
  • the TCR repertoire has extensive diversity created by the same gene rearrangement mechanisms used in antibody heavy and light chain genes (Tonegawa, S. (1988) Biosci. Rep.8:3-26).
  • TCR genes are available, such as the IMGT LIGM database, and methods for cloning TCRs are known in the art – for example, see Bentley and Mariuzza (1996) Ann. Rev. Immunol.14:563-590; Moysey et al., Anal Biochem. 2004 Mar 15;326(2):284-6; Wälchli, et al. (2011) A Practical Approach to T-Cell Receptor Cloning and Expression.
  • Immunoglobulin variable domains are known in the art and available from a wide variety of sources. Databases of sequences of antibody variable domains exist, such as IMGT and Kabat, and variable domains can be produced by cloning and expression of natural sequences, or synthesis of artificial nucleic acids according to established techniques. [00210] Methods for the construction of bacteriophage antibody display libraries and lambda phage expression libraries are well known in the art (McCafferty et al. (1990) Nature, 348: 552; Kang et al. (1991) Proc. Natl. Acad. Sci.
  • Immunoglobulin constant domains are preferably an antibody constant domain. Constant domains do vary in sequence between antibody subtypes; preferably, the constant domains are IgG constant domains. Preferably, the constant domains are CH1 constant domains. Antibody constant domains are well known in the art and available from a number of sources and databases, including the IMGT and Kabat databases.
  • Linkers can be used to connect TCR variable domain – Ig constant domain to the NHR2 multimerisation domain. This allows the TCR domains and the multimerisation domain to function without steric hindrance from each other or other molecules in the multimeric complex. Suitable linkers comprise, for example, glycine repeats, glycine-alanine repeats, Gly(4)Ser linkers, or flexible polypeptide linkers as set forth in Reddy Chichili et al., 2012 Protein Science 22:153-167.
  • the Ig Hinge domain herein preferably an antibody hinge domain, is the domain which links antibody constant regions in a natural antibody. This domain therefore provides for natural dimerization of molecules which include an antibody constant domain. It is present, for example, in a F(ab)2 antibody fragment, as well as whole antibodies such as IgG. This region comprises two natural interchain disulphide bonds, which connect the two CH1 constant domains together.
  • the multimerisation domain in one embodiment, may be attached to the Ig constant domain or to the hinge domain.
  • the multimerisation domain will form a TRC octamer, comprising four dimers of TCR variable-Ig Constant domains joined at a hinge region. Without the hinge region, the multimerisation domain will lead to the formation of a tetramer.
  • the multimerisation domain is attached to the C-terminal end of the constant domain or the hinge region.
  • EM biologically active molecules or effector molecules
  • the biologically active molecule can be a cytotoxic drug, toxin or a biologically active molecule such as a cytokine, as described in more detail below.
  • biologically active molecules include chemokines such as MIP-1b, cytokines such as IL-2, growth factors such as GM-CSF or G-CSF, toxins such as ricin, cytotoxic agents, such as doxorubicin or taxanes, labels including radioactive and fluorescent labels, and the like.
  • chemokines such as MIP-1b
  • cytokines such as IL-2
  • growth factors such as GM-CSF or G-CSF
  • toxins such as ricin
  • cytotoxic agents such as doxorubicin or taxanes
  • labels including radioactive and fluorescent labels and the like.
  • the biologically active molecule is, for example, selected from the group consisting of: a group capable of binding to a molecule which extends the half-life of the polypeptide ligand in vivo, and a molecule which extends the half-life of the polypeptide ligand in vivo.
  • a group capable of binding to a molecule which extends the half-life of the polypeptide ligand in vivo can be, for instance, HSA or a cell matrix protein
  • the group capable of binding to a molecule which extends the half-life of the TCR molecule in vivo is an antibody or antibody fragment specific for HSA or a cell matrix protein.
  • the biologically active molecule is a binding molecule, for example an antibody fragment.
  • the biologically active molecule can moreover be an effector group, for example an antibody Fc region.
  • Attachments to the N or C terminus may be made prior to assembly of the TCR molecule or engineered polypeptide into multimers, or afterwards.
  • the TCR fusion with an Ig Constant domain may be produced (synthetically, or by expression of nucleic acid) with an N or C terminal biologically active molecule already in place.
  • the addition to the N or C terminus takes place after the TCR fusion has been produced.
  • Fluorenylmethyloxycarbonyl chloride can be used to introduce the Fmoc protective group at the N- terminus of the TCR fusion.
  • Fmoc binds to serum albumins including HSA with high affinity, and Fmoc-Trp or FMOC-Lys bind with an increased affinity.
  • the peptide can be synthesised with the Fmoc protecting group left on, and then coupled with the scaffold through the cysteines.
  • An alternative is the palmitoyl moiety which also binds HSA and has, for example been used in Liraglutide to extend the half-life of this GLP-1 analogue.
  • the TCR fusinon can be modified at the N-terminus, for example with the amine- and sulfhydryl-reactive linker N-e-maleimidocaproyloxy)succinimide ester (EMCS). Via this linker the TCR can be linked to other polypeptides, for example an antibody Fc fragment.
  • the NHR2 domain [00225] AML1/ETO is the fusion protein resulting from the t(8;21) found in acute myeloid leukemia (AML) of the M2 subtype. AML1/ETO contains the N-terminal 177 amino acids of RUNX1 fused in frame with most (575 aa) of ETO.
  • the nervy homology domain 2 of ETO is responsible for many of the biological activities associated with AML1/ETO, including oligomerisation and protein-protein interactions. This domain is characterised in detail in Liu et al (2006). See Genbank accession number NG_023272.2.
  • the protein assembled into a soluble multivalent format is a TCR composed of either in part or all of the extracellular domains of the TCR ⁇ and ⁇ chains.
  • the TCR ⁇ and ⁇ chains are stabilized by immunoglobulin C H 1 and C L domains and could be arranged in the following configurations: 1. V ⁇ -C L and V ⁇ C H 1 2. V ⁇ -C H 1 and V ⁇ -C L 3.
  • V ⁇ C ⁇ -C L and V ⁇ C ⁇ -C H 1 4.
  • V ⁇ C ⁇ C H 1 and V ⁇ C ⁇ C L [00227]
  • the extracellular TCR domains are linked to immunoglobulin C H 1 and C L domains via an optional peptide linker (L) to promote protein flexibility and facilitate optimal protein folding.
  • L optional peptide linker
  • a tetramerisation domain such as NHR2 homotetramer domain is linked to the C-terminus of either the immunoglobulin C H 1 or C L domain, which is linked to the extracellular TCR ⁇ and ⁇ chain.
  • the NHR2 domain could be optionally linked to C H 1 or C L domain via a peptide linker.
  • the resulting tetravalent heterodimeric TCR protein could be arranged in the following configurations where (L) is an optional peptide linker: 1. V ⁇ -(L)-C L and V ⁇ -(L)-C H 1-(L)-TD 2.
  • V ⁇ C ⁇ -(L)-CL and V ⁇ C ⁇ -(L)-CH1-(L)-TD 4.
  • V ⁇ C ⁇ -(L)-C H 1-(L)-TD and V ⁇ C ⁇ -(L)-C L 5.
  • V ⁇ -(L)-C L -(L)-TD and V ⁇ -(L)-C H 1 6.
  • V ⁇ C ⁇ -(L)-C H 1and V ⁇ C ⁇ -(L)-C L -(L)-TD [00229]
  • the sensitivity of the soluble TCR for its cognate pMHC can be enhanced by increasing the avidity effect. This is achieved by increasing the number of antigen binding sites, facilitated by the tetramerisation domain. This in turn also increases the molecular weight of the protein molecule compared to a monovalent soluble TCR and thus extends serum retention in circulation. Increasing the serum half-life also enhances the likelihood of these molecules interacting with their cognate target antigens.
  • TCR ⁇ and ⁇ chain sequences used in this invention could be from a known TCR specific for a particular pMHC or identified de novo by screening using techniques known in the art, such as phage display.
  • TCR sequences are not limited to ⁇ and ⁇ chain in this invention but can also incorporate TCR ⁇ and ⁇ or ⁇ chain and sequence variations thereof either directly cloned from human T cells or identified by directed evolution using recombinant DNA technology.
  • the tetravalent heterodimeric soluble TCR protein molecules are preferentially produced in mammalian cells for optimal production of soluble, stable and correctly folded protein molecules.
  • Multimer eg, tetramer or octamer
  • multivalent TCR may be expressed in cells, such as mammalian cells, using any suitable vector system.
  • the pTT5 expression vector is one example of an expression system is used to express multivalent soluble TCR.
  • the pTT5 expression system allows for high-level transient production of recombinant proteins in suspension-adapted HEK293 EBNA cells (Zhang et al.2009).
  • tetravalent heterodimeric soluble TCR protein molecules or other multimers can be produced by transiently expressing genes from an expression vector.
  • tetravalent heterodimeric soluble TCR protein molecules or other multimers can be produced from an engineered stable cell line.
  • Cell lines can be engineered to produce the protein molecule using genome-engineering techniques known in the art where the gene(s) encoding for the protein molecule is integrated into the genome of the host cells either as a single copy or multiple copies.
  • the site of DNA integration can be a defined location within the host genome or randomly integrated to yield maximum expression of the desired protein molecule.
  • Genome engineering techniques could include but not limited to, homologous recombination, transposon mediated gene transfer such as PiggyBac transposon system, site specific recombinases including recombinase-mediated cassette exchange, endonuclease mediated gene targeting such as CRISPR/Cas9, TALENs, Zinc-finger nuclease, meganuclease and virus mediated gene transfer such as Lentivirus.
  • the tetravalent heterodimeric soluble TCR protein molecule or other multimer is produced by overexpression in the cytoplasm of E.
  • heterodimeric soluble TCR protein molecule or other multimer is not limited to mammalian or bacterial cells but can also be expressed and produced in insect cells, plant cells and lower eukaryotic cells such as yeast cells.
  • the heterodimeric soluble TCR molecule or other multimer is produced as an octavalent protein complex, eg, having up to eight binding sites for its cognate pMHC ( Figure 2).
  • the multiple antigen binding sites allow this molecule to bind up to eight pMHC displayed on one cell or bind pMHC displayed on up to eight different cells thus creating a highly sensitive soluble TCR.
  • the heterodimeric soluble TCR portion of the molecule is made into a bivalent molecule by fusing the immunoglobulin hinge domain to the C-terminus of either the C H 1 or C L domain, which is linked itself either to TCR ⁇ or ⁇ chain.
  • the hinge domain allows for the connection of two heavy chains giving a structure similar to IgG.
  • a tetramerisation domain such as NHR2 is linked via an optional peptide linker.
  • the self-assembly of the octavalent soluble TCR is via NHR2 monomer 2 and homodimer 2 intermediate protein complexes ( Figure 2).
  • the resulting octavalent heterodimeric soluble TCR protein molecule will have superior sensitivity for its cognate pMHC thus giving it a distinctive advantage of identifying unknown antigen or pMHC without having to affinity mature the TCR for its pMHC ligand much beyond affinities seen naturally.
  • a number of different configurations of the octavalent heterodimeric soluble TCR protein molecules can be produced. Some examples are shown below. 1.
  • V ⁇ -(L)-C L and V ⁇ -(L)-C H 1-Hinge-(L)-TD 2.
  • V ⁇ -(L)-C H 1-Hinge-(L)-TD and V ⁇ -(L)-C L 3.
  • V ⁇ -C ⁇ -(L)-CL and V ⁇ -C ⁇ -(L)-CH1-Hinge-(L)-TD 4.
  • V ⁇ -C ⁇ -(L)-C H 1-Hinge and V ⁇ -C ⁇ -(L)-C L -(L)-TD [00240]
  • the self-assembled multivalent protein preferentially tetravalent and octavalent heterodimeric soluble TCR are fused or conjugated to biologically active agent/effector molecule thus allowing these molecules to be guided to the desired cell population such as cancers cells and exert their therapeutic effect specifically.
  • tumour targeting ability of monoclonal antibodies to guide an effector molecule such as a cytotoxic drug, toxins or a biologically active molecule such as cytokines is well established (Perez et al.2014; Young et al.2014).
  • an effector molecule such as a cytotoxic drug, toxins or a biologically active molecule such as cytokines.
  • the multivalent soluble TCR molecules outlined in this invention can also be fused with effector proteins and polypeptide or conjugated to cytotoxic agents.
  • effector protein molecules suitable for use as a fusion protein with the multivalent protein complexes outlined in this invention include but are not limited to, IFN ⁇ , IFN ⁇ , IFN ⁇ , IL-2, IL-11, IL-13, granulocyte colony- stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], and tumor necrosis factor [TNF] ⁇ , IL-7, IL-10, IL-12, IL-15, IL-21, CD40L, and TRAIL, the costimulatory ligand is B7.1 or B7.2, the chemokines DC-CK1, SDF-1, fractalkine, lyphotactin, IP-10, Mig, MCAF, MlP-l ⁇ , MIP-1/3, IL-8, NAP-2, PF-4, and RANTES or an active fragment thereof.
  • the costimulatory ligand is B7.1 or B7.2
  • Examples of toxic agent suitable for use as a fusion protein or conjugated to the multivalent protein complexes described in this invention include but not limited to, toxins such as diphtheria toxin, ricin, Pseudomonas exotoxin, cytotoxic drugs such as auristatin, maytansines, calicheamicin, anthracyclines, duocarmycins, pyrrolobenzodiazepines.
  • the cytotoxic drug can be conjugated by a select linker, which is either non-cleavable or cleavable by protease or is acid-labile. [00241] To eliminate heterogeneity and improve conjugate stability the cytotoxic drug can be conjugated in a site-specific manner.
  • the multivalent protein complex is covalently linked to molecules allowing detection, such as fluorescent, radioactive or electron transfer agents.
  • an effector molecule is fused to the multivalent protein complex via the C-terminus of the tetramerisation domain such as NHR2 via an optional peptide linker. Fusion via the NHR2 domain can be arranged to produce multivalent protein complexes in a number of different configurations.
  • V ⁇ -(L)-C L and V ⁇ -(L)-C H 1-(L)-TD-(L)-EM 2.
  • V ⁇ -(L)-CH1-(L)-TD-(L)-EM and V ⁇ -(L)-CL 3.
  • V ⁇ -C ⁇ -(L)-C L and V ⁇ -C ⁇ -(L)-C H 1-(L)-TD-(L)-EM 4.
  • V ⁇ - (L)-C L -(L)-TD-(L)-EM and V ⁇ -(L)-C H 1 6.
  • V ⁇ -(L)-C H 1 and V ⁇ -(L)-C L -(L)-TD-(L)-EM 7.
  • V ⁇ -C ⁇ -(L)-C L -(L)-TD-(L)-EM and V ⁇ -C ⁇ -(L)-C H 1 8.
  • the effector molecule is fused to the multivalent protein complex at the C-terminus of either the immunoglobulin CH1 or CL1 domain via an optional peptide linker. Fusion of the EM via the immunoglobulin domain can be arranged to produce multivalent protein complexes in a number of different configurations. Examples of some of the protein configurations that can be produced using the tetravalent heterodimeric soluble TCR is shown below: 9.
  • V ⁇ - (L)-C L -(L)-EM and V ⁇ -(L)-C H 1-(L)-TD 10.
  • V ⁇ - (L)-C H 1-(L)-TD and V ⁇ -(L)-C L -(L)-EM 11.
  • V ⁇ -C ⁇ -(L)-C L -(L)-EM and V ⁇ -C ⁇ -(L)-C H 1-(L)-TD 12.
  • V ⁇ -C ⁇ -(L)-C H 1-(L)-TD and V ⁇ -C ⁇ -(L)-C L -(L)-EM 13.
  • V ⁇ -(L)-C L -(L)-TD and V ⁇ -(L)-C H 1-(L)-EM 14.
  • effector molecules are fused to the multivalent protein complex at the C-terminus of either the immunoglobulin CH1 or CL1 domain and also the C- terminus of the tetramerisation domain (e.g. NHR2) via an optional peptide linkers.
  • the multivalent protein complex is fused to a protein tag to facilitate purification.
  • Purification tags are known in the art and they include, without being limited to, the following tags: His, GST, TEV, MBP, Strep, FLAG.
  • the present invention provides a unique method for assembling proteins in a soluble multivalent format with potential to bind multiple interacting domains or antigens.
  • the protein can be a monomer, homodimer, heterodimer or oligomer preferentially involved either directly or indirectly in the immune system, or having the potential to regulate immune responses. Examples include, but not limited to, TCR, peptide MHC class I and class II, antibodies or antigen-binding portions thereof and binding proteins having alternative non-antibody protein scaffolds.
  • Non-TCR multimers may be multimers of antibodies or antibody fragments, such as dAbs of Fabs.
  • dAbs and Fabs in accordance with the invention include the following: [00250] Examples of multivalent dAbs 25. VH-(L)-NHR2 26. VL( ⁇ or ⁇ )-(L)-NHR2 27. VH-(L)-NHR2-(L)-EM 28.
  • VL( ⁇ or ⁇ )-CL-Hinge-(L)-NHR2 and VH-CH1 37.
  • variable light chain can be either V ⁇ or V ⁇ .
  • the assembled tetramerized protein molecule in one example could be a human pMHC for the application in drug discovery using animal drug discovery platforms (e.g. mice, rats, rabbits, chicken).
  • the tetramerisation domain is preferentially expressed and produced from genes originating from the animal species it is intended for.
  • One example of such drug discovery applications would be the use of the tetramerized human pMHC as an antigen for immunization in rats for example. Once rats are immunized with pMHC the immune response is directed specifically towards the human pMHC and not the tetramerisation domain of the protein complex.
  • Multivalent antibodies can be produced, for example using single domain antibody sequences, fused to the NHR2 multimerisation domain.
  • the tetravalent protein can be a peptide used as a probe for molecular imaging of tumour antigens.
  • the multivalent binding of such a probe will have distinctive advantage over monovalent molecular probes as it will have enhanced affinity, avidity and retention time in vivo and this in turn will enhance in vivo tumour targeting.
  • the multimerisation domain is the NHR2 domain set forth above.
  • polypeptides are stabilized and/or rendered soluble by the use of Ig constant domains fused to the polypeptides, such that the fusions provide tetramers of polypeptides.
  • Ig hinge domains can be used to provide octamers.
  • Multimeric TCR proteins according to the invention are useful in any application in which soluble TCR proteins are indicated.
  • the multivalent heterodimeric soluble TCR protein molecules of the invention can be used for selectively inhibiting immune responses, for example suppression of an autoimmune response.
  • the multivalent, for example tetravalent, nature of these soluble protein molecules gives it extraordinarily sensitivity and binding affinity to compete antigen-specific interactions between T cells and antigen presenting cells.
  • tetravalent heterodimeric soluble TCR protein molecules can be used to prevent tissue transplant rejection by selectively suppressing T cell recognition of specific transplantation antigen and self antigens binding to target molecule and thus inhibiting cell-to-cell interaction.
  • the tetravalent heterodimeric soluble TCR protein molecules can be used in clinical studies such as toxicity, infectious disease studies, neurological studies, behavior and cognition studies, reproduction, genetics and xenotransplantation studies.
  • the tetravalent heterodimeric soluble TCR protein molecules with enhanced sensitivity for cognate pMHC can be used for the purpose of diagnostics using biological samples obtained directly from human patients.
  • the enhanced sensitivity of the tetravalent heterodimeric soluble TCRs allows detection of potential disease-associated peptides displayed on MHC, which are naturally found to be expressed at low density. These molecules can also be used for patient stratification for enrolling patient onto relevant clinical trials.
  • octavalent heterodimeric soluble TCR protein molecules can be used in pharmaceutical preparations for the treatment of various diseases.
  • octavalent heterodimeric soluble TCR protein molecules can be used as a probe for tumour molecular imaging or prepared as a therapeutic protein.
  • the polypeptide comprises or consists of a polypeptide disclosed in Table 8.
  • the invention provides a multimer (eg, a dimer, trimer or tetramer, preferably a tetramer) of such a polypeptide.
  • the multimerization domain is a p53 domain (eg, a human p53 domain).
  • the multimerization domain (SAM) is an orthologue or homologue of a p53 domain (eg, a human p53 domain).
  • the invention provides a polypeptide (eg, said polypeptide or said first polypeptide), wherein the polypeptide comprises or consists of (in N- to C-terminal direction*); A.
  • a dAb and a self-associating multimersiation domain (SAM) B.
  • a first dAb, a SAM and a second dAb C.
  • polypeptide H, L, O or Q is associated with a second polypeptide, wherein the second polypeptide comprises (in N- to C-terminal direction) VL and CL, wherein the CL is associated with the CH1 of the first polypeptide.
  • polypeptide I, M, P or R is associated with a second polypeptide, wherein the second polypeptide comprises (in N- to C-terminal direction) VH and CH1, wherein the CH1 is associated with the CL of the first polypeptide.
  • the polypeptide is encoded by a nucleotide sequence disclosed in Table 9.
  • the polypeptide comprises or consists of an amino acid sequence disclosed in Table 10.
  • the polypeptide comprises (in N- to C-terminal direction); A.
  • a first scFv and a SAM D.
  • SAM self-associating multimersiation domain
  • a first scFv and a SAM D.
  • the SAM is a tetramerisation domain, eg, a p53 TD.
  • the first, second, third (when present) and fourth (when present) dAbs have the same antigen binding specificity.
  • first, second, third (when present) and fourth (when present) dAbs have the same different binding specificity.
  • first and second scFvs have the same antigen binding specificity. In an example the first and second scFvs have the same different antigen binding specificity.
  • first dAb, second dAb and first scFv have the same antigen binding specificity. In an example the first dAb, second dAb and first scFv have the same different antigen binding specificity.
  • a dAb is provided in the polypeptide
  • any different type of antigen binding domain such as a scFv or Fab or non-Ig binding domain (eg, an affibody, avimer or fibronectin domain).
  • a scFv is provided in the polypeptide
  • any different type of antigen binding domain such as a dAb or Fab or non-Ig binding domain (eg, an affibody, avimer or fibronectin domain).
  • a Fab is provided in the polypeptide
  • any different type of antigen binding domain such as a scFv or dAb or non-Ig binding domain (eg, an affibody, avimer or fibronectin domain).
  • Each antigen may be any antigen disclosed herein.
  • the CH1 (when present), CH2 and CH3 are a human Ig CH1, a CH2 a CH3, eg, a IgG1 CH1, CH2 and CH3.
  • the CH2 comprises a CH2 domain
  • the CH3 comprises a CH3 domain
  • the CH2 comprises a hinge amino acid sequence.
  • the CH2 comprises (in N- to C-terminal direction) the hinge amino acid sequence and the CH2 domain.
  • the hinge amino acid sequence (i) is a complete hinge; (ii) is a hinge amino acid sequence that is non-functional to dimerise the polypeptide with another such polypeptide; (iii) a hinge amino acid sequence devoid of a hinge core comprising the amino acid motif CXXC (and optionally also devoid of an upper hinge amino acid sequence); or (iv) an upper hinge fused to a lower hinge, but devoid of a hinge core comprising the amino acid motif CXXC; or (v) a lower hinge, but devoid of a hinge core comprising the amino acid motif CXXC (and optionally also devoid of an upper hinge amino acid sequence).
  • the CH2 is devoid of a functional hinge region, ie, wherein the hinge region is non-functional to dimerise the polypeptide with another such polypeptide.
  • the CH2 is devoid of a hinge region.
  • the CH2 is devoid of a complete hinge region sequence.
  • the CH2 is devoid of a core hinge region sequence.
  • the CH2 comprises (in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and wherein the CH2 (and the polypeptide) is devoid of a core hinge region that is functional to dimerise the polypeptide with another said polypeptide.
  • the CH2 comprises in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S).
  • the CH2 comprises in N- to C- terminal direction) an amino acid selected from SEQ IDs: 1*163-1*178 and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S).
  • the core hinge region amino acid sequence is selected from SEQ IDs: 1*180-1*182.
  • the CH2 (an the polyeptide) is devoid of amino acid sequences SEQ IDs: 1*183-1*187.
  • the CH2 domain is a human IgG1 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180.
  • any CH1 and CH3 present in the polypeptide are human IgG1 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CPPC (SEQ ID: 1*180).
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDKTHT (SEQ ID: 1*183) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180).
  • the CH2 domain is a human IgG2 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180.
  • any CH1 and CH3 present in the polypeptide are human IgG2 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ERKCCVE (SEQ ID: 1*184) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180).
  • the CH2 domain is a human IgG3 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*181.
  • any CH1 and CH3 present in the polypeptide are human IgG3 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ELKTPLGDTTHT (SEQ ID: 1*185) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181).
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDTPPP (SEQ ID: 1*186) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181).
  • the CH2 domain is a human IgG4 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*182.
  • any CH1 and CH3 present in the polypeptide are human IgG4 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ESKYGPP (SEQ ID: 1*187) and core hinge region amino acid sequence CPSC (SEQ ID: 1*182).
  • the CH2 of a polypeptide herein is devoid of a core hinge (and optionally also an upper hinge) amino acid sequence.
  • the CH2 of a polypeptide herein is devoid of a core hinge CXXC amino acid sequence, wherein X is any amino acid, preferably P, R or S, most preferably P.
  • the CH2 comprises an APELLGGPSV amino acid sequence, or an PAPELLGGPSV amino acid sequence.
  • the CH2 comprises an APPVAGPSV amino acid sequence, or an PAPPVAGPSV amino acid sequence.
  • the CH2 comprises an APEFLGGPSV amino acid sequence, or an PAPEFLGGPSV amino acid sequence.
  • the CH2 and CH3 of a polypeptide herein are human IgG1 CH2 and CH3 domains, wherein the CH2 is devoid of a core hinge (and optionally also an upper hinge) amino acid sequence, eg, wherein the CH2 is devoid of a CPPC sequence.
  • the CH2 comprises an APELLGGPSV amino acid sequence, or an EPKSCDKTHT[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional.
  • the CH2 and CH3 of a polypeptide herein are human IgG2 CH2 and CH3 domains, wherein the CH2 is devoid of a core hinge (and optionally also an upper hinge) amino acid sequence, eg, wherein the CH2 is devoid of a CPPC sequence.
  • the CH2 comprises an APPVAGPSV amino acid sequence, or an ERKCCVE[P]APPVAGPSV amino acid sequence, wherein the bracketed P is optional.
  • the CH2 and CH3 of a polypeptide herein are human IgG3 CH2 and CH3 domains, wherein the CH2 is devoid of a core hinge (and optionally also an upper hinge) amino acid sequence, eg, wherein the CH2 is devoid of a CPRC sequence.
  • the CH2 comprises an APELLGGPSV amino acid sequence, or an ELKTPLGDTTHT[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional.
  • the CH2 comprises an EPKSCDTPPP[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional.
  • the CH2 and CH3 of a polypeptide herein are human IgG4 CH2 and CH3 domains, wherein the CH2 is devoid of a core hinge (and optionally also an upper hinge) amino acid sequence, eg, wherein the CH2 is devoid of a CPSC sequence.
  • the CH2 comprises an APEFLGGPSV amino acid sequence, or an ESKYGPP[P]APEFLGGPSV amino acid sequence, wherein the bracketed P is optional.
  • a CH2 may also be present, but in this case optionally lacking the core hinge region (or at least a sequence selected from CXXC as disclosed herein and SEQ IDs: 1*180-1*182) and optionally lacking the upper and/or the lower hinge region to prevent F(ab')2 formation.
  • ASPECTS By way of example the invention provides the following Aspects, some of which have been exemplified herein. The following Aspects are not to be interpreted as Claims. The Claims start after the Examples section. 1.
  • a polypeptide comprising (in N- to C-terminal direction; or in C- to N-terminal direction) (a) An immunoglobulin superfamily domain; (b) An optional linker; and (c) A self-associating multimerisation domain (SAM) (optionally a self-associating tetramerisation domain (TD)).
  • SAM self-associating multimerisation domain
  • TD self-associating tetramerisation domain
  • each linker is a peptide linker comprising (or comprising up to, or consisting of) 40, 30, 25, 20, 19, 18, 17, 16, 1514, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4 or amino acids.
  • the domain of (a) is a non-Ig domain or comprises a non-Ig scaffold.
  • any other self-associating multimerization domain may be used.
  • the SAM eg, TD
  • the SAM is a human, dog, cat, horse, monkey (eg, cynomolgus monkey), rodent (eg, mouse or rat), rabbit, bird (eg, chicken) or fish SAM (or TD).
  • the domain of (a) is capable of specifically binding to an antigen selected from PD-L1, PD-1, 4-1BB, CTLA-4, 4-1BB, CD28, TNF alpha, IL17 (eg, IL17A), CD38, VEGF-A, EGFR, IL-6, IL-4, IL-6R, IL-4R (eg, IL-4Ra), OX40, OX40L, TIM-3, CD20, GITR, VISTA, ICOS, Death Receptor 5 (DR5), LAG-3, CD40, CD40L, CD27, HVEM, KRAS, haemagglutinin, transferrin receptor 1, amyloid beta, BACE1, Tau, TDP43, SOD1, Alpha Synculein and CD3.
  • an antigen selected from PD-L1, PD-1, 4-1BB, CTLA-4, 4-1BB, CD28, TNF alpha, IL17 (eg, IL17A), CD38, VEGF-A, EGFR
  • the antigen is a peptide-MHC.
  • the polypeptide comprises at least two binding moieties, eg, two dAbs, two scFvs, or a dAb and a scFv.
  • these binding moieties bind to the same antigen (eg, an antigen disclosed herein or in the immediately preceding paragraph herein).
  • the moieties bind to different antigens (eg, an antigen disclosed herein or in the immediately preceding paragraph herein).
  • variable domains or scFvs are capable of specifically binding to the same or different antigens selected from TNF alpha, CD38, IL17a, CD20, PD-1, PD-L1, CTLA-4 and 4-1BB.
  • one of the moieties binds to TNF alpha and the other binds to IL17a; one of the moieties binds to PD-1 and the other binds to 4-1BB; or one of the moieties binds to PD-L1 and the other binds to 4-1BB; one of the moieties binds to PD- 1 and the other binds to CTLA-4; or one of the moieties binds to PD-L1 and the other binds to CTLA-4.
  • variable domain herein is a VH (eg, comprised by a scFv or a Fab polypeptide chain).
  • VHH eg, comprised by a scFv or a Fab polypeptide chain
  • humanised VH, humanised VHH or a human VH eg, comprised by a scFv or a Fab polypeptide chain
  • VL eg, comprised by a scFv or a Fab polypeptide chain
  • it is a V ⁇ .
  • it is a V ⁇ .
  • the domain of (a) is a TCR variable domain (eg, a TCR ⁇ , TCR ⁇ , TCR ⁇ or TCR ⁇ ).
  • the immunoglobulin superfamily domain is an antibody single variable domain (dAb). 3. The polypeptide of any preceding Aspect, wherein the domain of (a) is selected from an antibody single variable domain, a VH and a VL; or wherein the domain is comprised by an scFv.
  • a single variable domain herein is a human or humanised dAb or nanobody; or is a camelid VHH domain.
  • the domain of (a) is comprised by a single-chain TCR (scTCR). 4. The polypeptide of any preceding Aspect, wherein (a) is joined directly to (c); or wherein (b) is joined directly to (a) and (c). 5. The polypeptide of any preceding Aspect, comprising (in N- to C-terminal direction) the SAM, (d) an optional second linker and (e) a second immunoglobulin superfamily domain. 6. The polypeptide of Aspect 5, wherein the second domain is selected from an antibody single variable domain, a VH and a VL; or wherein the domain is comprised by an scFv.
  • scTCR single-chain TCR
  • the single variable domain is a human or humanised dAb or nanobody; or is a camelid VHH domain.
  • the TD is a TD of a protein disclosed in Table 2.
  • the TD comprises an amino acid sequence that is at least 80% identical to SEQ ID: 1*10 or 1*126.
  • the polypeptide of any preceding Aspect comprising (f) an antibody variable domain, an antibody constant region or an antibody Fc region between (a) and (c). 13.
  • the polypeptide of Aspect 12 wherein (f) comprises (i) an antibody CH1 constant domain; or (ii) an antibody Fc region (ie, comprising a CH2-CH3). 14.
  • polypeptide comprises or consists of (in N- to C-terminal direction);
  • A. A first antibody single variable domain (dAb), an optional linker and said SAM;
  • B. A first antibody single variable domain, an optional linker, said SAM and a second antibody single variable domain;
  • C. A first scFv, an optional linker and said SAM;
  • D. A first scFv, an optional linker, said SAM and a second scFv;
  • E A first antibody single variable domain, an optional linker, said SAM and a first scFv;
  • F. A first scFv, an optional linker, said SAM and a first antibody single variable domain;
  • each variable domain is a VH or a VL (eg, a V ⁇ or a V ⁇ ).
  • each domain of the polypeptide herein is a human domain.
  • each domain of the polypeptide herein is a human or humanised domain. 17.
  • SAM self-associating multimersiation domain
  • a first dAb, a second dAb and a SAM O. A VH, a CH1 and a SAM; P. A VL, a CL and a SAM; Q. A VH, a CH1, a SAM and a first dAb; R. A VL, a CL, a SAM and a first dAb; S. A first dAb, a second dAb, a SAM and a third dAb; T. A first dAb, a second dAb, a SAM and a first scFv; U. A first dAb, a second dAb, a SAM, a third dAb and a fourth dAb; V.
  • A. A dAb and a self-associating multimersiation domain (SAM)
  • B. A first dAb, a SAM and a second dAb
  • C. A first scFv and a SAM
  • D. A first scFv, a SAM and a second scFv
  • E A first scFv, a SAM and a first dAb
  • the polypeptide comprises an antibody Fc region, wherein the Fc comprises the CH2 and CH3 domains. 18.
  • polypeptide of Aspect 16B, 16D, (i) 17B, (i) 17D, (i) 17N, (i) 17S, (i) 17T, (i) 17U, (i) 17X, (i) 17Y, (i) 17Z, (i) 17AA, (ii) 17B, (ii) 17D, (ii) 17N, (ii) 17S, (ii) 17T, (ii) 17U, (ii) 17X, (ii) 17Y, (ii) 17Z or (ii) 17AA wherein the single variable domains (dAbs) are identical; or wherein the scFvs are identical. 19.
  • polypeptide of Aspect 16B, 16D, (i) 17B, (i) 17D, (i) 17N, (i) 17S, (i) 17T, (i) 17U, (i) 17X, (i) 17Y, (i) 17Z, (i) 17AA, (ii) 17B, (ii) 17D, (ii) 17N, (ii) 17S, (ii) 17T, (ii) 17U, (ii) 17X, (ii) 17Y, (ii) 17Z or (ii) 17AA wherein the single variable domains are different; or wherein the scFvs are different. 20.
  • the polypeptide of Aspect 16G, 16J, 16K (i) 17H, (i) 17I, (i) 17L, (i) 17M, (i) 17O, (i) 17P, (i) 17Q, (i) 17R, (ii) 17H, (ii) 17I, (ii) 17L, (ii) 17M, (ii) 17O, (ii) 17P, (ii) 17Q or (ii) 17R
  • the first variable domain is a VH domain and the first constant domain is a CH1 domain
  • the polypeptide is associated with a second polypeptide, wherein the second polypeptide comprises an antibody CL constant domain that is paired with the CH1 domain;
  • the first variable domain is a VH domain and the first constant domain is a CL domain
  • optionally the polypeptide is associated with a second polypeptide, wherein the second polypeptide comprises an antibody CH1 constant domain that is paired with the CL domain;
  • This further variable domain may be different from the first single variable domain or may have a target binding specificity that is different from the target binding specificity of the first single variable domain or scFv. 22.
  • 25. The polypeptide of any one of Aspects 17 to 24, wherein the CH2 is devoid of an amino acid sequence CXXC or an amino acid sequence selected from SEQ IDs: 1*180-1*182; and optionally is devoid of amino acid sequences SEQ IDs: 1*183-1*187.
  • the CH2 is a CH2’ disclosed herein.
  • the CH2 comprises (in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and wherein the CH2 (and the polypeptide) is devoid of a core hinge region that is functional to dimerise the polypeptide with another said polypeptide.
  • the CH2 comprises in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S).
  • the CH2 comprises in N- to C- terminal direction) an amino acid selected from SEQ IDs: 1*163-1*178 and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S).
  • the core hinge region amino acid sequence is selected from SEQ IDs: 1*180-1*182.
  • the CH2 (an the polyeptide) is devoid of amino acid sequences SEQ IDs: 1*183-1*187.
  • the CH2 domain is a human IgG1 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180.
  • any CH1 and CH3 present in the polypeptide are human IgG1 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CPPC (SEQ ID: 1*180).
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDKTHT (SEQ ID: 1*183) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180).
  • the CH2 domain is a human IgG2 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180.
  • any CH1 and CH3 present in the polypeptide are human IgG2 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ERKCCVE (SEQ ID: 1*184) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180).
  • the CH2 domain is a human IgG3 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*181.
  • any CH1 and CH3 present in the polypeptide are human IgG3 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ELKTPLGDTTHT (SEQ ID: 1*185) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181).
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDTPPP (SEQ ID: 1*186) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181).
  • the CH2 domain is a human IgG4 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*182.
  • any CH1 and CH3 present in the polypeptide are human IgG4 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ESKYGPP (SEQ ID: 1*187) and core hinge region amino acid sequence CPSC (SEQ ID: 1*182).
  • ESKYGPP SEQ ID: 1*187
  • CPSC core hinge region amino acid sequence CPSC
  • each domain and SAM is a human domain and SAM respectively. 28.
  • each variable domain or scFv is capable of binding to an antigen.
  • the binding antagonises the antigen.
  • the polypeptide of any preceding Aspect wherein the polypeptide comprises binding specificity for more than one antigen, optionally 2, 3 or 4 different antigens.
  • the polypeptide comprises at least one anti-CTLA-4 binding domain (eg, dAb or scFv) and at least one anti-4-1BB binding domain.
  • the polypeptide comprises at least one anti-CTLA-4 binding domain (eg, dAb or scFv) and at least one anti-PD-L1 binding domain.
  • the polypeptide comprises at least one anti-CTLA-4 binding domain (eg, dAb or scFv) and at least one anti-PD-1 binding domain.
  • the polypeptide comprises at least one anti-TNF alpha binding domain (eg, dAb or scFv) and at least one anti-IL-17A binding domain.
  • the polypeptide comprises a first antigen binding domain (eg, a said VH, VL, VHH, dAb, scFv or Fab variable region) that is N-terminal of the SAM and a second antigen binding domain (eg, a said VH, VL, VHH, dAb, scFv or Fab variable region) that is C-terminal of the SAM.
  • a first antigen binding domain eg, a said VH, VL, VHH, dAb, scFv or Fab variable region
  • a second antigen binding domain eg, a said VH, VL, VHH, dAb, scFv or Fab variable region
  • the polypeptide comprises a third antigen binding domain (eg, a said VH, VL, VHH, dAb, scFv or Fab variable region) that is N-terminal of the SAM (eg, and also N-terminal of the first domain; or between the first domain and the SAM); and optionally the polypeptide a fourth antigen binding domain (eg, a said VH, VL, VHH, dAb, scFv or Fab variable region) that is C-terminal of the SAM (eg, and also C-terminal of the second domain; or between the second domain and the SAM).
  • a third antigen binding domain eg, a said VH, VL, VHH, dAb, scFv or Fab variable region
  • the polypeptide optionally the polypeptide a fourth antigen binding domain (eg, a said VH, VL, VHH, dAb, scFv or Fab variable region) that is C-terminal of
  • the first domain is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3) and the second binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3).
  • the domains have the same antigen binding specificity.
  • the domains have the same epitope binding specificity.
  • the domains have different antigen binding specificity.
  • the domains have different epitope binding specificity on the same antigen.
  • the domains bind TNF alpha. In an example, the domains bind CD20. In an example, the domains bind PD-1. In an example, the domains bind PD- L1. In an example, the domains bind CTLA-4. [00278] In an embodiment, the first domain is capable of specifically binding to 4-1BB, PD-1 or PD- L1 and the second binding site is capable of specifically binding to CTLA-4. In an embodiment, the second domain is capable of specifically binding to 4-1BB, PD-1 or PD-L1 and the first binding site is capable of specifically binding to CTLA-4.
  • the first domain is capable of specifically binding to 4-1BB
  • the second binding site is capable of specifically binding to CTLA-4
  • the third binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3)
  • the fourth binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3).
  • the first domain is capable of specifically binding to PD-1
  • the second binding site is capable of specifically binding to CTLA-4
  • the third binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3)
  • the fourth binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3).
  • the first domain is capable of specifically binding to PD-L1
  • the second binding site is capable of specifically binding to CTLA-4
  • the third binding site is capable of specifically binding to CTLA-4, PD-L1, CD3 or CD28
  • the fourth binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3).
  • an immune checkpoint or T-cell co-stimulatory antigen eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3.
  • the first domain is capable of specifically binding to TNF alpha
  • the second binding site is capable of specifically binding to IL-17 (eg, IL-17A).
  • the second domain is capable of specifically binding to TNF alpha and the first binding site is capable of specifically binding to IL-17 (eg, IL-17A).
  • the polypeptide comprises a cytokine, eg, an IL-2, IL-15 or IL-21.
  • the cytokine is a truncated cytokine, eg, a truncated IL-2, IL-15 or IL-21.
  • the cytokine is C-terminal of the SAM (eg, C-terminal of the C-terminal most antigen binding domain).
  • the cytokine is N-terminal of the SAM (eg, N-terminal of the N-terminal most antigen binding domain).
  • the first domain is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3).
  • the first domain is capable of specifically binding to 4-1BB, PD-1, PD-L1 or CTLA-4.
  • the second domain is capable of specifically binding to an immune checkpoint or T-cell co- stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3). In an embodiment of these examples, the second domain is capable of specifically binding to 4-1BB, PD-1, PD-L1 or CTLA-4. In an embodiment of these examples, the third domain is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3).
  • an immune checkpoint or T-cell co- stimulatory antigen eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3.
  • the third domain is capable of specifically binding to 4-1BB, PD-1, PD-L1 or CTLA-4.
  • the fourth domain is capable of specifically binding to an immune checkpoint or T-cell co- stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3).
  • the fourth domain is capable of specifically binding to 4-1BB, PD-1, PD-L1 or CTLA-4.
  • the multimer is a polypeptide trimer.
  • the multimer is a polypeptide tetramer.
  • 31. The polypeptide or multimer of any preceding Aspect, comprising eukaryotic cell glycosylation.
  • 32. The polypeptide or multimer of Aspect 31, wherein the cell is a HEK293, CHO or Cos cell.
  • 33. The polypeptide or multimer of any preceding Aspect for medical use.
  • a pharmaceutical composition comprising the polypeptide or multimer of any preceding Aspect.
  • 35. A nucleic acid encoding a polypeptide of any one of Aspects 1 to 29 and 31 to 33. 36.
  • a eukaryotic cell or vector comprising the nucleic acid of Aspect 35.
  • a method of binding multiple copies of an antigen comprising combining the copies with a multimer of any one of Aspects 30 to 33, wherein the copies are bound by polypeptides of the multimer, and optionally the method comprising isolating the multimer bound to the antigen copies.
  • the method of Aspect 37 wherein the method is a diagnostic method for detecting the presence of a substance in a sample, wherein the substance comprises the antigen, the method comprising providing the sample (eg, a bodily fluid, food, food ingredient, beverage, beverage ingredient, soil or forensic sample), mixing the sample with multimers according to any one of Aspects 30 to 33 and detecting the binding of multimers to the antigen in the sample.
  • the sample eg, a bodily fluid, food, food ingredient, beverage, beverage ingredient, soil or forensic sample
  • the sample eg, a bodily fluid, food, food ingredient, beverage, beverage ingredient, soil or forensic sample
  • the method is for pregnancy testing or diagnosing a disease or condition in a subject from which the sample has been previously obtained. 39.
  • a method of treating or reducing the risk of a disease or condition in a human or animal subject comprising administering the composition of Aspect 34 to the subject, wherein multimers comprised by the composition specifically bind to a target antigen in the subject, wherein said binding mediates the treatment or reduction in risk.
  • the antigen is an immune checkpoint or T-cell co- stimulatory antigen (eg, PD-L1, PD-1 or CTLA4); or wherein the antigen is TNF alpha or IL-17A.
  • the antigen mediates the disease or condition in the subject; and optionally wherein the binding antagonises the antigen.
  • 42. A composition comprising a plurality of polypeptides according to any one of Aspects 1 to 29 and 31 to 33, wherein at least 90% of the polypeptides are comprised by tetramers of said polypeptides.
  • at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% of the polypeptides are comprised by tetramers of said polypeptides.
  • composition of Aspect 42 or 43 wherein the remaining (ie, the balance to 100% of polypeptide) polypeptides are selected from one or more of polypeptide monomers, dimers and trimers.
  • a method of producing a composition (optionally a composition according to any one of Aspects 42 to 44) comprising a plurality of polypeptides according to any one of Aspects 1 to 29 and 31 to 33, the method comprising providing eukaryotic host cells according to Aspect 34, culturing the host cells, and allowing expression and secretion from the cells of tetramers of the polypeptides, and optionally isolating or purifying the tetramers.
  • the invention also provides polypeptides and multimers comprising antibody Fc region(s). This is useful, for example, to harness FcRn recycling when administered to a subject, such as a human or animal, which may contribute to a desirable half-life in vivo. Fc regions are also useful for providing Fc effector functions. For example, an IgG1 Fc may be useful when the multimer is used to treat a cancer or where cell killing is desired, eg, by ADCC.
  • the invention provides the following: A polypeptide comprising an antibody Fc region, wherein the Fc region comprises an antibody CH2 and an antibody CH3; and a self-associating multimerisation domain (SAM); wherein the CH2 comprises an antibody hinge sequence and is devoid of a core hinge region.
  • the polypeptide comprises an epitope binding site, eg, an antibody VH single variable domain or an antibody VH/VL pair that binds to an epitope. Additionally or alternatively, the polypeptide comprises an epitope which is cognate to an antibody.
  • the polypeptide can form a multimer that binds copies of the antibodies, such as when the multimer is contacted with a sample comprising the antibodies (eg, for medical use as disclosed herein).
  • the multimer can be used in a method of diagnosis or testing to determine the presence and/or quantity (or relative amount) of the antibody in the sample.
  • the multimer provides multiple copies of the epitope (at least one for each polypeptide comprised by the multimer), this can be useful to bind many copies of the antibody, which may be present in relatively small amounts in the sample, thereby having the effect of enhancing the chances of detecting (or amplifying) a positive signal denoting presence of the antibody.
  • the CH2 is devoid of (i) a core hinge CXXC amino acid sequence, wherein X is any amino acid or wherein each amino acid X is selected from a P, R and S; and/or (ii) an upper hinge amino acid sequence.
  • a core hinge CXXC amino acid sequence wherein X is any amino acid or wherein each amino acid X is selected from a P, R and S and the Fc does not directly pair with another Fc.
  • the CXXC sequence is selected from SEQ IDs: 1*180-1*182; or the CH2 is devoid of amino acid sequences SEQ IDs: 1*183-1*187.
  • the CH2 comprises A. amino acid sequence APELLGGPSV (SEQ ID: 1*163), or PAPELLGGPSV (SEQ ID: 1*164); B. amino acid sequence APPVAGPSV (SEQ ID: 1*165), or PAPPVAGPSV (SEQ ID: 1*166); C. amino acid sequence APEFLGGPSV (SEQ ID: 1*175), or PAPEFLGGPSV (SEQ ID: 1*176); D.
  • the CH2 comprises (in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and wherein the CH2 (and the polypeptide) is devoid of a core hinge region that is functional to dimerise the polypeptide with another said polypeptide.
  • the CH2 comprises in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S).
  • the CH2 comprises in N- to C- terminal direction) an amino acid selected from SEQ IDs: 1*163-1*178 and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S).
  • the core hinge region amino acid sequence is selected from SEQ IDS: 1*180-1*182.
  • the CH2 (an the polyeptide) is devoid of amino acid sequences SEQ IDs: 1*183- 1*187.
  • the CH2 domain is a human IgG1 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180.
  • any CH1 and CH3 present in the polypeptide are human IgG1 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CPPC (SEQ ID: 1*180).
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDKTHT (SEQ ID: 1*183) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180).
  • the CH2 domain is a human IgG2 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180.
  • any CH1 and CH3 present in the polypeptide are human IgG2 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ERKCCVE (SEQ ID: 1*184) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180).
  • the CH2 domain is a human IgG3 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*181.
  • any CH1 and CH3 present in the polypeptide are human IgG3 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ELKTPLGDTTHT (SEQ ID: 1*185) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181).
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDTPPP (SEQ ID: 1*186) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181).
  • the CH2 domain is a human IgG4 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*182.
  • any CH1 and CH3 present in the polypeptide are human IgG4 CH1 and CH3 respectively.
  • the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ESKYGPP (SEQ ID: 1*187) and core hinge region amino acid sequence CPSC (SEQ ID: 1*182).
  • the polypeptide comprises an antibody CH1-hinge sequence devoid of core region-CH2-CH3.
  • the CH2 and CH3 comprise A. human IgG1 CH2 and CH3 domains; B.
  • the CH2 and CH3 comprise (a) human IgG1 CH2 and CH3 domains and the hinge sequence and core hinge region is a human IgG1 hinge sequence and hinge region; (b) human IgG2 CH2 and CH3 domains and the hinge sequence and core hinge region is a human IgG2 hinge sequence and hinge region; (c) human IgG3 CH2 and CH3 domains and the hinge sequence and core hinge region is a human IgG31 hinge sequence and hinge region; or (d) human IgG4 CH2 and CH3 domains and the hinge sequence and core hinge region is a human IgG4 hinge sequence and hinge region [00298]
  • the CH2 domain comprises a human IgG1 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180, optionally wherein the CH2 is devoid of upper hinge region amino acid sequence EPKSCDKTHT (SEQ ID: 1*183);
  • the CH2 domain comprises a human IgG2 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180, optionally wherein the CH2 is devoid of upper hinge region amino acid sequence ERKCCVE (SEQ ID: 1*184);
  • C is a human IgG1 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180, optionally wherein the CH2 is devoid of upper hinge region amino acid sequence ERKCCVE (SEQ ID: 1*184);
  • the CH2 domain comprises a human IgG3 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*181, optionally wherein the CH2is devoid of upper hinge region amino acid sequence ELKTPLGDTTHT (SEQ ID: 1*185) or upper hinge region amino acid sequence EPKSCDTPPP (SEQ ID: 1*186); or D.
  • the CH2 domain comprises a human IgG4 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*182, and optionally wherein the CH2 is devoid of upper hinge region amino acid sequence ESKYGPP (SEQ ID: 1*187).
  • the polypeptide comprises (in N- to C-terminal direction) the Fc region and the SAM, the Fc region comprising (in N- to C-terminal direction) the hinge sequence, a CH2 domain and a CH3 domain.
  • the polypeptide comprises one or more epitope binding sites, eg, an antibody variable domain that is capable of specifically binding to a first epitope.
  • the first epitope is comprised by an antigen (eg, a human antigen) selected from the group consisting of ABCF1; ACVR1; ACVR1B; ACVR2; ACVR2B; ACVRL1; ADORA2A; Aggrecan; AGR2; AICDA; AWI; AIG1; AKAP1; AKAP2; AIYIH; AMHR2; ANGPT1; ANGPT2; ANGPTL3; ANGPTL4; ANPEP; APC; APOC1; AR; AZGP1 (zinc-a-glycoprotein); B7.1; B7.2; BAD; BAFF; BAG1; BAI1; BCL2; BCL6; BDNF; BLNK; BLRl (MDR15); BlyS; BM Pl; BMP2; BMP3B (GDFIO); BMP4; BMP6; BM P8; BMPRIA; BMPRIB; BM PR2; BPAG1 (plectin);
  • the second epitope (as discussed below) is comprised by the same antigen as the first epitope (eg, comprised by the same antigen molecule).
  • the second antigen is comprised by said group.
  • the first and second epitopes are comprised by different antigens selected from said group.
  • the polypeptide has 1, 2, 3, 4 or 5 epitope binding sites (optionally wherein the polypeptide comprises 2 or more binding sites (eg, single variable domains) that bind to different epitopes, or wherein the polypeptide binding sites are identical).
  • the SAM is a TD (eg, a p53 TD, such as a human p53 TD) and the polypeptide has 2, 3 or 4 binding sites, such as 3 sites or such as 4 sites.
  • the polypeptide has 3 binding sites.
  • the polypeptide has 4 binding sites.
  • the binding sites each binds TNF alpha (eg, wherein the binding sites are identical, eg, identical antibody single variable domains).
  • the multimer is an octavalent bispecific multimer comprising 4 copies of an anti-PD-L1binding site (eg, dAb) and 4 copies of an anti-4-1BB binding site (eg, dAb).
  • the multimer is a tetravalent multimer comprising copies of an anti-PD-L1 binding site (eg, dAb).
  • the multimer is an octavalent multimer comprising copies of an anti-PD-L1 binding site (eg, dAb).
  • the multimer is a 12-valent multimer comprising copies of an anti-PD-L1 binding site (eg, dAb).
  • the multimer is a 16- valent multimer comprising copies of an anti-PD-L1 binding site (eg, dAb).
  • the anti- PD-L1 binding site comprises an avelumab or atezolizumab binding site that specifically binds to PD- L1.
  • the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD.
  • each polypeptide comprises one copy of the binding site.
  • each polypeptide comprises 2 copies of the binding site.
  • each polypeptide comprises 3 copies of the binding site.
  • each polypeptide comprises 4 copies of the binding site.
  • the multimer is a tetravalent multimer comprising copies of an anti-PD-1 binding site (eg, dAb).
  • the multimer is an octavalent multimer comprising copies of an anti-PD-1 binding site (eg, dAb).
  • the multimer is a 12-valent multimer comprising copies of an anti-PD-1 binding site (eg, dAb).
  • the multimer is a 16-valent multimer comprising copies of an anti-PD-1 binding site (eg, dAb).
  • the anti- PD-1 binding site comprises a nivolumab or pembrolizumab binding site that specifically binds to PD-1.
  • the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD.
  • each polypeptide comprises one copy of the binding site.
  • each polypeptide comprises 2 copies of the binding site.
  • each polypeptide comprises 3 copies of the binding site.
  • each polypeptide comprises 4 copies of the binding site.
  • the multimer is a tetravalent multimer comprising copies of an anti-DR5 (Death Receptor 5) binding site (eg, dAb).
  • the multimer is an octavalent multimer comprising copies of an anti-DR5 binding site (eg, dAb).
  • the multimer is a 12-valent multimer comprising copies of an anti-DR5 binding site (eg, dAb).
  • the multimer is a 16-valent multimer comprising copies of an anti-DR5 binding site (eg, dAb).
  • the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD.
  • each polypeptide comprises one copy of the binding site.
  • each polypeptide comprises 2 copies of the binding site.
  • each polypeptide comprises 3 copies of the binding site.
  • each polypeptide comprises 4 copies of the binding site.
  • the multimer is a tetravalent multimer comprising copies of an anti-OX40 or OX40L binding site (eg, dAb).
  • the multimer is an octavalent multimer comprising copies of an anti-OX40 or OX40L binding site (eg, dAb).
  • the multimer is a 12-valent multimer comprising copies of an anti- OX40 or OX40L binding site (eg, dAb).
  • the multimer is a 16-valent multimer comprising copies of an anti- OX40 or OX40L binding site (eg, dAb).
  • the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD.
  • each polypeptide comprises one copy of the binding site.
  • each polypeptide comprises 2 copies of the binding site.
  • each polypeptide comprises 3 copies of the binding site.
  • each polypeptide comprises 4 copies of the binding site.
  • the multimer is a tetravalent multimer comprising copies of an anti- glucocorticoid-induced tumor necrosis factor receptor (GITR) binding site (eg, dAb).
  • GITR glucocorticoid-induced tumor necrosis factor receptor
  • the multimer is an octavalent multimer comprising copies of an anti-GITR binding site (eg, dAb).
  • the multimer is a 12-valent multimer comprising copies of an anti-GITR binding site (eg, dAb).
  • the multimer is a 16-valent multimer comprising copies of an anti-GITR binding site (eg, dAb).
  • the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD.
  • each polypeptide comprises one copy of the binding site.
  • each polypeptide comprises 2 copies of the binding site.
  • each polypeptide comprises 3 copies of the binding site.
  • each polypeptide comprises 4 copies of the binding site.
  • the multimer is a tetravalent multimer comprising copies of an anti-antibody kappa light chain (KLC) binding site (eg, dAb).
  • KLC anti-antibody kappa light chain
  • the multimer is an octavalent multimer comprising copies of an anti-KLC binding site (eg, dAb).
  • the multimer is a 12-valent multimer comprising copies of an anti-KLC binding site (eg, dAb).
  • the multimer is a 16-valent multimer comprising copies of an anti-KLC binding site (eg, dAb).
  • the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD.
  • each polypeptide comprises one copy of the binding site.
  • each polypeptide comprises 2 copies of the binding site.
  • the multimer is a tetravalent multimer comprising copies of an anti-VEGF binding site (eg, dAb).
  • the multimer is an octavalent multimer comprising copies of an anti-VEGF binding site (eg, dAb).
  • the multimer is a 12-valent multimer comprising copies of an anti-VEGF binding site (eg, dAb).
  • the multimer is a 16-valent multimer comprising copies of an anti-VEGF binding site (eg, dAb).
  • the anti-VEGF binding site comprises a VEGF receptor domain that specifically binds to VEGF (eg, a VEGF binding site of human flt (eg, flt-1) or KDR, eg, Ig domain 2 from VEGFR1 or Ig domain 3 from VEGFR2)).
  • the anti-VEGF binding site comprises an aflibercept, bevacizumab or ranibizumab binding site that specifically binds to VEGF.
  • the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD.
  • each polypeptide comprises one copy of the binding site.
  • each polypeptide comprises 2 copies of the binding site.
  • each polypeptide comprises 3 copies of the binding site.
  • each polypeptide comprises 4 copies of the binding site.
  • the multimer is a tetravalent multimer comprising copies of an anti-TNF alpha binding site (eg, dAb).
  • the multimer is a tetravalent multimer comprising copies of an anti-TNF alpha binding site (eg, dAb).
  • the multimer is an octavalent multimer comprising copies of an anti-TNF alpha binding site (eg, dAb).
  • the multimer is a 12- valent multimer comprising copies of an anti-TNF alpha binding site (eg, dAb).
  • the multimer is a 16-valent multimer comprising copies of an anti-TNF alpha binding site (eg, dAb).
  • the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD.
  • each polypeptide comprises one copy of the binding site.
  • each polypeptide comprises 2 copies of the binding site.
  • each polypeptide comprises 3 copies of the binding site.
  • each polypeptide comprises 4 copies of the binding site.
  • variable domain is selected from an antibody single variable domain, a VH and a VL; or wherein the domain is comprised by an scFv.
  • the domain is comprised by an antibody VH/VL pair that binds to said first epitope.
  • epitope binding herein is specific binding as herein defined.
  • the polypeptide comprises (in N- to C-terminal direction) A. the variable domain, the SAM and the Fc region; B. the Fc region, the SAM and the variable domain; C. the variable domain, the Fc region and the SAM; D. the SAM, the variable domain and the Fc region; or E. the SAM, the Fc region and the variable domain.
  • the polypepide comprises a second antibody variable domain N- or C-terminal to the SAM, wherein the second variable domain is capable of specifically binding to a second epitope, wherein the first and second epitopes are identical or different.
  • the SAM is a self-associating tetramerisation domain (TD); optionally wherein the TD is a p53, p63 or p73 TD or a homologue or orthologue thereof; or wherein the TD is a NHR2 TD or a homologue or orthologue thereof; or wherein the TD comprises an amino acid sequence that is at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*10 or 1*126.
  • the polypeptide comprises (in N- to C-terminal direction); A.
  • a first antibody single variable domain (dAb), an optional linker and said SAM; B. A first antibody single variable domain, an optional linker, said SAM and a second antibody single variable domain; C. A first scFv, an optional linker and said SAM; D. A first scFv, an optional linker, said SAM and a second scFv; E. A first antibody single variable domain, an optional linker, said SAM and a first scFv; F. A first scFv, an optional linker, said SAM and a first antibody single variable domain; G. A first antibody variable domain, an optional first linker, a first antibody constant domain, a second optional linker and said SAM; H.
  • Said SAM an optional linker and a first antibody single variable domain
  • I Said SAM, an optional linker and a first scFv
  • J Said SAM, an optional linker, a first antibody constant domain, a second optional linker and a first antibody variable domain
  • K Said SAM, an optional linker, a first antibody variable domain, a second optional linker and a first antibody constant domain
  • the polypeptide comprises (in N- to C-terminal direction);
  • B A first dAb, the SAM and a second dAb;
  • C A first scFv and the SAM; D.
  • a first dAb, a second dAb and the SAM O. A VH, a CH1 and the SAM; P. A VL, a CL and the SAM; Q. A VH, a CH1, the SAM and a first dAb; R. A VL, a CL, the SAM and a first dAb; S. A first dAb, a second dAb, the SAM and a third dAb; T. A first dAb, a second dAb, the SAM and a first scFv; U. A first dAb, a second dAb, the SAM, a third dAb and a fourth dAb; V.
  • W A first dAb, the Fc region, the SAM and a first scFv
  • X A first dAb, a second dAb, the Fc region and the SAM
  • Y A first dAb, a second dAb, the Fc region, the SAM and a third dAb
  • Z A first dAb, a second dAb, the Fc region, the SAM and a first scFv; or AA.
  • any single variable domain or dAb herein is a NanobodyTM or a Camelid VHH (eg, a humanised Camelid VHH).
  • variable domain such as a dAb (AKA antibody single variable domain) herein is a VH (eg, comprised by a scFv or a Fab polypeptide chain).
  • VHH eg, comprised by a scFv or a Fab polypeptide chain
  • humanised VH, humanised VHH or a human VH eg, comprised by a scFv or a Fab polypeptide chain
  • VL eg, comprised by a scFv or a Fab polypeptide chain
  • it is a V ⁇ .
  • V ⁇ a V ⁇ .
  • each polypeptide of the multimer is paired with a copy of a further polypeptide, wherein the further polypeptide comprises an antibody light chain constant region (eg, a C ⁇ or a C ⁇ ) that pairs with the Fc of the first polypeptide.
  • the first polypeptide comprises an antibody VH domain
  • the further polypeptide comprises an antibody VL domain (eg, a V ⁇ or a V ⁇ ), wherein the VH and VL form an epitope binding site.
  • the multimer may be a multimer of Fab-like structures, such as comprising multiple copies of an adalimumab (Humira) or avelumab (Bavencio) binding site as exemplified in the Examples below. All of the antibody domains in such a multimer may, for example, be human, and optionally the SAM is a human domain.
  • the SAM is a TD (eg a p53 TD)
  • the multimer comprises a tetramer of the VH/VL epitope binding sites.
  • the first polypeptide or the further polypetide may comprise a second epitope binding site, for example, wherein the multimer is octavalent.
  • the multimer may be octavalent and bispecific. If the first or further polypetide comprises yet another antigen binding site, the multimer may be 12-valent (and, eg, monospecific, bispecific or trispecific for antigen binding). If the first or further polypetide comprises yet another antigen binding site, the multimer may be 16-valent (and, eg, monospecific, bispecific, trispecific or tetraspecific for antigen binding).
  • the invention further provides:- A multimer (optionally a tetramer) of a polypeptide according to the invention; optionally wherein the multimer is for medical use.
  • the medical use herein is the treatment or prevention of a cancer, autoimmune disease or condition or any other disease or condition disclosed herein.
  • each polypeptide comprises an epitope binding domain or site as disclosed herein.
  • a pharmaceutical composition comprising the polypeptide or multimer of the invention.
  • a nucleic acid encoding a polypeptide of the invention optionally wherein the nucleic acid is comprised by a eukaryotic cell or a vector.
  • a method of binding multiple copies of an antigen the method comprising combining the copies with a multimer of or the composition of the invention, wherein the copies are bound by polypeptides of the multimer, and optionally the method comprising isolating the multimer bound to the antigen copies.
  • the multimer is contacted with a sample comprising the copies of the antigen and copies of the antigen are sequestered in the sample by binding to the multimer.
  • the multimer is administered to a human or animal patient (or an environment is exposed to the multimer) and antigen copies are sequestered in the human (eg, for said medical use), animal (eg, for said medical use) or environment.
  • the environment is comprised by a soil, water source, waterway or industrial fluid, eg, for environmental remediation, such as where the antigen is comprised by an environmental pollutant or contaminant.
  • the method is for purifying the sample or for isolating antigen comprised by the sample.
  • a method of treating or reducing the risk of a disease or condition in a human or animal subject comprising administering the composition of the invention to the subject, wherein multimers comprised by the composition specifically bind to a target antigen in the subject, wherein said binding mediates the treatment or reduction in risk of the disease or condition.
  • a method of producing a composition comprising a plurality of polypeptides according to the invention, wherein the SAM is a self-associating tetramerisation domain (TD), the method comprising providing eukaryotic host cells according to the invention, culturing the host cells, and allowing expression and secretion from the cells of tetramers of the polypeptides, and optionally isolating or purifying the tetramers.
  • TD self-associating tetramerisation domain
  • PARAGRAPHS The invention provides the following Paragraphs. The following Paragraphs are not to be interpreted as Claims. The Claims start after the Examples section. 1. A polypeptide (optionally according any polypeptide herein) comprising (a) An antibody Fc region, wherein the Fc region comprises an antibody CH2 domain and an antibody CH3 domain; and (b) A self-associating multimerisation domain (SAM); wherein the CH2 is devoid of a core hinge CXXC amino acid sequence, wherein X is any amino acid. 2. The polypeptide of Paragraph 1, wherein each amino acid X is selected from a P, R and S. 3. The polypeptide of Paragraph 1 or 2, wherein the CH2 is devoid of a complete upper hinge sequence.
  • the CH2 comprises (a) an APELLGGPSV amino acid sequence, or an PAPELLGGPSV amino acid sequence; (b) an APPVAGPSV amino acid sequence, or an PAPPVAGPSV amino acid sequence; or (c) an APEFLGGPSV amino acid sequence, or an PAPEFLGGPSV amino acid sequence.
  • the CH2 and CH3 are (a) human IgG1 CH2 and CH3 domains; (b) human IgG2 CH2 and CH3 domains; (c) human IgG3 CH2 and CH3 domains; or (d) human IgG4 CH2 and CH3 domains. 6.
  • the CH2 comprises (a) an APELLGGPSV amino acid sequence; (b) an EPKSCDKTHT[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional; (c) an APPVAGPSV amino acid sequence; (d) an ERKCCVE[P]APPVAGPSV amino acid sequence, wherein the bracketed P is optional; (e) an ELKTPLGDTTHT[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional; (f) an EPKSCDTPPP[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional; or (g) an APEFLGGPSV amino acid sequence; or (h) an ESKYGPP[P]APEFLGGPSV amino acid sequence, wherein the bracketed P is optional.
  • polypeptide of any preceding Paragraph wherein the CH2 is devoid of a sequence selected from CXXC disclosed herein and SEQ IDs: 1*180-1*182.
  • polypeptide comprises an antibody variable domain that is capable of specifically binding to a first epitope.
  • the variable domain selected from an antibody single variable domain, a VH and a VL; or wherein the domain is comprised by an scFv.
  • the Fc region is 3’ of the SAM. 12.
  • the polypeptide of Paragraph 12 comprising a second variable domain 5’ or 3’ of the SAM, wherein the second variable domain is capable of specifically binding to a second epitope, wherein the first and second epitopes are identical or different. 14.
  • the polypeptide of paragraph 13 wherein the epitopes are different epitopes of the same antigen, or are epitopes of different antigens.
  • the polypeptide of Paragraph 13 or 14 wherein the second variable domain is selected from an antibody single variable domain, a VH and a VL; or wherein the domain is comprised by an scFv. 16.
  • the SAM is a self-associating tetramerisation domain (TD). 18.
  • the polypeptide of Paragraph 17 wherein the TD is a p53, p63 or p73 TD or a homologue or orthologue thereof; or wherein the TD is a NHR2 TD or a homologue or orthologue thereof. 19.
  • 20. The polypeptide of any preceding Paragraph, comprising an antibody CH1 constant domain, optionally a CH1-CH2-CH3, wherein the CH2 and CH3 are comprised by said Fc region. 21.
  • polypeptide comprises or consists of (in N- to C-terminal direction);
  • A. A first antibody single variable domain (dAb), an optional linker and said SAM;
  • B. A first antibody single variable domain, an optional linker, said SAM and a second antibody single variable domain;
  • C. A first scFv, an optional linker and said SAM;
  • D. A first scFv, an optional linker, said SAM and a second scFv;
  • E A first antibody single variable domain, an optional linker, said SAM and a first scFv;
  • F. A first scFv, an optional linker, said SAM and a first antibody single variable domain;
  • a dAb and the self-associating multimersiation domain SAM
  • the polypeptide comprises (in C- to N-terminal direction);
  • A. A dAb and a self-associating multimersiation domain (SAM);
  • F A first dAb, the Fc region and the SAM
  • G A first scFv, the Fc region and the SAM
  • H A VH, a CH1, the Fc regionand the SAM
  • I A VL, a CL, the Fc region and the SAM
  • J A dAb
  • K A scFv; the SAM and the Fc region
  • M A VL, a CL, the SAM and the Fc region
  • N A first dAb, a second dAb and the SAM
  • O A first dAb, a second dAb and the SAM
  • X. A first dAb, a second dAb, the Fc region and the SAM;
  • Y. A first dAb, a second dAb, the Fc region, the SAM and a third dAb;
  • Z. A first dAb, a second dAb, the Fc region, the SAM and a first scFv; or AA.
  • 30. The polypeptide of any one of Paragraphs 21 to 29, wherein the first or each linker is a (G 4 S) n linker, wherein n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • a pharmaceutical composition comprising the polypeptide or multimer of any preceding Paragraph. 42.
  • 43. A eukaryotic cell or vector comprising the nucleic acid of Paragraph 42. 44.
  • a method of binding multiple copies of an antigen comprising combining the copies with a multimer of any one of Paragraphs 33 to 40, wherein the copies are bound by polypeptides of the multimer, and optionally the method comprising isolating the multimer bound to the antigen copies.
  • the method is a diagnostic method for detecting the presence of a substance in a sample, wherein the substance comprises the antigen, the method comprising providing the sample (eg, a bodily fluid, food, food ingredient, beverage, beverage ingredient, soil or forensic sample), mixing the sample with multimers according to any one of Paragraphs 33 to 40 and detecting the binding of multimers to the antigen in the sample. 46.
  • a method of treating or reducing the risk of a disease or condition in a human or animal subject comprising administering the composition of Paragraph 41 to the subject, wherein multimers comprised by the composition specifically bind to a target antigen in the subject, wherein said binding mediates the treatment or reduction in risk.
  • the antigen is an immune checkpoint antigen (eg, PD- L1, PD-1 or CTLA4); or wherein the antigen is TNF alpha or IL-17A.
  • the antigen mediates the disease or condition in the subject; and optionally wherein the binding antagonises the antigen.
  • a composition comprising a plurality of polypeptides according to any one of Paragraphs 1 to 32 and 38 to 40, wherein at least 90% of the polypeptides are comprised by tetramers of said polypeptides. 50. The composition of Paragraph 49, wherein at least 98% of the polypeptides are comprised by tetramers of said polypeptides. 51. The composition of Paragraph 49 or 50, wherein the remaining polypeptides are selected from one or more of polypeptide monomers, dimers and trimers. 52.
  • a method of producing a composition (optionally a composition according to any one of Paragraphs 49 to 51) comprising a plurality of polypeptides according to any one of Paragraphs 1 to 32 and 38 to 40, the method comprising providing eukaryotic host cells according to Paragraph 34, culturing the host cells, and allowing expression and secretion from the cells of tetramers of the polypeptides, and optionally isolating or purifying the tetramers.
  • CONCEPTS In certain embodiments, the invention is useful for providing multimers for treating cancer in humans or animals. In this respect, it may be useful to use the multimers to target tumours by binding to tumour-associated antigen and/or to bind to T-cells to modulate their activity.
  • the multimers may bind to an antigen on T regulatory cells (Tregs) to downregulate their activity. Additionally or alternatively, the multimers may bind to T effector (Teff) cells to upregulate their activity.
  • T regulatory cells Tregs
  • Teff T effector
  • the provision of an antibody Fc region in the polypeptides of multimers may be advantageous for providing Fc effector functions and/or cytotoxicity for killing tumour cells.
  • the invention exploits the ability to provide multiple identical antigen or epitope binding sites that can be used to bind to several copies of the same antigen or epitope on tumour cells, thereby providing for an avidity affect wherein the multimers bind preferentially to tumour cells over any non-target or normal cells, since the former surface-express more copies of the antigen than normal cells.
  • the multimer also comprises binding sites for an immune checkpoint regulator.
  • the regulator is an immune checkpoint inhibitor and the binding sites antagonise the inhibitor. This is useful, for example when the inhibitor is expressed by Teff cells, for upregulating Teff activity in the vicinity of tumour cells that are targeted by the multimer (eg, by binding TAA on the tumour cells).
  • the regulator is an immune checkpoint stimulator and the binding sites agonise the inhibitor. This is useful, for example when the inhibitor is expressed by Teff cells, for upregulating Teff activity in the vicinity of tumour cells that are targeted by the multimer (eg, by binding TAA on the tumour cells).
  • T-cell activity may be stimulated in the vicinity of tumour cells, rather in the vicinity of non-target (eg, normal or non-cancerous) cells.
  • the invention provides the following Concepts. The following Concepts are not to be interpreted as Claims. The Claims start after the Examples section. 1.
  • a polypeptide comprising a self-associating multimerisation domain (SAM), a first antigen binding site and a second antigen binding site, wherein the first site specifically binds to a first antigen or epitope, and the second binding site specifically binds to a second antigen or epitope, wherein each antigen or epitope is a tumour-associated antigen (TAA) or epitope, or an immune checkpoint regulator (eg, inhibitor) antigen or epitope.
  • TAA tumour-associated antigen
  • an immune checkpoint regulator eg, inhibitor
  • the polypeptide of Concept 1 wherein the first antigen is an immune checkpoint inhibitor and the second antigen is an immune checkpoint regulator (eg, inhibitor). 5. The polypeptide of Concept 3 or 4, wherein the binding sites are capable of specifically binding to the same epitope of the same antigen. 6. The polypeptide of Concept 3 or 4, wherein the binding sites are capable of specifically binding to different epitopes of the same antigen. 7.
  • the first antigen is selected from 4-1BB, 4-1BBL, CD28, OX40, OX40L, ICOS, ICOSL, GITR, CD40, CD27, CD27L, CD40L, LIGHT, CD70, CD80, CD86, HER2, HER3, PSMA, WT1, MUC1, LMP2, EGFRvIII, MAGE A3, GD2, CEA, Melan a/MART1, Bcr-Abl, Survivin, PSA, hTERT, EphA2, PAP, EpCAM, ERG, PAX3, ALK, Androgen receptor, Cyclin B1, RhoC, GD3, PSCA, PAX5, LCK, VEGFR2, MAD CT-1, FAP, MAD CT-2, PDGFR-beta, Fos related antigen 1, NY-BR-1, ETV6-AML, RGS5, SART3, SSX2, XAGE-1, STn, PAP and BCMA.
  • the second antigen is selected from PDL1, PD1, CTLA4, BTLA, KIR, LAG3, TIM3, A2aR, HVEM, GAL9, VISTA, SIRPa, CD47, CD160, CD155, IDO, CEACAM1, 2B4, CD48 and TIGIT.
  • the polypeptide comprises a third antigen binding site that is capable of specifically binding to a third antigen or epitope.
  • the third antigen is a TAA.
  • the third antigen is an immune checkpoint regulator (eg, inhibitor). 12.
  • the polypeptide of Concept 14, wherein the fourth antigen is a TAA.
  • the fourth antigen is an immune checkpoint regulator (eg, inhibitor). 17.
  • said first dAb or first scFv of the polypeptide herein is the first antigen binding site of these Concepts; and optionally when a further dAb or scFv binding site is present this is the second antigen binding site of the Concepts.
  • said first dAb or first scFv of the polypeptide herein is the second antigen binding site of these Concepts; and optionally when a further dAb or scFv binding site is present this is the first antigen binding site of the Concepts. 18.
  • the multimer of Concept 18 for administration to a human or animal subject for targeting of an immune checkpoint inhibitor and an immune co-stimulatory molecule for the treatment of cancer.
  • 20 A method of treating a cancer in a human or animal subject, the method comprising administering the multimer of claim 18 to the subject.
  • CLAUSES In a configuration, the invention provides the following Clauses. The following Clauses are not to be interpreted as Claims. The Claims start after the Examples section. 1.
  • TDs self-associating tetramerisation domains
  • each polypeptide comprises first and second copies of said protein domain or peptide, wherein the polypeptide comprises in (N- to C-terminal direction) (i) a first of said copies – TD – the second of said copies; (ii) TD – and the first and second copies; or (iii) said first and second copies – TD. 6.
  • the TDs are NHR2 TDs and the domain or peptide is not a NHR2 domain or peptide; or wherein the TDs are p53 TDs and the domain or peptide is not a p53 domain or peptide. 7.
  • the engineered polypeptide comprises one or more copies of a second type of protein domain or peptide, wherein the second type of protein domain or peptide is different from the first protein domain or peptide.
  • the domains are immunoglobulin superfamily domains.
  • the domain or peptide is an antibody variable or constant domain, a TCR variable or constant domain, an incretin, an insulin peptide, or a hormone peptide. 10.
  • the multimer comprises first, second, third and fourth identical copies of a said engineered polypeptide, the polypeptide comprising a TD and one (but no more than one), two (but no more than two) or more copies of the said protein domain or peptide.
  • the engineered polypeptide comprises an antibody or TCR variable domain (V1) and a NHR2 TD. 12.
  • each engineered polypeptide comprises (in N- to C- terminal direction) V1-an optional linker- TD, wherein V1 is an antibody or TCR variable domain and each engineered polypeptide is paired with a respective second engineered polypeptide that comprises V2, wherein V2 is a an antibody or TCR variable domain respectively that pairs with V1 to form an antigen or pMHC binding site, and optionally one polypeptide comprises an antibody Fc, or comprises antibody CH1 and the other polypeptide comprises an antibody CL that pairs with the CH1.
  • the TD comprises (i) an amino acid sequence identical to SEQ ID: 1*10 or 1*126 or at least 80% identical thereto; or (ii) an amino acid sequence identical to SEQ ID: 1*120 or 1*123 or at least 80% identical thereto. 16.
  • the multimer comprises a tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer or an octamer) of an antigen binding site of an antibody selected from the group consisting of ReoProTM; Abciximab; RituxanTM; Rituximab; ZenapaxTM; Daclizumab; SimulectTM; Basiliximab; SynagisTM; Palivizumab; RemicadeTM; Infliximab; HerceptinTM; MylotargTM; Gemtuzumab; CampathTM; Alemtuzumab; ZevalinTM; Ibritumomab; HumiraTM; Adalimumab; XolairTM; Omalizumab; BexxarTM; Tositumomab; RaptivaTM; Efalizumab; ErbituxTM; Cetuximab; A
  • the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer or an octamer) of any preceding Clause, wherein the mulitmer, tetramer, octamer, dodecamer, hexadecamer or 20-mer is (a) soluble in aqueous solution; (b) secretable from a eukaryotic cell; and/or (c) an expression product of a eukaryotic cell. 19.
  • a tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer or an octamer) of (a) TCR V domains or TCR binding sites, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is soluble in aqueous solution; (b) antibody single variable domains, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is soluble in aqueous solution; (c) TCR V domains or TCR binding sites, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is capable of being intracellularly and/or extracellularly expressed by HEK293 cells; or (d) antibody variable domains, wherein the tetramer, octamer, dodecamer,
  • a pharmaceutical composition comprising the multimer(s), tetramer(s), octamer(s), dodecamer(s), hexadecamer(s) or 20-mer(s) (eg, tetramer(s) or octamer(s)) of any preceding Clause and a pharmaceutically acceptable carrier, diluent or excipient.
  • a cosmetic, foodstuff, beverage, cleaning product, detergent comprising the multimer(s), tetramer(s), octamer(s), dodecamer(s), hexadecamer(s) or 20-mer(s) (eg, tetramer(s) or octamer(s)) of any one of Clauses 1 to 24.
  • An engineered (and optionally isolated) polypeptide (P1) which comprises (in N- to C- terminal direction):- (a) TCR V1 –TCR C1 – antibody CH1 – optional linker – TD, wherein (i)V1 is a V ⁇ and C1 is a C ⁇ ; (ii)V1 is a V ⁇ and C1 is a C ⁇ ; (iii)V1 is a V ⁇ and C1 is a C ⁇ ; or (iv) V1 is a V ⁇ and C1 is a C ⁇ ; or (b) TCR V1 – antibody CH1– optional linker – TD, wherein (i)V1 is a V ⁇ ; (ii)V1 is a V ⁇ ; (iii)V1 is a V ⁇ ; or (iv) V1 is a V ⁇ ; or (c) antibody V1 – antibody CH1– optional linker – TD, wherein (i)V1 is a VH; or (ii)V1
  • a eukaryotic host cell comprising the nucleic acid or vector of Clause 31 for intracellular and/or secreted expression of the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer, octamer), engineered polypeptide or monomer of any one of Clauses 1 to 24.
  • a nucleic acid or vector according to Clause 31 in a method of manufacture of protein multimers for producing intracellularly expressed and/or secreted multimers, wherein the method comprises expressing the multimers in and/or secreting the multimers from eukaryotic cells comprising the nucleic acid or vector.
  • a mixture comprising (i) a eukaryotic cell line encoding an engineered polypeptide according to any one of Clauses 27 to 29; and (ii) multimers, tetramers, octamers, dodecamers, hexadecamers or 20-mers (eg, tetramers or octamers)as defined in any one of Clauses 1 to 24. 36.
  • the secretion products comprise said multimers, tetramers, octamers, dodecamers, hexadecamers or 20-mers (eg, tetramers or octamers). 37.
  • a method producing (a) TCR V domain multimers, the method comprising the soluble and/or intracellular expression of TCR V-NHR2 TD or TCR V- p53 TD fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers; (b) antibody V domain multimers, the method comprising the soluble and/or intracellular expression of antibody V -NHR2 TD or V- p53 TD fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers; (c) incretin peptide multimers, the method comprising the soluble and/or intracellular expression of incretin peptide-NHR2 TD or incretin peptide-p53 TD fusion proteins expressed in eukaryotic cells, such as HEK293T cells; the method optionally comprising isolating a plurality of said multimers; or (d) peptide hormone multimers, the method comprising
  • TD self-associating tetramerisation domains
  • TD self-associating tetramerisation domains
  • any one of Clauses 39 to 42 wherein the yield of tetramers is at least 10x the yield of monomers and/or dimers.
  • the use of any one of Clauses 39 to 43, wherein the ratio of tetramers produced : monomers and/or dimers produced in the method is at least 90:10.
  • any one of Clauses 39 to 46, wherein the method comprises expressing the tetramers from a eukaryotic cell line.
  • a multivalent heterodimeric soluble T cell receptor capable of binding pMHC complex comprising: (a) TCR extracellular domains; (b) immunoglobulin constant domains; and (c) an NHR2 multimerisation domain of ETO.
  • a multimeric immunoglobulin comprising (i) immunoglobulin variable domains; and (ii) an NHR2 multimerisation domain of ETO. 50.
  • a method for assembling a soluble, multimeric polypeptide comprising: (a) providing a monomer of the said multimeric polypeptide, fused to an NHR2 domain of ETO; and (b) causing multiple copies of said monomer to associate, thereby obtaining a multimeric, soluble polypeptide.
  • the or each constant region or domain, the CH2, the CH3, the CH2 and CH3 or the Fc is respectively a constant region or domain, the CH2, the CH3, the CH2 and CH3 or the Fc of a human constant region.
  • the constant region is selected from the group IGHA1*01, IGHA1*02, IGHA1*03, IGHA2*01, IGHA2*02, IGHA2*03, IGHD*01, IGHD*02, IGHE*01, IGHE*02, IGHE*03, IGHE*04, IGHEP1*01, IGHEP1*02, IGHEP1*03, IGHEP1*04, IGHG1*01, IGHG1*02, IGHG1*03, IGHG1*04, IGHG1*05, IGHG1*06, IGHG1*07, IGHG1*08, IGHG1*09, IGHG1*10, IGHG1*11, IGHG1*12, IGHG1*13, IGHG1*14, IGHG2*01, IGHG2*02, IGHG2*03, IGHG2*04, IGHG2*05, IGHG2*01,
  • the constant region is a non-human (eg, mammal, rodent, mouse, rat, dog, cat or horse) constant region, such as a homologue of a human constant region listed in said group.
  • the polypeptide comprises (in N- to C-terminal direction) a first antigen binding site (eg, a dAb), an antibody CH1 (eg, human IgG1 CH1), a hinge sequence comprising a lower hinge and devoid of a core hinge region (and optionally devoid of an upper hinge region), an antibody Fc region and a SAM (eg, a TD, such as a p53 TD).
  • a first antigen binding site eg, a dAb
  • an antibody CH1 eg, human IgG1 CH1
  • a hinge sequence comprising a lower hinge and devoid of a core hinge region (and optionally devoid of an upper hinge region)
  • an antibody Fc region eg, a TD, such as a p53
  • the core hinge region sequence is a CXXC amino acid sequence.
  • the polypeptide may comprise another antigen binding site (eg a dAb or scFv) between the first binding site and the CH1, between the Fc and SAM and/or C- terminal to the SAM.
  • the multimer comprises a plurality (eg, 4 copies) of such polypeptide, for example wherein each polypeptide is paired with a further polypeptide comprising (in N- to C-terminal direction) a second antigen binding site (eg, a dAb), an antibody CL (eg, a human C ⁇ ) and optionally a third antigen binding site.
  • the binding sites have the same antigen specificity (eg, all bind TNF alpha).
  • the first and second (and optionally said another binding site) bind to different antigens.
  • the or each binding site can bind any antigen disclosed herein, eg, each binding site binds TNF alpha (as shown in Example 17).
  • the first antigen binding site is a VH of an antigen binding site of a predetermined antibody that specifically binds to the antigen (and the CH1 is optionally the CH1 of the antibody), and the second binding site of the further polypeptide is a VL of the antigen binding site of the predetermined antibody (and the CL is optionally the CL of the antibody), wherein the VH and VL pair to form a VH/VL binding site which has binding specificity for the antigen.
  • the predetermined antibody may be a marketed antibody, for example, as shown in Example 19.
  • the VH/VL binding site specifically binds to CTLA-4, eg, wherein the predetermined antibody is ipilimumab (or YervoyTM).
  • the VH/VL binding site specifically binds to TNF alpha, eg, wherein the predetermined antibody is adalimumab, golimumab, infliximab (or HumiraTM, SimponiTM or RemicadeTM).
  • the VH/VL binding site specifically binds to PD-L1, eg, wherein the predetermined antibody is avelumab (or BavencioTM) or atezolizumab (or TecentriqTM).
  • the VH/VL binding site specifically binds to PD-1, eg, wherein the predetermined antibody is nivolumab (or OpdivoTM) or pembrolizumab (or KeytrudaTM).
  • the VH/VL binding site specifically binds to VEGF, eg, wherein the predetermined antibody is bevacizumab (or AvastinTM) or ranibizumab (or LucentisTM).
  • the polypeptide comprises (in N- to C-terminal direction) a first VEGF binding site, an optional second VEGF binding site, an antibody CH1 (eg, human IgG1 CH1), a hinge sequence comprising a lower hinge and devoid of a core hinge region (and optionally devoid of an upper hinge region), an antibody Fc region and a SAM (eg, a TD, such as a p53 TD).
  • the first binding site is a Ig domain 2 from VEGFR1 and the second binding site is Ig domain 3 from VEGFR2 (as shown in Example 20).
  • the first binding site is a Ig domain 3 from VEGFR2 and the second binding site is Ig domain 2 from VEGFR2.
  • the first and second binding domains are (in N- to C-terminal direction) the first and second VEGF binding sites of aflibercept (or EyleaTM).
  • Suitable predetermined antibodies are ReoProTM; Abciximab; RituxanhTM; Rituximab; ZenapaxhTM; Daclizumab; SimulecthTM; Basiliximab; SynagisTM; Palivizumab; RemicadehTM; Infliximab; HerceptinhTM; Trastuzumab; MylotarghTM; Gemtuzumab; CampathhTM; Alemtuzumab; ZevalinhTM; Ibritumomab; HumirahTM; Adalimumab; XolairTM; Omalizumab; BexxarhTM; Tositumomab; RaptivahTM; Efalizumab; ErbituxhTM; Cetuximab; Avastinh
  • the multimer of the invention comprises a plurality (eg, 4, 8, 12, 16 or 20) copies of the VH/VL antigen binding site of any of these antibodies, eg, wherein the VH of the binding site is comprised by a polypeptide of the invention that comprises a SAM (eg, a TD) and each polypeptide is paired with a further polypeptide comprising the VL that pairs with the VH, thus forming an antigen binding site.
  • a polypeptide of the invention that comprises a SAM (eg, a TD) and each polypeptide is paired with a further polypeptide comprising the VL that pairs with the VH, thus forming an antigen binding site.
  • SAM eg, a TD
  • the polypeptide comprising the SAM also comprises a CH1 which pairs with a CL of the further polypeptide.
  • the binding site of the polypeptide of the multimer comprises a VH of the binding site of the antibody and also the CH1 of the antibody (ie, in N- to C-terminal direction the VH-CH1 and SAM).
  • the polypeptide may be paired with a further polypeptide comprising (in N- to C-terminal direction a VL-CL, eg, wherein the CL is the CL of the antibody).
  • the predetermined antibody is Avastin.
  • the predetermined antibody is Actemra.
  • the predetermined antibody is Erbitux. [00298] In one embodiment, the predetermined antibody is Lucentis. [00299] In one embodiment, the predetermined antibody is sarilumab. [00300] In one embodiment, the predetermined antibody is dupilumab. [00301] In one embodiment, the predetermined antibody is alirocumab. [00302] In one embodiment, the predetermined antibody is evolocumab. [00303] In one embodiment, the predetermined antibody is pembrolizumab. [00304] In one embodiment, the predetermined antibody is nivolumab. [00305] In one embodiment, the predetermined antibody is ipilimumab.
  • the predetermined antibody is remicade. [00307] In one embodiment, the predetermined antibody is golimumab. [00308] In one embodiment, the predetermined antibody is ofatumumab. [00309] In one embodiment, the predetermined antibody is Benlysta. [00310] In one embodiment, the predetermined antibody is Campath. [00311] In one embodiment, the predetermined antibody is rituximab. [00312] In one embodiment, the predetermined antibody is Herceptin. [00313] In one embodiment, the predetermined antibody is durvalumab. [00314] In one embodiment, the predetermined antibody is daratumumab.
  • the core hinge region sequence is a CXXC amino acid sequence.
  • the polypeptide may comprise another antigen binding site (eg a dAb or scFv) between the Fc and SAM and/or C-terminal to the SAM.
  • the multimer comprises a plurality (eg, 4 copies) of such polypeptide.
  • the binding sites have the same antigen specificity (eg, all bind TNF alpha).
  • the first and second (and optionally said another binding site) bind to different antigens.
  • each binding site can bind any antigen disclosed herein, eg, each binding site binds PD-L1, or the first binding site binds PD-L1 and the second binding site binds 41- BB, or the first binding site binds 4-1BB and the second binding site binds PD-L1 (as shown in Example 18).
  • the polypeptide may comprise another antigen binding site (eg a dAb or scFv) C-terminal to the SAM.
  • the multimer comprises a plurality (eg, 4 copies) of such polypeptide, for example wherein each polypeptide is paired with a further polypeptide comprising (in N- to C-terminal direction) a third antigen binding site (eg, a dAb), an optionaly fourth antigen binding site (eg, a dAb), an antibody CL (eg, a human C ⁇ or C ⁇ ) and optionally a furhter antigen binding site.
  • the fourth and further binding sites are omitted.
  • the third and fourth binding sites, but not the further binding site are present.
  • the third and further (but not the fourth) binding sites are present.
  • the binding sites have the same antigen specificity (eg, all bind TNF alpha).
  • the first and second (and optionally said another said binding site) bind to different antigens.
  • the or each binding site can bind any antigen disclosed herein, eg, each binding site binds TNF alpha (as shown in Examples 21 and 22).
  • the first and third, or the second and third binding sites pair to form a VH/VL pair that is identical to the VH/VL binding site of an anti-TNF alpha antibody, such as adalimumab, golimumab, infliximab (or HumiraTM, SimponiTM or RemicadeTM).
  • an anti-PD-L1 antibody such as avelumab (or BavencioTM) or atezolizumab (or TecentriqTM).
  • the first and third, or the second and third binding sites pair to form a VH/VL pair that is identical to the VH/VL binding site of an anti-VEGF antibody, such as bevacizumab (or AvastinTM) or ranibizumab (or LucentisTM).
  • an anti-VEGF antibody such as bevacizumab (or AvastinTM) or ranibizumab (or LucentisTM).
  • Predetermined antibodies as discussed above can be used as the source of the VH/VL pairs.
  • the polypeptide of the invention is any Quad polypeptide disclosed herein, eg, comprising the Quad amino acid shown in any of the Tables herein (eg, any one of SEQ IDs: 1*81- 1*115, 1*151-1*162, 1*190, 1*191, 1*209-1*224 and 1*179) or encoded by any of the Quad nucleotide sequences in any of the Tables herein (eg, Table 9, 14 or 17), or having the structure of a polypeptide shown in Table 8.
  • the SAM may be any SAM disclosed herein, eg, any p53 or homologue TD disclosed in any Table herein (eg, as shown in Table 7 or comprised by a protein in Table 13).
  • amino acid sequences are shown with plural histidines at their C-terminus (eg, “HHHHHH” optionally followed by “..AAA”), such histidines and the optional ..AAA are in one embodiment omitted and the corresponding nucleotides encoding this are omitted from the nucleic acid encoding the amino acid sequence.
  • amino acid sequences are shown with a DYKDDDDK motif (eg, a DYKDDDDKHHHHHH or DYKDDDDKHHHHHH..AAA)
  • a motif is in one embodiment omitted and the corresponding nucleotides encoding this are omitted from the nucleic acid encoding the amino acid sequence.
  • the invention provides configurations in which the polypeptide a self- associating multimerisation domain (SAM, eg, a TD) and a peptide, domain or an epitope or antigen binding site (eg, a dAb or an antibody variable domain).
  • SAM self- associating multimerisation domain
  • the SAM is a TD, such a p53 TD as disclosed herein.
  • the polypeptide comprises (eg, in N- to C-terminal direction) at least an extracellular domain (ECD) of a cell-surface protein that is a receptor for a virus or required for virus activation.
  • ECD extracellular domain
  • the protein poteolytically cleaves and activates a spike glycoprotein of the virus (eg, Coronoavirus or any other virus disclosed herein, such as in Table 19).
  • a spike glycoprotein of the virus eg, Coronoavirus or any other virus disclosed herein, such as in Table 19.
  • the entire cell-surface portion of the receptor is comprised by the polypeptide of the invention.
  • the virus is capable of infecting human cells and the receptor is a cell-surface protein found on human cells (such as lung cells).
  • the virus is capable of infecting non-human animal cells and the receptor is a cell-surface protein found on cells of such animal (such as lung cells).
  • the virus is capable of infecting plant cells and the receptor is a cell-surface protein found on cells of such plant (such as a crop, wheat, corn, barley, tobacco, grass, fruiting plant or tree).
  • a cell-surface protein found on cells of such plant such as a crop, wheat, corn, barley, tobacco, grass, fruiting plant or tree.
  • the invention provides a method of treating a viral infection in a human or animal subject, the method comprising administering a composition comprising a plurality of the multimers to a human or animal subject (eg, intravenously or by inhalation), wherein the subject is suffering from a virus infection and copies of the multimer bind to copies of the virus, thereby reducing the severity of the infection and/or reducing progression of the infection and/or reducing one or more symptoms of the infection (such as a inflammatory response).
  • a composition comprising a plurality of the multimers to a human or animal subject (eg, intravenously or by inhalation), wherein the subject is suffering from a virus infection and copies of the multimer bind to copies of the virus, thereby reducing the severity of the infection and/or reducing progression of the infection and/or reducing one or more symptoms of the infection (such as a inflammatory response).
  • the composition can be used prophylactically; thus the invention provides a method of preventing or reducing the risk of a viral infection or a symptom thereof in a human or animal subject, the method comprising administering a composition comprising a plurality of the multimers to a human or animal subject (eg, intravenously or by inhalation), wherein the subject is at risk of suffering from a virus infection, thereby preventing or reducing the risk of the viral infection and/or preventing or reducing one or more symptoms of the infection (such as a inflammatory response).
  • the virus is a Coronavirus.
  • the virus is a virus selected from Table 19.
  • the virus is a Coronavirus, a MERS-Cov, a SARS-Cov, SARS-Cov-1 or preferably SARS-Cov-2.
  • the receptor may be ACE2.
  • the cell- surface protein is a TMPRSS protein, preferably a TMPRSS2 protein.
  • the polypeptide of the invention in this example comprises an ACE2 extracellular domain and a TMPRSS protein extracellular domain, optionally wherein the domains are human domains and the polypeptides (or multimers according to the invention comprising copies of such a polypeptide) are for treating or preventing a Coronavirus infection in a human.
  • the SAM is a TD, such a p53 TD as disclosed herein.
  • TMPRSS2 protein eg, human TMPRSS2 protein (UniProtKB - O15393 (TMPS2_HUMAN), the sequence with of which with identifier O15393-1 is explicitly incorporated herein for use in the invention and possible inclusion in one or more claims herein).
  • the polypeptide of the invention comprises amino acids of human TMPRSS2 protein from amino acid 106 to 492.
  • the virus is selected from Coronavirus 229E (HCoV-229E), Coronavirus EMC (HCoV-EMC), Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV), and influenza A virus (eg, strains H1N1, H3N2 and H7N9).
  • the polypeptide comprises an angiotensin converting enzyme 2 (ACE2) protein as disclosed in any of US9,561,263; US 8,586,319; or EP2089715, EP2047867, EP2108695, EP2543724, EP2155871, EP2274005, EP3375872, EP2222330, EP2943216, EP2332582 or any US counterpart patent application or patent of any of these that shares a common priority.
  • ACE2 angiotensin converting enzyme 2
  • the peptide or domain of the polypeptide of the invention comprises an ECD of entire ACE2 protein as disclosed in any one of these European and US patents and applications.
  • Each such protein and sequence is also individually and explicitly incorporated herein such that any one of such proteins or sequences can be included in any claim herein as a component of a polypeptide or multimer of the invention.
  • Also explicitly incorporated herein are the uses and medical diseases and conditions disclosed in any of such European and US patents and applications and the polypeptide or multimer or method or use of the present invention may be for treating, preventing or reducing the risk of any of such diseases or conditions and may be included in any claim herein.
  • a polypeptide of the invention may comprises amino acid sequence from an ACE2 protein.
  • polypeptide comprising an amino acid sequence selected from SEQ IDs: 1*229-1*231.
  • polypeptide comprising an amino acid sequence selected from SEQ IDs: 1*229-1*231 with the exception that the polypeptide comprises an alternative SAM other than the p53 TD disclosed in such sequence.
  • the SAM is a p63, p73 or homologue TD as disclosed herein.
  • polypeptide comprising an ACE2 amino acid sequence as comprised by any one of SEQ IDs: 1*229- 1*231.
  • the invention also provides a tetramer of the invention comprising 4 copies of such a polypeptide, as well as a composition of the invention comprising such a tetramer.
  • a multimer or composition may preferably be for use in a method of treating, preventing or reducing the risk of a viral infection (eg, a Coronavirus, or preferably SARS-Cov-2 infection), hypertension or a lung condition (eg, an acute lung injury or inflammation) in a human.
  • a viral infection eg, a Coronavirus, or preferably SARS-Cov-2 infection
  • a lung condition eg, an acute lung injury or inflammation
  • a polypeptide of the invention (eg, for treating or preventing a viral infection, preferably a Coronavirus, a MERS-Cov, a SARS-Cov, SARS-Cov-1 or SARS-Cov-2 infection) comprises the amino acid sequence from amino acid 18 to 615; or from 18 to 656 of SEQ ID NO: 1 disclosed in US9,561,263, which sequences are explicitly incorporated herein by reference for use in the present invention and for possible inclusion in one or more claims herein.
  • the polypeptide comprises the amino acid sequence from amino acid 18 to 615; or from 18 to 656; or from 18 to 740 of SEQ ID NO: 1 disclosed in US9,561,263, but does not comprise any other amino acids from such SEQ ID NO: 1.
  • the polypeptide comprises the amino acid sequence of SEQ ID NO: 2 disclosed in EP2332582, or an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% homologous thereto, which sequences are explicitly and individually incorporated herein by reference for use in the invention and possible inclusion in one or more claims herein.
  • N-glycosylation sites of Asn53, Asn90, Asn103, Asn322, Asn432, Asn546 and Asn690 of SEQ ID NO:1 are sialyzed, eg, as disclosed in US8,568,319, which disclosure of sialyzation is explicitly incorporated herein for use in the invention.
  • the invention instead provides polypeptides, multimers, methods and uses for treating, preventing or reducing the risk of inflammation in the subject (eg, in a human suffering from lung inflammation or at risk of such).
  • the invention instead provides polypeptides, multimers, methods and uses for treating, preventing or reducing the risk of hypertension, heart failure (eg, congestive heart failure or chronic heart failure or acute heart failure), myocardial infarction, atherosclerosis, renal failure or insufficiency, polycystic kidney disease (PKD), or a pulmonary disease.
  • heart failure eg, congestive heart failure or chronic heart failure or acute heart failure
  • myocardial infarction eg., atherosclerosis, renal failure or insufficiency
  • PPD polycystic kidney disease
  • the invention instead provides polypeptides, multimers, methods and uses for treating, preventing or reducing the risk of an acute lung injury (ALI), eg, ARDS (Adult Respiratory Distress Syndrome), SARS (Severe Acute Respiratory Syndrome) or MERS (Middle East Respiratory Syndrome).
  • ALI acute lung injury
  • ARDS Adult Respiratory Distress Syndrome
  • SARS severe Acute Respiratory Syndrome
  • MERS Middle East Respiratory Syndrome
  • the polypeptide of the invention comprises eukaryotic cell, mammalian or human cell glycosylation eg, CHO or HEK293 or Cos cell glycosylation.
  • the invention provides a composition (eg, for medical use as described herein, such as for treating, preventing or reducing the risk of a viral infection) comprising a plurality of polypeptides of the invention, wherein less than 15, 10, 5, 4, 3, 2, or 1% of all the polypeptides are comprised by the group consisting of polypeptide monomers, dimers and trimers. Additionally or alternatively, at least 80, 85, 90, 95, 96, 97, 98 or 99% of all of the polypeptides are comprised by multimers comprising 4 copies of the SAM (eg, p53 TD).
  • a composition eg, for medical use as described herein, such as for treating, preventing or reducing the risk of a viral infection
  • a composition eg, for medical use as described herein, such as for treating, preventing or reducing the risk of a viral infection
  • a composition comprising a plurality of polypeptides of the invention, wherein less than 15, 10, 5, 4, 3, 2, or 1% of all the
  • the invention instead provides polypeptides, multimers, methods and uses for treating, preventing or reducing the risk of hypertension in the subject (eg, in a human suffering from a lung or cardiovascular condition or at risk of such).
  • the polypeptide of the invention comprises one or more binding sites for an antigen comprised by the extracellular part of a cell-surface protein that is a receptor (eg, ACE2 or a homologue or orthologue) for a virus or a protein (eg, TMPRSS2 protein) required for virus activation.
  • binding sites are comprised by the polypeptide or by a multimer of the invention comprising copies of the polypeptide.
  • each binding site is comprised by a dAb, Fv or scFv.
  • the multimer comprises a plurality (eg, 4 and no more and no less than 4) copies of a polypepide of the invention comprising a SAM (eg, a TD) and each polypeptide as paired with a respective copy of a further polypeptide, wherein each polypeptide pair comprises a VH/VL antigen binding site.
  • the binding site specifically binds to a spike glycoprotein of the virus, eg, any virus disclosed herein, preferably a Coronavirus, more preferably SARS-Cov-2. In an example, the binding site binds to 2 or more different Coronaviruses, eg, SARS-Cov-1 and SARS-Cov-2.
  • multimers comprising 4 (and no more or less than 4) copies of a heavy chain polypeptide comprising an amino acid sequence selected from SEQ IDs: 1*225-1*227, wherein each copy is paired with a copy of a polypeptide comprising the amino acid of SEQ ID: 1*228 will bind to a virus, such as a Coronavirus (eg, SAR-Cov-1 and/or SARS-Cov- 2) and preferably SAR-Cov-1 and SARS-Cov-2.
  • a virus such as a Coronavirus (eg, SAR-Cov-1 and/or SARS-Cov- 2) and preferably SAR-Cov-1 and SARS-Cov-2.
  • the binding site is a VH/VL antigen binding site of a SAR-Cov antibody, such as antibody CR3022, CR3006, CR3013 or CR3014 disclosed in PLoS Med.2006 Jul;3(7):e237; “Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants”, ter Meulen J et al and J Virol.2005 Feb; 79(3): 1635–1644; doi: 10.1128/JVI.79.3.1635-1644.2005; PMCID: PMC544131; PMID: 15650189, “Molecular and Biological Characterization of Human Monoclonal Antibodies Binding to the Spike and Nucleocapsid Proteins of Severe Acute Respiratory Syndrome Coronavirus”, Edward N.
  • a SAR-Cov antibody such as antibody CR3022, CR3006, CR3013 or CR3014 disclosed in PLoS Med.2006 Jul;3(7):e237;
  • the polypeptide of the invention comprises a first SAR-Cov antigen binding site and a second SAR-Cov antigen binding site wherein the first site comprises a VH/VL binding site of CR3022 and the second site compriss a VH/VL binding site of an antibody selected from CR3006, CR3013 and CR3014 (eg, CR3022/3014; CR3022/3006; CR3022/3013 or CR3022/3014).
  • the multimer of the invention comprises a first SAR-Cov antigen binding site and a second SAR-Cov antigen binding site wherein the first site comprises a VH/VL binding site of CR3022 and the second site compriss a VH/VL binding site of an antibody selected from CR3006, CR3013 and CR3014 (eg, CR3022/3014; CR3022/3006; CR3022/3013 or CR3022/3014).
  • the polypeptide of the invention comprises one or more binding sites for human TMPRSS2 protein, for example, the polypeptide comprises a binding site for TMPRSS2 protein as disclosed in US20190300625, eg, the VH/VL pair of any anti-TMPRSS2 antibody disclosed in US20190300625, eg wherein the binding site comprises SEQ ID NOs: 17 and 18 disclosed in US20190300625; all of these sequences and binding site disclosures are incorporated herein by reference for use in the present invention and for possible inclusion in one or more claims herein.
  • the polypeptide of the invention comprises one or more binding sites for human IL-6R, for example, the polypeptide comprises the VH/VL pair of sarilumab.
  • the polypeptide of the invention comprises one or more binding sites for human IL-4R, for example, the polypeptide comprises the VH/VL pair of dupilumab.
  • the polypeptide of the invention comprises one or more binding sites for human OX40L or OX40, eg, the VH/VL pair of oxelumab.
  • the multimer of the invention comprises binding sites for human TMPRSS2 protein, for example, the multimer comprises a plurality of copies of a binding site for TMPRSS2 protein as disclosed in US20190300625, eg, the VH/VL pair of any anti-TMPRSS2 antibody disclosed in US20190300625, eg wherein the binding site comprises SEQ ID NOs: 17 and 18 disclosed in US20190300625; all of these sequences and binding site disclosures are incorporated herein by reference for use in the present invention and for possible inclusion in one or more claims herein.
  • the multimer of the invention comprises a plurality of copies of a binding sites for human IL-6R, for example, the VH/VL pair of sarilumab.
  • the multimer of the invention comprises a plurality of copies of a binding sites for human IL-4R, for example, the VH/VL pair of dupilumab.
  • the multimer of the invention comprises binding sites for human OX40L or OX40, eg, a plurality of clpies of the VH/VL pair of oxelumab.
  • generally multimers of the invention may advantageously be cross-reactive to more than one antigen (ie, bind to more than one antigen, such as first and second antigens which are different from each other); or may be capable of binding to an antigen using binding sites of the multimer, wherein the binding site as a monomer or dimer is not capable of binding to the antigen.
  • the binding by the multimer and by the monomer or dimer form are tested under identical conditions (eg, of temperature, pH, time and antigen concentration).
  • the binding site as a monomer or dimer means that one or two copies (but no more than one or two respectively) of the binding site when comprised by a protein are not capable of binding to the antigen (first antigen).
  • the protein is monovalent or bivalent for the antigen.
  • the binding site is a VH/VL binding site of a 4-chain antibody having 2 copies (but no more than 2) of the antigen binding site, wherein the antibody is not capable of binding to the antigen (eg, TACI); optionally the antigen is an antigen that is cognate to a receptor or ligand (eg, APRIL when the antigen is TACI; eg, the antigen is a ligand is cognate to a receptor (or another, second ligand); or the antigen is a receptor and is cognate to a ligand) wherein the receptor or first ligand is capable of binding to a second antigen and the antibody is capable of binding to the second antigen (eg, BCMA when the first antigen is TACI), and wherein a multimer of the invention is capable of binding to the first and second antigens.
  • a receptor or ligand eg, APRIL when the antigen is TACI
  • the first antigen is TACI and the second antigen is BCMA, and the multimer of the invention is capable of binding to TACI and BCMA.
  • the first antigen is a SARS-Cov-2 antigen (eg, spike protein antigen) and the second antigen is a SARS-Cov-1 antigen (eg, spike protein antigen), and optionally the multimer of the invention is capable of binding to the first and second antigens.
  • the first antigen is an antigen (eg, spike protein) of a first virus and the second antigen is an antigen (eg, spike protein) of a second virus, and optionally the multimer of the invention is capable of binding to the first and second antigens.
  • the viruses are different, eg, the viruses are Coronaviruses; eg, the viruses are different strains of influenza viruses.
  • the first and second antigens are HIV antigens (eg, for the treatment or prevention of HIV infection or a symptom thereof); or P. falciparum antigens, such first and second CSP epitopes (eg, for the treatment or prevention of malaria or a symptom thereof); or Salmonella typhimurium antigens (eg, for the treatment or prevention of Salmonella infection or a symptom thereof.
  • a multimer of the invention specifically binds to human BCMA and human TACI, and optionally the multimer comprises a plurality (eg, 4 and no more or less than 4) of a polypeptide of the invention wherein the polypeptide comprises a BCMA binding site as disclosed herein, such as in the next paragraph. Multimers that bind in these ways can be used in any method or use disclosed herein.
  • the invention thus, provides: A method of expanding the antigen binding specificity of a binding site, wherein the binding site binds a first antigen, but not a second antigen (eg, when administered to humans) when the binding site is comprised in monovalent or bivalent form by a protein that specifically binds to the first antigen, the method comprising providing a plurality of copies of a polypeptide of the invention, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens.
  • the invention provides: Use of a polyepeptide of the invention in a method of manufacturing a multimer for expanding the antigen binding specificity of a binding site, wherein the binding site binds a first antigen, but not a second antigen (eg, when administered to humans) when the binding site is comprised in monovalent or bivalent form by a protein that specifically binds to the first antigen, wherein the method comprises providing a plurality of copies of a polypeptide of the invention, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens.
  • the polypeptide comprises a SAM which is a TD, eg, a p53 TD.
  • the polypeptide comprises one (and no more than one) copy of the binding site.
  • the polypeptide comprises two (and no more or less than two) copies of the binding site.
  • the binding site is a VH/VL binding site or a dAb.
  • each antigen is a cell surface receptor or ligand, eg, a human cell surface receptor or ligand.
  • each antigen is a cell surface receptor for a common ligand.
  • a “4-chain antibody”, as the skilled addressee will understand, is a conventional antibody format having 2 copies of a heavy chain and 2 copies of a light chain, wherein each heavy chain is paired with a respective light chain and the heavy chain Fc regions pair to form heavy chain dimers.
  • the invention by providing the ability to create multimers with broadened antigen specificity, provides useful multimers, compositions, methods and uses to target viruses whose antigens evolve through mutation during the natural history of a viral infection.
  • the invention may provide broadly-antigen-neutralising multimers, which can be useful for treatment or prevention of HIV infections, CoV (eg Cov-1 or Cov-2) infections or malaria.
  • the invention may find application to shift antigen-binding specificity of a predetermined binding site against a first antigen so that the multimer additionally or alternatively binds to a second antigen.
  • a predetermined binding site specifically binds to BCMA
  • the multimer of the invention binds to BCMA and TACI.
  • the predetermined binding site is the BCMA binding site of JNJ64007957 (Johnson & Johnson), AMG420 (Amgen), AMG701 (Amgen), CC-93269 (Cellgene), RGN5458, (Regeneron), PF-06863135 (Pfizer), SEA-BCMA (Seattle Genetics), MEDI2228 (AstraZeneca), belantamab (GlaxoSmithKline), idecabtagene vicleucel (Celgene), JNJ-4528 (Johnson & Johnson, Nanjing Legend Biotech), P-BCMA-01 (Poseidon Therapeutics), bb21217 (Bluebird Bio), JCARH125 (Celgene, Juno) or ALLO-715 (Allogene).
  • the binding site is the BCMA binding site of JNJ64007957.
  • the binding site is the BCMA binding site of JNJ-4528.
  • the binding site is the BCMA binding site of RGN5458.
  • the multimer in this paragraph is for treating a cancer, eg, multiple myeloma.
  • the polypeptide of the invention optionally comprises A: one or more epitope binding sites, optionally wherein the binding site binds to (i) a SARS- Cov-2 antigen (eg, a SARS-Cov-1 antigen and a SARS-Cov-2 antigen); (ii) BCMA (B-cell maturation antigen) and TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor); (iii) first and second Coronovirus antigens; (iv) first and second HIV antigens; (v) first and second P falciparum antigens; (vi) first and second Salmonella antigens; (vii) a TMPRSS protein (eg, a TMPRSS2 antigen); or (viii) a ACE2 antigen; or B: one, two or more copies of an ACE2 peptide (eg, an ACE2 extracellular domain) and/or a TM
  • SARS- Cov-2 antigen eg
  • Such a polypeptide may be useful for producing multimers of the invention, and such multimers may be used for any method or use disclosed herein, such as for cancer (eg, multiple myeloma) treatment when the polypepide is according to option A(ii); or for treatment or prevention of a viral (eg, Covidvirus) infection when the polypepide is according to option A ((i), (iii), (vi) or (viii) or option B, C, D or E.
  • cancer eg, multiple myeloma
  • a viral infection eg, Covidvirus
  • the multimer is useful for binding to a first epitope and a second epitope which is a mutant of the first epitope, ie, wherein the second epitope differs from the first epitope by one or more amino acids or one or more sugar residues.
  • the epitopes differ by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids or sugar residues.
  • multimerization of polypeptides described herein may produce multimers that can use the same binding site to bind more than one (eg, 2) different epitopes or antigens.
  • the first epitope is comprised by a first antigen and the second epitope is comprised by a second antigen, eg, the antigens are different receptors (such as cell-surface receptors), or different ligands (such as different forms of spike protein of a virus).
  • the virus is a SARS virus (eg, SARS-Cov, SARS-Cov-2 or MERS-Cov), HIV or influenza virus.
  • the virus is HIV and the epitope is an Env epitope, gp41 epitope or gp120 epitope.
  • the virus is influenza virus and the epitope is an epitope of haemagglutinin or matrix protein 2.
  • the multimer is useful for treating or preventing or reducing a seasonal viral infection in humans or animals.
  • the multimer is useful for treating, preventing or reducing infection by a virus comprising a first form of spike protein
  • the multimer is useful for treating, preventing or reducing infection by a virus comprising a second form of the spike protein.
  • the multimer is useful for treating or preventing viral infection in a first and second season wherein humans are infected in the first season by the virus comprising the first spike form and humans are infected in the second season by the virus comprising the second spike form.
  • the epitope may be a different virus antigen, such as a capsid or tail protein.
  • the multimer therefore, is capable of binding to different strains of a virus and preferably neutralises the virus (eg, renders it non-infective and/or reduces proliferation of the virus).
  • the invention provides a seasonal virus treatment or prophylaxis medicament for administration to a human or animal subject, wherein the medicament comprises a plurality of multimers of the invention, such as multimers according to this paragraph, wherein the medicament comprises a pharmaceutically acceptable diluent, carrier or excipient.
  • diluents, carriers and excipients are well known to the skilled person.
  • the invention therefore provides in an embodiment: a multi-seasonal (eg, 2-seasonal or 3-seasonal) anti-viral medicament comprising a plurality of multimers of the invention which are capable of binding to first and second strains of the virus, wherein the strains differ in a surface-exposed antigen to which the multimers can bind.
  • the seasons are a first year and a second year (eg, two consecutive years or two consecutive winters thereof, or two consecutive summers thereof, or two consecutive springs thereof, or two consecutive falls/autumns thereof).
  • the virus is a SARS virus (eg, SARS-Cov, SARS-Cov-2, MERS-Cov), HIV, ebola virus, zika virus, norovirus, rotovirus, respiratory synctial virus (RSV), an exanthematous virus, papilloma virus, hepatitis (eg, A, B, C, D or E) virus, Lassa fever virus, dengue fever virus, yellow fever virus, Marburg fever virus, Crimean- Congo fever virus, polio virus, viral meningitis virus, viral encephalitis virus, rabies virus, smallpox virus, hantavirus or influenza virus.
  • SARS virus eg, SARS-Cov, SARS-Cov-2, MERS-Cov
  • HIV ebola virus
  • zika virus norovirus
  • rotovirus rotovirus
  • respiratory synctial virus RSV
  • an exanthematous virus papilloma virus
  • hepatitis eg, A
  • the animal may be a livestock animal, such as a pig, poultry (eg, chicken, duck or turkey), sheep, cow, goat, fish or shellfish.
  • the animal is a bat, racoon dog, dog, cat, palm civet or camelid (eg, a camel or dromedary).
  • the animal is a bird.
  • the multimers comprise a plurality (eg, 4, 8, 12, 16 or 20) of copies of a peptide, wherein the peptide comprises an epitope of a pathogen, such as a surface-exposed epitope of a virus or bacterium.
  • the peptide comprises a first and/or second epitope as described in the immediately preceding paragraph.
  • each polypeptide of the multimer comprises a first peptide comprising a first said epitope of the pathogen and a second peptide comprising a second said epitope of the pathogen.
  • the polypeptide comprises 2, 3, 4, 5, 6, 7, 8, 9 or 10 (eg, 2 or 3) said epitopes of the pathogen.
  • the polypeptide comprises 2, 3, 4, 5, 6, 7, 8, 9 or 10 (eg, 2 or 3) different epitopes of the pathogen.
  • the virus is Coronavirus, eg, SARS-Cov, SARS-Cov-2, a SARS-related coronavirus (a SARSr-Cov), HCoV-OC43, HCoV-HKU1, HCoV-NL63, HCoV-229E.
  • the virus is SARS-CoV ZXC21, ZC45, RaTG13, CUHK-W1, Urbani, GZ02, A031, A022, WIV16, WIV1, Rp3, Rs672 or HKU4.
  • the virus is Coronavirus is a group 1, group 2 or group 3 Coronavirus.
  • the multimer is a vaccine antigen composition comprising copies of a polypeptide of the invention.
  • the polypeptide comprises one or more S epitopes of said virus.
  • the polypeptide of the invention comprises a S1 and/or S2 epitope of said virus; or a S A and/or S B epitope of said virus (eg, a SARS-Cov-2 S A and/or S B epitope, preferably SARS-Cov-2 S B epitope).
  • the polypeptide comprises a peptide which comprises all or part of the S A domain and/or all or part of the S B domain.
  • the polypeptide comprises a peptide which comprises all or part of the S B domain and all or part of the S2 subunit, and optionally also the S1/ S2 boundary.
  • the polypeptide comprises a peptide which comprises the virus spike protein S1 subunit/ S2 subunit boundary. Additionally or alternatively, the polypeptide comprises a peptide which comprises the virus spike protein furin cleavage site.
  • the multimer comprises a plurality of binding sites for one or more of the epitopes, wherein the multimer comprises copies of a polypeptide of the invention wherein the polypeptide comprises one or more epitope binding sites, each epitope being an epitope as described in this paragraph.
  • the SARS-Cov epitope comprises one or more N-linked glycans, eg, where each N is an N selected from the following table or is a corresponding N in the virus.
  • the virus is selected from SARS-CoV-2 (YP_009724390.1), SARSr- CoV RaTG13 (QHR63300.2), SARS-CoV Urbani (AAP13441.1), SARS-CoV CUHK-W1 (AAP13567.1), SARS-CoV GZ02 (AAS00003.1), SARS-CoV A031 (AAV97988.1), SARS-CoV A022 (AAV91631.1), WIV-16 (ALK02457.1), WIV-1 (AGZ48828.1), SARSr-CoV ZXC21 (AVP78042.1), SARSr-CoV ZC45 (AVP78031.1), SARSr-CoV Rp3 (Q3I5J5.1), SARSr-CoV Rs672 (ACU31032.1).
  • the pathogen is HIV and the polypeptide comprises a gp120 epitope and a gp41 epitope, eg, the polypeptide comprises a SOSIP peptide.
  • the pathogen is a Coronavirus (eg, SARS-Cov, SARS-Cov-2 or MERS- Cov) and the polypeptide comprises a first spike epitope and a second spike epitope, wherein the epitopes are different from each other.
  • the first epitope and/or second epitope comprises a sugar residue.
  • the first epitope comprises a viral contact residue for ACE2 and/or the second epitope comprises a viral contact reside for TMPRSS2 and optionally the virus is SARS-Cov or SARS-Cov-2.
  • the first epitope comprises a viral contact residue for DPP4 and/or the second epitope comprises a viral contact reside for TMPRSS2 and optionally the virus is MERS-Cov.
  • the pathogen is influenza and the polypeptide comprises one or more haemagglutinin epitopes.
  • any influenza herein is influenza A, B or H1N1.
  • the pathogen is HIV and the polypeptide comprises a plurality of Env epitopes.
  • the pathogen is a virus (eg, a Coronavirus) and the polypeptide comprises a plurality of spike epitopes.
  • the pathogen is a virus and the polypeptide comprises a plurality of capsid or tail epitopes.
  • the virus is a bacteriophage that is capable of infecting a host bacterial cell; or the virus is a virus that is capable of infecting an archaeal cell.
  • the pathogen is a bacterium selected from .
  • Bacillus anthracis Bacillus cereus . Bartonella henselae . Bartonella quintana . Bordetella pertussis . Borrelia burgdorferi . Borrelia garinii . Borrelia afzelii . Borrelia recurrentis . Brucella abortus . Brucella canis . Brucella melitensis . Brucella suis . Campylobacter jejuni . Chlamydia pneumoniae . Chlamydia trachomatis . Chlamydophila psittaci . Clostridium botulinum . Clostridium difficile .
  • Clostridium perfringens Clostridium tetani . Corynebacterium diphtheriae . Enterococcus faecalis . Enterococcus faecium . Escherichia coli . Francisella tularensis . Haemophilus influenzae . Helicobacter pylori . Legionella pneumophila . Leptospira interrogans . Leptospira santarosai . Leptospira wellii . Leptospira noguchii . Listeria monocytogenes . Mycobacterium leprae . Mycobacterium tuberculosis .
  • Mycobacterium ulcerans Mycoplasma pneumoniae . Neisseria gonorrhoeae . Neisseria meningitidis . Pseudomonas aeruginosa . Rickettsia rickettsii . Salmonella typhi . Salmonella typhimurium . Shigella sonnei . Staphylococcus aureus . Staphylococcus epidermidis . Staphylococcus saprophyticus . Streptococcus agalactiae . Streptococcus pneumoniae . Streptococcus pyogenes . Treponema pallidum .
  • the invention provides a protein comprising 4, 12, 16, 20, 24, 28 or 32 copies of an epitope disclosed herein, optionally also comprising 4, 12, 16, 20, 24, 28 or 32 copies of a second second epitope disclosed herein.
  • the protein is useful as a vaccine for treating or preventing an infection of a virus or bacterium in a human or animal subject, wherein the virus or bacterium comprises the epitope(s).
  • the protein is a multimer as disclosed herein, the multimer comprising four copies of a polypeptide, wherein the polypeptide comprises 1, 2, 3, 4, 5, 6, 7, or 8 copies of the first epitope (and optionally comprises 1, 2, 3, 4, 5, 6, 7, or 8 copies of the second epitope).
  • the invention provides a protein comprising 4, 12, 16, 20, 24, 28 or 32 copies of a binding site that is capable of binding to an epitope disclosed herein, optionally also comprising 4, 12, 16, 20, 24, 28 or 32 copies of a second binding site that is capable of binding to a second epitope disclosed herein.
  • the protein is useful as a therapy for treating or preventing an infection of a virus or bacterium in a human or animal subject, wherein the virus or bacterium comprises the epitope(s).
  • the protein is a multimer as disclosed herein, the multimer comprising four copies of a polypeptide, wherein the polypeptide comprises 1, 2, 3, 4, 5, 6, 7, or 8 copies of the first epitope (and optionally comprises 1, 2, 3, 4, 5, 6, 7, or 8 copies of the second epitope).
  • the protein is useful as an assay reagent for detecting a virus of bacterium comprising the epitope(s).
  • a first method of detecting the virus or bacterium in a sample comprising contacting the sample with the protein to allow the protein to bind to one or more copies of the virus or bacterium in the sample, and detecting the binding, eg, using a detection reagent that binds to virus or bacteria that have bound to the protein.
  • a method of detecting antibodies that are capable of binding (and optionally neutralising) the virus or bacterium in a sample comprising contacting the sample with the protein to allow the protein to bind to such antibodies in the sample, and detecting the binding, eg, using a detection reagent that binds to the antibodies that have bound to the protein.
  • the detection reagent may be an anti-virus or bacterium agent (such as a labelled antibody) in the first method; or an anti-antibody (eg, anti-IgG or anti-IgM) agent (such as a labelled antibody) in the second method.
  • the label may, for example, be a fluorescence label, eg, GFP.
  • the sample may be a blood, spit, sputum or cell sample, eg, a patient sample, such as a patient that is suffering from, is suspected of suffering from or has suffered from an infection by the virus or bacterium.
  • the protein or multimer of the invention is immobilised on a solid surface, eg, a petri dish or test tube surface, or a flow chamber surface.
  • the surface is a particle surface, eg, a bead surface, such a magenetic bead, magnetisable bead, metal or ferrous bead.
  • the protein or multimer of the invention is comprised by a fluid, eg, a liquid, eg, a liquid in a droplet, such as an emulsion droplet.
  • a fluid eg, a liquid, eg, a liquid in a droplet, such as an emulsion droplet.
  • the protein or multimer is useful in a microfluidics method of detecting the virus, bacterium or antibody (eg, IgG or IgM that binds the virus or bacterium).
  • the polypeptide comprises one or more (eg, 1, 2, 3 or 4) protein G peptides each of which is capable of binding to IgG, or the protein or multimer comprises a plurality of such polypeptides.
  • Such a multimer or protein is useful to capture IgG when the protein or sample is contacted with a sample (eg, blood, sputum, saliva, semen or cell sample), such as wherein the contacting is carried out in vitro, such as in an in vitro assay.
  • a sample eg, blood, sputum, saliva, semen or cell sample
  • the avidity effect of the multimer’s plurality of protein G peptides is useful to enhance IgG detection sensitivity .
  • the invention therefore, provides such an assay method and a kit comprising the protein or multimer (optionally immobilised on a solid surface, such as on the surface of a container) and a detection reagent.
  • the reagent comprises an antigen or epitope that is bound (eg, specifically bound) by the captured IgG.
  • the epitope is a viral or bacterial epitope, eg, a viral spike, capsid or tail fibre epitope; or eg, a bacterial cell surface epitope.
  • the epitope is a virus spike epitope, eg, a Coronavirus spike epitope, such as a SARS-CoV or SARS-Cov-2 or MERS-CoV spike epitope.
  • the reagent comprises a label that is detectable, such as a fluorescence marker, eg, GFP or an Alexa fluor marker.
  • the polypeptide, multimer or protein comprises one or more protein A peptides that are each capable of binding to an antibody Fc, such as a Fc of an anti-viral or anti-bacterial antibody from a patient sample.
  • the polypeptide, multimer or protein comprises one or more protein L peptides that are each capable of binding to an antibody light chain , such as a light chain of an anti-viral or anti-bacterial antibody from a patient sample (eg, an IgG, IgM, IgA, IgE or IgD antibody).
  • the invention provides any reagent or combination of reagents disclosed in that figure, such as the reagent of any one of A-E or the configuration of reagents disclosed in any one of F to P.
  • the protein or multimer comprises binding sites for ACE2
  • the protein or multimer may be used for treating or preventing hypertension in a human or animal subject.
  • the protein or multimer comprises one or more ACE2 epitopes, wherein the protein or multimer may be used for treating or preventing hypertension in a human or animal subject, such as by administration of the protein or multimer to the subject to raise antibodies against ACE2 in the subject.
  • the treatment or prevention is an inflammatory condition (eg, lung inflammation), pneumonia, COPD, asthma or any treatment or prevention of a condition disclosed in US20110020315A1, the disclosure of which is incorporated herein by reference.
  • the protein or multimer may be used for treating or preventing a cancer (eg, prostate cancer) or viral infection (eg, influenza infection) in a human or animal subject.
  • the protein or multimer comprises one or more TMPRSS2 epitopes, wherein the protein or multimer may be used for treating or preventing a cancer (eg, prostate cancer) or viral infection (eg, influenza infection) in a human or animal subject, such as by administration of the protein or multimer to the subject to raise antibodies against TMPRSS2in the subject.
  • the treatment or prevention is any treatment or prevention of a condition disclosed in US 9,498,529, the disclosure of which is incorporated herein by reference.
  • the inflammation is local inflammation of a tissue or an organ and/or a systemic inflammation.
  • the inflammation comprises sepsis.
  • the inflammation comprises an autoimmune disease.
  • the binding site may be the binding site of antibody 80R, CR3014, CR3006, CR3013 or CR3022.
  • the VH and VL domain sequences of these antibodies are incorporated herein by reference for possible inclusion in a protein or multimer of the invention.
  • the binding site is capable of binding to amino acid residues 426-492, 318-510, or 318-510 of S1 subunit of SARS-CoV, and wherein optionally the protein or multimer binds SARS-CoV and SARS-CoV-2.
  • the protein or multimer herein is for treating or preventing viral pneumonia in a human or animal subject, eg, wherein the subject is suffering from or is at risk of suffering from a Coronavirus infection.
  • the protein or multimer herein is for treating or preventing Coronavirus viral pneumonia in a human or animal subject.
  • the protein or multimer herein is for treating or preventing Coronavirus viral pneumonia in a human or animal subject, wherein the binding sites are capable of binding to a Pseudomonoas aeruginosa epitope, or wherein the protein or multimer comprises Pseudomonoas aeruginosa epitopes.
  • the protein or multimer herein is for treating or preventing a viral infection or symptom thereof in a human or animal subject, wherein the binding sites are capable of binding to a Cathepsin L epitope, or wherein the protein or multimer comprises Cathepsin L epitopes.
  • the virus is Ebola virus or a SARS virus or a Coronavirus (eg, SARS-CoV or SARS- CoV-2).
  • the protein or multimer herein is for treating or preventing a Coronavirus infection or symptom thereof in a human or animal subject
  • the binding sites are capable of binding SARS-CoV S1 RBD or RBDR
  • the protein or multimer comprises SARS-CoV S1 RBD or RBDR.
  • the receptor-binding determining region (RBDR) that recognizes ACE2.
  • the binding sites are capable of binding the peptide S 471–503 of the RBD; or the protein or multimer comprises copies of S 471–503 of the RBD.
  • the protein or multimer herein is for treating or preventing a Coronavirus infection or symptom thereof in a human or animal subject
  • the binding sites are capable of binding SARS-CoV-2 S1 RBD or RBDR
  • the protein or multimer comprises SARS-CoV-2 S1 RBD or RBDR.
  • the receptor-binding determining region (RBDR) that recognizes ACE2.
  • the binding sites are capable of binding the peptide S 471–503 (ALNCYWPLNDYGFYTTTGIGYQPYRVVVLSFEL) (SEQ ID: 1*500) of the RBD; or the protein or multimer comprises copies of S 471–503 of the RBD.
  • the protein or multimer comprises copies of a peptide comprises by the amino acid sequence from position 318 to 536 of SARS-CoV or the equivalent amino acid sequence of SARS-CoV-2, wherein the peptide comprises the amino acid sequence from position 424 to position 494.
  • the peptide is RBD219-N1 (see For example, Chen, W.; Hotez, P.J.; Bottazzi, M.E. Potential for Developing a SARS-CoV Receptor Binding Domain (RBD) Recombinant Protein as a Heterologous Human Vaccine against Coronavirus Infectious Disease (COVID)-19.
  • the protein or multimer of the invention comprises one or more copies of the antigen binding site of an antibody shown in Table 1 or 2 of Chen, W.; Hotez, P.J.; Bottazzi, M.E., “Potential for Developing a SARS-CoV Receptor Binding Domain (RBD) Recombinant Protein as a Heterologous Human Vaccine against Coronavirus Infectious Disease (COVID)-19”, Preprints 2020, 2020020449; or shown in Table 1 or 2 of Asian Pac J Allergy Immunol.2020 Mar;38(1):10-18.
  • RBD SARS-CoV Receptor Binding Domain
  • the protein or multimer comprises copies of a peptide, wherein the peptide comprises (i) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 amino acids corresponding to amino acids selected from 415T, 439N, 449Y, 453Y, 455L, 486F, 487N, 489Y, 493Q, 498Q, 500T, 501N, 502G and 505Y of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), (ii) amino acids corresponding to amino acids 486F, 487N, 489Y, 493Q, 498Q, 500T, 501N, 502G and 505Y of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), (iii) an amino acid corresponding to amino acid 415T of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), or (iv)
  • the protein or multimer comprises copies of a peptide, wherein the peptide comprises (i) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 amino acids corresponding to amino acids selected from 415T, 439R, 449Y, 453Y, 455Y, 486L, 487N, 489Y, 493N, 498Y, 500T, 501T, 502G and 505Y of SARS-CoV (eg, SARS-CoV Urbani), (ii) amino acids corresponding to amino acids 486L, 487N, 489Y, 493N, 498Y, 500T, 501T, 502G and 505Y of SARS-CoV (eg, SARS-CoV Urbani), (iii) an amino acid corresponding to amino acid 415T of SARS-CoV (eg, SARS-CoV Urbani), or (iv) amino acids corresponding to amino acids 439R, 449Y, 453Y, 455Y of SARS-CoV (e)
  • the protein or multimer comprises copies of binding site that binds to a peptide
  • the peptide comprises (i) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 amino acids selected from 415T, 439N, 449Y, 453Y, 455L, 486F, 487N, 489Y, 493Q, 498Q, 500T, 501N, 502G and 505Y of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), (ii) amino acids c 486F, 487N, 489Y, 493Q, 498Q, 500T, 501N, 502G and 505Y of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), (iii) amino acid 415T of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), or (iv) amino acids 439N, 4
  • the protein or multimer comprises copies of a comprises copies of binding site that binds to a peptide
  • the peptide comprises (i) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 amino acids selected from 415T, 439R, 449Y, 453Y, 455Y, 486L, 487N, 489Y, 493N, 498Y, 500T, 501T, 502G and 505Y of SARS-CoV (eg, SARS-CoV Urbani), (ii) amino acids 486L, 487N, 489Y, 493N, 498Y, 500T, 501T, 502G and 505Y of SARS-CoV (eg, SARS-CoV Urbani), (iii) amino acid 415T of SARS-CoV (eg, SARS-CoV Urbani), or (iv) amino acids 439R, 449Y, 453Y, 455Y of SARS-CoV (eg, SARS-CoV Urbani)
  • the binding sites are capable of binding the P6 peptide (EEQAKTFLDKFNHEAEDLFYQSSGLGKGDFR) (SEQ ID: 1*501) of the RBD; or the protein or multimer comprises copies of the P6 peptide (EEQAKTFLDKFNHEAEDLFYQSSGLGKGDFR) of the RBD.
  • the binding site is the antigen binding site of an antibody selected from 80R, m396, F26G19, s230, CR3014, and CR3022.
  • the binding site of the invention may, for example, comprise the VH/VL or scFv of antibody A, B, C, D or E in Fig 3 of this reference, the sequence of which is incorporated herein by reference for use in the invention; and optionally the virus is a Coronavirus, such as SARS-CoV or SARS-CoV-2.
  • the protein or multimer of the invention is for treating or preventing HIV and comprises one or more copies of the antigen binding site of an antibody shown in Table 1 or Fig 4 of Annu. Rev. Immunol.2016.34:635–59, doi: 10.1146/annurev-immunol-041015-055515, “Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design”, Dennis R. Burton and Lars Hangartner; the disclosures of all of which (including the VH and VL sequences of said antibodies) are incorporated herein by reference for use in the invention.
  • the protein or multimer comprises a plurality of (eg, 4, 8, 12, 12, 16, 20, 24, 28 or 32) copies of a peptide disclosed herein, eg, a peptide disclosed in the immediately preceding paragraph.
  • the protein or multimer herein is for treating or preventing a RSV infection or symptom thereof in a human or animal subject, wherein the binding sites are palivizumab binding sites.
  • the binding site of the protein, multimer or polypeptide of the invention disclosed herein comprises a binding site for a peptide or epitope disclosed herein, or for a peptide or epitope whose amino acid sequence is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of a peptide or epitope disclosed herein.
  • the protein, multimer or polypeptide binding site competes (eg, in SPR) with a binding site disclosed in the first sentence of this paragraph.
  • the invention provides a RNA (eg, mRNA or self-amplifying mRNA, or saRNA) that encodes a polypeptide or protein of the invention.
  • a medicament eg, a vaccine
  • the RNA is for administration to a human or animal subject for treating or preventing a disease or condition in the subject, wherein the RNA is expressed in the subject to produce polypeptides, proteins or multimers of the invention.
  • the medicament is a vaccine and the condition is a virial or bacterial infection, such as when the encoded polypeptide comprises an epitope of the virus or bacterium or a binding site that is capable of binding to such an epitope.
  • the polypeptide, protein or multimer can comprise multiple (i.e.2, 3 or 4) different peptides of the target virus or bacterium (eg, peptides of cell-surface proteins) for use as vaccine.
  • a composition comprising first and a second multimer or protein of the invention wherein the multimers/proteins comprise peptides of the target virus or bacterium (eg, peptides of cell-surface proteins) for use as vaccine, wherein the peptides of the first multimer or protein differ from the peptides of the second multimer or protein.
  • the proteins or multimers do not comprise a common such peptide.
  • the second multimer or protein comprises a such peptide that is not comprised by the first protein or multimer.
  • the composition comprises a third protein or multimer which is different from the first and second proteins/multimers, wherein the third protein or multimer comprises a said peptide that is not comprised by the first and second proteins/multimers.
  • the peptide or epitope is not limited to a spike epitope (eg, S1 or S2 subunit epitope); the virus epitope could be from any region of the virus, preferably a region that is exposed on the cell surface of the viral host.
  • Multimerizing virus or bacterial peptides or epitopes according to the invention may advantageously enhance immunogenicity in the subject and thus promote generation of anti-viral/bacterial antibodies that are desirably affinity matured and may give rise to antibodies with a broad epitope coverage (ie, more recognising more than one epitope) of the virus/bacterium.
  • the multimerization also or alternatively can greatly enhance binding strength for an antigen, such as a viral antigen, thereby providing multimer format that are useful for human or animal therapy and for highly sensitive assays, eg, to detect antigen or virus in a sample, such as a serum sample of a subject.
  • highly sensitive assaying is exemplified herein.
  • the invention may render therapeutically- or prophylactically-useful a binding site that has hitherto been useless for therapy of prophylaxis of a disease or condition (eg, infection by a certain virus) in humans or animals.
  • the multimerization of the invention converts binding based on anti-SARS-CoV-2 binding sites from therapeutically- or prophylactically-useless to therapeutically- or prophylactically- useful for administration of the multimer of the invention to a human or animal subject for treating (eg, reducing) or preventing a SARS-CoV-2 infection.
  • the invention enables re-purposing of pre-existing antigen binding sites to provide for possible new applications for treatement, prevention or detection of a disease, condition or infection.
  • the invention provides: A protein multimer (first multimer) comprising more than 2 copies of a binding site, wherein the binding site is capable of binding to a first antigen, optionally wherein the multimer is capable of binding to the first antigen and a second antigen, wherein the antigens are different.
  • the multimer comprises from 4 to 32 (eg, from 4 to 24, or from 4 to 20, or from 4 to 16) copies of the binding site, ie, this means that the multimer does not comprise any more or less than said number.
  • the multimer comprises, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 copies of the binding site.
  • the multimer contains from 4 to 32 (eg, from 4 to 24, or from 4 to 20, or from 4 to 16) copies of the binding site, ie, this means that the multimer does not have any more or less than said number.
  • the multimer contains, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 copies of the binding site.
  • the binding site is any binding site mentioned herein, for example, any VH, VL, VHH, dAb, nanobody, VH/VL pair, sybody or scFv.
  • a control protein multimer comprising 1 or 2 (but no more than 1 or 2 respectively) of said binding sites is not capable of binding to the first antigen; or is capable of binding to the first antigen, but not to the second antigen.
  • Binding may be determined by an ELISA assay, such as by determining OD 450 , for example in an ELISA assay described herein.
  • the first antigen is BCMA and the second antigen is TACI.
  • the antigens are human antigens.
  • the antigens are bacterial, archaeal or fungal antigens.
  • the antigens are different viral antigens, or antigens of first and second viruses which viruses are different from each other, eg, SARS-CoV and SARS-CoV-2.
  • the virus antigens are spike proteins.
  • the virus antigens are nucleocapsid (N) proteins.
  • the virus antigens are envelope (E) proteins.
  • the virus antigens are membrane (M) proteins.
  • the antigens of first and second viruses are different and the viruses are different strains of the same type of virus (eg, SARS-CoV strains; or SARS-CoV-2 strains; or influenza strains).
  • the antigens of first and second viruses are different and the viruses are different types of virus, eg, SARS-CoV and SARS-CoV-2.
  • the invention also provides multimers of binding sites that bind to virus antigens, as expemplified herein.
  • a protein multimer (first multimer) comprising more than 2 copies of a binding site, wherein the binding site is capable of binding to a virus protein (eg, a virus spike, E, M or N protein) of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different. This is exemplified herein for 2 different viruses.
  • the multimer comprises 4 copies of the binding site, wherein the binding site is capable of binding to the virus protein (first virus protein) and a second virus protein which is a mutated version of the first virus protein, wherein the second virus protein is found in a second virus that is infectious to humans.
  • the first and second viruses are SARS viruses or coronaviruses, eg, SARS-CoV-2 viruses.
  • the first protein is a SARS-CoV-2 spike protein comprising the amino acid N501 (ie, asparagine at position 501) and the second protein is a a SARS-CoV-2 spike protein comprising the amino acid Y501 (ie, tyrosine at position 501) or T501.
  • the first protein comprises E484 and the second protein comprises K484; and/or the first protein comprises K417 and the second protein comprises N417 or T417. Additionally or alternatively, compared to the first protein, the second protein comprises deletion ⁇ HV69-70, ⁇ Y144 or ⁇ LLA242- 244.
  • the first protein comprises A222 and the second protein comprises V222; and/or the first protein comprises N439 and the second protein comprises K439; and/or the first protein comprises S477 and the second protein comprises N477; and/or the first protein comprises Y453 and the second protein comprises F453; and/or the first protein comprises F486 and the second protein comprises L486; and/or the first protein comprises G261 and the second protein comprises D261; and/or the first protein comprises V367 and the second protein comprises F367.
  • multimers comprising at least 4 copies of a binding site that binds to SARS-CoV-2 spike protein, such as the RBD (and preferably the inner face of the RBD) are particularly useful as medicaments (or diagnostic agents to idenfity the presence of the virus).
  • a multimer that recognises the epitope recognised by QB-GB binding site is capable of binding to several such mutant forms of SARS-CoV-2 spike and is well suited for administration to patients (or a human population) for treating or preventing SARS-CoV-2 infection, such as where some degree of resistance to mutants occurring during the life history of the virus is desired.
  • each virus is a coronavirus.
  • one of the viruses is SARS-Cov and the other virus is SARS-Cov-2.
  • the first virus is SARS-CoV and the second virus is SARS- Cov-2.
  • the first virus is SARS-CoV-2 and the second virus is SARS-Cov.
  • the multimer comprises 4 copies of the binding site.
  • the multimer comprises 4 (but no more than 4) copies of the binding site.
  • the multimer comprises 8 (but no more than 8) copies of the binding site.
  • the multimer comprises 12 (but no more than 12) copies of the binding site.
  • the multimer comprises 16 (but no more than 16) copies of the binding site.
  • the multimer comprises 20 (but no more than 20) copies of the binding site.
  • the multimer comprises 24 (but no more than 24) copies of the binding site.
  • the multimer comprises 4, 8, 12, 16, 20 or 24 copies of the binding site.
  • (a) the binding of the multimer to the first antigen (or first virus protein) is stronger than the binding of a second multimer (eg, an immunoglobulin, such as an IgG) to the first antigen (or first virus protein), wherein the second multimer comprises 2 (but no more than 2) copies of said binding site; and/or (b) the binding of the multimer to the second antigen (or a protein of the second virus, eg, a spike, E, M or N protein of the second virus) is stronger than the binding of a or said second multimer (eg, an immunoglobulin, such as an IgG) to the second antigen (or second virus protein), wherein the second multimer comprises 2 (but no more than 2) copies of said binding
  • the binding of the multimer to the first virus spike protein is stronger than the binding of a second multimer (eg, an immunoglobulin, such as an IgG) to the first antigen (or first virus spike protein), wherein the second multimer comprises 2 (but no more than 2) copies of said binding site; and/or (b) the binding of the multimer to a spike protein of the second virus is stronger than the binding of a or said second multimer (eg, an immunoglobulin, such as an IgG) to the second virus spike protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site.
  • a second multimer eg, an immunoglobulin, such as an IgG
  • the binding of the multimer to the first virus nucleocapsid (N) protein is stronger than the binding of a second multimer (eg, an immunoglobulin, such as an IgG) to the first virus N protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site; and/or (b) the binding of the multimer to a N protein of the second virus is stronger than the binding of a or said second multimer (eg, an immunoglobulin, such as an IgG) to the second virus N protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site.
  • a second multimer eg, an immunoglobulin, such as an IgG
  • the binding of the multimer to the first virus membrane (M) protein is stronger than the binding of a second multimer (eg, an immunoglobulin, such as an IgG) to the first virus M protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site; and/or (b) the binding of the multimer to a M protein of the second virus is stronger than the binding of a or said second multimer (eg, an immunoglobulin, such as an IgG) to the second virus M protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site.
  • a second multimer eg, an immunoglobulin, such as an IgG
  • binding of the multimer to the first virus envelope (E) protein is stronger than the binding of a second multimer (eg, an immunoglobulin, such as an IgG) to the first virus E protein), wherein the second multimer comprises 2 (but no more than 2) copies of said binding site; and/or (b) the binding of the multimer to a E protein of the second virus is stronger than the binding of a or said second multimer (eg, an immunoglobulin, such as an IgG) to the second virus E protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site.
  • binding or binding strength is determined by ELISA, eg, by determining OD 450 .
  • an ELISA herein may be carried out at room temperature and pressure (rtp), or preferably at 20 or 25 degrees centigrade and 1 atmosphere.
  • the first multimer binds to the first antigen (or first virus protein, eg, spike protein) with an OD 450 from 1 to 3 (such as from 1 to 2 or from 2 to 3) in an ELISA assay in which the first antigen or protein is at a concentration of 1 nM in the assay (and optionally the second multimer binds to the first antigen or protein with an OD 450 less than 0.5 in an ELISA assay in which the antigen or protein is at a concentration of 1 nM in the assay); (b) the first multimer (i) binds to a first virus spike protein trimer with an OD 450 from 2 to 3 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay and (ii) binds to a first virus spike protein monomer
  • the multimer binds according to (a). In an example, the multimer binds according to (b). In an example, the multimer binds according to (c). In an example, the multimer binds according to (a) and (b). In an example, the multimer binds according to (a) and (c). In an example, the multimer binds according to (a), (b) and (c). In an example, the multimer binds according to (b) and (c). These are exemplified herein.
  • Binding of the the first multimer with said OD 450 indicates that the first multimer (ie, multimer of the invention) is useful for medical use, ie, therapy or prophylaxis of a disease or condition in a human or animal subject wherein the disease or condition is mediated by the first antigen (or a pathogen comprising the first antigen).
  • Binding of the the second multimer (eg, IgG having only 2 of said binding sites) with said OD 450 indicates that the second multimer is not useful for medical use or said therapy or prophylaxis.
  • Binding of the the first multimer with said OD 450 indicates that the first multimer (ie, multimer of the invention) is useful for assaying for detecting the presence of the first antigen or antibodies against the first antigen in a bodily fluid sample of a human or animal, eg, a serum, saliva or cell sample obtained from a human or animal, wherein the human or animal (i) is suffering from, has suffered from or is suspected of suffering from a disease or conditionthat is mediated by the first antigen, or (ii) is suffering from, has suffered from or is suspected of suffering from an infection by a pathogen that comprises the first antigen, such as a virus, bacterium or fungus (eg, a yeast).
  • a pathogen that comprises the first antigen such as a virus, bacterium or fungus (eg, a yeast).
  • Binding of the the second multimer (eg, IgG having only 2 of said binding sites) with said OD 450 indicates that the second multimer is not useful for such assaying or detection.
  • an Ig eg, IgG
  • the binding site of the multimer of the invention is an antigen binding site of an Ig (eg, IgG) Fab fragment that binds to the antigen with an affinity (Kd) higher than 0.1, 1, 10, 100 or 1000 mM (eg, higher than 1 or 10 mM).
  • the Ig is said second multimer.
  • the multimer of the invention binds to the antigen with an apparent affinity (avidity) of lower than 0.1 mM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM, 1 pM or 100 fM.
  • affinities are amenable to medical use. Affinities are may be determined by any standard method, for example by surface plasmon resonance (SPR) or ELISA, or bilayer interferometry (eg, as per the example below). The method may be carried out at rtp, or optionally at 20 or 25 degrees centrigrade and 1 atm and optionally at a pH from 6.5 to 7.5 (eg, at pH 7).
  • a multimer of the invention comprising 4 copies of the CR3022 binding site will have a Kd in the low pM range, thereby greatly improving on the apparent affinity and rendering the multimer useful as a medicament.
  • affinity expected to be in the double of single digit pM range or less
  • RBD of the CoV-1 strain.
  • Binding assays may be performed by biolayer interferometry (BLI) using an Octet Red® instrument (FortéBio).
  • His6-tagged antigen eg, S or RBD protein
  • 1x kinetics buffer (1x PBS, pH 7.4, 0.01% BSA and 830.002% Tween 20
  • HIS1K Anti-Penta-HISTM
  • the assay comprises fivesteps: 1) baseline: 60 s with 1x kinetics buffer; 2) loading: 300 s with his6-tagged proteins; 3) baseline: 60 s with 1x kinetics buffer; 4) association: 120 s with samples (Fab or IgG or multimer); and 5) dissociation: 120 s with 1x kinetics buffer.
  • a 1:1 binding model is used for estimating the exact Kd.
  • Example ELISA assay ELISAs are performed in duplicates to compare the binding affinities of the different product formats. Recombinant antigen is diluted to 1 ug/ml in ELISA coating buffer (50 mM carbonate/bicarbonate).
  • detection antibody anti-His-HRP, A7058, Sigma; or anti- Human-IgG HRP, 31410, Thermo Fisher Scientific; or Protein L HRP, M00098, Genscript
  • blocking buffer according to the manufacturers’ recommendations
  • 25 ul of TMB substrate solution is added to each well. The reaction is terminated after ⁇ 15 min by the addition of 25 ul 3 M HCl.
  • the absorbance at 450 nm is read using a CLARIOstarTM microplate reader (BMG Labtech).
  • Example SPR binding assay The SPR is carried out at a detergent level of no greater than 0.05% by volume, eg, in the presence of P20 (polysorbate 20; eg, Tween-20TM) at 0.05% and EDTA at 3 mM.
  • the SPR is carried out at 25° C. or 37° C. in a buffer at pH7.6, 150 mM NaCl, 0.05% detergent (eg, P20) and 3 mM EDTA.
  • the buffer can contain 10 mM Hepes.
  • the SPR is carried out at 25° C. or 37° C. in HBS-EP.
  • HBS-EP is available from Teknova Inc (California; catalogue number H8022).
  • the affinity (eg, of a VH/VL binding site) is determined using SPR by using any standard SPR apparatus, such as by BiacoreTM or using the ProteOn XPR36TM (Bio-Rad®).
  • the binding data can be fitted to 1:1 model inherent using standard techniques, eg, using a model inherent to the ProteOn XPR36TM analysis software.
  • the first multimer binds to the first antigen (or first virus protein, eg, spike protein) with an OD 450 from 1 to 3 (such as from 1 to 2 or from 2 to 3) in an ELISA assay in which the antigen or protein is at a concentration of 1 nM in the assay (and optionally the second multimer binds to the first antigen or protein with an OD 450 less than 0.5 in an ELISA assay in which the antigen or protein is at a concentration of 1 nM in the assay); (b) the first multimer (i) binds to a first virus spike protein trimer with an OD 450 from 2 to 3 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay and (ii) binds to a first virus spike protein monomer with an OD 450 from 1 to 2 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay
  • the multimer binds according to (a). In an example, the multimer binds according to (b). In an example, the multimer binds according to (c). In an example, the multimer binds according to (a) and (b). In an example, the multimer binds according to (a) and (c). In an example, the multimer binds according to (a), (b) and (c). In an example, the multimer binds according to (b) and (c). These are exemplified herein.
  • binding of the first multimer to the first antigen or protein is saturated as determined by OD450 in an ELISA assay in which the antigen or protein is at a concentration between 10 and 100 nM in the assay (and optionally the second multimer binds to the first antigen or protein with an OD 450 less than 2.5 (eg, from 2 to 2.5) in an ELISA assay in which the antigen or protein is at a concentration between 10 and 100 nM in the assay).
  • the first multimer binds to the second antigen (or second virus protein, eg, spike protein) with an OD 450 from 1 to 2 in an ELISA assay in which the second antigen or protein is at a concentration of 1 nM in the assay (and optionally the second multimer binds to the second antigen or protein with an OD 450 less than 0.5 in an ELISA assay in which the antigen or protein is at a concentration of 1 nM in the assay); and/or (b) the first multimer binds to the second antigen (or second virus protein, eg, spike protein) with an OD 450 from 2 to 3 (optionally from 2.5 to 3) in an ELISA assay in which the second antigen or protein is at a concentration of 10 nM in the assay (and optionally the second multimer binds to the second antigen or protein with an OD 450 from 0.5 to 1.5 (eg, 0.5 to 1) in an ELISA assay in
  • binding of the first multimer to the second antigen or protein is saturated as determined by OD 450 in an ELISA assay in which the antigen or protein is at a concentration between 10 and 100 nM in the assay (and optionally the second multimer binds to the second antigen or protein with an OD 450 less than 1.5 (eg, from 1 to 1.5) in an ELISA assay in which the antigen or protein is at a concentration between 10 and 100 nM in the assay).
  • the multimer is capable of detectably binding to antibodies that bind to the first antigen or the second antigen or virus protein (eg, anti-virus protein antibodies, such as anti-SARS- Cov spike antibodies or anti-SARS-Cov-2 spike antibodies or anti-influenza haemagglutinin antibodies) in an ELISA assay, wherein detection of the multimer binding is measured by OD 450 and the assay comprises (a) Optionally diluting a serum sample of a mammal between 100 and 10 6 -fold; (b) Contacting the antigen or protein (eg, SARS-Cov-2 spike protein) with the a serum sample of a mammal (which optionally has been diluted in step (a)) whereby anti-antigen or protein antibodies present in the sample bind to the antigen or protein, wherein the antigen or protein is immobilised on a solid surface; (c) Contacting the bound antibodies with copies of the multimer; and (d) Detecting multimer bound to antibody.
  • anti-virus protein antibodies such
  • ELISA herein may be a sandwich ELISA.
  • the dilution is from 10 to 10 4 , 10 5 or 10 6 -fold.
  • the dilution is from 100 to 10 4 , 10 5 or 10 6 -fold.
  • the dilution is from 1000 to 10 4 , 10 5 or 10 6 -fold.
  • the dilution is 1000 to 1,000,000-fold (such as 1000 to 100,000-fold or 1000 to 10,000-fold).
  • dilution is dilution with water or an aqueous solution, eg, PBS, such as PBS containing from 0.1 to 0.05% (eg, either 0.1% or 0.05%) Tween-20.
  • the spike protein is a trimer of polypeptides.
  • the binding site is an antibody VH/VL pair or an antibody single variable domain (such as a nanobody, VHH or a dAb).
  • the binding site is (a) The spike protein binding site of an antibody selected from CR3022, CR3014, or any other anti-coronavirus antibody disclosed herein (eg, an antibody of Table 21); (b) An ACE2 protein which is capable of binding to the first virus spike protein; or (c) A TMPRSS2 protein which is capable of binding to the first virus spike protein.
  • the binding site comprises or consists of an ACE2 extracellular protein.
  • the ACE2 protein is human ACE2 protein.
  • an extracellular protein of ACE2 having UNIPROT number Q9BYF1 the sequence of such ACE2 and the extracellular domain thereof being incorporated herein by reference, along with the nucleotide sequence encoding such.
  • ACE2 extracellular protein comprises or consists of positions 18 to 615 or 18 to 740 of ACE2 having UNIPROT number Q9BYF1, the sequence comprising or consisting of positions 18 to 740 being incorporated herein by reference, along with the nucleotide sequence encoding such.
  • the binding site comprises or consists of an TMPRSS2 extracellular protein.
  • the TMPRSS2 protein is human TMPRSS2 protein.
  • TMPRSS2 extracellular protein comprises or consists of positions 106 to 492 of TMPRSS2 having UNIPROT number O15393, the sequence comprising or consisting of positions 106 to 492 being incorporated herein by reference, along with the nucleotide sequence encoding such.
  • the binding site is an antibody VH/VL pair, wherein the VH comprises an amino acid sequence of a VH disclosed in Table 23 and the VL comprises the amino acid sequence of the cognate VL disclosed in Table 23.
  • the binding site comprises an scFv disclosed in Table 23.
  • the binding site comprises an antibody single variable domain (eg, a VHH, nanobody, dAb, VH or VL) disclosed in Table 23, Table 32 or elsewhere herein.
  • the binding site is an antibody VH/VL pair, wherein the VH comprises an amino acid sequence of a VH disclosed in Table 32 and the VL comprises the amino acid sequence of the cognate VL disclosed in Table 32.
  • the binding site comprises an scFv disclosed in Table 32.
  • the multimer comprises a multimer of a polypeptide disclosed in Table 23, optionally wherein the polypeptide is a polypeptide in the Table that comprises a TD.
  • the multimer comprises a multimer of a polypeptide disclosed in Table 32, optionally wherein the polypeptide is a polypeptide in the Table that comprises a TD.
  • Any amino acid sequence in Table 23, Table 32 or elsewhere herein that ends at its C- terminus in TVS may in the alternative be provided as the indentical sequence except that the alternative ends in TVSS.
  • the multimer may be a multimer of any format disclosed herein.
  • the multimer may be a multimer of any polypeptide dislosed herein.
  • the multimer comprises more than 2 (eg, comprises 4) copies of a heavy/light chain pair, wherein each heavy chain comprises (in N- to C-terminal direction) a VH and an antibody constant region (eg, an Fc) and wherein each light chain comprises (in N- to C-terminal direction) a VL and an antibody constant region (eg, a CL), wherein the binding site of the multimer comprises the VH paired with the VL; optionally wherein each heavy chain comprises a self-assembly multimerization domain (such as a tetramerization domain, such as a p53 TD).
  • each heavy chain comprises a hinge region as disclosed herein.
  • the multimer comprises more than 2 (eg, comprises 4) copies of a polypeptide, wherein the polypeptide comprises (in N- to C-terminal direction) a single variable domain and a multimerization domain (eg, a tetramerization domain, such as a p53 TD), and optionally an antibody constant region (eg, an Fc or CL) between the single variable domain and the multimerization domain, or the multimersiation domain is between the single variabl domain and the constant region.
  • a multimerization domain eg, a tetramerization domain, such as a p53 TD
  • an antibody constant region eg, an Fc or CL
  • the invention provides assays and methods:- A method for detecting the presence of an antigen in a sample, the method comprising combining the sample with a multimer of the invention, allowing antigen in the sample to bind multimers to form antigen/multimer complexes and detecting antigen/multimer complexes.
  • the antigen may be a virus antigen, eg, a spike, M, E or N antigen, or a coronavirus antigen.
  • the antigen may be comprised by an antibody present in the sample, eg, an antibody that is capable of binding do an antigen of an infectious disease pathogen (such as a virus or bacterium) or an antigen that is capable of binding to a human protein.
  • the sample may be a blood sample, serum sample, sputum sample, cell sample, saliva sample, bodily fluid sample of an animal or human subject.
  • the sample is diluted before said detection, eg, before said combining. Dilution may be any fold dilution disclosed herein, eg, and dilution by a PBS solution or water.
  • the antigen is immobilised on a solid surface before or after said combining. Immobilisation may be carried out by binding the antigen to an anti-antigen immunoglobulin or superantigen that is bound to the solid surface. Examples of superantigens are Proteins A, L and G or antibody-binding fragments thereof.
  • Immobilisation may be carried out by binding the antigen to a multimer of the invention that is bound to the solid surface, wherein the binding sites of the multimer are capable of binding to the antigen, eg wherein the antigen is comprised by an antibody.
  • the binding site is an antibody binding site of Protein G, A or L.
  • the antigen is comprised by antibodies that are capable of binding to a second antigen (eg, a human, bacteria, fungal or viral protein, such as a viral spike, M, E or N protein), wherein the second antigen is immobilised on a solid surface, the surface is contacted with the sample, wherein antibodies comprised by the sample bind to the second antigen to form second antigen/antibody complexes, and complexes are contacted with multimers of the invention wherein multimers bind to antibodies whereby second antigen/antibody/multimer complexes are formed, and second antigen/antibody/multimer complexes are detected thereby determining the presence of said antibodies in the sample.
  • a second antigen eg, a human, bacteria, fungal or viral protein, such as a viral spike, M, E or N protein
  • the antibodies are IgM, IgG, IgD, IgE or IgA antibodies, preferably IgM, IgG or IgA antibodies.
  • the method further comprises isolating complexes and optionally obtaining sequence information of antigen (first antigen, eg, antibodies) comprised by complexes.
  • the sequence may be inserted into an expression vector and expressed to produce proteins, eg, wherein the proteins are isolated.
  • VH and/or VL domain amino acid sequence of antibodies comprised by complexes is obtained and use to express copies of the VH and/or VL in an expression host, eg, CHO or HEK cell.
  • the method is an ELISA method, eg, a sandwich ELISA.
  • the method is carried out in vitro.
  • Suitable assay example formats are shown Figures 50-55, as well as reagents and polypeptides for making multimers of the invention that are useful for the methods and assays.
  • the examples show assay formats relating to SARS-CoV and SARS-CoV2, but they are equally applicable mutatis mutandis to detecting pathogens (eg, any virus, bacterium or fungus) other than SARS-CoV and SARS-CoV2 and the disclosures of Figures 50-55can therefore in the alternative be read as relating to any pathogen, any pathogen antigen or protein, any anti-pathogen antibody and any other suitable multimer of the invention.
  • pathogens eg, any virus, bacterium or fungus
  • the invention provides an assay comprising a format shown in any of Figures 50-55 for detecting the presence of a pathogen (eg, any virus, bacterium or fungus), anti-pathogen antibodies or a pathogen protein in a sample (eg, in serum, blood, saliva or any other sample disclosed herein).
  • a pathogen eg, any virus, bacterium or fungus
  • anti-pathogen antibodies or a pathogen protein in a sample (eg, in serum, blood, saliva or any other sample disclosed herein).
  • a pathogen eg, any virus, bacterium or fungus
  • a pathogen protein eg, in serum, blood, saliva or any other sample disclosed herein.
  • the pathogen is a coronavirus, eg, SARS-CoV or SARS-CoV-2, or infuenza virus or HIV, or any other virus disclosed herein.
  • a method of detecting the presence of anti-SARS-Cov-2 protein (eg, spike, M, E or N) antibodies in a serum sample comprising carrying out an ELISA assay (eg, an assay disclosed herein), and the assay comprises (a) Optionally diluting the serum sample from 10 to 10 6 -fold; (b) contacting the SARS-Cov-2 protein with the serum sample (which optinally is diluted in step (a)) whereby anti-SARS-Cov-2 protein antibodies present in the sample bind to the virus protein to produce virus protein/antibody complexes; and (c) contacting anti-SARS-Cov-2 virus protein antibodies with copies of the multimer of the invention; and (d) detecting multimer bound to virus protein/antibody complexes, the detecting comprising detection of the multimer binding, optionally by determining optical density (eg, OD 450 ); wherein the steps can be carried out in the order (a) (b) (
  • the antibodies are antibodies that bind to a protein of SARS-Cov or a different coronavirus.
  • the antibodies are antibodies that bind to a N, M or E proteins of a coronavirus, eg SARS-Cov or SARS-Cov-2.
  • the presence of anti-antigen or protein antibodies eg, anti-virus protein antibodies, such as anti-SARS-Cov-2 spike antibodies
  • the optical density eg, OD 450
  • the spike protein is immobilised on a solid surface.
  • the multimers are immobilised on a solid surface.
  • the dilution is 1000 to 1,000,000-fold (such as 1000 to 100,000-fold or 1000 to 10,000-fold) or any other fold dilution disclosed herein.
  • the dilution is from 10 to 10 4 , 10 5 or 10 6 -fold.
  • the dilution is from 100 to 10 4 , 10 5 or 10 6 -fold.
  • the dilution is from 1000 to 10 4 , 10 5 or 10 6 -fold.
  • dilution is dilution with water or an aqueous solution, eg, PBS, such as PBS containing from 0.1 to 0.05% (eg, either 0.1% or 0.05%) Tween-20.
  • PBS aqueous solution
  • the spike protein is a trimer of polypeptides.
  • the spike protein is a monomer of either S1 or S2 spike ectodomain, a trimer of the spike, monomer of the spike receptor binding domain (RBD domain); or a RBD multimer, such as a dimer, trimer, tetramer or octamer of the RBD.
  • the multimer of may bind a Nucleocapsid (N protein), membrane protein (M protein) or envelope protein (E protein) and the disclsoures herein referring to spike protein binding can apply mutatis mutandis to those alternatives.
  • the serum sample may have been obtained by taking a blood sample or other bodily fluid sample from a mammal (eg, a human or animal, such as any animal disclosed herein).
  • the human is a human suspected of having previously been infected or currently infected by a pathogen, eg a virus, bacterium or fungus comprising the antigen (first antigen), eg, SARS-CoV or SARS-Cov-2.
  • a pathogen eg a virus, bacterium or fungus comprising the antigen (first antigen), eg, SARS-CoV or SARS-Cov-2.
  • the human is a male, female, adult, teenager, child, baby or a human of at least 10, 20, 30, 40, 50, 60, 70 or 80 years’ of age (preferably over 50).
  • the binding site of the multimer is (a) The spike protein binding site of an antibody, optionally an antibody selected from CR3022, CR3014, or any other anti-coronavirus antibody disclosed herein (eg, an antibody of Table 21); (b) An ACE2 protein which is capable of binding to the spike protein; or (c) A TMPRSS2 protein which is capable of binding to the spike protein.
  • the multimer is a multimer of a polypeptide disclosed in Table 24, optionally wherein the polypeptide is a polypeptide in the Table that comprise a TD.
  • the multimer comprises a plurality of copies of an Ig binding domain disclosed in Table 25, optionally wherein the multimer further comprises a plurality of copies of a further (ie, different) Ig binding domain disclosed in Table 25,
  • the binding site of the multimer is alternatively capable of binding to an antibody (eg, an antibody that is capable of binding a human antigen, viral antigen, bacterial antigen or fungal antigen, such as an anti-SARS-Cov2 antibody, optionally wherein the binding site is comprised by (a) Protein G or a fragment thereof; (b) Protein A or a fragment thereof; (c) Protein L or a fragment thereof; or (d) An scFv or antibody single variable domain.
  • an antibody eg, an antibody that is capable of binding a human antigen, viral antigen, bacterial antigen or fungal antigen, such as an anti-SARS-Cov2 antibody, optionally wherein the binding site is comprised by (a) Protein G or a fragment thereof; (b) Protein A or a fragment
  • step (c) is carried out before step (b), wherein the protein A, G, L or fragment, scFv or variable domain binding sites of the multimers bind a plurality of copies of the antibody (eg, anti-SARS-Cov2 antibody).
  • the multimers may be immobilised on a solid support.
  • the multimers are immobilised on a solid surface.
  • the step of determining optical density comprises labelling complexes comprising first antigen or protein (eg, spike protein) and multimers with horseradish peroxidase (HRP) and detecting the label (optionally at a wavelength of 450 nm).
  • first antigen or protein eg, spike protein
  • HRP horseradish peroxidase
  • the HRP is contacted with tetramethyl benzidine and abosorbance is read at 450 nm, whereby OD 450 is determined.
  • the invention also provides:- A pharmaceutical composition or assay reagent comprising a plurality of multimers of the invention, optionally wherein the reagent comprises said multimers immobilised on a solid support.
  • the following provide the solid support: Beads, petri dish, a laboratory apparatus, flow cell or a swab or dipstick.
  • the support may be sterile or suitable for medical use.
  • the pharmaceutical composition comprises a pharmaceutically-acceptable carrier, diluent or excipient.
  • the invention also provides:- A multimer of the invention for administration to a human or animal subject for medical use.
  • a pathogen eg, a virus, bacterium or fungus
  • a method of treating a disease, condition or symptom thereof in a human or animal subject the method comprising administering to the subject a plurality of multimers of the invention.
  • the disease, condition or symptom is caused by the first antigen or protein (or by a pathogen that comprises the first antigen or protein, such as a virus that comprises the antigen or protein).
  • a method of treating a viral infection or symptom thereof in a human or animal subject the method comprising administering to the subject a plurality of multimers of the invention.
  • composition or multimers of the invention may be admistered in said use or method to the subject by any means, such as intravenously, orally, by inhalation or any other route disclosed herein.
  • the invention also provides:- An assay kit comprising a reagent of the invention and an amount of the first antigen or protein (eg, viral spike protein), optionally wherein the reagent and protein are comprised by different containers.
  • the first antigen or protein eg, viral spike protein
  • Examples 23 -26 demonstrate how advantageously multimerization of the invention can repurpose a binding site which otherwise would not be useful or much less useful, such as for medical use (eg, for treatment or prophylaxis of a disease or condition mediated by or associated with an antigen to which the binding site binds), or for assay use (eg, detecting a pathogen or antigen that mediates, causes or is adversely associated with a a disease or condition in a subject).
  • medical use eg, for treatment or prophylaxis of a disease or condition mediated by or associated with an antigen to which the binding site binds
  • assay use eg, detecting a pathogen or antigen that mediates, causes or is adversely associated with a a disease or condition in a subject.
  • very high-order multimers eg, containing 8-24 copies of a binding site
  • a stable multimer that can be readily expressed, such as in eukaryotic expression systems and host cells (as demonstrated in the exemplification herein).
  • the high-order multimers usefully can repurpose binding sites that individually have relatively low binding strength for an antigen, wherein in the multimers an avidity effect is produced rendering the combined binding strength of copies of the binding site well suited to medical applications or very sensitive assay detection of low levels of antigens in samples.
  • an avidity effect is produced rendering the combined binding strength of copies of the binding site well suited to medical applications or very sensitive assay detection of low levels of antigens in samples.
  • the antigen is an antigen of a pathogen (eg, a virus, bacterium or fungus that causes disease, such as in humans, animals or plants); or where the antigen is comprised by antibodies produced by a human or animal subject in response to immunisation, such as in response to a pathogen or a human protein in the subject.
  • a pathogen eg, a virus, bacterium or fungus that causes disease, such as in humans, animals or plants
  • the antigen is comprised by antibodies produced by a human or animal subject in response to immunisation, such as in response to a pathogen or a human protein in the subject.
  • the invention provides:- A method of expanding a utility of an antigen (eg, a protein) binding site, the method comprising producing a multimer of the invention, wherein the multimer comprises a plurality of copies (eg, at least 4 or 8 copies) of the binding site.
  • the utility is a medical utility, such as treating or preventing a disesase or condition mediated by the antigen in a human or animal subject (eg, an infection caused by a pathogen comprising the antigen).
  • the utility is an assay or detection method for determining the presence or relative amount of the antigen (or a pathogen comprising the antigen) or antibodies that bind the antigen in a sample (eg, an environmental sample or any sample of a human or animal subject disclosed herein).
  • the method increases the sensitivity of assaying for the antigen or antibodies in a sample.
  • the sample is a blood or serum or saliva sample which has been diluted, such as diluted with fold dilution disclosed herein.
  • the utlity is a reduced propensity for producing false positive results in assaying for the presence of the antigen or antibodies that bind the antigen in a sample.
  • exemplary Polypeptides & Multimers [00435]
  • the invention provides a polypeptide comprising one or more copies of an antigen binding domain (BD), the polypeptide comprising or consisting of, in N- to C-terminal direction (a) BD-TD; (b) TD-BD; (c) BD-BD-TD; (d) TD-BD-BD (e) BD-TD-BD-BD (f) BD-BD-TD-BD (g) BD-BD-TD-BD-BD.
  • BD-TD-TD antigen binding domain
  • TD is a p53 TD, eg, a human p53TD.
  • the BD is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH, eg, a single variable domain comprising SEQ ID: 1*288, preferably Nb-112).
  • BD comprises the amino acid of QB-GB (SEQ ID: 1*307).
  • BD comprises the amino acid of QB-BG.
  • the BD comprises the amino acid of QB-FE.
  • BD comprises the amino acid of SEQ ID: 1*288.
  • the BD comprises an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*288.
  • BD comprises the amino acid sequence of a VH or VL disclosed in Table 32 (optionally wherein in the multimer each said VH is paired with the cognate VL shown in Table 32; or optionally wherein in the multimer each said VL is paired with the cognate VH shown in Table 32, eg, the pair comprises the VH and VL of regdanvimab OR REGKINORATM, REGN10987, REGN10933 or CB6).
  • BD comprises the VH or VL of REGN10987 (optionally wherein in the multimer each said VH is paired with the VL of REGN10987; or optionally wherein in the multimer each said VL is paired with the VH of REGN10987).
  • BD comprises the VH or VL of REGN10933 (optionally wherein in the multimer each said VH is paired with the VL of REGN10933; or optionally wherein in the multimer each said VL is paired with the VH of REGN10933).
  • BD comprises the VH or VL of CB6 (optionally wherein in the multimer each said VH is paired with the VL of CB6; or optionally wherein in the multimer each said VL is paired with the VH of CB6).
  • Antibody CB6 is also known as LY-CoV555.
  • An optional peptide linker may be between the TD and a domain (eg, the CH1) that is immediately N- terminal to the TD in the polypeptide. Multimerisation of 4 copies of the polypeptide using TDs produces a multimer (ie, tetramer) comprising 4 identical antigen binding sites, see, eg, Figure 53A. The invention provides such a multimer.
  • BD and BD2 respectively comprise the VH and VL of an antibody selected from regdanvimab OR REGKINORATM, REGN10987, REGN10933 and CB6 (see Table 32 for sequences).
  • the multimer comprises the monomer (middle schematic) shown in any of Figs 16-A to 16-C.
  • BD and BD2 respectively comprise the VH and VL of an antibody selected from regdanvimab OR REGKINORATM, REGN10987, REGN10933, CB6, rRBD-15 (ABLINK Biotech Co., Ltd / Chengdu Medical College), B38, H4 (Capital Medical University, Beijing), FYB-207 (Formycon AG), ABP300 (Abpro Corporation), BRII-198 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), BRII-196 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), CT-P59 (Celltrion), HFB-3013, or HFB30132A (HiFiBiO Therapeutics), MW33 (Mabwell), SAB-185 (SAB Biotherapeutics), Etesevimab (Junshi Biosciences), SCTA01 or H014 (University of Chinese Academy of Sciences), STI-1499 or COVI-GU
  • the effector domain or binding domain or binding site of a polypeptide herein comprises the VH and/or VL of an antibody selected from regdanvimab OR REGKINORATM, REGN10987, REGN10933, CB6, rRBD-15 (ABLINK Biotech Co., Ltd / Chengdu Medical College), B38, H4 (Capital Medical University, Beijing), FYB-207 (Formycon AG), ABP300 (Abpro Corporation), BRII-198 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), BRII-196 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), CT-P59 (Celltrion), HFB-3013, or HFB30132A (HiFiBiO Therapeutics), MW33 (Mabwell), SAB-185 (SAB Biotherapeutics), Etesevimab (Junshi Biosciences), SCTA01 or H014 (University of Chinese Academy of
  • the multimer herein comprises at least 4 copies (eg, 4, 8, 12, 16, 20, 24 or 28 copies) of the VH and/or VL of an antibody selected from regdanvimab OR REGKINORATM, REGN10987, REGN10933, CB6, rRBD-15 (ABLINK Biotech Co., Ltd / Chengdu Medical College), B38, H4 (Capital Medical University, Beijing), FYB-207 (Formycon AG), ABP300 (Abpro Corporation), BRII-198 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), BRII- 196 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), CT-P59 (Celltrion), HFB-3013, or HFB30132A (HiFiBiO Therapeutics), MW33 (Mabwell), SAB-185 (SAB Biotherapeutics), Etesevimab (Junshi Biosciences), SCTA01 or H0
  • the multimer may comprise no more than said number of copies.
  • a tetramer of an antibody or a fragment of an antibody, eg, a Fab of an antibody
  • the tetramer is tetramersised using tetramerization domains (TDs).
  • TDs tetramerization domains
  • the tetramer has the configuration shown in the right-hand-side schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the tetramer that are not shown in said Figure).
  • an antibody or a fragment of an antibody, eg, a Fab of an antibody
  • the antibody or fragment comprises a TD (eg, a p53 TD), preferably wherein the TD is at the N-terminus of at least one of the polypeptide chains of the antibody or fragment.
  • TD eg, a p53 TD
  • the heavy chains of the antibody or fragment comprise a TD at its N-terminus.
  • one or both of the light chains of the antibody or fragment comprise a TD at its N-terminus.
  • the antibody or fragment has the configuration shown in the middle schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the antibody or fragment that are not shown in said Figure).
  • the antibody is an antibody disclosed in the immediately preceding paragraph.
  • a multimer or tetramer herein may have the configuration shown in the any one of the Figures herein (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the multimer or tetramer that are not shown in said Figure).
  • a multimer or tetramer herein may have the configuration shown in the right-hand-side schematic of any one of Figures 14A to 14-F, 15-A to 15-L and 16-A to 16-C (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the multimer or tetramer that are not shown in said Figure).
  • a polypeptide or monomer herein may have the configuration shown in any one of the Figures herein (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the polypeptide or monomer that are not shown in said Figure).
  • a polypeptide or monomer herein may have the configuration shown in the middle schematic of any one of Figures 14A to 14-F, 15-A to 15-L and 16-A to 16-C (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the polypeptide or monomer that are not shown in said Figure).
  • the multimer or tetramer may comprise 4 VH/VL pairs, such as shown in the right-hand-side schematic of any one of Figures 14A to 14-F, 15-A to 15-L and 16-A to 16-C.
  • each of said VH/VL pairs is a VH/VL antigen binding site comprised by an antibody disclosed herein eg, any antibody selected from regdanvimab OR REGKINORATM, REGN10987, REGN10933, CB6, rRBD-15 (ABLINK Biotech Co., Ltd / Chengdu Medical College), B38, H4 (Capital Medical University, Beijing), FYB-207 (Formycon AG), ABP300 (Abpro Corporation), BRII-198 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), BRII-196 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), CT-P59 (Celltrion), HFB-3013, or HFB30132A (HiFiBiO Therapeutics), MW33 (Mabwell), SAB-185 (SAB Biotherapeutics), Etesevimab (Junshi Biosciences), SCTA01 or H014 (University of Chinese Academy
  • each multimer comprises 4 copies of an antigen binding site that is capable of binding to a first antigen; and a second of said multimers comprises 4 copies of an antigen binding site that is capable of binding to a second antigen, optionally the antigens are identical and the binding sites bind different epitopes comprised by the antigen, or the antigens are different.
  • the or each antigen is an antigen of a virus, eg, SARS-CoV or SARS-Cov-2 antigen, such as spike antigen, or the virus is influenza virus or any other virus disclosed herein.
  • a first of said multimers comprises 4 copies of the SARS-CoV-2 antigen binding site of REGN10987
  • a second of said multimers comprises 4 copies of the SARS-CoV-2 antigen binding site of REGN10933.
  • the binding site (eg, BD or BD2) of a polypeptide or multimer herein comprises the variable domain of Nb11-59 (Shanghai Novamab Biopharmaceuticals Co., Ltd.), MERS VHH-55, SARS VHH-72 or VHH30372-Fc.
  • the binding site (eg, BD or BD2) of a polypeptide or multimer herein comprises a Darpin of MP0420 or MP0423.
  • An optional peptide linker may be between the TD and a domain (eg, the CH3) that is immediately N-terminal to the TD in the polypeptide.
  • Multimerisation of 4 copies of the polypeptide using TDs produces a multimer (ie, tetramer) comprising 4 identical antigen binding sites, see, eg, Figure 53C.
  • the invention provides such a multimer.
  • example (a) is BD-Fc-TD (eg, see Figures 54C, 55C) and multimers thereof are also provided by the invention, such as tetramers of such polypeptide.
  • the invention provides a polypeptide comprising an antigen binding domain (BD), the polypeptide comprising or consisting of, in N- to C-terminal direction BD-Fc- Td, wherein Fc is an antibody Fc region.
  • BD antigen binding domain
  • the BD is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH).
  • dimer or tetramer BD comprises the amino acid of QB-GB (SEQ ID: 1*307), QB-DD, QB-BG or QB-FE (see Table 23 for sequences).
  • the invention provides a provides polypeptide comprising an antigen binding domain (BD), the polypeptide comprising or consisting of, in N- to C-terminal direction BD-CH1-Fc-Td, wherein Fc is an antibody Fc region.
  • BD antigen binding domain
  • the dimer of first and second copies of such a polypeptide wherein the Fc of the first polypeptide is associated with the Fc of the second polypeptide.
  • each polypeptide is paired with a further polypeptide, wherein the further polypeptide comprises, in N- to C-terminal direction, BD2-CL, wherein the CH1 pairs with the CL.
  • the BD is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH).
  • the BD2 is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH).
  • BD and BD2 are a VH/VL pair that binds an antigen.
  • the CL of said further polypeptide associates with the CH1 of the other polypeptide (see, eg, Fig 12E).
  • dimer or tetramer BD comprises the amino acid of QB-GB (SEQ ID: 1*307), QB-BG or QB-FE (see Table 23 for sequences).
  • the invention provides a provides polypeptide comprising an antigen binding domain (BD), the polypeptide comprising or consisting of, in N- to C-terminal direction BD-CH1-Td, wherein CH1 is an antibody CH1.
  • a dimer of first and second copies of such a polypeptide eg, wherein the TDs of the polypeptides are associated together.
  • a dimer of such a dimer eg, as shown in Fig 12I
  • each polypeptide is paired with a further polypeptide, wherein the further polypeptide comprises, in N- to C-terminal direction, BD2-CL, wherein the CH1 pairs with the CL.
  • the BD is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH).
  • the BD2 is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH).
  • BD and BD2 are a VH/VL pair that binds an antigen.
  • the CL of said further polypeptide associates with the CH1 of the other polypeptide (see, eg, Fig 12I.
  • dimer or tetramer BD comprises the amino acid of QB-GB (SEQ ID: 1*307), QB-DD, QB-BG or QB-FE (see Table 23 for sequences).
  • BD and BD2 may be a VH/VL pair of an antigen binding site of an antibody selected from the group consisting of regdanvimab OR REGKINORATM, REGN10987, REGN10933 and CB6.
  • a protein multimer comprising 4 copies of an antigen binding site of an antibody, wherein the antibody is selected from regdanvimab OR REGKINORATM, REGN10987, REGN10933 and CB6.
  • the multimer comprises antibody single variable domain Nb11-59 or an antibody single variable domain comprising SEQ ID: 1*293, or an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of Nb11-59 or SEQ ID: 1*293.
  • the multimer comprises an antibody single variable domain selected from nanobodies A to W disclosed in Koenig et al, the sequences of which are incorporated in their entirety herein for use in a multimer or polypeptide as described herein.
  • the domain is nanobody E, U, V or W.
  • each copy of the variable domain comprises an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*288, wherein the variable domain is capable of binding to a SARS-CoV-2 antigen, eg, spike.
  • each copy of the variable domain is Nb11-59 or an antibody single variable domain comprising SEQ ID: 1*293.
  • an antibody single variable domain is used wherein the domain comprises a HCDR3 comprising SEQ ID: 1*294.
  • the invention provides a pharmaceutical composition for inhaled delivery to a patient (eg, a patient suffering from or at risk of SARS-CoV-2 infection), wherein the composition comprises a multimer of the invention.
  • the multimer comprises copies of Nb-112 or a variable domain comprising SEQ ID: 1*288.
  • the multimer comprises copies of Nb11-59 or an antibody single variable domain comprising SEQ ID: 1*293, or an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of Nb11-59 or SEQ ID: 1*293.
  • the invention also provides a nebuliser or inhaler device comprising such a composition.
  • a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing a lung condition.
  • a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing a SARS-CoV-2 infection is also provided.
  • a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing an inflammatory condition There is also provided a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing pneumonia. There is also provided a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing a cough. There is also provided a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing loss of smell and/or taste.
  • the multimer may comprise mammalian cell glycosylation.
  • the multimer may, for example, comprise 8, 12, 16, 20 or 24 copies of the binding site (eg, VHH).
  • the multimer may contain 4 (but no more than 4) copies of the binding site (eg, VHH).
  • the binding site may be anti-SARS-CoV-2 antigen VH/VL pair comprised by the antibody.
  • a VH or VHH herein may be a VH3 family VH or VHH.
  • multimerization of such a variable domain can surprisingly produce a multimer of the invention that can be readily purified by binding to protein A.
  • the multimer can be devoid of an affinity tag, such as a His tag.
  • any Fc may be a human antibody Fc.
  • an Fc may be a gamma antibody Fc, mu antibody Fc, delta antibody Fc, epsilon antibody Fc or alpha antibody Fc, preferably a gamma (eg, gamma-1, gamma-2, gamma-3 or gamma-4) antibody Fc (preferably a gamma-1 antibody Fc).
  • the invention provides a protein multimer comprising the configuration of ACE2-TD shown in Figure 54B.
  • the multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure.
  • the invention provides a protein multimer comprising the configuration of ACE2 monomeric Ig-TD shown in Figure 54C.
  • the multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure.
  • the invention provides a protein multimer comprising the configuration of ACE2 dimer-TD shown in Figure 54D.
  • the multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure.
  • the invention provides a protein multimer comprising the configuration of ACE2- Ig-TD shown in Figure 54E.
  • the multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure.
  • the invention provides a protein multimer comprising the configuration of BD- Heavy Chain Only -TD shown in Figure 55C.
  • the multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure.
  • the invention provides a protein multimer comprising the configuration of BD- Ig-TD shown in Figure 55B.
  • the multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure.
  • the invention provides a protein multimer comprising the configuration of BD- Fab-like -TD shown in Figure 55B.
  • the multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure.
  • the invention provides a protein multimer comprising the configuration of BD- Fab-like monomeric Ig-TD shown in Figure 55E.
  • the multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure.
  • the invention provides a protein multimer comprising the configuration of Dimeric-TD shown in Figure 55H.
  • the multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure.
  • the invention provides a protein multimer comprising the configuration of BD- Fab’-like -TD shown in Figure 55F.
  • the multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure.
  • the invention provides a protein multimer comprising the configuration of BD- monomeric Ig-TD shown in Figure 55G.
  • the multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure.
  • BD-TD denotes the binding domain directly linked N-terminal to the TD.
  • TD-BD denotes the binding domain directly linked C-terminal to the TD.
  • BD-BD denotes the binding domains directly linked to each other.
  • 2 copies of the polypeptide are associated or joined together so that the N- and C-termini of each polypeptide is not directly joined to the other polypeptide to form a polypeptide dimer (eg, see Figure 54D or 55C).
  • the polypeptides of the dimer are disulphide bonded to each other.
  • Fc dimerisation between 2 copies of the polypeptide produce a dimer, wherein the polypeptide comprises an antibody Fc.
  • the invention in an embodiment, provides a multimer (ie, tetramer) comprising 2 identical copies of the dimer (ie, comprising 4 copies of the polypeptide), wherein the multimer comprises at least 4 copies of BD.
  • each polyeptide has only one BD, wherein the multimer has 4 copies of BD.
  • each polyeptide has only 2 copies of BD, wherein the multimer has 8 copies of BD.
  • each polyeptide has only 3 copies of BD, wherein the multimer has 12 copies of BD.
  • the BD or binding domain herein may be a binding domain disclosed in Table 23, eg, QB- GB, QB-BG or QB-FE (see Table 23 for sequences), or as disclosed in Table 32.
  • the VH/VL pair may be a VH/VL pair of antibody CR3022: CR3022 VH (ie, QMQLVQSGTEVKKPGESLKISCKGSGYGFITYWIGWVRQMPGKGLEWMGIIYPGDSETR YSPSFQGQVTISADKSINTAYLQWSSLKASDTAIYYCAGGSGISTPMDVWGQGTTVTV) paired with CR3022 VL (ie, DIQLTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPKLLIYWASTRE SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPYTFGQGTKVEIK).
  • VH ie, QMQLVQSGTEVKKPGESLKISCKGSGYGFITYWIGWVRQMPGKGLEWMGIIYPGDSETR YSPSFQGQVTISADKSINTAYLQWSSLKASDTAIYY
  • the polypeptide comprises or contains a peptide (eg, an insulin peptide or a superantigen peptide or domain) or a receptor (eg, ACE2 ECD).
  • a peptide eg, an insulin peptide or a superantigen peptide or domain
  • a receptor eg, ACE2 ECD
  • Exemplary superantigens eg protein G, A or L
  • peptides and domains thereof are disclosed herein.
  • the invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 copies of a binding domain or a peptide.
  • the binding domain may be any binding domain disclosed herein.
  • the invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 8 copies of a binding domain or a peptide.
  • the binding domain may be any binding domain disclosed herein.
  • the invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 16 copies of a binding domain or a peptide.
  • the binding domain may be any binding domain disclosed herein.
  • the invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 20 copies of a binding domain or a peptide.
  • the binding domain may be any binding domain disclosed herein.
  • the invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 24 copies of a binding domain or a peptide.
  • the binding domain may be any binding domain disclosed herein.
  • the multimer may, for example, comprise no more than said number of the domain or peptide.
  • the multimer may contain exactly said number of copies of the binding domain or peptide.
  • the invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 copies of a first binding domain or a peptide; and 4 copies of a second binding domain or a peptide, wherein the first and second binding domains are different (eg, they bind to different antigens of a virus, eg, a coronavirus or HIV or influenza, or immune checkpoint antigens, or cytokine antigens, or growth factor antigens, or venom (eg, snake venom) antigens).
  • the first binding domain may be any binding domain disclosed herein.
  • the second binding domain may be any binding domain disclosed herein.
  • the invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 or 8 copies of a first binding domain or a peptide; and 4 copies of a second binding domain or a peptide, wherein the first and second binding domains are different (eg, they bind to different antigens of a virus, eg, a coronavirus or HIV or influenza, or immune checkpoint antigens, or cytokine antigens, or growth factor antigens, or venom (eg, snake venom) antigens).
  • the first binding domain may be any binding domain disclosed herein.
  • the second binding domain may be any binding domain disclosed herein.
  • the invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 or 8 copies of a first binding domain or a peptide; and 8 copies of a second binding domain or a peptide, wherein the first and second binding domains are different (eg, they bind to different antigens of a virus, eg, a coronavirus or HIV or influenza, or immune checkpoint antigens, or cytokine antigens, or growth factor antigens, or venom (eg, snake venom) antigens).
  • the first binding domain may be any binding domain disclosed herein.
  • the second binding domain may be any binding domain disclosed herein.
  • the invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 copies of a first binding domain or a peptide; 4 copies of a second binding domain or a peptide; and 4 copies of a third binding domain or a peptide, wherein the first, seond and third binding domains are different from each other (eg, they bind to different antigens of a virus, eg, a coronavirus or HIV or influenza, or immune checkpoint antigens, or cytokine antigens, or growth factor antigens, or venom (eg, snake venom) antigens).
  • the first binding domain may be any binding domain disclosed herein.
  • the second binding domain may be any binding domain disclosed herein.
  • the third binding domain may be any binding domain disclosed herein.
  • the invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 copies of a first binding domain or a peptide; 4 copies of a second binding domain or a peptide; 4 copies of a third binding domain or a peptide; and 4 copies of a fourth binding domain or a peptide, wherein the first, second, third and fourth binding domains are different from each other (eg, they bind to different antigens of a virus, eg, a coronavirus or HIV or influenza, or immune checkpoint antigens, or cytokine antigens, or growth factor antigens, or venom (eg, snake venom) antigens).
  • the first binding domain may be any binding domain disclosed herein.
  • the second binding domain may be any binding domain disclosed herein.
  • the third binding domain may be any binding domain disclosed herein.
  • the fourth binding domain may be any binding domain disclosed herein.
  • the multimer comprises said number of first and second binding domains.
  • the multimer comprises said number of first and second peptides.
  • the multimer comprises mammalian cell (eg, human cell) glycosylation.
  • the multimer binds to the antigen with an affinity of less than 200, 150, 100, 90, 80, 70, 60, 50, 40, 35, 30, 25, 20, 15 or 10 pM (preferably less than 40 or 20 pM) in an ELISA assay, such as an ELISA assy disclosed herein.
  • the multimer binds to the antigen with an affinity of less than 200, 150, 100, 90, 80, 70, 60, 50, 40, 35, 30, 25, 20, 15 or 10 pM (preferably less than 40 or 20 pM) in an SPR assay, such as an SPR assy disclosed herein.
  • the multimer comprises or contains 16 copies of a binding domain or peptide.
  • the multimer neutralises the antigen with an IC 50 of less than 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 nM (preferably from 0.06 to 0.01 nM) in an ELISA assay, such as an ELISA assay disclosed herein.
  • the multimer neutralises the antigen with an IC 50 of less than 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 nM (preferably from 0.06 to 0.01 nM) in an SPR assay, such as an SPR assay disclosed herein.
  • the multimer comprises or contains 16 copies of a binding domain or peptide.
  • the multimer comprises anti-coronavirus (eg, SARS-Cov-2) spike protein binding sites or receptor peptides, wherein the multimer binds to spike trimer or spike RBD.
  • the binding is with an affinity of less than 200, 150, 100, 90, 80, 70, 60, 50, 40, 35, 30, 25, 20, 15 or 10 pM (preferably less than 40 or 20 pM) in an SPR assay, such as an SPR assay disclosed herein; or in an ELISA assay, such as an ELISA assay disclosed herein (eg, an assay as disclosed in Example 28).
  • An antigen binding domain or site comprised by a polypeptide or multimer of the invention may be any binding domain or binding site selected from those disclosed herein (eg, any VH, VL, dAb, VHH or scFv) or may be a binding domain or binding site that comprises an amino acid sequence that is at least 70, 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of said selected domain or site.
  • An antigen binding domain or site comprised by a polypeptide or multimer of the invention may be any binding domain or binding site selected from those disclosed herein (eg, any VH, VL, dAb, VHH or scFv) or may be a binding domain or binding site that comprises an amino acid sequence that is identical to the amino acid sequence of said selected domain or site except for 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid differences (eg, conseravative amino acid changes).
  • An antigen binding domain or site comprised by a polypeptide or multimer of the invention may be a domain or site that competes with any binding domain or binding site selected from those disclosed herein (eg, any VH, VL, dAb, VHH or scFv) for binding to the antigen. Competition may be determined by a standard competition assay, such as an SPR competition assay or an ELISA assay.
  • a polypeptide of the invention may have a configuration shown for a polypeptide in any of the figures herein.
  • a multimer (eg, polyeptide dimer or tetramer) of the invention may have a configuration shown for a multimer in any of the figures herein.
  • the invention provides: A protein multimer comprising or containing 8 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different).
  • the term “comprising” is open language wherein more than 8 copies of the peptide or binding site are possible in embodiments of the multimer.
  • the term “containing” is closed language wherein 8 (but not more or less than 8) copies are present in the multimer.
  • the term “comprising or containing” or “comprises or contains” herein is to be construed accordingly.
  • the multimer comprises or contains 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 copies of the peptide or binding site.
  • the multimer comprises or contains 4, 8, 12, 16, 20, 24, 28, 32 or 36 copies of the peptide or binding site.
  • the binding site is a VH/VL pair comprising VH-ICC paired with VL-ICC or VH-IHG paired with VL-IHG.
  • the binding site comprises QB-GB, QB-DD, QB-BG or QB-FE.
  • the multimer comprises or contains 16 copies of the peptide or binding site.
  • the multimer comprises (i) 4 copies of a polypeptide, wherein each polypeptide copy comprises a tetramerization domain and 2 or more (eg, 2, 3 or 4) copies of the peptide or binding site; or (ii) 4 copies of a dimer of a polypeptide, wherein each polypeptide copy comprises a tetramerization domain and 1 or more (eg, 2) copies of the peptide or binding site.
  • the polypeptide comprises a self-assembly multimerization domain (SAM) (preferably a tetramerization domain (TD)) and one or more copies of an antigen binding site (BD), the polypeptide comprising or consisting of, in N- to C-terminal direction BD-TD; TD-BD; BD-BD-TD; TD-BD-BD; BD-TD-BD-BD; BD-BD-TD-BD; or BD-BD-TD-BD-BD.
  • SAM self-assembly multimerization domain
  • BD antigen binding site
  • the polypeptide comprising or consisting of, in N- to C-terminal direction BD-TD; TD-BD; BD-BD-TD; TD-BD-BD; BD-TD-BD-BD; BD-BD-TD-BD; or BD-BD-TD-BD-BD.
  • the BD is a single variable domain.
  • the BD comprises the amino acid sequence of QB-GB (SEQ ID: 1*307), QB-DD, QB-BG or QB-FE.
  • the polypeptide comprises, in N- to C-terminal direction, BD-CH1-TD, BD-CL-TD, BD-CH1-Fc-TD or BD-Fc-TD, where BD is an antibody V domain (eg, a VH), Fc is an antibody Fc region, and CH1 is an antibody CH1 domain; and optionally each BD-CH1-TD or BD- CH1-Fc-TD polypeptide of the multimer is paired with a respective second polypeptide, wherein the second polypeptide comprises, in N- to C-terminal direction BD2-CL, wherein BD2 is an antibody V domain (eg, a VL or single variable domain), wherein the CH1 pairs with the CL.
  • tandam dAbs are provided N-termial to the TD, preferably at the N- terminus of the polypeptide.
  • the polypeptide comprises, in N- to C-terminal direction, BD’-optionaly linker-BD-CH1-TD, BD’-optionaly linker-BD -CL-TD, BD’-optionaly linker-BD - CH1-Fc-TD or BD’-optionaly linker-BD -Fc-TD, wherein each of BD and BD’ is an antibody single variable domain (eg, a nanobody), Fc is an antibody Fc region, and CH1 is an antibody CH1 domain.
  • BD and BD’ is an antibody single variable domain (eg, a nanobody)
  • Fc is an antibody Fc region
  • CH1 is an antibody CH1 domain.
  • the dimer comprises a first polypeptide comprising, in N- to C-terminal direction, BD-hinge-TD; BD’-optional linker-BD-Hinge-TD; or BD-optional linker-CH1-Hinge-TD.
  • the first polypeptide is associated with a second polypeptide.
  • the second polypeptide comprises, in N- to C-terminal direction, BD’’-optional Linker 1-BD-optional linker 2-CL (kappa or lambda) (eg, BD’’- Linker 1-BD-optional linker 2-CL; BD’’-BD-optional linker-CL; or BD’’-BD-CL), wherein the first polyeptide comprises a CH1 domain that is paired with the CL, and wherein each of BD and BD’ is an antibody single variable domain (eg, a nanobody).
  • each of BD and BD2 is an antibody single variable domain; or (ii) BD1 is an antibody VH domain and BD2 is an antibody VL domain, wherein the VH and VL form a VH/VL pair comprising an antigen binding site.
  • the polypeptide comprises, in N- to C-terminal direction, BD-CH1-Fc-TD or BD-CH1-Linker-Fc-TD (optionally wherein the Linker is an antibody hinge, wherein the hinge is devoid of a core hinge region).
  • the invention further provides:- A protein dimer containing 2 copies of the polypeptide.
  • a protein dimer comprising first and second polypeptides, wherein each polypeptide is a polypeptide disclosed herein.
  • a 4-chain multimer eg, an antibody
  • a dimer of the invention comprising a dimer of the invention, wherein a first polypeptide of the dimer is associated with a second polypeptide of the dimer, wherein a third polypeptide is associated with the first polypeptide and a fourth polypeptide is associated with the second polypeptide.
  • the first and second polypeptides are antibody heavy chains and the third and fourth polypeptides are light chains.
  • the first and third polypetides are associated together and comprise a first antigen binding site that is capable of binding to a first antigen; and the second and fourth polypeptides are associated together and comprise a second antigen binding site that is capable of binding to a second antigen.
  • the first and second antigens are different.
  • the first and second binding sites are different.
  • each binding site comprises a VH/VL pair.
  • the first and third polypeptides comprise first and second single variable domains, wherein each single variable domain is capable of binding a respective antigen (eg, different antigens) and/or (i) the second and fourth polypeptides comprise third and fourth single variable domains, wherein each single variable domain is capable of binding a respective antigen (eg, different antigens) or (ii) the second and fourth polypeptides are associated together and comprise a VH/VL pair that is capable of binding to an antigen.
  • a multimer herein is multispecific for antigen binding, eg, bispecific, trispecific or tetraspecific.
  • polypeptides are associated together, eg, a Fc region of a first polypeptide of the dimer is associated with a Fc of a second polypeptide of the dimer.
  • each polypeptide comprises a TD.
  • the (or the first) polypeptide comprises, in N- to C-terminal direction, BD- TD.
  • the 2 copies of the polypeptide are disulphide bonded together in the dimer.
  • the invention also provides: A protein dimer containing 2 copies of a polypeptide recited herein, wherein the polypeptide comprises BD-CH1-Fc-TD, wherein the Fc regions of the polypeptides associate with each other to form the dimer.
  • the invention also provides: A multimer comprising or containing 4 copies of the dimer of the invention.
  • the invention also provides: [00509] A polypeptide as recited for the multimer or dimer of the invention. Optionally, the polypeptide is isolated or recombinant.
  • the multimer, dimer or polypeptide may be comprised by a medical or sterile container, eg, a syringe, vial, IV bag, container connected to a needle or a subcutaneous injection administration device.
  • the antigen is a viral antigen, bacterial antigen, fungal antigen, toxin antigen, venom antigen, immune checkpoint protein antigen, cytokine antigen, growth factor antigen, hormone antigen (eg, chorionic gonadotropin), sugar antigen, lipid antigen or protein antigen.
  • BD and BD2 are different from each other and each comprises a binding site for an antigen of a virus, an antigen of a bacterium, an antigen of a fungus, an antigen of a toxin, an antigen of a venom, an antigen of an immune checkpoint protein, an antigen of a cytokine, an antigen of a growth factor antigen or an antigen of a hormone; optionally wherein both BD and B2 comprises a binding site for a virus.
  • the multimer binds to the antigen with an affinity of less than 200 pM in an ELISA assay; and/or the multimer neutralises the antigen with an IC 50 of less than 0.2 nM in an ELISA assay.
  • the multimer is capable of detectably binding to anti-first antigen antibodies (optionally anti-SARS-Cov-2 spike antibodies) in an ELISA assay, wherein detection of the multimer binding is measured by OD 450 and the assay comprises (a) Diluting a serum sample of a mammal between 100 and 10 6 -fold; (b) Contacting the antigen (eg, SARS-Cov-2 spike protein) with the serum sample (which has been diluted in step (a)) whereby anti-first antigen (eg, anti-SARS-Cov-2 spike) antibodies present in the sample bind to the antigen (eg, spike protein), wherein the antigen protein is immobilised on a solid surface; (c) Contacting the bound antibodies with copies of the multimer of any preceding claim and (d) Detecting multimer bound to antibody.
  • antigen eg, SARS-Cov-2 spike protein
  • the dilution is 1000 to 1,000,000, 100,000 or 10000-fold (preferably 10,000 to 100,000-fold).
  • a method of detecting the presence of anti-first antigen antibodies (eg, anti-SARS-Cov-2 spike antibodies) in a bodily fluid sample of a human or animal comprising carrying out an ELISA assay, and the assay comprises (a) Optionally diluting the serum sample from 10 to 10 6 -fold; (b) contacting the first antigen (eg, SARS-Cov-2 spike protein) with the sample (optionally which has been diluted in step (a)) whereby anti-first antigen (eg, anti- SARS-Cov-2 spike) antibodies present in the sample bind to the first antigen (eg, spike protein) to produce antigen/antibody complexes; and (c) contacting and binding the first antigen or anti-first antigen (eg, anti-SARS-Cov-2 spike) antibodies with copies of the multimer of any one of
  • the presence of anti-first antigen antibodies in the sample is detected when the optical density (eg, OD 450 ) is greater than 0.1 or 0.5 (optionally, greater than 1, 1.5 or 2) in the assay.
  • the dilution is 1000 to 1,000,000, 100,000 or 10000-fold (preferably 10,000 to 100,000-fold).
  • the binding site is (a) QB-GB, QB-DD, QB-FE or QB-BG; (b) The spike protein binding site of an antibody selected from 80R, CR3014, CR3006, CR3013 and CR3022; (c) An anti-SARS-Cov-2 antigen binding site of an antibody selected from regdanvimab OR REGKINORATM, REGN10987, REGN10933, CB6, rRBD-15, B38, H4, FYB- 207, ABP300, BRII-198, BRII-196, CT-P59, HFB-3013, HFB30132A, MW33, SAB- 185, Etesevimab, SCTA01, H014, STI-1499, COVI-GUARDTM, TY027, COVI- AMGTM, STI-2020, HLX70, ADM03820, an XAV-19 antibody, BGB DXP-593, DXP-604, VIR-
  • the multimers are immobilised on a solid surface; or the first antigen is immobilised on a solid surface.
  • determining optical density comprises labelling complexes comprising spike protein and multimers with horseradish peroxidase (HRP) and detecting the label (eg, at a wavelength of 450 nm).
  • HRP horseradish peroxidase
  • each multimer may comprise a polypeptide; or variable domain or binding site amino acid disclosed herein.
  • the invention provides: A multimer comprising 4 copies of a binding site for an antigen, wherein the multimer comprises a dimer of an antibody or a dimer of an antigen binding fragment (eg, Fab) of an antibody, optionally wherein the multimer is according to any preceding claim.
  • the multimer comprises a dimer of an antibody or a dimer of an antigen binding fragment (eg, Fab) of an antibody, optionally wherein the multimer is according to any preceding claim.
  • the antibody can be any antibody disclosed herein, eg, an antibody selected from regdanvimab or REGKINORATM, regdanvimab OR REGKINORATM, REGN10987, REGN10933, CB6, rRBD-15, B38, H4, FYB- 207, ABP300, BRII-198, BRII-196, CT-P59, HFB-3013, HFB30132A, MW33, SAB-185, Etesevimab, SCTA01, H014, STI-1499, COVI-GUARDTM, TY027, COVI-AMGTM, STI-2020, HLX70, ADM03820, an XAV-19 antibody, BGB DXP-593, DXP-604, VIR-7831, GSK4182136, AZD8895, AZD1061, HBM9022, 47D11, Ab8, MAbCo19, AR-701, AR-711, DXP-604, Centi- B9, GIGA-20
  • the multimer may be a tetramer having a configuration shown in the right-hand-side schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C (eg, Fig 16A, 16B or 16C, optionally wherein the VH and VL pair is a VH/VL pair of an antigen binding site of an antibody selected from the group consisting of regdanvimab or REGKINORATM, REGN10987, REGN10933 and CB6); or wherein the polypeptdide herein may be a polypeptide having a configuration shown in the middle schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C; or the dimer may be a dimer of any such polypeptide.
  • the multimer may be a tetramer having a configuration shown in the right-hand-side schematic of Figure 62A or 62B.
  • the multimer is a tetramer having a configuration shown in the right-hand-side schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C (eg, Fig 16A, 16B or 16C, optionally wherein the VH and VL pair is a VH/VL pair of an antigen binding site of an antibody selected from the group consisting of regdanvimab or REGKINORATM, REGN10987, REGN10933 and CB6); or wherein the polypeptdide is a polypeptide having a configuration shown in the middle schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C; or the dimer is a dimer of any such polypeptide; optionally wherein each VH and each
  • any multimer herein comprises 4 (eg, no more than 4) copies of any antibody variable domain disclosed herein, eg, a variable domain comprising SEQ ID: O or P.
  • the invention provides: A pharmaceutical composition or assay reagent comprising a plurality of multimers of the invention, optionally wherein the reagent comprises said multimers immobilised on a solid support.
  • a multimer of the invention (or a combination of at least 2 or 3 multimers of the invention claim) for administration to a human or animal subject for medical use.
  • a composition comprising a multimer of the invention, eg, for medical use or for use in vitro.
  • a VH herein may be a VH encoded by a VH DNA sequence shown in Table 21(b) and a VL herein may be a VL encoded by the cognate VL DNA sequence shown in Table 21(b) , wherein the VH and VL form an antigen binding VH/VL pair (eg, that is capable of binding to a SARS-CoV-2 antigen, such as spike antigen).
  • the VH sequence is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VH DNA sequence; and/or the VL sequence is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VL DNA sequence.
  • the VH DNA sequence is VH-ICC (see Table 21(b)) or a VH sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VH-ICC DNA sequence; and the VL DNA sequence is VL-ICC (see Table 21(b)) or a VL sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VL-ICC DNA sequence.
  • the VH DNA sequence is VH-IHG (see Table 21(b)) or a VH sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VH-IHG DNA sequence; and the VL DNA sequence is VL-IHG (see Table 21(b)) or a VL sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VL-IHG DNA sequence.
  • a VH herein may comprise the amino acid sequence of SEQ ID: 1*288 or an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*288.
  • a VH is unpaired with a second variable domain (eg, a VL), since the VH in this instance is a single variable domain, it is able to bind to a SARS-Cov-2 antigen (eg, spike) without requirement for pairing.
  • a VH herein may comprise antibody single variable domain Nb11-59 (Novamab Biopharmaceuticals Co. Ltd) or an antibody single variable domain of ALX-0171 (Ablynx).
  • a VH herein may comprise antibody single variable domain comprising SEQ ID: 1*203, or an antibody single variable domain comprising amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of Nb11-59 or SEQ ID: 1*293.
  • the combination comprises first and second multimers of the invention, wherein the first multimer comprises a binding site comprising a first VH/VL pair and the second multimer comprises a second VH/VL pair which is different from the first VH/VL pair.
  • the VH of the first VH/VL pair is encoded by the DNA sequence of VH-ICC and the VL is encoded by the DNA sequence of VL-ICC.
  • the VH of the first VH/VL pair is encoded by the DNA sequence of VH-IHG and the VL is encoded by the DNA sequence of VL-IHG.
  • the VH of the first VH/VL pair is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VH-ICC and the VL is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VL-ICC.
  • the VH of the first VH/VL pair is encoded by the DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VH-IHG and the VL is encoded by the DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VL-IHG.
  • the multimer comprises first and second antigen binding sites which are different from each other.
  • the first binding site comprises a first VH/VL pair and the second binding site comprises a second VH/VL pair.
  • the VH of the first VH/VL pair is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to a first VH DNA sequence disclosed in Table 21(b) and the VL is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the cognate VL DNA sequence disclosed in Table 21(b); and the VH of the second VH/VL pair is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to a second VH DNA sequence disclosed in Table 21(b) and the VL is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the cognate VL DNA sequence disclosed
  • the first VH DNA sequence is the sequence of VH-IHI (see Table 21(b)), the cognate VH DNA sequence is VL-IHI; and the second VH DNA sequence is the sequence of VH-IHG, VH-ICC, VH-ICD, VH-IGG, VH-IFD, VH-IED, VH-IHD or VH-IHF.
  • the first VH DNA sequence is the sequence of VH-IHG (see Table 21(b)), the cognate VH DNA sequence is VL-IHG; and the second VH DNA sequence is the sequence of VH-IHI, VH-ICC, VH-ICD, VH-IGG, VH-IFD, VH-IED, VH-IHD or VH-IHF.
  • the first VH DNA sequence is the sequence of VH-ICC (see Table 21(b)), the cognate VH DNA sequence is VL-ICC; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHQ, VH-ICD, VH-IGG, VH- IFD, VH-IED, VH-IHD or VH-IHF.
  • the first VH DNA sequence is the sequence of VH-ICD (see Table 21(b)), the cognate VH DNA sequence is VL-ICD; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHI, VH-ICC, VH-IGG, VH-IFD, VH-IED, VH-IHD or VH-IHF.
  • the first VH DNA sequence is the sequence of VH-IGG (see Table 21(b)), the cognate VH DNA sequence is VL-IGG; and the second VH DNA sequence is the sequence of VH- ICC, VH-ICD, VH-IHI, VH-IFD, VH-IED, VH-IHD or VH-IHF.
  • the first VH DNA sequence is the sequence of VH-IFD (see Table 21(b)), the cognate VH DNA sequence is VL-IFD; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHI, VH-ICC, VH-ICD, VH-GG, VH-IED, VH-IHD or VH-IHF.
  • the first VH DNA sequence is the sequence of VH-IED (see Table 21(b)), the cognate VH DNA sequence is VL-IED; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHI, VH-ICC, VH-ICD, VH-IGG, VH-IFD, VH-IHD or VH-IHF.
  • the first VH DNA sequence is the sequence of VH-IHD (see Table 21(b)), the cognate VH DNA sequence is VL-IHD; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHI, VH-ICC, VH-ICD, VH-GG, VH-IFD, VH-IED, or VH-IHF.
  • the first VH DNA sequence is the sequence of VH-IHF (see Table 21(b)), the cognate VH DNA sequence is VL-IHF; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHI, VH-ICC, VH-ICD, VH-GG, VH-IFD, VH-IED or VH-IHD.
  • the second VH DNA sequence is VH-ICC or VH-IHG.
  • the multimer comprises first and second antigen binding sites which are different from each other.
  • the first binding site comprises a first VH/VL pair and the second binding site comprises a second VH/VL pair.
  • the VH of the first VH/VL pair is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VH-ICC and the VL is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VL-ICC; and the VH of the second VH/VL pair is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VH-IHG and the VL is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VL-IHG.
  • the multimer comprises (i) at least 4, 8, 12, 16, 20, 24 or 28 (optionally no more than 4, 8, 12, 16, 20, 24 or 28 respectively) copies of a further antibody variable domain that is different from the domain of (i).
  • each domain is capable of specifically binding to a SARS-CoV-2 antigen.
  • the multimer comprises a tetramer of a polyeptide dimer, wherein the dimer comprises a first polypeptide associated with a second polypeptide, wherein the first polypeptide comprises at least one copy of a first peptide or a first antigen binding site and a teramerisation domain (TD), the second polypeptide comprises at least one copy of a second peptide or a second antigen binding site and a teramerisation domain (TD).
  • the TDs of the first and second polypeptides are identical.
  • the TDs are p53 TDs, such as human p53 TDs.
  • each of the first and second polypeptides comprises a said peptide and the first and second peptides are different. In one embodiment, each of the first and second polypeptides comprises a said peptide and the first and second peptides are the same. In one embodiment, each of the first and second polypeptides comprises a said binding site and the first and second binding sites are different. [00538] In one embodiment, each of the first and second polypeptides comprises a said binding site and the first and second binding sites are the same. In an example, in each dimer the first and second polypeptides are disulphide bonded together.
  • each dimer the first polypeptide comprises an antibody CH3 domain (eg, a CH2-CH3) and the second polypeptide comprises an antibody CH3 domain (eg, a CH2-CH3), wherein the CH3 domains associate together to form said dimer.
  • each of the first and second polypeptides comprises, in N- to C-terminal direction, a peptide or antigen binding site -TD – optional CH2 domain -CH3 domain, wherein the CH3 domains are associated together.
  • each of the first and second polypeptides comprises, in N- to C-terminal direction, a peptide or antigen binding site – optional CH2 domain - CH3 domain - TD, wherein the CH3 domains are associated together.
  • “Knobs into holes” technology for making bispecific antibodies was described in [ 1 ] and in US5,731,168, both incorporated herein by reference. The principle is to engineer paired CH3 domains of heterodimeric heavy chains so that one CH3 domain contains a “knob” and the other CH3 domains contains a “hole” at a sterically opposite position. Knobs are created by replacing small amino acid side chain at the interface between the CH3 domains, while holes are created by replacing large side chains with smaller ones.
  • the knob is designed to insert into the hole, to favour heterodimerisation of the different CH3 domains while destabilising homodimer formation.
  • the proportion of IgG molecules having paired heterodimeric heavy chains is thus increased, raising yield and recovery of the active molecule
  • Mutations Y349C and/or T366W may be included to form “knobs” in an IgG CH3 domain.
  • Mutations E356C, T366S, L368A and/or Y407V may be included to form “holes” in an IgG CH3 domain.
  • Knobs and holes may be introduced into any human IgG CH3 domain, e.g., an IgG1, IgG2, IgG3 or IgG4 CH3 domain.
  • a preferred example is IgG4.
  • the IgG4 may include further modifications such as the “P” and/or “E” mutations.
  • a "P” substitution at position 228 in the hinge (S228P) stabilises the hinge region of the heavy chain.
  • An “E” substitution in the CH2 region at position 235 (L235S) abolishes binding to Fc ⁇ R.
  • a bispecific antibody of the present invention may contain an IgG4 PE human heavy chain constant region, optionally comprising two such paired 1 Ridgway et al Protein Eng 9:617-6211996 constant regions, optionally wherein one has "knobs” mutations and one has “holes” mutations.
  • knobs-into-holes technology involves engineering amino acid side chains to create complementary molecular shapes at the interface of the paired CH3 domains in the bispecific heterodimer, another way to promote heterodimer formation and hinder homodimer formation is to engineer the amino acid side chains to have opposite charges.
  • WO2006/106905 described a method for producing a heteromultimer composed of more than one type of polypeptide (such a heterodimer of two different antibody heavy chains) comprising a substitution in an amino acid residue forming an interface between said polypeptides such that heteromultimer association will be regulated, the method comprising: (a) modifying a nucleic acid encoding an amino acid residue forming the interface between polypeptides from the original nucleic acid, such that the association between polypeptides forming one or more multimers will be inhibited in a heteromultimer that may form two or more types of multimers; (b) culturing host cells such that a nucleic acid sequence modified by step (a) is expressed; and (c) recovering said heteromultimer from the host cell culture, wherein the modification of step (a) is
  • An example of this is to suppress association between heavy chains by introducing electrostatic repulsion at the interface of the heavy chain homodimers, for example by modifying amino acid residues that contact each other at the interface of the CH3 domains, including: (a) positions 356 and 439 (b) positions 357 and 370 (c) positions 399 and 409, the residue numbering being according to the EU numbering system. [00544] By modifying one or more of these pairs of residues to have like charges (both positive or both negative) in the CH3 domain of a first heavy chain, the pairing of heavy chain homodimers is inhibited by electrostatic repulsion.
  • amino acids at the heavy chain constant region CH3 interface of the dimer of the invention are modified to introduce charge pairs, the mutations being listed in Table 1 of WO2006/106905. It was reported that modifying the amino acids at heavy chain positions 356, 357, 370, 399, 409 and 439 to introduce charge-induced molecular repulsion at the CH3 interface had the effect of increasing efficiency of formation of the intended bispecific antibody.
  • WO2006/106905 also exemplified bispecific IgG antibodies in which the CH3 domains of IgG4 were engineered with knobs-into-holes mutations.
  • Further examples of charge pairs are disclosed in WO2013/157954, which described a method for producing a heterodimeric CH3 domain-comprising molecule from a single cell, the molecule comprising two CH3 domains capable of forming an interface.
  • the method comprised providing in the cell (a) (a) a first nucleic acid molecule encoding a first CH3 domain-comprising polypeptide chain, this chain comprising a K residue at position 366 according to the EU numbering system and (b) (b) a second nucleic acid molecule encoding a second CH3 domain-comprising polypeptide chain, this chain comprising a D residue at position 351 according to the EU numbering system, the method further comprising the step of culturing the host cell, allowing expression of the two nucleic acid molecules and harvesting the heterodimeric CH3 domain-comprising molecule from the culture.
  • CH3-CH3 interface Another example of engineering at the CH3-CH3 interface that can be used in the dimer of the invention is strand-exchange engineered domain (SEED) CH3 heterodimers.
  • SEED strand-exchange engineered domain
  • the CH3 domains are composed of alternating segments of human IgA and IgG CH3 sequences, which form pairs of complementary SEED heterodimers referred to as “SEED-bodies” [ 2 ; WO2007/110205].
  • Bispecifics have also been produced with heterodimerised heavy chains that are differentially modified in the CH3 domain to alter their affinity for binding to a purification reagent such as Protein A.
  • WO2010/151792 described a heterodimeric bispecific antigen-binding protein comprising (a) a first polypeptide comprising, from N-terminal to C-terminal, a first epitope-binding region that selectively binds a first epitope, an immunoglobulin constant region that comprises a first CH3 region of a human IgG selected from IgG1, IgG2, and IgG4; and (b) a second polypeptide comprising, from N-terminal to C-terminal, a second epitope- 2 Davis JH et al., PEDS 23:195-202) binding region that selectively binds a second epitope, an immunoglobulin constant region that comprises a second CH3 region of a human IgG selected from IgG1, IgG2, and IgG
  • the CH3 of one (but not the other) of the first and second polypeptides comprises a modification that reduces or eliminates binding of the respective CH3 domain to Protein A.
  • Dimers and antibodies of the present invention may employ any of these techniques and molecular formats as desired.
  • each of the first and second polypeptides comprises an antigen binding site, wherein each binding site is an antibody single variable domain (eg, a VHH or nanobody).
  • the dimer comprises a third polypeptide and a fourth polypeptide, wherein the third polypeptide is associated with the first polypeptide, and the fourth polypeptide is associated with the second polypeptide, wherein each polyeptide comprises an antibody variable domain, wherein (i) the variable domain of the first polypeptide is paired with the variable domain of the third polypepeptide to form a first VH/VL binding site for binding a first antigen; (ii) and the variable domain of the second polypeptide is paired with the variable domain of the fourth polypepeptide to form a second VH/VL binding site for binding a second antigen.
  • the first antigen is different from the second antigen.
  • the first and second antigens are the same.
  • the variable domain of the first polypeptide is a VH and the variable domain of the third polypeptide is a VL.
  • the variable domain of the first polypeptide is a VL and the variable domain of the third polypeptide is a VH.
  • the variable domain of the second polypeptide is a VH and the variable domain of the fourth polypeptide is a VL.
  • the variable domain of the second polypeptide is a VL and the variable domain of the fourthe polypeptide is a VH.
  • the first polypeptide comprises a CH1 domain that associates with a CL domain that is comprised by the third polypeptide and/or the second polypeptide comprises a CH1 domain that associates with a CL domain that is comprised by the fourth polypeptide.
  • the first polypeptide comprises, in N- to C-terminal direction, a peptide or a variable domain of a first VH/VL antigen binding site - CH1 domain – optional hinge region -TD – [a Fc region comprising a CH2 domain and aCH3 domain]; and (ii) the second polypeptide comprises, in N- to C-terminal direction, a peptide or a variable domain of a second VH/VL antigen binding site - CH1 domain – optional hinge region -TD – [a Fc region comprising a CH2 domain and a CH3 domain], wherein the CH3 domains of the first and second polypeptides are associated together.
  • the third polypeptide comprises, in N- to C-terminal direction, a peptide or a variable region of the first antigen binding site – CL;
  • the fourth polypeptide comprises, in N- to C-terminal direction, a peptide or a variable region of the second antigen binding site – CL, wherein (iii) said variable domains or the first and third polypeptides form the first VH/VL binding site (eg, wherein the variable domain of the first polypeptide is a VH and the variable domain of the third polypeptide is a cognate VL), (iv) said variable domains of the second and fourth polypeptides form the second VH/VL binding site (eg, wherein the variable domain of the second polypeptide is a VH and the variable domain of the fourth polyeptide is a cognate VL), (v) the CH1 of the first polypeptide is associated with the CL of the third polypeptide, (vi) the CH1 of the second polypeptid
  • the multimer of the invention may be a multimer for administration to a human or animal subject for treatment or prevention of a disease or condition (eg, an infection by the first and/or second virus, or a symptom of such an infection (eg, an unwanted inflammatory response)) in the subject.
  • a disease or condition eg, an infection by the first and/or second virus, or a symptom of such an infection (eg, an unwanted inflammatory response)
  • the invention provides: A method for the treatment or prevention of a disease or condition (eg, an infection by the first and/or second virus, or a symptom of such an infection (eg, an unwanted inflammatory response)) in a human or animal subject , the method comprising administering to the subject a plurality of multimers of the invention.
  • a disease or condition eg, an infection by the first and/or second virus, or a symptom of such an infection (eg, an unwanted inflammatory response)
  • An assay kit comprising an assay reagent as mentioned above and an amount of the first antigen (eg, viral spike protein), optionally wherein the reagent and protein are comprised by different containers.
  • a method for detecting the presence of an antigen in a sample comprising combining the sample with a multimer of the invention, allowing antigen in the sample to bind multimers to form antigen/multimer complexes and detecting antigen/multimer complexes.
  • a method of expanding a utility of an antigen (eg, a protein) binding site the method comprising producing a multimer of the invention, wherein the multimer comprises a plurality of copies (eg, at least 8 or 16 copies) of the binding site.
  • the multimer comprises a tetramer of a polyeptide dimer, wherein the dimer comprises a first polypeptide associated with a second polypeptide, wherein the first polypeptide comprises at least one copy of a first peptide or a first antigen binding site and a teramerisation domain (TD), the second polypeptide comprises at least one copy of a second peptide or a second antigen binding site and a teramerisation domain (TD).
  • each of the first and second polypeptides comprises a said binding site and the first and second binding sites are different.
  • the first polypeptide comprises an antibody CH3 domain (eg, a CH2-CH3) and the second polypeptide comprises an antibody CH3 domain (eg, a CH2-CH3), wherein the CH3 domains associate together to form said dimer.
  • each of the first and second polypeptides comprises, in N- to C-terminal direction, (i) a peptide or antigen binding site -TD – optional CH2 domain -CH3 domain, wherein the CH3 domains of the first and second polypeptides are associated together; or (ii) a peptide or antigen binding site – optional CH2 domain - CH3 domain - TD, wherein the CH3 domains of the first and second polypeptide are associated together.
  • each of the first and second polypeptides comprises an antigen binding site, wherein each binding site is an antibody single variable domain (eg, a VHH or nanobody).
  • the dimer is associated with a third polypeptide and a fourth polypeptide, wherein the third polypeptide is associated with the first polypeptide, and the fourth polypeptide is associated with the second polypeptide, wherein each polyeptide comprises an antibody variable domain, wherein (i) the variable domain of the first polypeptide is paired with the variable domain of the third polypepeptide to form a first VH/VL binding site for binding a first antigen; and (ii) the variable domain of the second polypeptide is paired with the variable domain of the fourth polypepeptide to form a second VH/VL binding site for binding a second antigen.
  • the first and second antigens are different.
  • variable domain of the first polypeptide is a VH and the variable domain of the third polypeptide is a VL and/or the variable domain of the second polypeptide is a VH and the variable domain of the fourth polypeptide is a VL.
  • the first polypeptide comprises a CH1 domain that associates with a CL domain that is comprised by the third polypeptide and (ii) the second polypeptide comprises a CH1 domain that associates with a CL domain that is comprised by the fourth polypeptide; or (B) (i) the first polypeptide comprises a CH1 domain that associates with a CL domain that is comprised by the third polypeptide and (ii) the second polypeptide comprises a CL domain that associates with a CH1 domain that is comprised by the fourth polypeptide.
  • the third and fourth polypeptides are identical. Thus, a common chain or polypeptide is used.
  • the common polypeptide associates with each of the first and second polypeptides. This may simplify production by requiring only 3, instead of 4 different polypeptides to be expressed together.
  • Option (B) is useful to reduce chances of undesirable light chain pairing, ie, the fourth polypeptide pairing with the first polypeptide and/or the third polypeptide pairing with the second polypeptide.
  • the CH1 in the first polypeptide and the CL in the third polypeptide this avoids the risk of the third polypeptide pairing with the second polypeptide, since these two polypeptides comprise CL domains that do not pair with each other.
  • the CH domains of the first and fourth polypeptides do not pair with each other.
  • the first/third polypeptide pair comprises the following configuration wherin the first polypeptide comprises in N- to C-terminal direction [VH-CL-Hinge-CH2-CH3-TD] paired with the third polypeptide wherein the third polypeptide comprises in N- to C-terminal direction [VL-CH1]; and
  • the second/fourth polypeptide pair comprises the following configuration wherein the second polyeptide comprises in N- to C-terminal direction [VH-CH1-Hinge-CH2-CH3-TD] paired with the fourth polypeptide wherein the fourth polypeptide comprises in N- to C-terminal direction [VL-CL].
  • the first polypeptide comprises, in N- to C-terminal direction, a variable domain of a first VH/VL antigen binding site - CH1 domain – optional hinge region – [a Fc region comprising a CH2 domain and a CH3 domain]
  • the second polypeptide comprises, in N- to C-terminal direction, a variable domain of a second VH/VL antigen binding site - CH1 domain – optional hinge region – [a Fc region comprising a CH2 domain and a CH3 domain]
  • the third polypeptide comprises, in N- to C-terminal direction, a variable region of the first antigen binding site – CL
  • the fourth polypeptide comprises, in N- to C-terminal direction, a variable region of the second antigen binding site – CL
  • said variable domains or the first and third polypeptides form the first VH/VL binding site (eg, wherein the
  • each of the first and second polypeptides comprises a respective TD between the CH1 and the Fc thereof; (ii) each of the first and second polypeptides comprises a hinge reion and each of said polypeptides comprises a respective TD between the hinge region and the Fc thereof; or (iii) each of the first and second polypeptides comprises in N- to C-terminal direction the Fc thereof and a respective TD.
  • the first/third polypeptide pair comprises a configuration wherein the first polypeptide comprises in N- to C-terminal direction [VH-CL-Hinge-CH2-CH3-TD] paired with the third polypeptide comprising in N- to C-terminal direction [VL-CH1]; and (ii) the second/fourth polypeptide pair comprises a wherein the second polyeptide comprises in N- to C-terminal direction [VH-CH1-Hinge-CH2-CH3-TD] paired with the fourth polypeptide wherein the fourth polypeptide comprises in N- to C-terminal direction [VL-CL].
  • the Fc regions of the first and second polypeptides are associated using knob-in-hole technology, wherein (i) the Fc of the first polypeptide comprises a CH3 domain having a knob that associates with a hole of a CH3 domain of the Fc of the second polypeptide; or (ii) the Fc of the first polypeptide comprises a CH3 domain having a hole that associates with a knob of a CH3 domain of the Fc of the second polypeptide.
  • the Fc regions of the first and second polypeptides are associated using charge pairing technology, wherein (i) the Fc of the first polypeptide comprises a first amino acid positive charge that associates with a second amino acid negative charge of the Fc of the second polypeptide; or (ii) the Fc of the first polypeptide comprises a first amino acid negative charge that associates with a second amino acid positive charge of the Fc of the second polypeptide.
  • the first, but not the second, polypeptide comprises a TD.
  • each of the first and second polypeptides are devoid of a TD.
  • the dimer of the invention may be devoid of a TD, wherein the Fc regions of the first and second polypeptides are associated together in the dimer.
  • the dimer is devoid of a TD
  • all other features of the dimer disclosed herein are otherwise applicable mutatis mutandis and combinable with the alternative emobidment that is devoid of a TD.
  • the Fc regions may be associated using any technology described herein, such as using knob-in-hole or charge pairing technology.
  • the first polyeptide comprises a first antigen binding site (eg, a single variable domain or a variable domain that is paired with a variable domain of the third polypeptide (when present) to form a first VH/VL binding site) and/or the second polyeptide comprises a second antigen binding site (eg, a single variable domain or a variable domain that is paired with a variable domain of the fourth polypeptide (when present) to form a second VH/VL binding site).
  • the dimer is an antibody and the first polypeptide is a first heavy chain, the second polypeptide is a second heavy chain, the third polypeptide is a first light chain and the fourth polypeptide is a second light chain.
  • the first and second heavy chains are identical. In an example, they are different (eg, they comprise different peptides or they comprise different antigen binding sites or V domains).
  • the first and second light chains are identical. In an example, they are different (eg, they comprise different different peptides or they comprise different antigen binding sites or V domains).
  • a V domain of the first heavy chain is paired with a V domain of the first light chain and is comprised by a first VH/VL binding site that is capable of binding to a first antigen; and/or a V domain of the second heavy chain is paired with a V domain of the second light chain and is comprised by a first VH/VL binding site that is capable of binding to a second antigen.
  • the antigens in this case are different, eg, different antigens of a virus, bacterium or cell.
  • each single variable domain is selected from a variable domain disclosed herein.
  • each VH/VL binding site is a VH/VL binding site comprised by an antibody disclosed herein (or encoded by VH and VL DNA sequences disclosed herein).
  • the antigen is a viral antigen (eg, a coronavirus or SARS-CoV or SARS-Cov-2 antigen, such as RBD or spike antigen) and each single variable domain is an anti-viral antigen variable domain (eg, nanobody or VH or VHH) disclosed herein, such as a variable domain that comprises the amino acid sequence of QB-GB (SEQ ID: 1*307), QB-DD, QB-BG or QB-FE).
  • the first and second antigen binding sites are different. Optionally, they are the same.
  • the first and second VH/VL sites are different.
  • they are the same.
  • the first VH/VL site is (i) a VH/VL binding site comprising a VH and a VL encoded by a VH DNA sequence and the cognate VL DNA sequence shown in Table 21(b), or (ii) a VH/VL binding site of any antibody disclosed in Table 21(a).
  • the VH and VL are encoded by VH-ICC and VL-ICC DNA sequences.
  • the second VH/VL site is (i) a VH/VL binding site comprising a VH and a VL encoded by a VH DNA sequence and the cognate VL DNA sequence shown in Table 21(b), or (ii) a VH/VL binding site of any antibody disclosed in Table 21(a).
  • the VH and VL are encoded by VH-IHG and VL-IHG DNA sequences.
  • the first and second VH/VL sites are the same. In another embodiment, they are different.
  • a polypeptide herein comprises in N-to C-terminal direction (i) a first antibody single variable domain, a second antibody single variable domain and TD; or a first antibody single variable domain, a second antibody single variable domain and Fc; or (iii) a first antibody single variable domain, a second antibody single variable domain and CH1.
  • Each single variable domain is capable of binding to a respective antigen.
  • the antigens are different, although they may be the same.
  • the single variable domains are directly connected together.
  • the first and third polypeptides comprise a respective variable domain, wherein the variable domains are comprised by a VH/VL pair that is capable of binding a first antigen; and wherein the second polypeptide comprises a first antibody single variable domain that is capable of binding a second antigen; and the fourth polypeptide comprises a second antibody variable domain that is capable of binding a third antigen.
  • the first antigen is different from the second and third antigens.
  • the second and third antigens are the same, or they may be different.
  • Each single variable domain (dAb) may, for example, be a nanobody.
  • each single variable domain (dAb) may, for example, be a human dAb.
  • the second polypeptide comprises a configuration of, in N- to C-terminal direction, V3-CH1-Hinge-CH2-CH3(with optional hole that pairs with the knob; or optionally a second charged amino acid that pairs with the first charged amino acid)-TD
  • the fourth polypeptide comprises a configuration of,
  • hinge is absent from the first and second polypeptides.
  • the first charge is a positive charge and the second charge is a negative charge.
  • the second charge is a positive charge and the first charge is a negative charge.
  • the dimer comprises the first and second polypeptides and a third (but not fourth) polypeptide, wherein the first polypeptide is associated with the third polypeptide, the first and third polypeptides comprise a respective variable domain, wherein the variable domains are comprised by a VH/VL pair that is capable of binding a first antigen; and wherein the second polypeptide comprises a first antibody single variable domain that is capable of binding a second antigen.
  • the first antigen is different from the second antigen.
  • the second polypeptide is devoid of a CH1 domain.
  • the first and second antigens are the same, or they may be different.
  • the single variable domain (dAb) may, for example, be a nanobody.
  • the single variable domain (dAb) may, for example, be a human dAb.
  • hinge is absent from the first and second polypeptides.
  • the first charge is a positive charge and the second charge is a negative charge.
  • the second charge is a positive charge and the first charge is a negative charge.
  • a inhalable pharmaceutical composition (or dose of said composition) which comprises particles of any multimer disclosed herein in the size range from 0.5 to 5.0 ⁇ m. For example, at least 60% (eg, 60-80% or 60-90%) of particles are in said size range.
  • At least 20% (eg, 20-40% or 20-35% or 20-30%) of particles are in the size range >4.7 ⁇ m (coarse particles), and optionally in the size range >4.7 ⁇ m but no more than 5.0 ⁇ m.
  • at least 50% (eg, at least 60%, 50-80%, 50-75%, 50-70% 50-65%) of particles are in the size range ⁇ 4.7 ⁇ m (fine particles).
  • at least 15% (eg, at least 10%, at least 5%, at least 4, 3, 2 or 1%) of particles are in the size range ⁇ 1.0 ⁇ m (ultra-fine particles).
  • the particles are nebulised particles.
  • the composition or dose is comprised by a nebuliser.
  • the composition or dose is comprised by an inhaler.
  • the composition or dose is obtainable by nebulising the multimer, eg, using an Aeroneb SoloTM nebuliser.
  • the composition or dose comprises the multimer and a pharmaceutically acceptable carrier; such carriers for inhalable formulations will be familiar to the skilled addressee.
  • a) at least 20% (eg, 20-40% or 20-35% or 20-30%) of multimer particles are in the size range >4.7 ⁇ m, and optionally in the size range >4.7 ⁇ m but no more than 5.0 ⁇ m; b) at least 50% (eg, at least 60%, 50-80%, 50-75%, 50-70% 50-65%) of multimer particles are in the size range ⁇ 4.7 ⁇ m; and c) at least 15% (eg, at least 10%, at least 5%, at least 4, 3, 2 or 1%) of multimer particles are in the size range ⁇ 1.0 ⁇ m (ultra fine particles).
  • a) at least 20% of multimer particles are in the size range >4.7 ⁇ m, and optionally no more than 5.0 ⁇ m; and b) at least 50% of multimer particles are in the size range ⁇ 4.7 ⁇ m, and optionally at least 15% of multimer particles are in the size range ⁇ 1.0 ⁇ m.
  • a) at least 20% of multimer particles are in the size range >4.7 ⁇ m, and optionally no more than 5.0 ⁇ m; b) at least 50% of multimer particles are in the size range ⁇ 4.7 ⁇ m; and c) at least 15% of multimer particles are in the size range ⁇ 1.0 ⁇ m.
  • the composition may comprise particles of the multimer and the median mass aerodynamic particle diameter (MMAD) is 2 to 4.5, eg, 2.5 to 4 or 3 to 3.5 ⁇ m.
  • the multimer comprises at least 4 copies of an antibody single variable domain, eg, a that specifically binds to a virus antigen, for example a RSV or SARS-CoV-2 antigen, eg, RBD or NTD.
  • a virus antigen for example a RSV or SARS-CoV-2 antigen, eg, RBD or NTD.
  • the variable domain is CoVnb-112 (also called Nb-112 herein (SEQ ID: 1*288)
  • the virus antigen is a SARS-CoV-2 antigen
  • Nb11-59 Novamab Biopharmaceuticals Co.
  • the virus antigen is a SARS-CoV-2 antigen) or a variable domain of ALX-0171 (Ablynx BV, and the virus antigen is an RSV antigen).
  • the polypeptide herein comprises the amino acid sequence of any one of SEQ IDs: 1*289 to 1*292.
  • the multimer herein comprises 4 copies of a polypeptide that comprises the amino acid sequence of any one of SEQ IDs: 1*289 to 1*292, or an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of any one of SEQ IDs: 1*289 to 1*292.
  • the pharmaceutical composition herein may comprise such a multimer, eg, for administration to a human or animal subject for treating or preventing a lung condition.
  • the lung condition may be a lung infection, such as a viral infection, or symptom thereof.
  • MULTIMERS FOR RESISTING SARS-COV-2 MUTATION [00590]
  • the polypeptide described herein may, for example, comprise a SARS-CoV-2 antigen binding domain disclosed herein or a binding domain (eg, an antibody single variable domain) that competes with a SARS-CoV-2 antigen binding domain disclosed herein for binding to SARS-CoV-2 spike in an in vitro competition assay. In vitro competition may be determined by standard SPR or ELISA, for example.
  • SPR surface plasmon resonance
  • the polypeptide described herein may, for example, comprise a SARS-CoV-2 antigen binding domain disclosed herein or a binding domain (eg, an antibody single variable domain) that binds to the same SARS-CoV-2 spike epitope (or an overlapping epitope) as a SARS-CoV-2 antigen binding domain disclosed herein.
  • the polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike.
  • the polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state.
  • the multimer herein may comprise copies of such a binding domain.
  • the multimer described herein may, for example, bind to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike.
  • the multimer described herein may, for example, bind to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state.
  • the multimer described herein may, for example, comprise copies of a SARS-CoV-2 antigen binding domain, wherein the multimer competes with a SARS-CoV-2 antigen binding domain- containing multimer (eg, Q185B see right-hand-side schematic in Figure 14B, a tetramer of SEQ ID: 1*236) disclosed herein for binding to SARS-CoV-2 spike in an in vitro competition assay.
  • a SARS-CoV-2 antigen binding domain- containing multimer eg, Q185B see right-hand-side schematic in Figure 14B, a tetramer of SEQ ID: 1*236) disclosed herein for binding to SARS-CoV-2 spike in an in vitro competition assay.
  • In vitro competition may be determined by standard SPR or ELISA, for example.
  • Any SPR herein is, for example, surface plasmon resonance (SPR) at 37°C and pH 7.6.
  • the multimer described herein may, for example, comprise copies of a SARS-CoV-2 antigen binding domain, wherein the multimer binds to the same SARS-CoV-2 spike epitope (or an overlapping epitope) as a SARS-CoV-2 antigen binding domain-containing multimer (eg, Q185B see right-hand-side schematic in Figure 14B, a tetramer of SEQ ID: 1*236) disclosed herein.
  • the polypeptide described herein may, for example, comprise binding domain QB-GB or a binding domain (eg, an antibody single variable domain) that competes with QB-GB for binding to SARS-CoV-2 spike in an in vitro competition assay.
  • the polypeptide described herein may, for example, comprise binding domain QB-GB or a binding domain (eg, an antibody single variable domain) that binds to the same SARS-CoV-2 spike epitope (or an overlapping epitope) as QB-GB.
  • the polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike.
  • the polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state.
  • the multimer herein may comprise copies of such a binding domain.
  • Quad multimers that have such features have been found to be highly advantageous and may be more resistant to receptor-driven selection pressure associated with SARS-Cov-2 mutation.
  • a method of producing a polypeptide multimer comprising multimerising first, second, third and fourth copies of a polypeptide (eg, any polypeptide disclosed herein) that comprises at least one copy of an SARS-CoV-2 antigen binding domain (eg, QB-GB or a binding domain (eg, an antibody single variable domain) that competes with QB-GB for binding to SARS-CoV-2 spike in an in vitro competition assay, and optionally formulating the multimer in a pharmaceutical composition for administration (eg, injected or pulmonary administration) to a human or animal subject to treat or prevent a coronavirus (preferably, SARS- CoV-2) infection.
  • a polypeptide eg, any polypeptide disclosed herein
  • an SARS-CoV-2 antigen binding domain eg, QB-GB or a binding domain (eg, an antibody single variable domain) that competes with QB-GB for binding to SARS-CoV-2 spike in an in vitro competition assay
  • a pharmaceutical composition for administration
  • a method of producing a polypeptide multimer comprising multimerising first, second, third and fourth copies of a polypeptide (eg, any polypeptide disclosed herein) that comprises at least one copy of an SARS-CoV-2 antigen binding domain (such as an antibody variable domain) that binds to the same SARS-CoV-2 spike epitope (or an overlapping epitope) as QB-GB, and optionally formulating the multimer in a pharmaceutical composition for administration (eg, injected or pulmonary administration) to a human or animal subject to treat or prevent a coronavirus (preferably, SARS-CoV-2) infection.
  • a polypeptide eg, any polypeptide disclosed herein
  • an SARS-CoV-2 antigen binding domain such as an antibody variable domain
  • a method of producing a polypeptide multimer comprising multimerising first, second, third and fourth copies of a polypeptide (eg, any polypeptide disclosed herein) that comprises at least one copy of an SARS-CoV-2 antigen binding domain (such as an antibody variable domain) that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike, and optionally formulating the multimer in a pharmaceutical composition for administration (eg, injected or pulmonary administration) to a human or animal subject to treat or prevent a coronavirus (preferably, SARS-CoV-2) infection.
  • a polypeptide eg, any polypeptide disclosed herein
  • an SARS-CoV-2 antigen binding domain such as an antibody variable domain
  • a method of producing a polypeptide multimer comprising multimerising first, second, third and fourth copies of a polypeptide (eg, any polypeptide disclosed herein) that comprises at least one copy of an SARS-CoV-2 antigen binding domain (such as an antibody variable domain) that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state, and optionally formulating the multimer in a pharmaceutical composition for administration (eg, injected or pulmonary administration) to a human or animal subject to treat or prevent a coronavirus (preferably, SARS-CoV-2) infection.
  • a polypeptide eg, any polypeptide disclosed herein
  • an SARS-CoV-2 antigen binding domain such as an antibody variable domain
  • the binding domain may be an immunoglobulin domain (eg, an antibody variable domain or single variable domain (dAb or nanboby), or any other type of binding site or domain disclosed herein.
  • Compositions comprising a multimer of the invention (eg, QB-GB or a multimer that competes with QB-BB (or QB-GB) for binding to SARS-CoV-2 spike) and an anti-spike antibody (eg, wherein the antibody is regdanvimab, REGKINORATM, REGN10987, REGN10933 or CB6) may be useful for resisting mutation in the viral spike protein and/or for enhancing efficacy of treatment or prevention of SARS-CoV-2 (or SARS-CoV-1 or another coronavirus) infection or a symptom thereof in a human or animal subject.
  • novel Antibody Variable Domains & Multimers The invention provides novel antibody variable domains that are capable of binding to coronavirus spike protein.
  • An antibody variable domain that binds to coronavirus virus spike eg, SARS-CoV-2 spike, SARS- CoV-1 spike or beta-coronavirus spike
  • coronavirus virus spike eg, SARS-CoV-2 spike, SARS- CoV-1 spike or beta-coronavirus spike
  • SEQ IDs eg, SARS-CoV-2 spike, SARS- CoV-1 spike or beta-coronavirus spike
  • All sequences of the variable domains are written herein in the N- to C-terminal direction.
  • the number of changes may be 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.
  • the number of differences is preferably 14 or less, eg, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.
  • the number of differences may be 1-3.
  • the number of differences may be 1.
  • the number of differences may be 2.
  • the number of differences may be 3.
  • the number may be 8.
  • at least one of said differences is a substitution of an amino acid of said selected sequence for the amino acid found at the corresponding position of the amino acid sequence of human germline gene segment IGHV3-23 (optionally IGHV3-23*01 or IGHV3-23*04).
  • variable domain or products comprising the variable domain eg, a multimer herein
  • a human subject such as to treat or prevent a coronaviral infection or a symptom thereof.
  • Proteins with human germline residues are likely to be more compatible (eg, less immunogenic) to human recipients than proteins with non-human residues at the equivalent positions, for example.
  • one aspect is the discovery by design of positions in the novel anti-spike sequences (SEQ IDs: A-L, S and T) that are permissive for change (eg, change to a human germline amino acid) and those positions that are desirably left untouched for providing desirable antigen-binding affinity and/or expression in mammalian cells (see Examples 38-40 herein).
  • the novel variable domains are based on human IGHV3-23 gene segment and, thus, we provide information to enable design of humanised versions where amino acids can be reverted to the amino acids found at equivalent positions in human IGHV3-23.
  • said selected sequence is SEQ ID: A.
  • said selected sequence is SEQ ID: I.
  • it may be advantageous for neutralization potency that there is no said difference at the amino acid corresponding to position 35 or 50 of the selected sequence (Example 39). For example, there may be no said difference at both of these positions. Additionally or alternatively, there may be a said difference at the amino acid position corresponding to position 61 of the selected sequence.
  • An amino acid “position” of the variable domain of the invention is a position that corresponds to the position in the selected sequence (eg, in SEQ ID: A).
  • corresponding positions can be conventionally determined by sequence alignment.
  • the alignment is made routinely by taking into account such addition and deletion, in order to provide optimal alignment (with introduction of notional “gaps” in the alignment, for example, to account for additions of amino acids versus the selected sequence).
  • the amino acid corresponding to position 61 of the selected sequence is an amino acid other than a threonine, optionally wherein the amino acid is an alanine; or (b) the amino acid corresponding to position 61 of the selected sequence is a threonine.
  • the amino acid corresponding to position 61 of the selected sequence is an amino acid other than a threonine, optionally wherein the amino acid is an alanine.
  • the amino acid corresponding to position 35 of the selected sequence is a serine or the amino acid corresponding to position 50 of the selected sequence is an alanine; or (b) the amino acid corresponding to position 35 of the selected sequence is a glycine or the amino acid corresponding to position 50 of the selected sequence is a threonine.
  • the amino acid corresponding to position 35 of the selected sequence is a serine or the amino acid corresponding to position 50 of the selected sequence is an alanine.
  • the amino acid corresponding to position 37 of the selected sequence is a phenylalanine and/or the amino acid corresponding to position 47 of the selected sequence is a phenylalanine.
  • the amino acid sequence of the variable domain comprises (a) one or more amino acids selected from a glutamic acid at a position corresponding to position 1 of the selected sequence, a leucine at a position corresponding to position 5 of the selected sequence and a proline at a position corresponding to position 14 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids; (b) a serine or glycine at a position corresponding to position 35 of the selected sequence; (c) one or more amino acids selected from a glycine at a position corresponding to position 44 of the selected sequence, a leucine at a position corresponding to position 45 of the selected sequence and a serine at a position corresponding to position 49 of the selected sequence, optionally wherein the amino acid sequence comprises
  • the amino acid sequence of the variable domain comprises (a) a glutamic acid at a position corresponding to position 1 of the selected sequence, a leucine at a position corresponding to position 5 of the selected sequence and a proline at a position corresponding to position 14 of the selected sequence; (b) a serine or glycine (preferably a serine) at a position corresponding to position 35 of the selected sequence; (c) a glycine at a position corresponding to position 44 of the selected sequence, a leucine at a position corresponding to position 45 of the selected sequence and a serine at a position corresponding to position 49 of the selected sequence; (d) a serine at a position corresponding to position 75 of the selected sequence, a leucine at a position corresponding to position 79 of the selected sequence, an arginine at a position corresponding to position 87 of the selected sequence, an alanine at a position corresponding to position 88 of the selected sequence and a glutamic acid at a position
  • the amino acid of the variable domain may comprise residues as follows:- (a) all of the amino acids according to claim 8(a), (c), (d) and (e); and (b) an amino acid according to claim 8(b).
  • the amino acid of the variable domain may comprise residues as follows:- (a) an arginine or phenylalanine at a position corresponding to position 27 of the selected sequence; (b) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and/or (c) an alanine or serine at a position corresponding to position 49 of the selected sequence.
  • the amino acid of the variable domain may comprise residues as follows:- A: (a) an arginine at a position corresponding to position 27 of the selected sequence; (b) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and (c) a serine at a position corresponding to position 49 of the selected sequence; or B: (d) a phenylalanine at a position corresponding to position 27 of the selected sequence; (e) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and (f) a serine at a position corresponding to position 49 of the selected sequence.
  • the amino acid of the variable domain may comprise residues as follows:- (a) a phenylalanine at a position corresponding to position 27 of the selected sequence; (b) a serine at a position corresponding to position 31 of the selected sequence; and/or (c) a glycine at a position corresponding to position 53 of the selected sequence.
  • the framework 1 (FR1) of the variable domain may comprise SEQ ID: X or 309.
  • each of said differences may be in the FR1, complementarity determining region 1 (CDR1), FR2, CDR2, FR3 or FR4.
  • Each said difference may be an amino acid substitution, ie, a replacement of an amino acid of the selected sequence with a different amino acid. In this case, there are no additions or deletions of amino acids, such that the lengths of said amino acid sequence of the variable domain and the selected sequence are the same.
  • Each amino acid difference in the amino acid sequence of the variable domain compared to the selected sequence may be a substitution, addition or deletion.
  • the amino acid sequence of the domain may comprise one or more sequence motifs selected from (a) EVQLLESGGGLVQP (SEQ ID: X) at the N-terminal end of FR1 or EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID: Y) in FR1; (b) GRTFSEYAMS (SEQ ID: Z) or GRTFSEYAMG (SEQ ID: AA) in CDR1; (c) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence and/or GLEFVS (SEQ ID: CC) in FR2 wherein the F in SEQ ID: CC is at a position that corresponds to position 47 in the selected sequence; or (ii) WFRQAPGKGLEFVS (SEQ ID: DD) in FR2; (d) (i) AISW (SEQ ID: DD) in FR
  • the amino acid sequence of the variable domain comprises a tryptophan at a position corresponding to position 53 of the selected sequence.
  • the amino acid sequence of the variable domain comprises a glycine at a position corresponding to position 53 of the selected sequence.
  • the amino acid sequence of the variable domain comprises (a) a glutamic acid at a position corresponding to position 1 of the selected sequence, a leucine at a position corresponding to position 5 of the selected sequence and a proline at a position corresponding to position 14 of the selected sequence; (b) a serine or glycine (preferably a serine) at a position corresponding to position 35 of the selected sequence; (c) a glycine at a position corresponding to position 44 of the selected sequence, a leucine at a position corresponding to position 45 of the selected sequence and a serine at a position corresponding to position 49 of the selected sequence; (d) a serine at a position corresponding to position 75 of the selected sequence, a leucine at a position corresponding to position 79 of the selected sequence, an arginine at a position corresponding to position 87 of the selected sequence, an alanine at a position corresponding to position 88 of the selected sequence and a glutamic acid at a position
  • the amino acid sequence of the domain comprises:- (a) EVQLLESGGGLVQP (SEQ ID: X) at the N-terminal end of FR1; (b) GRTFSEYAMS (SEQ ID: Z) or GRTFSEYAMG (SEQ ID: AA) in CDR1; (c) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence and GLEFVS (SEQ ID: CC) in FR2 wherein the F in SEQ ID: CC is at a position that corresponds to position 47 in the selected sequence; (d) (i) AISW (SEQ ID: DD) at the N-terminal end of CDR2 and TYYA (SEQ ID: EE) at the C-terminal end of CDR2; (e) (i) YADSV (SEQ ID: LL) at the N-terminal end of FR1; (
  • the amino acid sequence of the variable domain comprises TISW (SEQ ID: KK).
  • the amino acid sequence of the variable domain comprises YTDSV (SEQ ID: MM) or YTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA (SEQ ID: NN).
  • the invention provides:- An isolated nucleic acid (eg, a DNA or RNA, such as mRNA or cDNA) encoding the antibody variable domain, optionally wherein the nucleic acid is comprised by an expression vector for expressing the variable domain or a polypeptide comprising the variable domain.
  • the nucleic acid or vector may be comprised by a host cell, such as a mammalian cell (eg, a HEK, CHO or Cos cell) for expression of the domain or polypeptide.
  • a host cell such as a mammalian cell (eg, a HEK, CHO or Cos cell) for expression of the domain or polypeptide.
  • the invention provides:- A polypeptide comprising the amino acid sequence of an antibody variable domain of any preceding claim and one or more further amino acid sequences, optionally wherein the polypeptide comprises a self-assembly multimerization domain (SAM domain).
  • SAM may be any SAM, such as a tetramerisation domain (TD), disclosed herein, eg, a p53 tetramerisation domain (p53 TD).
  • the polypeptide may be isolated or recombinant.
  • the polypeptide comprises at least 2 copies of the amino acid sequence of the variable domain (the polypeptide may comprise 2, 3, 4, 5, 6, 7, 8, 9 or 10 copies (but no more than said number) of the variable domain).
  • the polypeptide may comprise an amino acid sequence encoding an ACE2 peptide (eg, an ACE2 extracellular domain or any other ACE2 amino acid sequence disclosed herein).
  • the polypeptide comprises (in N- to C-terminal direction):- (i) A said ACE2 peptide, TD (eg, p53 TD) and said variable domain; (ii) Said variable domain, TD (eg, p53 TD) and a said ACE2 peptide; (iii) A said ACE2 peptide, an antibody Fc region and said variable; or (iv) Said variable domain, an antibody Fc region and a said ACE2 peptide.
  • the invention provides:- A multimer comprising a plurality (optionally comprising 4) copies of the variable domain or polypeptide.
  • the multimer may comprise 4, 18, 12, 16, 20, 24, 28 or 42 copies (but no more than said number) of the variable domain.
  • the multimer may comprise 4 (but no more than 4) copies of the polypeptide.
  • SAM domain self-assembly multimerization domain
  • each copy comprises a self-assembly multimerization domain (SAM domain), eg, a p53 domain.
  • the composition comprises an anti-inflammatory agent (eg, an anti-IL6R antibody), anti-viral agent (eg, an anti-caronavirus antibody (such as an anti-SARS-CoV-2 antibody) or vaccine), immunosuppressant and/or an ACE2 peptide (eg, ACE2 extracellular domain) or ACE2 receptor mutimer.
  • the composition may comprise an antibody medicament, eg, an anti-inflammatory antibody, such as an anti-IL-6R (eg, sarilumab or tocilizumab) or TNF alpha antibody (eg, adalimumab).
  • the composition may comprise an ACE2 peptide multimer, eg, a dimer, trimer or tetramer of an ACE2 peptide-Fc polypeptide.
  • the ACE2 peptide may comprise any ACE2 amino acid sequence disclosed herein, eg, ACE2(18-740) or ACE2(18-615).
  • a medical device eg, a syringe, inhaler or IV bag comprising the composition.
  • a method of treating or preventing a coronavirus virus eg, SARS-CoV-2, SARS-CoV-1 or beta- coronavirus
  • a coronavirus virus eg, SARS-CoV-2, SARS-CoV-1 or beta- coronavirus
  • the method comprising administering the composition to the subject.
  • a coronavirus virus eg, SARS-CoV-2, SARS-CoV-1 or beta- coronavirus
  • the subject may be a male or female.
  • the subject may have a Body Mass Index (BMI) greater than 25, 28, 30, 32, 33, 34, 35, 36, 37, 38, 39 or 40, preferably greater than 30.
  • BMI Body Mass Index
  • the subject may be a BAME (Black, Asian or Minority Ethnic) human.
  • the subject may be at least 80, 75, 70, 65, 60, 55, 5045, 40, 35, 30, 25 or 28 years of age, preferably at least 70 years of age.
  • the subject may have a cardiovascular disease, diabetes, chronic respiratory disease or cancer.
  • the subject may have previously suffered from such a condition.
  • the virus is a SARS virus, eg, SARS-CoV-2.
  • Administration to the subject may be into the bloodstream (eg, IV administration).
  • Administration to the subject may be inhaled administration (eg, using a nebulizer or inhaler device).
  • Administration may be intravenously, intraperitoneal or subcuteaneous. Any route of administration disclosed herein may be used. Any nebulised or inhalable formulation disclosed herein may be applied mutatis mutandis to the administration or forumulation of the variable domain, multimer, tetramer or pharmaceutical composition.
  • the invention provides:- A method of detecting the presence of a virus in a sample (eg, a biological sample), the method comprising contacting the variable domain, polypeptide, multimer or tetramer with the sample and detecting virus or virus spike protein is bound to the variable domain, polypeptide, multimer or tetramer.
  • the spike protein may be all or part of the spike.
  • the sample is, eg, a blood sample, nasal swab sample, oral cavity sample or sputum sample.
  • the sample may be a sample that has been obtained from a human or animal subject.
  • ELISA detection or any other routine method can be used, as will be familiar to the skilled person.
  • the sample may be immobilised on a solid support or comprised by a liquid.
  • virus or coronavirus virus herein is, eg, SARS-CoV-2, SARS-CoV-1 or a beta- coronavirus.
  • Multimer Purification, Assay & Diagnostics Methods [00660] In experiments we observed that multimers of the invention comprising at least 4 copies of an antibody VH domain with or without an antibody Fc region could be usefully purified without the need for affinity tags (such as a His tag) by binding to Protein A. Binding was observed to be much greater than binding of VH monomer to Protein A.
  • the protein A may be immobilised on a solid support, eg, a resin.
  • the purification of multimers in this way may be advantageous where the VH is a IGHV3 variable domain (ie, a recombinant of a human IGHV3 gene segment), as such VH bind particularly well to the protein A.
  • the invention provides:- A method of binding a multimer to a solid support, the method comprising contacting a solid support (eg, a gel, resin or bead) with the multimer, wherein protein A is immobilised on the solid support prior to said contacting and the multimer is bound by protein A, optionally further comprising separating the bound multimer from the protein A.
  • a solid support eg, a gel, resin or bead
  • a method of isolating a multimer from a sample comprising the multimer comprising contacting the sample with a solid support (eg, a gel, resin or bead), wherein protein A is immobilised on the solid support prior to said contacting and the multimer is bound by protein A, optionally further comprising separating the bound multimer from the protein A.
  • a solid support eg, a gel, resin or bead
  • protein A is immobilised on the solid support prior to said contacting and the multimer is bound by protein A, optionally further comprising separating the bound multimer from the protein A.
  • the sample may be any sample disclosed herein.
  • the sample may be a product of chemical or biological experiment (eg, that has been carried out in vivo).
  • the method may be a forensics method or food or medical testing method.
  • the method may be a method of diagnosis (eg, to detect the presence of the multimer in the sample).
  • the multimer comprises 4 (eg, no more than 4) copies of an antibody VH domain.
  • the multimer comprises 4, 8, 12, 16, 20, 24, 28 or 32 (eg, no more than said number) copies of an antibody VH domain.
  • the VH may be a human IGHV3 variable domain (eg, a recombinant of human gene segment VH3-23, eg, VH3-23*01 or *04).
  • the method may comprise detecting the binding of the multimer to the protein A. The skilled person will know of conventional assay techniques for this purpose.
  • the VH may be any suitable variable domain disclosed herein.
  • the multimer may comprise one or more antibody Fc regions.
  • the multimer may be devoid of an antibody Fc region.
  • Examples of Determining Competition Antigen binding affinity by SPR [00665] Antigen binding ability, specificity and affinity (Kd, K off and/or K on ) can be determined by any routine method in the art, e.g. by surface plasmon resonance (SPR).
  • SPR surface plasmon resonance
  • Kd or “K D ”, as used herein, is intended to refer to the equilibrium dissociation constant of a particular binding moieity (eg, multimer or binding domain)-antigen interaction.
  • binding measurements can be made using a variety of binding assays known in the art, e.g.
  • the surface plasmon resonance (SPR) is carried out at 25 o C. In another non-limiting embodiment, the SPR is carried out at 37 o C.
  • the SPR is carried out at physiological pH, such as about pH7 or at pH7.6 (e.g. using Hepes buffered saline at pH 7.6 (also referred to as HBS-EP)).
  • the SPR is carried out at a physiological salt level, e.g.150 mM NaCl.
  • the SPR is carried out at a detergent level of no greater than 0.05% by volume, e.g. in the presence of P20 (polysorbate 20; e.g. Tween 20 TM ) at 0.05% and EDTA at 3 mM.
  • the SPR is carried out at 25 o C or 37 o C in a buffer at pH 7.6, 150 mM NaCl, 0.05% detergent (e.g. P20) and 3mM EDTA.
  • the buffer can contain 10 mM Hepes.
  • the SPR is carried out at 25 o C or 37 o C in HBS-EP.
  • HBS-EP is available from Teknova Inc. (California; catalogue number H8022).
  • the affinity of an antigen binding multimer is determined using SPR by: a) Coupling anti-antibody constant region (such as when the multimer comprises an Fc (or coupling any other polypeptide capture reagent) (e.g. Biacore TM BR-1008-38) to a biosensor chip (e.g.
  • GLM chip b) Exposing the capture reagent to a test multimer to capture the test multimer on the chip; c) Passing the test antigen over the chip’s capture surface at 1024 nM, 256 nM, 64 nM, 16 nM, 4 nM with a 0 nM (i.e. buffer alone); and d) Determining the affinity of binding of test multimer to test antigen using surface plasmon resonance, e.g. under an SPR condition discussed above (e.g. at 25 o C in physiological buffer).
  • SPR can be carried out using any standard SPR apparatus, such as by Biacore TM or using the ProteOn XPR36 TM (Bio-Rad ® ).
  • Regeneration of the capture surface can be carried out with 10 mM glycine at pH 1.7. This removes the captured multimer and allows the surface to be used for another interaction.
  • the binding data can be fitted to 1:1 model inherent using standard techniques, e.g. using a model inherent to the ProteOn XPR36 TM analysis software.
  • Antigen binding affinity by ELISA [00673] Another non-limiting method for determining antigen binding affinity or the functional affinity (i.e.
  • the overall binding strength for the antigen) of a given molecule could be by using a standard ELISA binding assay as described below: [00674] High protein binding ELISA plates are coated overnight at 4 o C either directly with antigen or with capture antibody such as anti-IgG at concentration between 1 - 5 ug/mL prepared in PBS [00675] Coated ELISA plate is washed 3x with wash buffer (PBS containing 0.1% Tween 20). [00676] Plate is blocked with blocking buffer (1% BSA in PBS) except where capture antibody is used in the first step. In this case, target antigen at 1 – 5 ug/ml is added to the plate and incubated at room temperature for 1 hour before performing the blocking step.
  • Test-multimer (or binding domain, site or polypeptide) is serially diluted in sample dilution buffer (0.1% BSA in PBS) before adding to the coated ELISA plate and the plate is incubated at room temperature for 1 hour after 3 washes with wash buffer.
  • Detection antibody such as anti-IgG or anti-His tag conjugated to HRP is added to the plate and incubated at room temperature for 1 hour after 3 washes with wash buffer.
  • Antigen binding signal is developed through the addition of TMB after 3 washes with wash buffer. The plate is incubated in the dark for 5 – 30 mins before the reaction is stop with the addition of 1M sulfuric acid.
  • Assay signal is determined by measuring absorbance at 450nm using a plate reader.
  • Half-maximal binding concentration of the test-multimer can be determined as readout of antigen binding affinity.
  • Competition Binding Assays [00682] Competition binding assays can be used to determine whether a given molecule competes for the sample binding epitope or binding region on an antigen of interest compared to a test-multimer (or binding domain, site or multimer). In addition, competition assays can be used as a screening method to discover similar antigen binding molecules or molecules that compete with the test-multimer. There are multiple routine methods for performing competition assays such as those based on SPR, flow cytometry or ELISA.
  • Test-antigen is immobilized on CM5 sensor chip.
  • test multimer or binding domain, site or polypeptide
  • a second injection containing a mixture of test-multimer (binding domain, site or polypeptide) and competitor antigen binding molecule at the same concentration is injected
  • Competition for binding to the test-multimer antigen binding site can be determined by reduction in test-multimer Kd with the addition of the competitor molecule.
  • Non-Limiting Flow Cytometry-based competition assay A dilution series of competitor molecule is generated in FACS buffer (PBS + 2% FCS) from 1 ug/ml and mixed with a fixed concentration of test-multimer (or binding domain, site or polypeptide) conjugated to Alexa647.
  • FACS buffer PBS + 2% FCS
  • Antigen expressing cells are prepared through series of washes with PBS and resuspended in FACS buffer at 10 6 cells/ml.
  • plate is incubated at room temperature for 1 hour with 3x plate washes using wash buffer (0.1% Tween 20 in PBS).
  • wash buffer (0.1% Tween 20 in PBS).
  • ELISA plate is blocked with 200 ul blocking buffer (1% BSA in PBS) and incubated at room temperature for 1 hour.
  • sample buffer (0.1% BSA in PBS) containing a fixed amount of biotinylated test- multimer (or binding domain, site or polypeptide). The mixture is incubated at room temperature for 30 mins before adding 100 ul of the mix to the plate after step 3.
  • Assay signal is determined by measuring absorbance at 450nm using a plate reader.
  • Competition for test-multimer antigen binding site is measured by the reduction in assay signal intensity.
  • competition is determined by a SPR competition assay.
  • competition is determined by an ELISA competition assay.
  • competition is determined by flow cytometry competition assay.
  • the assay may be any competition assay disclosed herein.
  • compositions comprising a multimer of the invention (eg, QB-GB or a multimer that competes with QB-BB for binding to SARS-CoV-2 spike) and an anti-spike antibody (eg, wherein the antibody is regdanvimab, REGKINORATM, REGN10987, REGN10933 or CB6) may be useful for resisting mutation in the viral spike protein and/or for enhancing efficacy of treatment or prevention of SARS-CoV-2 (or SARS-CoV-1 or another coronavirus) infection or a symptom thereof in a human or animal subject.
  • PARAGRAPHS- There are provided the following Paragraphs. 1.
  • a method of detecting the presence of an antigen (eg, a viral antigen) in a sample comprising contacting the multimer, dimer, polypeptide, kit or composition of the invention with the sample and detecting antigen (eg, virus spike protein) is bound to the multimer, dimer or polypeptide.
  • an antigen eg, a viral antigen
  • a pharmaceutical composition comprising (i) a multimer of the invention and (ii) an anti-SARS- CoV-2 antibody (eg, an anti-spike antibody) or an ACE2 peptide multimer, optionally wherein the multimer is according to any multimer disclosed herein.
  • composition of Paragraph 2 wherein the polypeptide comprises a tetramerization domain (TD) and one or more copies of an antigen binding site or domain (BD), the polypeptide comprising or consisting of, in N- to C- terminal direction (a) BD-TD; (b) TD-BD; (c) BD-BD-TD; (d) TD-BD-BD; (e) BD-TD-BD-BD; (f) BD-BD-TD-BD; or (g) BD-BD-TD-BD-BD; wherein (a) BD is a binding domain (eg, an antibody single variable domain) that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike; or (b) the multimer binds to the inner face of the RBD of SARS-CoV-2 spike.
  • TD-TD tetramerization domain
  • BD-BD-TD antigen binding site or domain
  • composition of Paragraph 2 or 3 wherein the antibody is selected from any antibody recited herein, optionally wherein the antibody is regdanvimab, REGKINORATM, REGN10987, REGN10933 or CB6.
  • the composition of Paragraph 2 or 3, wherein the ACE2 peptide multimer comprises 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 copies of an ACE2 peptide (eg, ACE2 extracellular domain, ACE2(18-615) or ACE2(18-740)).
  • the composition of Paragraph 5 wherein the ACE2 multimer is a multimer disclosed herein. 7.
  • composition of any one Paragraphs 2 to 6 further comprising an anti-inflammatory medicament (eg, an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)) or an immunosuppressant.
  • an anti-inflammatory medicament eg, an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)
  • an immunosuppressant eg, an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)
  • an immunosuppressant eg, an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)
  • an immunosuppressant eg,
  • the second binding site is a spike binding site of an antibody recited herein, optionally wherein the antibody is regdanvimab, REGKINORATM, REGN10987, REGN10933 or CB6.
  • SAM eg, a tetramerization domain (TD)
  • TD tetramerization domain
  • a multimer comprising 4 copies of the polypeptide of any one of Paragraphs 9 to 12.
  • a pharmaceutical composition comprising a polypeptide or multimer of any one of Paragraphs 9 to 13 and an excipient, diluent or carrier.
  • the composition of Paragraphs 14, further comprising an anti-inflammatory medicament eg, an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)
  • an immunosuppressant eg, an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)
  • a medical device eg, an inhaler, IV bag or syringe comprising the composition of Paragraphs 14 or 15.
  • a protein multimer comprising 4 copies of a binding site, wherein the binding site is capable of binding to a virus spike protein of a coronavirus.
  • the binding site may be any binding site, eg, VH or VL (or VH/VL pair) disclosed herein.
  • the multimer of Concept 1 wherein said virus is a first virus and the multimer is capable of binding to a second coronavirus, wherein the first and second viruses are different virus strains; optionally wherein the viruses are different SARS-CoV-2 strains.
  • the multimer of Concept 2 wherein the viruses have different forms of virus spike proteins and the multimer is capable of binding to the spike proteins.
  • the multimer of any preceding Concept, wherein the binding site is an antibody single variable domain. 5.
  • the multimer of any preceding Concept, wherein the binding site is a) an antigen binding site that is capable of binding to a SARS-CoV-2 spike glycoprotein; or b) an ACE2 or TMPRSS2 peptide. 6. The multimer of any preceding Concept, wherein the binding site is capable of binding to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike. 7.
  • the binding site comprises (i) an antibody VH domain comprising the SEQ ID: 1*307 or (ii) an antibody VH domain that comprises an amino acid sequence that is at least 70% identical to SEQ ID: 1*307 or that competes in an in vitro competition assay with the antibody VH domain of (i) for binding to SARS-CoV-2 spike; b) comprising 4 copies of an antigen binding site of an antibody, wherein the antibody is selected from a VH domain comprising the amino acid sequence of SEQ ID: 1*288 (or an antibody variable domain comprising an amino acid sequence that is at least 80% identical to SEQ ID: 1*288), REGN10987, REGN10933 and CB6; or c) comprising 4 copies of an antigen binding site of an antibody, wherein the multimer comprises a dimer of the antibody, wherein the antibody is selected from REGN10987, REGN10933 and CB6.
  • the multimer comprises at least 4 copies of a polypeptide, wherein the polypeptide comprises a self-assembly multimerization domain (SAM) (optionally a tetramerization domain, TD) and one or more copies of the antigen binding site.
  • SAM self-assembly multimerization domain
  • TD tetramerization domain
  • any one of Concepts 1-7 wherein the multimer is a protein dimer comprising 2 copies of a) the polypeptide defined in Concept 8, optionally wherein the polypeptide comprises (in N- to C-terminal direction) BD-BD-SAM, wherein BD is the binding site; or b) a polypeptide comprising one or more copies of the binding site and an antibody Fc region, wherein the multimer is a dimer and the Fc regions of the 2 polypeptide copies are associated together in the dimer. 10.
  • the binding of the multimer (first multimer) to the first virus spike protein is stronger than the binding of a second multimer to the first virus spike protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site and wherein a) the first multimer binds to the first virus spike protein with an OD 450 from 1 to 3 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay (and optionally the second multimer binds to the first virus spike protein with an OD 450 less than 0.5 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay); b) the first multimer (i) binds to a first virus spike protein trimer with an OD 450 from 2 to 3 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay and (ii) binds to a first virus spike protein monomer with an OD 450
  • compositions comprising a multimer of any preceding Concept, optionally wherein the composition is a nebulised composition.
  • compositions comprising particles of the multimer and (a) at least 20% of multimer particles are in the size range >4.7 ⁇ m, and optionally no more than 5.0 ⁇ m; and (b) at least 50% of multimer particles are in the size range ⁇ 4.7 ⁇ m, and optionally at least 15% of multimer particles are in the size range ⁇ 1.0 ⁇ m; or (ii) the composition comprises particles of the multimer and the median mass aerodynamic particle diameter (MMAD) is 3 to 3.5 ⁇ m. 15.
  • MMAD median mass aerodynamic particle diameter
  • composition of Concept 13 or 14 further comprising an anti-inflammatory medicament (eg, an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)) or an immunosuppressant.
  • an anti-inflammatory medicament eg, an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)
  • an immunosuppressant eg., an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)
  • an immunosuppressant eg., an inhalation device (optionally a nebuliser or inhaler) comprising the composition of any of Concepts 13 to 15. 17.
  • a method of expanding the antigen binding specificity of a binding site, wherein the binding site binds or neutralises a first antigen, but not a second antigen when the binding site is comprised in monovalent form by a protein that specifically binds to the first antigen comprising providing a plurality of copies of a polypeptide, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens; optionally wherein the multimer is according to any one of Concepts 1-12. 19.
  • a pharmaceutical composition comprising a multimer of any one of Concepts 1-12 and 19, optionally wherein the composition is comprised by a sterile medical container or device, such as a syringe, vial, inhaler or injection device.
  • 21. The multimer or composition of any one of Concepts 1-12, 19 and 20 for use as a medicament, optionally for treating or preventing viral pneumonia in a human or animal subject, such as wherein the subject is suffering from or is at risk of suffering from a coronavirus infection. 22.
  • a method of binding multiple copies of an antigen comprising combining the copies with a multimer or composition of Concepts 1-12, 19 and 21, wherein the copies are bound by the multimer, and optionally the method comprising isolating the multimer bound to the antigen copies.
  • a method of detecting the presence of anti-first antigen antibodies in a bodily fluid sample of a human or animal comprising carrying out an ELISA assay, wherein the assay comprises a) Optionally diluting the serum sample from 10 to 10 6 -fold; b) contacting the first antigen with the sample (optionally which has been diluted in step (a)) whereby anti-first antigen antibodies present in the sample bind to the first antigen (eg, spike protein) to produce antigen/antibody complexes; and c) contacting and binding the first antigen or anti-first antigen antibodies with copies of the multimer defined in one of Concepts 1-12, 19 and 21; and d) detecting multimer bound to antigen/antibody complexes, such as by determining optical density; wherein the steps can be carried out in the order (a) (b) (c) and (d) or (a) (c) (b) and (d), or wherein steps (b) and (c) are carried out simultaneously and between steps (a) and
  • a method for detecting the presence of an antigen in a sample comprising combining the sample with a multimer as defined in one of Concepts 1-12, 19 and 21, allowing antigen in the sample to bind multimers to form antigen/multimer complexes and detecting antigen/multimer complexes.
  • 25. A method of expanding a utility of an antigen binding site, the method comprising producing a multimer as defined in one of Concepts 1-12, 19 and 21, wherein the multimer comprises at least 4 copies of the binding site.
  • 26. A method for the treatment or prevention of a disease or condition in a human or animal subject), the method comprising administering to the subject a plurality of multimers as defined in one of Concepts 1-12, 19 and 21.
  • a medicament for administration to a human or animal subject for treating or preventing a seasonal virus wherein the medicament comprises a plurality of multimers according to any one of Concepts 1-12, 19 and 21, wherein the medicament comprises a pharmaceutically acceptable diluent, carrier or excipient.
  • the medicament is a multi-seasonal anti-viral medicament comprising a plurality of said multimers, wherein the multimers are capable of binding to first and second strains of the virus, wherein the strains differ in a surface-exposed antigen (optionally spike) to which the multimers can bind.
  • variable domains comprising one or more of the following features are able to neutralize divergent strains of SARS-CoV-2, such as delta and omicron:-
  • a variable domain that comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S- V, or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences.
  • the amino acid sequence of the variable domain comprises (a) a glutamic acid at a position corresponding to position 1 of the selected sequence and a proline at a position corresponding to position 14 of the selected sequence; (b) an arginine at a position corresponding to position 87 of the selected sequence and a glutamic acid at a position corresponding to position 89 of the selected sequence; and/or (c) a leucine at a position corresponding to position 120 of the selected sequence.
  • the amino acid corresponding to position 37 of the selected sequence is a phenylalanine and/or the amino acid corresponding to position 47 of the selected sequence is a phenylalanine.
  • the amino acid of the variable domain comprises (a) an arginine at a position corresponding to position 27 of the selected sequence; and/or (b) a glutamic acid at a position corresponding to position 31 of the selected sequence.
  • the amino acid sequence of the domain comprises (d) a glutamic acid at position 1; (e) a proline at position 14; (f) an arginine at position 27; (g) a glutamic acid at position 31; (h) a phenylalanine at position 37; (i) a phenylalanine at position 47; (j) an arginine at position 87; (k) a glutamic acid at position 89; and (l) a leucine at position 120.
  • the amino acid sequence of the domain comprises one or more sequence motifs selected from (a) GRTFSEYAMG (SEQ ID: AA) in CDR1; (b) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence; and (c) AAGLGTVVSEWDYDYDYW (SEQ ID: II) in CDR3.
  • the domain comprises all of these preferred features of paragraph [00706].
  • Variable domain Q225 is an example and this is surprisingly effective for neutralizing divergent SARS-Cov-2 strains such as delta and omicron.
  • Multimers of such a variable domain are useful to treat humans against multiple coronavirus strains.
  • Aspects 1 An antibody variable domain for use as a medicament for treating humans against multiple different strains of SARS-CoV-2, wherein the variable domain is capable of binding and neutralising a SARS-CoV-2 virus and the variable domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V, or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences.
  • Aspect 1 provides: An antibody variable domain for use as a medicament effective for treating a human subject against a plurality of strains of SARS-CoV-2, wherein the variable domain is capable of binding and neutralising a SARS-CoV-2 virus and the variable domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V, or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences.
  • the sequence is I.
  • the sequence is V. 3.
  • the virus is delta, alpha, the L strain, a virus strain comprising a spike containing a D614G mutation or a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron.
  • the genome comprises up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron. 4.
  • any preceding Aspect wherein said strains comprise SARS-CoV-2 omicron; and optionally one or more virus strains selected from delta, alpha, the L strain, a virus strain comprising a spike containing a D614G mutation and a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron.
  • the strains comprise delta and optionally a virus strain comprising a spike containing a D614G mutation.
  • the genome comprises up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron. 5.
  • variable domain of any preceding Aspect wherein said strains comprise SARS-CoV-2 delta, omicron and a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 delta or omicron.
  • the genome comprises up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron. 6.
  • the variable domain of any preceding Aspect for treating a human subject against SARS-CoV-2 omicron or a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron.
  • the genome comprises up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron.
  • S nucleotide sequence
  • the treating is therapeutically or prophylactically treating.
  • said selected sequence is SEQ ID: V or I.
  • a multimer comprising a plurality of copies of a variable domain according to any preceding Aspects.
  • Multimers comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of REGN10933, (iv) 4 copies of an antigen binding site of CB6, or (v) 4 copies of an antigen binding site of regdanvimab can neutralise SARS-CoV-2 (as explained above) and are useful for treating or preventing infection of humans (or a human) against multiple strains of SARS-CoV-2 wherein the strains comprise omicron.
  • Aspect 9 provides:- A multimer comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of REGN10933, (iv) 4 copies of an antigen binding site of CB6, or (v) 4 copies of an antigen binding site of regdanvimab. 10.
  • the multimer of Aspect 9 or 10 wherein the multimer comprises a plurality of antibody Fc regions.
  • the multimer of Aspect 9, 10 or 11 wherein the multimer comprises a plurality of copies of a polypeptide, wherein the polypeptide comprises at least one (preferably 2) copy(ies) of the variable domain or binding site and an antibody Fc region.
  • the multimer comprises at least 2 (and optionally no more than 2, or optionally no more than 4) copies of the polypeptide.
  • the polypeptide comprises in N- to C- terminal direction: V-V-Fc, wherein V is a variable domain according to any of Aspects 1-7.
  • Example 41 Such a format has been demonstrated in Example 41 to provide multimers that can recognise and neutralise multiple strains of SARS-Cov-2.
  • the polypeptide comprises in N- to C- terminal direction: V-V-Fc-V-V.
  • the multimer may be comprised by a medical or sterile container, eg, a syringe, vial, IV bag, container connected to a needle or a subcutaneous injection administration device. 13.
  • a pharmaceutical composition comprising the multimer of any one of Aspects 9 to 12 and a pharmaceutically acceptable diluent, carrier or excipient. 14.
  • a method of treating a human for a SARS-CoV-2 virus infection wherein the infection is an infection of SARS-CoV-2 delta or omicron; or a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron, wherein the method comprises administering (optionally by injection or inhalation) a medicament comprising (i) a multimer of a variable domain that is capable of binding and neutralising a SARS-CoV-2 virus and the variable domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V, or an amino acid sequence that is identical to a said selected sequence except for 1- 25 amino acid differences; or (ii) a multimer comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of RE
  • a multimer of a first antibody variable domain for use as a medicament in a method for treating humans against multiple different strains of SARS-CoV-2 wherein the multimer is capable of inhibiting infection of human cells (eg, HEK293 cells) by SARS-CoV-2 omicron and the first variable domain is capable of inhibiting the binding of a second antibody variable domain to SARS-CoV-2 omicron spike, wherein the second domain comprises the amino acid sequence of SEQ ID: U; and wherein said strains comprise SARS-CoV-2 omicron.
  • Concept 1 provides:- A multimer for use as a medicament in a method for treating humans against multiple different strains of SARS-CoV-2, wherein the multimer is capable of inhibiting infection of human cells (eg, HEK293 cells) by SARS-CoV-2 omicron, the multimer comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of REGN10933, (iv) 4 copies of an antigen binding site of CB6, or (v) 4 copies of an antigen binding site of regdanvimab.
  • human cells eg, HEK293 cells
  • Inhibition of infection may be inhibition of infection by at least 60, 70, 80, 90 or 95% compared to a control in a virus or pseudovirus neutralisation assay. Inhibition of infection may be inhibition of infection by 100% compared to a control in a virus or pseudovirus neutralisation assay.
  • the control comprises contacting human cells with SARS-CoV-2 omicron in the absence of the multimer. As will be clear to the skilled person, the test and control samples are otherwise tested under identical conditions. 2.
  • the multimer of Concept 1 wherein the multimer comprises 4 copies of the first variable domain or binding site, and optionally the multimer comprises no more than 4, 8 or 16 copies of said first domain or binding site. Preferably, the multimer comprises 4 copies (but no more than 4 copies) of the first domain or binding site.
  • the multimer comprises 8 copies (but no more than 8 copies) of the first domain or binding site.
  • the multimer comprises 16 copies (but no more than 16 copies) of the first domain or binding site.
  • the multimer of Concept 1 or 2 wherein the multimer comprises a plurality of copies of a polypeptide, wherein the polypeptide comprises at least one (preferably 2) copy(ies) of the variable domain or binding site and an antibody Fc region.
  • the multimer of Concept 3 wherein the polypeptide comprises in N- to C-terminal direction: V- V-Fc, wherein V is the first variable domain. 5.
  • the multimer of any preceding Concept wherein the first variable domain is capable of inhibiting the binding of the second antibody variable domain with SARS-CoV-2 omicron spike as determined by a surface plasmon resonance (SPR) or ELISA competition assay. Inhibition of binding may be by at least 60, 70, 80, 90 or 95% as determined by a surface plasmon resonance (SPR) or ELISA assay. 6.
  • the multimer is comprised by a medical or sterile container, optionally wherein the multimer is comprised by a syringe, vial, IV bag, container connected to a needle or a subcutaneous injection administration device.
  • the container may comprise an immunosuppressant or anti-inflammatory agent, eg, an anti-IL6 antibody, anti-IL-6R antibody or a steroid.
  • an immunosuppressant or anti-inflammatory agent eg, an anti-IL6 antibody, anti-IL-6R antibody or a steroid.
  • the multimer is capable of inhibiting infection of human HEK293 cells by SARS-CoV-2 omicron virus or pseudovirus comprising omicron spike in a virus neutralisation assay with an IC 50 ⁇ 0.1 nM (preferably ⁇ 0.02 nM) and/or the method comprises administering the multimer to a human subject or human subjects and inhibiting infection of human cells of the subject(s) by SARS-CoV-2 virus with an IC 50 ⁇ 0.1 nM (preferably ⁇ 0.02 nM), optionally wherein the virus is SARS-CoV-2 omicron or a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike
  • the neutralisation assay may be a pseudovirus assay, as will be apparent to the skilled addressee.
  • said strains comprise one or more virus strains selected from delta, alpha, the L strain (Wuhan strain), a virus strain comprising a spike containing a D614G mutation and a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron.
  • strains comprise SARS-CoV-2 delta and optionally a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron.
  • S nucleotide sequence
  • the changes may be up to 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60.
  • the changes are no more than 7 or 8.
  • said first domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V (preferably I or V) or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences.
  • an antibody variable domain for use as the first domain of the multimer of any preceding Concept, wherein the domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L, S and T (preferably I), or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences, wherein the variable domain is capable of inhibiting the binding of a second antibody variable domain to SARS-CoV-2 omicron spike, wherein the second domain comprises the amino acid sequence of SEQ ID: U. 12.
  • variable domain of Concept 11 wherein the variable domain is capable of inhibiting the binding of the second antibody variable domain to a SARS-CoV-2 strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron.
  • variable domain of any one of Concepts 11-14 wherein the amino acid sequence comprises (a) a glutamic acid at position 1; (b) a proline at position 14; (c) an arginine at position 27; (d) a glutamic acid at position 31; (e) a phenylalanine at position 37; (f) a phenylalanine at position 47; (g) an arginine at position 87; (h) a glutamic acid at position 89; and (i) a leucine at position 120. 16.
  • the antibody variable domain of any one of Concepts 11-16 wherein there is no said difference at the amino acid corresponding to position 35 and/or 50 of the selected sequence; and/or wherein there is a said difference at the amino acid position corresponding to position 61 of the selected sequence. 18.
  • the antibody variable domain of any one of Concepts 11-17 wherein (a) the amino acid corresponding to position 61 of the selected sequence is an amino acid other than a threonine, optionally wherein the amino acid is an alanine; or (b) the amino acid corresponding to position 61 of the selected sequence is a threonine. 19.
  • the antibody variable domain of any one of Concepts 11-18 wherein (a) the amino acid corresponding to position 35 of the selected sequence is a serine or the amino acid corresponding to position 50 of the selected sequence is an alanine; or (b) the amino acid corresponding to position 35 of the selected sequence is a glycine or the amino acid corresponding to position 50 of the selected sequence is a threonine. 20. The antibody variable domain of any one of Concepts 11-19, wherein the amino acid corresponding to position 37 of the selected sequence is a phenylalanine and/or the amino acid corresponding to position 47 of the selected sequence is a phenylalanine. 21.
  • the amino acid sequence of the variable domain comprises (a) one or more amino acids selected from a glutamic acid at a position corresponding to position 1 of the selected sequence, a leucine at a position corresponding to position 5 of the selected sequence and a proline at a position corresponding to position 14 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids; (b) a serine or glycine at a position corresponding to position 35 of the selected sequence; (c) one or more amino acids selected from a glycine at a position corresponding to position 44 of the selected sequence, a leucine at a position corresponding to position 45 of the selected sequence and a serine at a position corresponding to position 49 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids (d) one or more amino acids selected from a serine at a position corresponding to position 75 of the selected sequence, a leucine at a position corresponding to position corresponding to position corresponding to position
  • the antibody variable domain of any one of Concepts 11-21 wherein the amino acid of the variable domain comprises residues (f) all of the amino acids according to Concept 21(a), (c), (d) and (e); and (g) an amino acid according to Concept 21(b).
  • variable domain of any one of Concepts 11-23 wherein the amino acid of the variable domain comprises A: (a) an arginine at a position corresponding to position 27 of the selected sequence; (b) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and (c) a serine at a position corresponding to position 49 of the selected sequence; or B: (d) a phenylalanine at a position corresponding to position 27 of the selected sequence; (e) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and (f) a serine at a position corresponding to position 49 of the selected sequence. 25.
  • the antibody variable domain of any one of Concepts 11-24 wherein the amino acid of the variable domain comprises (a) a phenylalanine at a position corresponding to position 27 of the selected sequence; (b) a serine at a position corresponding to position 31 of the selected sequence; and/or (c) a glycine at a position corresponding to position 53 of the selected sequence.
  • 26. The antibody variable domain of any one of Concepts 11-25, wherein framework 1 (FR1) of the variable domain comprises at the N-terminal end of FR1, the amino acid sequence EVQLLESGGGLVQP (SEQ ID: W) or EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID: X).
  • CDR1 complementarity determining region 1
  • FR2 complementarity determining region 1
  • FR3 complementarity determining region 1
  • the antibody variable domain of any one of Concepts 11-29 wherein said amino acid sequence of the domain comprises one or more sequence motifs selected from (a) EVQLLESGGGLVQP (SEQ ID: W) at the N-terminal end of FR1 or EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID: X) in FR1; (b) GRTFSEYAMS (SEQ ID: Z) or GRTFSEYAMG (SEQ ID: AA) in CDR1; (c) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence and/or GLEFVS (SEQ ID: CC) in FR2 wherein the F in SEQ ID: CC is at a position that corresponds to position 47 in the selected sequence; or (ii) WFRQAPGKGLEFVS (SEQ ID: DD) in FR2; (d) (i)
  • the antibody variable domain of any one of Concepts 11-30, wherein said amino acid sequence of the domain comprises (h) a glutamic acid at position 1; (i) a proline at position 14; (j) an arginine at position 27; (k) a glutamic acid at position 31; (l) a phenylalanine at position 37; (m) a phenylalanine at position 47; (n) an arginine at position 87; (o) a glutamic acid at position 89; and (p) a leucine at position 120. 32.
  • the antibody variable domain of any one of Concepts 11-31 wherein said amino acid sequence of the domain comprises (a) GRTFSEYAMG (SEQ ID: AA) in CDR1; (b) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence; and (c) AAGLGTVVSEWDYDYDYW (SEQ ID: II) in CDR3.
  • An isolated nucleic acid encoding an antibody variable domain of any one of Concepts 11-32, optionally wherein the nucleic acid is comprised by an expression vector for expressing the variable domain or a polypeptide comprising the variable domain. 34.

Abstract

The invention relates to novel antibody variable domains that bind to coronavirus virus spike (eg, SARS-CoV-2 spike, SARS-CoV-1 spike or beta-coronavirus spike). Also provided are multimers, such as multimers comprising 4 copies of such a variable domain. Advantageously and surprisingly, such multimers are capable of neutralising divergent strains of SARS-Cov-2 such as delta and omicron.

Description

NOVEL DOMAINS & MULTIMERS TECHNICAL FIELD [0001] The invention relates to novel antibody variable domains that bind to coronavirus virus spike (eg, SARS-CoV-2 spike, SARS-CoV-1 spike or beta-coronavirus spike). Also provided are multimers, such as multimers comprising 4 copies of such a variable domain.multimers, methods and uses to expand antigen specificity of binding sites, as well as vaccines, methods of vaccination and assay methods and reagents. [0002] The invention also relates to multimers such as dimers or tetramers of polypeptides; and tetramers or higher-order multimers (eg, octamers, dodecamers and hexadecamers) of epitopes or effector domains, such as antigen binding sites (eg, antibody or TCR binding sites that specifically bind to antigen or pMHC, or variable domains thereof) or peptides such as incretin, insulin or hormone peptides. BACKGROUND [0003] Multimers of effector domains have recognized utility in medical and non-medical applications for combining and multiplying the activity and presence of effector domains, eg, to provide for higher avidity of antigen binding (for effector domains that are antibody or TCR binding domains, for example) or for enhancing biological or binding activity, such as for providing bi- or multi-specific targeting or interaction with target ligands in vivo or in vitro. [0004] Multimerisation domains which cause self-assembly of protein monomers into multimers are known in the art. Examples include domains found in transcription factors such as p53, p63 and p73, as well as domains found in ion channels such as TRP cation channels. The transcription factor p53 can be divided into different functional domains: an N-terminal transactivation domain, a proline-rich domain, a DNA-binding domain, a tetramerisation domain and a C-terminal regulatory region. The tetramerisation domain of human p53 extends from residues 325 to 356, and has a 4-helical bundle fold (Jeffrey et al., Science (New York, N.Y.) 1995, 267(5203):1498-1502). The TRPM tetramerisation domain is a short anti-parallel coiled-coil tetramerisation domain of the transient receptor potential cation channel subfamily M member proteins 1-8. It is held together by extensive core packing and interstrand polar interactions (Fujiwara et al., Journal of Molecular Biology 2008, 383(4):854-870). Transient receptor potential (TRP) channels comprise a large family of tetrameric cation-selective ion channels that respond to diverse forms of sensory input. Another example is the potassium channel BTB domain. This domain can be found at the N terminus of voltage-gated potassium channel proteins, where represents a cytoplasmic tetramerisation domain (T1) involved in assembly of alpha-subunits into functional tetrameric channels (Bixby et al., Nature Structural Biology 1999, 6(1):38-43). This domain can also be found in proteins that are not potassium channels, like KCTD1 (potassium channel tetramerisation domain-containing protein 1; Ding et al., DNA and Cell Biology 2008, 27(5):257-265). [0005] Multimeric antibody fragments have been produced using a variety of multimerisation techniques, including biotin, dHLX, ZIP and BAD domains, as well as p53 (Thie et al., Nature Boitech., 2009:26, 314-321). Biotin, which is efficient in production, is a bacterial protein which induces immune reactions in humans. [0006] Human p53 (UniProtKB - P04637 (P53_HUMAN)) acts as a tumor suppressor in many tumor types, inducing growth arrest or apoptosis depending on the physiological circumstances and cell type. It is involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. Human p53 is found in increased amounts in a wide variety of transformed cells. It is frequently mutated or inactivated in about 60% of cancers. Human p53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma. [0007] Nine isoforms of p53 naturally occur and are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine. SUMMARY OF THE INVENTION [0008] The invention provides; A protein multimer comprising 4 copies of a binding site, wherein the binding site is capable of binding to a virus spike protein of a coronavirus. [0009] There is also provided:- . a pharmaceutical composition (eg, an inhalable pharmaceutical composition) comprising such a multimer; . an inhalation device (optionally a nebuliser or inhaler) comprising the composition; . a mixture of at least 2 different multimers wherein a first of said multimers comprises 4 copies of an antigen binding site that is capable of binding to a first spike antigen and a second of said multimers comprises 4 copies of an antigen binding site that is capable of binding to a second spike antigen, and the antigens are different; . a method of expanding the antigen binding specificity of a binding site, wherein the binding site binds or neutralises (eg, when administered to humans) a first antigen, but not a second antigen when the binding site is comprised in monovalent form by a protein that specifically binds to the first antigen, the method comprising providing a plurality of copies of a polypeptide, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens; . a multimer obtainable by said method of expanding wherein the multimer is for targeting a virus whose antigens evolve through mutation during viral infection of a human subject, optionally for treating a coronavirus infection; . a method of binding multiple copies of an antigen, the method comprising combining the copies with the multimer or composition, wherein the copies are bound by the multimer, and optionally the method comprising isolating the multimer bound to the antigen copies; . a method of detecting the presence of anti-first antigen antibodies in a bodily fluid sample of a human or animal, the method comprising carrying out an ELISA assay; . a method for detecting the presence of an antigen in a sample, the method comprising combining the sample with the multimer, allowing antigen in the sample to bind multimers to form antigen/multimer complexes and detecting antigen/multimer complexes; . a method of expanding a utility of an antigen binding site, the method comprising producing the multimer, wherein the multimer comprises at least 4 copies of the binding site; . a method for the treatment or prevention of a disease or condition in a human or animal subject), the method comprising administering to the subject a plurality of the multimers; . a multimer that is capable of binding to different forms of a virus spike protein for treating, preventing or reducing in a human or animal infection by a virus comprising a first form of spike protein, and for treating, preventing or reducing infection by a virus comprising a second form of the spike protein; . a multimer that is capable of binding to different forms of a virus spike protein for treating or preventing or reducing a seasonal viral infection in a human or animal; and . a medicament for administration to a human or animal subject for treating or preventing a seasonal virus, wherein the medicament comprises a plurality of the multimers, wherein the medicament comprises a pharmaceutically acceptable diluent, carrier or excipient. [0010] The invention provides: A polypeptide comprising an antibody Fc region, wherein the Fc region comprises an antibody CH2 and an antibody CH3; and a self-associating multimerisation domain (SAM); wherein the CH2 comprises an antibody hinge sequence and is devoid of a core hinge region. Advantageously, the Fc does not directly pair with another Fc, which is useful for producing multimers by multimerization using SAM domains. For example, a benefit may be aiding desired multimer formation and/or enhancing multimer purity formed by such multimerization. [0011] The invention also provides: A multimer of a plurality of antibody Fc regions, wherein each Fc is comprised by a respective polypeptide and is unpaired with another Fc region; optionally wherein the multimer is for medical use. [0012] The invention also provides:- [0013] In a First Configuration A protein multimer of at least first, second, third and fourth copies of an effector domain (eg, a protein domain or a peptide), wherein the multimer is multimerised by first, second, third and fourth self- associating tetramerisation domains (TDs) which are associated together, wherein each tetramerisation domain is comprised by a respective engineered polypeptide comprising one or more copies of said protein domain or peptide. [0014] In a second Configuration An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a TCR binding site, insulin peptide, incretin peptide or peptide hormone; or a plurality of said tetramers or octamers. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an antibody binding site or an antibody variable domain (eg, a single variable domain); or a plurality of said tetramers or octamers. In an example the tetramer or octamer is soluble in aqueous solution (eg, aqueous eukaryotic cell culture medium). In an example the tetramer or octamer is expressible in a eukaryotic cell. Exemplification is provided below. [0015] In a third Configuration A tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, a tetramer or octamer) of (a) TCR V domains or TCR binding sites, wherein the tetramer or octamer is soluble in aqueous solution (eg, an aqueous eukaryotic cell growth medium or buffer); (b) antibody single variable domains, wherein the tetramer or octamer is soluble in aqueous solution (eg, an aqueous eukaryotic cell growth medium or buffer); (c) TCR V domains or TCR binding sites, wherein the tetramer or octamer is capable of being intracellularly and/or extracellularly expressed by HEK293 cells; or (d) antibody variable domains (eg, antibody single variable domains), wherein the tetramer or octamer is capable of being intracellularly and/or extracellularly expressed by HEK293 cells. [0016] In a fourth Configuration An engineered polypeitide or monomer of a multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, a tetramer or octamer) of the invention. [0017] In a fifth Configuration An engineered (and optionally isolated) engineered polypeptide (P1) which comprises (in N- to C- terminal direction):- (a) TCR V1 –TCR C1 – antibody CH1 (eg, IgG CH1) – optional linker – TD, wherein (i) V1 is a Vα and C1 is a Cα; (ii) V1 is a Vβ and C1 is a Cβ; (iii) V1 is a Vγ and C1 is a Cγ; or (iv) V1 is a Vδ and C1 is a Cδ; or (b) TCR V1 – antibody CH1 (eg, IgG CH1) – optional linker – TD, wherein (i) V1 is a Vα; (ii) V1 is a Vβ; (iii) V1 is a Vγ; or (iv) V1 is a Vδ; or (c) antibody V1 – antibody CH1 (eg, IgG CH1) – optional linker – TD, wherein (i) V1 is a VH; or (ii) V1 is a VL (eg, a Vλ or a Vκ); or (d) antibody V1 – optional antibody CH1 (eg, IgG CH1) – antibody Fc (eg, an IgG Fc) – optional linker – TD, wherein (i) V1 is a VH; or (ii) V1 is a VL (eg, a Vλ or a Vκ); or (e) antibody V1 – antibody CL (eg, a Cλ or a Cκ) – optional linker – TD, wherein (i) V1 is a VH; or (ii) V1 is a VL (eg, a Vλ or a Vκ); or (f) TCR V1 –TCR C1 – optional linker – TD, wherein (i) V1 is a Vα and C1 is a Cα; (ii) V1 is a Vβ and C1 is a Cβ; (iii) V1 is a Vγ and C1 is a Cγ; or (iv) V1 is a Vδ and C1 is a Cδ. [0018] In a sixth Configuration A nucleic acid encoding an engineered polypeptide or monomer of the invention, optionally wherein the nucleic acid is comprised by an expression vector for expressing the polypeptide. [0019] In a seventh Configuration Use of a nucleic acid or vector of the invention in a method of manufacture of protein multimers for producing intracellularly expressed and/or secreted multimers, wherein the method comprises expressing the multimers in and/or secreting the multimers from eukaryotic cells comprising the nucleic acid or vector. [0020] In an eighth Configuration A method producing (a) TCR V domain multimers, the method comprising the soluble and/or intracellular expression of TCR V-TD (eg, NHR2 TD or TCR V- p53 TD) fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers; (b) antibody V domain multimers, the method comprising the soluble and/or intracellular expression of antibody V (eg, a single variable domain)-TD (eg, V-NHR2 TD or V- p53 TD) fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers; (c) incretin peptide (eg, GLP-1, GIP or insulin) multimers, the method comprising the soluble and/or intracellular expression of incretin peptide-TD (eg, incretin peptide-NHR2 TD or incretin peptide-p53 TD) fusion proteins expressed in eukaryotic cells, such as HEK293T cells; the method optionally comprising isolating a plurality of said multimers; or (d) peptide hormone multimers, the method comprising the soluble and/or intracellular expression of peptide hormone-TD (eg, peptide hormone-NHR2 TD or peptide hormone- p53 TD) fusion proteins expressed in eukaryotic cells, such as HEK293T cells; the method optionally comprising isolating a plurality of said multimers. [0021] In a ninth Configuration Use of a nucleic acid or vector of the invention in a method of manufacture of protein multimers for producing glycosylated multimers in eukaryotic cells comprising the nucleic acid or vector. [0022] In a tenth Configuration Use of self-associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue thereof) in a method of the manufacture of a tetramer of polypeptides, for producing a higher yield of tetramers versus monomer and/or dimer polypeptides. [0023] In an eleventh Configuration Use of an engineered polypeptide in a method of the manufacture of a tetramer of a polypeptide comprising multiple copies of a protein domain or peptide, for producing a higher yield of tetramers versus monomer and/or dimer polypeptides, wherein the engineered polypeptide comprises one or more copies of said protein domain or peptide and further comprises a self-associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue). [0024] In a twelfth Configuration Use of self-associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue thereof) in a method of the manufacture of a tetramer of a polypeptide, for producing a plurality of tetramers that are not in mixture with monomers, dimers or trimers. [0025] In a thirteenth Configuration A eukaryotic host cell comprising the nucleic acid or vector for intracellular and/or secreted expression of the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer, octamer), engineered polypeptide or monomer of the invention. [0026] In a fourteenth Configuration [0027] Use of an engineered polypeptide in a method of the manufacture of a tetramer of a polypeptide comprising multiple copies of a protein domain or peptide, for producing a plurality of tetramers that are not in mixture with monomers, dimers or trimers, wherein the engineered polypeptide comprises one or more copies of said protein domain or peptide and further comprises a self-associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue). [0028] In a fifteenth Configuration A multivalent heterodimeric soluble T cell receptor capable of binding pMHC complex comprising: (i) TCR extracellular domains; (ii) immunoglobulin constant domains; and (iii) an NHR2 multimerisation domain of ETO. [0029] In a sixteenth Configuration A multimeric immunoglobulin, comprising (i) immunoglobulin variable domains; and (ii) an NHR2 multimerisation domain of ETO. [0030] In a seventeenth Configuration A method for assembling a soluble, multimeric polypeptide, comprising: (a) providing a monomer of the said multimeric polypeptide, fused to an NHR2 domain of ETO; (b) causing multiple copies of said monomer to associate, thereby obtaining a multimeric, soluble polypeptide. [0031] In an eighteenth Configuration A mixture comprising (i) a cell line (eg, a eukaryotic, mammalian cell line, eg, a HEK293, CHO or Cos cell line) encoding a polypeptide of the invention; and (ii) tetramers of the invention. [0032] In a ninteenth Configuration A method for enhancing the yield of tetramers of an protein effector domain (eg, an antibody variable domain or binding site), the method comprising expressing from a cell line (eg, a mammalian cell, CHO, HEK293 or Cos cell line) tetramers of a polypeptide, wherein the polypeptide is a polypeptide of the invention and comprises one or more effector domains; and optionally isolating said expressed tetramers. [0033] In a twentieth Configuration A polypeptide comprising (in N- to C-terminal direction; or in C- to N-terminal direction) (i) An immunoglobulin superfamily domain; (ii) An optional linker; and (iii) A self-associating multimerisation domain (SAM) (optionally a self-associating tetramerisation domain (TD)). [0034] In a twenty-first Configuration A method of expanding the antigen binding specificity of a binding site, wherein the binding site binds a first antigen, but not a second antigen (eg, when administered to humans) when the binding site is comprised in monovalent or bivalent form by a protein that specifically binds to the first antigen, the method comprising providing a plurality of copies of a polypeptide of the invention, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens. [0035] In a twenty-second Configuration Use of a polyepeptide of the invention in a method of manufacturing a multimer for expanding the antigen binding specificity of a binding site, wherein the binding site binds a first antigen, but not a second antigen (eg, when administered to humans) when the binding site is comprised in monovalent or bivalent form by a protein that specifically binds to the first antigen, wherein the method comprises providing a plurality of copies of a polypeptide of the invention, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens. [0036] In an embodiment, the polypeptide comprises aspects useful for treating or preventing a viral infection or cancer wherein the polypeptide comprises A: one or more epitope binding sites, optionally wherein the binding site binds to (i) a SARS- Cov-2 antigen (eg, a SARS-Cov-1 antigen and a SARS-Cov-2 antigen); (ii) BCMA (B-cell maturation antigen) and TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor); (iii) first and second Coronovirus antigens; (iv) first and second HIV antigens; (v) first and second P falciparum antigens; (vi) first and second Salmonella antigens; (vii) a TMPRSS protein (eg, a TMPRSS2 antigen); or (viii) a ACE2 antigen; or B: one, two or more copies of an ACE2 peptide (eg, an ACE2 extracellular domain) and/or a TMPRSS2 peptide (eg, a TMPRSS protein extracellular domain); or C: a first binding site that binds to a Coronavirus antigen (eg, a SARS-Covantigen, preferably a SARS-Cov-1 or -2 antigen) and one or more copies of an ACE2 peptide (eg, an ACE2 extracellular domain) and/or a TMPRSS2 peptide (eg, a TMPRSS protein extracellular domain); or D: a first binding site that binds to a ACE2 extracellular domain; and one or more copies of an ACE2 peptide (eg, an ACE2 extracellular domain) and/or a TMPRSS2 peptide (eg, a TMPRSS protein extracellular domain); or E: a first binding site that binds to a TMPRSS2 peptide extracellular domain; and one or more copies of an ACE2 peptide (eg, an ACE2 extracellular domain) and/or a TMPRSS2 peptide (eg, a TMPRSS protein extracellular domain). [0037] The invention also provides: A protein multimer comprising more than 2 copies of a binding site, wherein the binding site is capable of binding to a first antigen, optionally wherein the multimer is capable of binding to the first antigen and a second antigen, wherein the antigens are different. For example, the multimer comprises from 4 to 32 (eg, from 4 to 24, or from 4 to 20, or from 4 to 16) copies of the binding site, ie, this means that the multimer does not comprise any more or less than said number. In an embodiment, the multimer comprises, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 copies of the binding site. For example, the multimer contains from 4 to 32 (eg, from 4 to 24, or from 4 to 20, or from 4 to 16) copies of the binding site, ie, this means that the multimer does not contain any more or less than said number. In an embodiment, the multimer contains, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 copies of the binding site. In an embodiment, a control protein multimer comprising 1 or 2 (but no more than 1 or 2 respectively) of said binding sites is not capable of binding to the first antigen; or is capable of binding to the first antigen, but not to the second antigen. Binding may be determined by an ELISA assay, such as by determining OD450, for example in an ELISA assay described herein. An aspect provides: A protein multimer comprising more than 2 copies of a binding site, wherein the binding site is capable of binding to a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different. This is exemplified herein for 2 different viruses. An aspect provides:- A method for detecting the presence of an antigen in a sample, the method comprising combining the sample with a multimer of the invention, allowing antigen in the sample to bind multimers to form antigen/multimer complexes and detecting antigen/multimer complexes. A method of expanding a utility of an antigen (eg, a protein) binding site, the method comprising producing a multimer of the invention, wherein the multimer comprises a plurality of copies (eg, at least 4 or 8 copies) of the binding site. [0038] The invention also provides a pharmaceutical composition, cosmetic, foodstuff, beverage, cleaning product, detergent comprising the multimer(s), tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer(s) or octamer(s)) of the invention. [0039] A multimer herein is, eg, a dimer, trimer, tetramer, octamer, dodecamer, hexadecamer or 20- mer. [0040] As demonstrated in Example 22, dodecamer and hexadecamer multimers surprisingly display a very high functional affinity for antigen binding due to the increasing avidity effect. The functional affinity for these going from 8 to 12 binding sites (compare Tables 15 and 16) or from 8 to 16 binding sites is much more than additive; a synergistic increase is seen as a result of enhanced avidity. Thus, in one embodiment, a multimer which is 12-valent for an antigen (ie, a dodecamer as described herein) is preferred; in another embodiment a multimer which is 16-valent for an antigen (ie, hexadecamer as described herein) is preferred. [0041] Thus, a further configuration of the invention provides: A protein multimer comprising or containing 4 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different). A protein multimer comprising or containing 8 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different). A protein multimer comprising or containing 12 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different). A protein multimer comprising or containing 16 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different). A protein multimer comprising or containing 20 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different). A protein multimer comprising or containing 24 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different). [0042] In a twenty-third configuration As demonstrated in Example 32, multimers comprising 4 copies of an antigen binding site of REGN10987, REGN10933 or CB6 surprisingly display much improved neutralization potency of the Quad formats over the parental IgG format (Figure 61-J), with a a 600-fold improvement in neutralization potency over the parental mAb being surprisingly achieved. Furthermore, surprisingly, multimers comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of REGN10933, (iv) 4 copies of an antigen binding site of CB6, or (v) 4 copies of an antigen binding site of regdanvimab are able to neturalise the omicron strain of SARS-CoV-2. In one preferred embodiment, the multimer is according to option (i). In one preferred embodiment, the multimer is according to option (ii). In one preferred embodiment, the multimer is according to option (iii). In one preferred embodiment, the multimer is according to option (iv). For example, such multimer is able to neturalise a virus comprising the SARS-CoV-2 spike protein in a virus (eg, pseudovirus) assay. Thus, such multimers are useful for neturalising one or more strains of SARS-CovV-2 wherein the strain(s) comprise omicron. Thus, such multimers are useful for use as a medicament for treating or preventing SARS-CovV-2 omicron infection in a human or animal subject. Thus, such multimers are useful for use as an assay reagent in a method for detecting SARS-CovV-2 omicron in a biological sample (eg, sputum, urine, faeces or blood sample), wherein the method comprises contacting the sample with the reagent and detecting SARS-CoV-2 omicron (or spike thereof) that is bound by the reagent. Thus, the present configuration provides: A protein multimer comprising 4 copies of an antigen binding site of an antibody, wherein the antibody is selected from regdanvimab or REGKINORA™, REGN10987, REGN10933REGN10987, REGN10933 and CB6. A protein multimer comprising 4 copies of an antigen binding site of an antibody, wherein the multimer comprises a dimer of an antibody or a fragment thereof (eg, a Fab), wherein the antibody is selected from regdanvimab OR REGKINORA™, REGN10987, REGN10933 and CB6. A protein multimer comprising a dimer of an antibody or a fragment thereof (eg, a Fab), wherein the antibody is selected from regdanvimab OR REGKINORA™, REGN10987, REGN10933 and CB6. Advantageously, the multimer may comprise mammalian cell glycosylation. The multimer may, for example, comprise 8, 12, 16, 20 or 24 copies of said binding site in certain aspects of the configuration. [0043] In a twenty-fourth configuration As demonstrated in Example 33, multimers comprising 4 copies of antigen binding domain Nb-112 (a VHH domain comprising the amino acid sequence of SEQ ID: 1*288) surprisingly display much improved neutralization potency of the Quad formats over the parental VHH format (Figures 62D & 62E), with a substantial improvement in neutralization potency over the parental VHH being surprisingly achieved. As demonstrated in Example 33, such multimers also surprisingly show substantially higher binding to protein A, which aids purification. Thus, the present configuration provides: A protein multimer comprising 4 (and optionally no more than 4) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 4 (and optionally no more than 4) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 8 (and optionally no more than 8) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 8 (and optionally no more than 8) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 12 (and optionally no more than 12) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 12 (and optionally no more than 12) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 16 (and optionally no more than 16) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 16 (and optionally no more than 16) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 20 (and optionally no more than 20) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 20 (and optionally no more than 20) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 24 (and optionally no more than 24) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 24 (and optionally no more than 24) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 28 (and optionally no more than 28) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 28 (and optionally no more than 28) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. Advantageously, the multimer may comprise mammalian cell glycosylation. [0044] In a twenty-fifth configuration A method of purifying a multimer of the invention from a composition comprising the multimer, the method comprising contacting the composition with an antigen (eg, a supergantigen) and binding the multimer to the antigen, and optionally isolating antigen/multimer complexes. The multimer may be obtained from the complexes. Preferably, the multimer comprises at least 4 copies (eg, 4, 8, 12, 16, 20, 24 or 28 copies) of a VH3 family domain and the superantigen is Protein A. Preferably, the multimer comprises at least 4 copies (eg, 4, 8, 12, 16, 20, 24 or 28 copies) of a Vκ domain and the superantigen is Protein L. [0045] In a twenty-sixth configuration The polypeptide described herein may, for example, comprise binding domain QB-GB or a binding domain (eg, an antibody single variable domain) that competes with QB-GB for binding to SARS- CoV-2 spike in an in vitro competition assay. The polypeptide described herein may, for example, comprise binding domain QB-GB or a binding domain (eg, an antibody single variable domain) that binds to the same SARS-CoV-2 spike epitope (or an overlapping epitope) as QB-GB. The polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike. The polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state. Similarly, the multimer herein may comprise copies of such a binding domain. The multimer described herein may, for example, bind to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike. The multimer described herein may, for example, bind to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state. As explained in Example 37 Quad multimers that have such features have been found to be highly advantageous and may be more resistant to receptor-driven selection pressure associated with SARS- Cov-2 mutation. [0046] In a twenty-seventh configuration An antibody variable domain for use as a medicament for treating humans against multiple different strains of SARS-CoV-2, wherein the variable domain is capable of binding and neutralising SARS- CoV-2 omicron and the variable domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V, or an amino acid sequence that is identical to a said selected sequence except for 1- 25 amino acid differences; wherein said strains comprise SARS-CoV-2 omicron. An antibody variable domain that binds to coronavirus virus spike (eg, SARS-CoV-2 spike, SARS- CoV-1 spike or beta-coronavirus spike) and comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L, S and T or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences. An isolated nucleic acid encoding the antibody variable domain, optionally wherein the nucleic acid is comprised by an expression vector for expressing the variable domain or a polypeptide comprising the variable domain. A method of treating a human for a SARS-CoV-2 virus infection, wherein the infection is an infection of SARS-CoV-2 delta or omicron; or a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron, wherein the method comprises administering (optionally by injection or inhalation) a medicament comprising a multimer of the variable domain. A method of treating a human for a SARS-CoV-2 virus infection, wherein the infection is an infection of SARS-CoV-2 delta or omicron; or a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron, wherein the method comprises administering (optionally by injection or inhalation) a medicament comprising a multimer comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of REGN10933, (iv) 4 copies of an antigen binding site of CB6, or (v) 4 copies of an antigen binding site of regdanvimab. An antibody variable domain that binds to coronavirus virus spike (eg, SARS-CoV-2 spike, SARS- CoV-1 spike or beta-coronavirus spike) and comprises an amino acid sequence selected from SEQ IDs: A-L, S and T, or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences. An isolated nucleic acid encoding the antibody variable domain, optionally wherein the nucleic acid is comprised by an expression vector for expressing the variable domain or a polypeptide comprising the variable domain. A polypeptide comprising the amino acid sequence of the antibody variable domain and one or more further amino acid sequences, optionally wherein the polypeptide comprises a self-assembly multimerization domain (SAM domain), eg, a p53 domain. A tetramer of the polypeptide is also provided. A multimer comprising a plurality (optionally comprising 4) copies of the variable domain. A pharmaceutical composition comprising the variable domain, polypeptide, multimer or tetramer and a pharmaceutically acceptable excipient, diluent or carrier, optionally wherein the composition comprises an anti-inflammatory agent (eg, an anti-IL6R antibody), anti-viral agent (eg, an anti- caronavirus antibody (such as an anti-SARS-CoV-2 antibody) or vaccine), immunosuppressant and/or an ACE2 peptide (eg, ACE2 extracellular domain or a part thereof) or ACE2 peptide mutimer. A method of treating or preventing a coronavirus virus (eg, SARS-CoV-2, SARS-CoV-1 or beta- coronavirus) infection in a human or animal subject or a symptom thereof (eg, an immune or inflammatory response), the method comprising administering the composition to the subject. Use of the composition of the variable domain, the polypeptide, the multimer or the tetramer in the manufacture of a pharmaceutical composition for administration to a human or animal subject for treating or preventing a coronavirus virus (eg, SARS-CoV-2, SARS-CoV-1 or beta-coronavirus) infection in a human or animal subject or a symptom thereof (eg, an immune or inflammatory response). A multimer of this Configuration may have any of the formats disclosed herein or comprise any of the variable domains disclosed herein. [0047] In a twenty-eighth configuration A multimer of comprising 4 copies of a first polypeptide for use as a medicament in a method for treating humans against multiple different strains of SARS-CoV-2, wherein the multimer is capable of inhibiting infection of human cells by SARS-CoV-2 omicron, wherein the first polypeptide is according to any one of (a)-(r), (a) V-TD (b) V-CH2-CH3-TD (c) V-CH1-CH2-CH3-TD (d) V-CH1-TD (e) V-V-TD (f) V-V-CH2-CH3-TD (g) V-V-TD (h) V1-V2-TD (i) V1-V2-CH2-CH3-TD (j) V1-V2-TD (k) V-V-CH1-TD (l) V-V-TD-V (m) V-V-TD-V-V (n) V-V-TD-V (o) V-V-TD-V-V (p) V-V-CH1-TD-V-V (q) V-V-CH1-CH2-CH3-TD (r) V1-V2-CH1-CH2-CH3-TD wherein (s) when the multimer comprises copies of first polypeptide (c), (d) or (p), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V-CL, wherein the CL is paired with CH1 of the respective first polypeptide; (t) when the multimer comprises copies of first polypeptide (k) or (q), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V-V-CL, wherein the CL is paired with CH1 of the respective first polypeptide; (u) when the multimer comprises copies of first polypeptide (r), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V1-V2-CL, wherein the CL is paired with CH1 of the respective first polypeptide; (v) each V is an antibody variable domain (eg, an antibody single variable domain) that is capable of specifically binding to an antigen; and V1 and V2 are different variable domains and capable of specifically binding to different antigens or epitopes; (w) each V or V1 specifically binds to SARS-CoV-2 omicron spike; and (x) TD is a self-associating tetramerisation domain. There is also provided:- A multimer of comprising 4 copies of a first polypeptide for treating or preventing a SARS-CoV-2 omicron infection in a human or animal, wherein the first polypeptide is according to any one of (a)- (r), (a) V-TD (b) V-CH2-CH3-TD (c) V-CH1-CH2-CH3-TD (d) V-CH1-TD (e) V-V-TD (f) V-V-CH2-CH3-TD (g) V-V-TD (h) V1-V2-TD (i) V1-V2-CH2-CH3-TD (j) V1-V2-TD (k) V-V-CH1-TD (l) V-V-TD-V (m) V-V-TD-V-V (n) V-V-TD-V (o) V-V-TD-V-V (p) V-V-CH1-TD-V-V (q) V-V-CH1-CH2-CH3-TD (r) V1-V2-CH1-CH2-CH3-TD wherein (s) when the multimer comprises copies of first polypeptide (c), (d) or (p), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V-CL, wherein the CL is paired with CH1 of the respective first polypeptide; (t) when the multimer comprises copies of first polypeptide (k) or (q), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V-V-CL, wherein the CL is paired with CH1 of the respective first polypeptide; (u) when the multimer comprises copies of first polypeptide (r), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V1-V2-CL, wherein the CL is paired with CH1 of the respective first polypeptide; (v) each V is an antibody variable domain (eg, an antibody single variable domain) that is capable of specifically binding to an antigen; and V1 and V2 are different variable domains and capable of specifically binding to different antigens or epitopes; (w) each V or V1 specifically binds to SARS-CoV-2 omicron spike; and (x) TD is a self-associating tetramerisation domain. [0048] The invention also provides polypeptide dimers, as well as tetramers of dimers. BRIEF DESCRIPTION OF THE DRAWINGS Drawing 1: New VH Single Variable Domains & Quad Formats. A human IGHV3-23. B. Amino acid sequence alignment of novel anti-SARS-CoV-2 spike VH versions 1 to 5. Amino acid residues human germlined are highlighted in bold. C. SDS-PAGE analysis of tetrameric Quad proteins based on versions 1, 3-5 shown in lanes 1-4 respectively. D. In vitro neutralization ELISA comparing neutralization potency of the VHs. Drawing 2: Optimization of Q195. A. Amino acid sequence alignment of humanized sequence Q195 and four additional derivative human germlined versions labeled versions 6 to 9. Amino acids selected for analysis are shown with an arrow and underlined where changed in individual sequences. The phenylalanine residues in FR2 important for retaining antigen binding and stability are shown with asterisks. B. SDS-PAGE analysis of the germlined tetrameric Quad proteins (containing VH versions 6 to 9 in lanes 1 to 4 respectively). C. In vitro neutralization ELISA comparing neutralization potency of the VHs against Q195. Drawing 3: Optimization of Q225. Sequence alignment of Q225 and additional germlined VH sequences (versions 10 – 12) based on Q225 sequence where additional amino acid residues differing in CDR-1 and -2 from human IGHV3-23 germline that can be germlined. Drawing 4: Schematic structural representation and pseudovirus neutralization activity of hexadecavalent GB-based VHH Quad molecules with either IgG Fc fusion (A) or without (B) IgG Fc fusion. Drawing 5: (A) Starting from Q225, we carried out CDR mutation to revert residues back to germline compared to germline IGHGV3-23*01 sequence; this yield two variable domains (Q279 and Q280) and their amino acid sequences are shown; and (B) we carried out pseudovirus neutralisation assays and found that Q279 and Q280 were similarly as effective as Q225. [0049] All of Figures 1-63 herein are indentical to Figures 1-63 respectively of WO2021/190980, which Figures of WO2021/190980 and the description of such Figures under “BRIEF DESCRIPTION OF THE DRAWINGS” in WO2021/190980 in their entirety are expressly incorporated herein.  [0050] All polypeptide schematics and amino acid sequences herein are written N- to C-terminal. All nucleotide sequences herein are written 5’ to 3’.  [0051] SEQ IDs: 1*1 to 1*307 are identical to SEQ IDs: 1 to 307 respectively as written in WO2021/190980, which sequences of WO2021/190980 in their entirety are expressly incorporated herein. References to numbered Tables herein are references to the equivalent Table as written in WO2021/190980, which Tables of WO2021/190980 in their entirety are expressly incorporated herein.    DETAILED DESCRIPTION [0052] The invention relates to multimers such as tetramers of polypeptides and tetramers, octamers, dodecamers, hexadecamers or 20-mers (eg, tetramers and octamers) of epitopes or effector domains (such as antigen binding sites (eg, antibody or TCR binding sites that specifically bind to antigen or pMHC, or variable domains thereof)) or peptides such as incretin, insulin or hormone peptides. In embodiments, multimers of the invention are usefully producible in eurkaryotic systems and can be secreted from eukaryotic cells in soluble form, which is useful for various industrial applications, such as producing pharmaceuticals, diagnostics, as imaging agents, detergents etc. Higher order multimers, such as tetramers or octamers of effector domains or peptides are useful for enhancing antigen or pMHC binding avidity. This may be useful for producing an efficacious medicine or for enhancing the sensitivity of a diagnostic reagent comprising the multimer, such as tetramer or octamer. An additional or alternative benefit is enhanced half-life in vivo when the multimers of the invention are administered to a human or animal subject, eg, for treating or preventing a disease or condition in the subject. Usefully, the invention can also provide for multi-specific (eg, bi- or tri-specific) multivalent binding proteins. Specificity may related to specificity of antigen or pMHC binding. By using a single engineered polypeptide comprising binding domains or peptides, the invention in certain examples usefully provides a means for producing multivalent (eg, bi-specific) proteins at high purity. Use of a single species of engineered polypeptide monomer avoids the problem of mixed products seen when 2 or more different polypeptide species are used to produce multi- (eg, bi-) specific or multivalent proteins. [0053] The invention also relates to methods and uses to expand antigen specificity of binding sites, as well as vaccines, methods of vaccination and assay methods and reagents. [0054] The invention provides the following Clauses, Aspects, Paragraphs and Concepts (which are not intended to represent “Claims”; Claims are presented towards the end of this disclosure after the Examples and Tables). Any Clause herein can be combined with any Aspect or Concept herein. Any Aspect herein can be combined with any Concept herein. [0055] ASPECTS: The following Aspects are not to be interpreted as Claims. The Claims start after the Examples section. 1. A protein multimer of at least first, second, third and fourth copies of an effector domain (eg, a protein domain) or a peptide, wherein the multimer is multimerised by first, second, third and fourth self-associating tetramerisation domains (TDs) which are associated together, wherein each tetramerisation domain is comprised by a respective engineered polypeptide comprising one or more copies of said protein domain or peptide. [0056] In an example, each TD is a TD of any one of proteins 1 to 119 listed in Table 2. In an example, each TD is a p53 TD or a homologue or orthologue thereof. In an example, each TD is a NHR2 TD or a homologue or orthologue thereof. In an example, each TD is a p63 TD or a homologue or orthologue thereof. In an example, each TD is a p73 TD or a homologue or orthologue thereof. In an example, each TD is not a NHR2 TD. In an example, each TD is not a p53 TD. In an example, each TD is not a p63 TD. In an example, each TD is not a p73 TD. In an example, each TD is not a p53, 63 or 73 TD. In an example, each TD is not a NHR2, p53, 63 or 73 TD. [0057] By being “associated together”, the TDs in Aspect 1 multimerise first, second, third and fourth copies of the engineered polypeptide to provide a multimer protein, for example, a multimer that can be expressed intracellulary in a eukaryotic or mammalian cell (eg, a HEK293 cell) and/or which can be extracellularly secreted from a eukaryotic or mammalian cell (eg, a HEK293 cell) and/or which is soluble in an aqueous medium (eg, a eukaryotic or mammalian cell (eg, a HEK293 cell) culture medium). Examples are NHR TD, p53 TD, p63 TD and p73 TD (eg, human NHR TD, p53 TD, p63 TD and p73 TD) or an orthologue or homologue thereof. [0058] In an example, the TD is not a p53 TD (or homologue or orthologue thereof), eg, it is not a human p53 TD (or homologue or orthologue thereof). In an example, the TD is a NHR2 TD or a homologue or orthologue thereof, but excluding a p53 TD or a homologue or orthologue thereof. In an example, the TD is a human NHR2 TD or a homologue or orthologue thereof, but excluding a human p53 TD or a homologue or orthologue thereof. In an example, the TD is human NHR2. In an example, the amino acid sequence of the TD is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to the sequence of human NHR2. In an example, the domain or peptide is not naturally comprised by a polypeptide that also comprise a NHR2 TD. [0059] In an example, all of the domains of the polypeptide are human. [0060] The engineered polypeptide may comprise one or more copies of said domain or peptide N- terminal to a copy of said TD. Additionally or alternatively, the engineered polypeptide may comprise one or more copies of said domain or peptide C- terminal to a copy of said TD. In an example, the engineered polypeptide comprises a first said domain or peptide and a TD, wherein the first domain or peptide is spaced by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 contiguous amino acids from the TD, wherein there is no further said domain or peptide between the first domain or peptide and the TD. [0061] In an example, the multimer (eg, tetramer of said engineered polypeptide) comprises 4 (but no more than 4) TDs (eg, identical TDs) and 4, 8, 12 or 16 (but no more than said 4, 8, 12 or 16 respectively) copies of said domain or peptide. In an example, each TD and each said domain or peptide is human. [0062] In an example, the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer or octamer) comprises first, second, third and fourth identical copies of an engineered polypeptide, the polypeptide comprising a TD and one (but no more than one), two (but no more than two), or more copies of the said protein domain or peptide. For example, a tetramer of the epitope or effector domain has 4 identical copies of the polypeptide comprising a TD and each polypeptide has 1 such epitope or effector domain. For example, an octamer of the epitope or effector domain has 4 identical copies of the polypeptide comprising a TD and each polypeptide has 2 such epitope or effector domain. For example, a dodecamer of the epitope or effector domain has 4 identical copies of the polypeptide comprising a TD and each polypeptide has 3 such epitope or effector domain. For example, a hexadecamer of the epitope or effector domain has 4 identical copies of the polypeptide comprising a TD and each polypeptide has 4 such epitope or effector domain. For example, a 20-mer of the epitope or effector domain has 4 identical copies of the polypeptide comprising a TD and each polypeptide has 5 such epitope or effector domain. Generally, for example, a X-mer of the epitope or effector domain has 4 identical copies of the polypeptide comprising a TD and each polypeptide has X/4 such epitope or effector domain, where X= any multiple of 4, eg, 4, 8, 12, 16, 20, 24, 28 or 32. [0063] In some embodiments, by requiring just one type of engineered polypeptide to form the multimer, eg, tetramer or octamer, of the invention, the invention advantageously provides a format that can be readily isolated in pure (or highly pure, ie >90, 95, 96, 97, 98 or 99% purity) format, as well as a method for producing such a format in pure (or highly pure) form. Purity is indicated by the multimer of the invention not being in mixture in a composition with any other multimer or polypeptide monomer, or wherein the multimer of the invention comprises >90, 95, 96, 97, 98 or 99% of species in a composition comprising the multimer of the invention and other multimers and/or polypeptide monomers which comprise the engineered polyeptide. Thus, mixtures of different types of polypeptide in these embodiments are avoided or minimised. This advantageously also provides, therefore, plurality of multimers (eg, a plurality of tetramers or octamers or dodecamers or hexadecamers) that comprise only one (and no more than one) type of engineered polypeptide, wherein the multimers are monospecific (but multivalent) for antigen binding, or alternatively bi- or multi-specific for antigen binding. Thus, the invention provides a plurality of multimers (eg, a plurality of tetramers or octamers or dodecamers or hexadecamers, each polypeptide being at least tetra-valent for antigen binding and (i) bi-specific (ie, capable of specifically binding to 2 different antigens) or (ii) mono-specific and at least tetravalent for antigen binding. Herein, where antigen binding is mentioned this can instead be pMHC binding when the domain is a TCR V domain. Advantageously, the plurality is in pure form (ie, not mixed with multimers (eg, tetramers or octamers or dodecamers or hexadecamers) that comprise more than one type of polypeptide monomer. In an example, the multimer comprises at least 2 different types of antigen binding site. In an example, the multimer is bi-specific, tri-specific or tetra-specific. In an example, the multimer has an antigen binding site or pMHC binding site valency of 4, 6, 8, 10 or 12, preferably 4 or 8. [0064] In an example, a peptide MHC (pMHC) is a class I or class II pMHC. [0065] By the term "specifically binds," as used herein, eg, with respect to a domain, antibody or binding site, is meant a domain, antibody or binding site which recognises a specific antigen (or pMHC) with a binding affinity of 1mM or less as determined by SPR [0066] Target binding ability, specificity and affinity (KD (also termed Kd), Koff and/or Kon) can be determined by any routine method in the art, eg, by surface plasmon resonance (SPR). The term “KD”, as used herein, is intended to refer to the equilibrium dissociation constant of a particular binding site/ligand, receptor/ligand or antibody/antigen interaction. In one embodiment, the surface plasmon resonance (SPR) is carried out at 25° C. In another embodiment, the SPR is carried out at 37° C. In one embodiment, the SPR is carried out at physiological pH, such as about pH7 or at pH7.6 (eg, using Hepes buffered saline at pH7.6 (also referred to as HBS-EP)). In one embodiment, the SPR is carried out at a physiological salt level, eg, 150 mM NaCl. In one embodiment, the SPR is carried out at a detergent level of no greater than 0.05% by volume, eg, in the presence of P20 (polysorbate 20; eg, Tween-20™) at 0.05% and EDTA at 3 mM. In one example, the SPR is carried out at 25° C. or 37° C. in a buffer at pH7.6, 150 mM NaCl, 0.05% detergent (eg, P20) and 3 mM EDTA. The buffer can contain 10 mM Hepes. In one example, the SPR is carried out at 25° C. or 37° C. in HBS-EP. HBS-EP is available from Teknova Inc (California; catalogue number H8022). In an example, the affinity (eg, of a VH/VL binding site) is determined using SPR by using any standard SPR apparatus, such as by Biacore™ or using the ProteOn XPR36™ (Bio-Rad®). The binding data can be fitted to 1:1 model inherent using standard techniques, eg, using a model inherent to the ProteOn XPR36™ analysis software. [0067] In an example, a multimer, tetramer or octamer or dodecamer or hexadecamer or 20-mer of the invention is an isolated multimer, tetramer or octamer or dodecamer or hexadecamer or 20-mer. In an example, a multimer, tetramer or octamer of the invention consists of copies of said engineered polypeptide. Optionally the multimer, tetramer or octamer or dodecamer or hexadecamer or 20-mer of the invention comprises 4 or 8 or 12 or 16 or 20 but not more than 4 or 8 or 12 or 16 or 20 copies respectively of the engineered polypeptide. [0068] By “engineered” is meant that the polypeptide is not naturally-occurring, for example the protein domain or peptide is not naturally comprised by a polypeptide that also comprises said TD. [0069] Each said protein domain or peptide may be a biologically active domain or peptide (eg, biologically active in humans or animals), such as a domain that specifically binds to an antigen or peptide-MHC (pMHC), or wherein the domain is comprised by an antigen or pMHC binding site. In an alternative, the domain or peptide is a carbohydrate, glucose or sugar-regulating agent, such as an incretin or an insulin peptide. In an alternative, the domain or peptide is an inhibitor or an enzyme or an inhibitor of a biological function or pathway in humans or animals. In an alternative, the domain or peptide is an iron-regulating agent. Thus, in an example, each protein domain or peptide is selected from an antigen or pMHC binding domain or peptide; a hormone; a carbohydrate, glucose or sugar- regulating agent; an iron-regulating agent; and an enzyme inhibitor. 2. The multimer of any preceding Aspect, wherein the multimer is a tetramer, octamer, 12-mer, 16-mer or 20-mer (eg, a tetramer, octamer, 12-mer or 16-mer) of said domain or peptide. 3. The multimer of any Aspect 1 or 2, comprising a tetramer, octamer, 12-mer, 16-mer or 20- mer (eg, a tetramer, octamer, 12-mer or 16-mer) of an immunoglobulin superfamily binding site (eg, an antibody or TCR binding site, such as a scFv or scTCR). [0070] The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily based on shared structural features with immunoglobulins (also known as antibodies); they all possess a domain known as an immunoglobulin domain or fold. Members of the IgSF include cell surface antigen receptors, co-receptors and co- stimulatory molecules of the immune system, molecules involved in antigen presentation to lymphocytes, cell adhesion molecules, certain cytokine receptors and intracellular muscle proteins. They are commonly associated with roles in the immune system. [0071] T-cell receptor (TCR) domains can be Vα (eg. paired with a Vβ), Vβ (eg. paired with a Vα), Vγ (eg, paired with a Vδ) or Vδ (eg, paired with a Vγ). 4. The multimer of Aspect 3, wherein the binding site comprises a first variable domain paired with a second variable domain. [0072] In a first example, the first and second variable domains are comprised by the engineered polypeptide. In another example, the first domain is comprised by the engineered polypeptide and the second domain is comprised a by a further polypeptide that is different from the engineered polypeptide (and optionally comprises a TD or is devoid of a TD). [0073] In the alternative, the domains are constant region domains. In an alternative, the domains are FcAbs. In an alternative, the domains are non-Ig antigen binding sites or comprises by a non-Ig antigen binding site, eg, an affibody. ANTIGEN BINDING SITES & EFFECTOR DOMAINS [0074] In an example, the or each antigen binding site (or effector domain) is selected from the group consisting of an antibody variable domain (eg, a VL or a VH, an antibody single variable domain (domain antibody or dAb), a camelid VHH antibody single variable domain, a shark immunoglobulin single variable domain (NA V), a Nanobody™ or a camelised VH single variable domain); a T-cell receptor binding domain; an immunoglobulin superfamily domain; an agnathan variable lymphocyte receptor (J Immunol; 2010 Aug l;185(3):1367-74; "Alternative adaptive immunity in jawless vertebrates; Herrin BR & Cooper M D.); a fibronectin domain (eg, an Adnectin™); an scFv; an (scFv)2; an sc-diabody; an scFab; a centyrin and an antigen binding site derived from a scaffold selected from CTLA-4 (Evibody™); a lipocalin domain; Protein A such as Z-domain of Protein A (eg, an Affibody™ or SpA); an A-domain (eg, an Avimer™ or Maxibody™); a heat shock protein (such as and epitope binding domain derived from GroEI and GroES); a transferrin domain (eg, a trans-body); ankyrin repeat protein (eg, a DARPin™); peptide aptamer; C-type lectin domain (eg, Tetranectin™); human γ- crystallin or human ubiquitin (an affilin); a PDZ domain; scorpion toxin; and a kunitz type domain of a human protease inhibitor. [0075] Further sources of antigen binding sites are variable domains and VH/VL pairs of antibodies disclosed in WO2007024715 at page 40, line 23 to page 43, line 23. This specific disclosure is incorporated herein by reference as though explicitly written herein to provide basis for epitope binding moieties for use in the present invention and for possible inclusion in claims herein. [0076] A "domain" is a folded protein structure which has tertiary structure independent of the rest of the protein. Generally, domains are responsible for discrete functional properties of proteins and in many cases may be added, removed or transferred to other proteins without loss of function of the remainder of the protein and/or of the domain. A "single antibody variable domain" is a folded polypeptide domain comprising sequences characteristic of antibody variable domains. It therefore includes complete antibody variable domains and modified variable domains, for example, in which one or more loops have been replaced by sequences which are not characteristic of antibody variable domains, or antibody variable domains which have been truncated or comprise N- or C-terminal extensions, as well as folded fragments of variable domains which retain at least the binding activity and specificity of the full-length domain [0077] The phrase "immunoglobulin single variable domain" or "antibody single variable domain" refers to an antibody variable domain (VH, VHH, VL) that specifically binds an antigen or epitope independently of a different V region or domain. An immunoglobulin single variable domain can be present in a format (e.g., homo- or hetero-multimer) with other, different variable regions or variable domains where the other regions or domains are not required for antigen binding by the single immunoglobulin variable domain (i.e., where the immunoglobulin single variable domain binds antigen independently of the additional variable domains). A "domain antibody" or "dAb" is the same as an "immunoglobulin single variable domain" which is capable of binding to an antigen as the term is used herein. An immunoglobulin single variable domain may be a human antibody variable domain, but also includes single antibody variable domains from other species such as rodent (for example, as disclosed in WO 00/29004), nurse shark and Camelid VHH immunoglobulin single variable domains. Camelid VHH sre immunoglobulin single variable domain polypeptides that are derived from species including camel, llama, alpaca, dromedary, and guanaco, which produce heavy chain antibodies naturally devoid of light chains. Such VHH domains may be humanised according to standard techniques available in the art, and such domains are still considered to be "domain antibodies" according to the invention. As used herein "VH includes camelid VHH domains. NA V are another type of immunoglobulin single variable domain which were identified in cartilaginous fish including the nurse shark. These domains are also known as Novel Antigen Receptor variable region (commonly abbreviated to V(NAR) or NARV). For further details see Mol. Immunol.44, 656-665 (2006) and US20050043519A. CTLA-4 (Cytotoxic T Lymphocyte-associated Antigen 4) is a CD28- family receptor expressed on mainly CD4+ T-cells. Its extracellular domain has a variable domain- like Ig fold. Loops corresponding to CDRs of antibodies can be substituted with heterologous sequence to confer different binding properties. CTLA-4 molecules engineered to have different binding specificities are also known as Evibodies. For further details see Journal of Immunological Methods 248 (1-2), 31-45 (2001). Lipocalins are a family of extracellular proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids and lipids. They have a rigid β-sheet secondary structure with a numer of loops at the open end of the conical structure which can be engineered to bind to different target antigens. Anticalins are between 160-180 amino acids in size, and are derived from lipocalins. For further details see Biochim Biophys Acta 1482: 337-350 (2000), US7250297B1 and US20070224633. An affibody is a scaffold derived from Protein A of Staphylococcus aureus which can be engineered to bind to antigen. The domain consists of a three- helical bundle of approximately 58 amino acids. Libraries have been generated by randomisation of surface residues. For further details see Protein Eng. Des. Sel.17, 455-462 (2004) and EP1641818A1. Avimers™ are multidomain proteins derived from the A-domain scaffold family. The native domains of approximately 35 amino acids adopt a defined disulphide bonded structure. Diversity is generated by shuffling of the natural variation exhibited by the family of A-domains. For further details see Nature Biotechnology 23(12), 1556 - 1561 (2005) and Expert Opinion on Investigational Drugs 16(6), 909-917 (June 2007). A transferrin is a monomeric serum transport glycoprotein. Transferrins can be engineered to bind different target antigens by insertion of peptide sequences in a permissive surface loop. Examples of engineered transferrin scaffolds include the Trans-body. For further details see J. Biol. Chem 274, 24066-24073 (1999). Designed Ankyrin Repeat Proteins (DARPins™) are derived from ankyrin which is a family of proteins that mediate attachment of integral membrane proteins to the cytoskeleton. A single ankyrin repeat is a 33 residue motif consisting of two a-helices and a β- turn. They can be engineered to bind different target antigens by randomising residues in the first a- helix and a β-turn of each repeat. Their binding interface can be increased by increasing the number of modules (a method of affinity maturation). For further details see J. Mol. Biol.332, 489-503 (2003), PNAS 100(4), 1700-1705 (2003) and J. Mol. Biol.369, 1015-1028 (2007) and US20040132028A1. Fibronectin is a scaffold which can be engineered to bind to antigen. Adnectins™ consist of a backbone of the natural amino acid sequence of the 10th domain of the 15 repeating units of human fibronectin type III (FN3). Three loops at one end of the β-sandwich can be engineered to enable an Adnectin to specifically recognize a therapeutic target of interest. For further details see Protein Eng. Des. Sel.18, 435- 444 (2005), US20080139791 , WO2005056764 and US6818418B1. Peptide aptamers are combinatorial recognition molecules that consist of a constant scaffold protein, typically thioredoxin (TrxA) which contains a constrained variable peptide loop inserted at the active site. For further details see Expert Opin. Biol. Ther.5, 783-797 (2005). Microbodies are derived from naturally occurring microproteins of 25-50 amino acids in length which contain 3-4 cysteine bridges - examples of microproteins include KalataBI and conotoxin and knottins. The microproteins have a loop which can be engineered to include upto 25 amino acids without affecting the overall fold of the microprotein. For further details of engineered knottin domains, see WO2008098796. Other epitope binding moieties and domains include proteins which have been used as a scaffold to engineer different target antigen binding properties include human γ-crystallin and human ubiquitin (affilins), kunitz type domains of human protease inhibitors, PDZ- domains of the Ras-binding protein AF-6, scorpion toxins (charybdotoxin), C-type lectin domain (tetranectins) are reviewed in Chapter 7 - Non- Antibody Scaffolds from Handbook of Therapeutic Antibodies (2007, edited by Stefan Dubel) and Protein Science 15:14-27 (2006). [0078] In an example, the or each antigen binding site (or effector domain) comprises a non-Ig scaffoled, eg, is selected from the group consisting of Affibodies, Affilins, Anticalins, Atrimers, Avimers, Bicycle Peptides, Cys-knots, DARpins, Fibronectin type III, Fyomers, Kunitz Domain, OBodies, Aptamers, Adnectins, Armadillo Repeat Domain, Beta-Hairpin mimetics and Lipocalins. 5. The multimer of any preceding Aspect, wherein each polypeptide comprises first and second copies of said protein domain or peptide, wherein the polypeptide comprises in (N- to C-terminal direction) (i) a first of said copies – TD – the second of said copies; (ii) TD – and the first and second copies; or (iii) said first and second copies – TD. 6. The multimer of any preceding Aspect, wherein the TDs are NHR2 TDs and the domain or peptide is not a NHR2 domain or peptide; or wherein the TDs are p53 TDs and the domain or peptide is not a p53 domain or peptide. 7. The multimer of any preceding Aspect, wherein the engineered polypeptide comprises one or more copies of a second type of protein domain or peptide, wherein the second type of protein domain or peptide is different from the first protein domain or peptide. [0079] For example, the polypeptide comprises in N-terminal direction (i) P1– TD –P2; or (ii) TD – P1-P2, wherein P1=a copy of a domain or peptide of the first type (ie, the type of domain or peptide of the multimer of Aspect 1); and P2=a copy of a domain or peptide of said second type. 8. The multimer of any preceding Aspect, wherein the domains are immunoglobulin superfamily domains. 9. The multimer of any preceding Aspect, wherein the domain or peptide is an antibody variable or constant domain (eg, an antibody single variable domain), a TCR variable or constant domain, an incretin, an insulin peptide, or a hormone peptide. 10. The multimer of any preceding Aspect, wherein the multimer comprises first, second, third and fourth identical copies of a said engineered polypeptide, the polypeptide comprising a TD and one (but no more than one), two (but no more than two) or more copies of the said protein domain or peptide. 11. The multimer of any preceding Aspect, wherein the engineered polypeptide comprises an antibody or TCR variable domain (V1) and a NHR2 TD. 12. The multimer of Aspect 11, wherein the polypeptide comprises (in N- to C-terminal direction) (i) V1-an optional linker-NHR2 TD; (ii) V1-an optional linker-NHR2 TD-optional linker-V2; or (iii) V1-an optional linker-V2 – optional linker - NHR2 TD, wherein V1 and V2 are TCR variable domains and are the same or different, or wherein V1 and V2 are antibody variable domains and are the same or different. 13. The multimer of Aspect 12, wherein V1 and V2 are antibody single variable domains. 14. The multimer of aspect 11, wherein each engineered polypeptide comprises (in N- to C- terminal direction) V1-an optional linker-NHR2 TD, wherein V1 is an antibody or TCR variable domain and each engineered polypeptide is paired with a respective second engineered polypeptide that comprises V2, wherein V2 is a an antibody or TCR variable domain respectively that pairs with V1 to form an antigen or pMHC binding site, and optionally one polypeptide comprises an antibody Fc, or comprises antibody CH1 and the other polypeptide comprises an antibody CL that pairs with the CH1. 15. The multimer of any preceding Aspect, wherein the TD comprises (i) an amino acid sequence identical to SEQ ID: 1*10 or 1*126 or at least 80% identical thereto; or (ii) an amino acid sequence identical to SEQ ID: 1*120 or 1*123 or at least 80% identical thereto. 16. The multimer of any preceding Aspect, wherein the multimer comprises a tetramer, octamer, 12-mer, 16-mer or 20-mer (eg, a tetramer, octamer, 12-mer or 16-mer; or a tetramer or octamer) of an antigen binding site of an antibody selected from the group consisting of ReoPro™; Abciximab; Rituxan™; Rituximab; Zenapax™; Daclizumab; Simulect™; Basiliximab; Synagis™; Palivizumab; Remicade™; Infliximab; Herceptin™; Mylotarg™; Gemtuzumab; Campath™; Alemtuzumab; Zevalin™; Ibritumomab; Humira™; Adalimumab; Xolair™; Omalizumab; Bexxar™; Tositumomab; Raptiva™; Efalizumab; Erbitux™; Cetuximab; Avastin™; Bevacizumab; Tysabri™; Natalizumab; Actemra™; Tocilizumab; Vectibix™; Panitumumab; Lucentis™; Ranibizumab; Soliris™; Eculizumab; Cimzia™; Certolizumab; Simponi™; Golimumab, Ilaris™; Canakinumab; Stelara™; Ustekinumab; Arzerra™; Ofatumumab; Prolia™; Denosumab; Numax™; Motavizumab; ABThrax™; Raxibacumab; Benlysta™; Belimumab; Yervoy™; Ipilimumab; Adcetris™; Brentuximab; Vedotin™; Perjeta™; Pertuzumab; Kadcyla™; Ado-trastuzumab; Keytruda™, Opdivo™, Gazyva™ and Obinutuzumab. Optionally, the binding site of the polypeptide of the multimer comprises a VH of the binding site of the antibody and also the CH1 of the antibody (ie, in N- to C-terminal direction the VH-CH1 and SAM). In an embodiment, the polypeptide may be paired with a further polypeptide comprising (in N- to C-terminal direction a VL-CL, eg, wherein the CL is the CL of the antibody). [0080] For example, a said protein domain of the engineered polypeptide is a V domain (a VH or VL) of an antibody binding site of an antibody selected from said group, wherein the multimer comprises a further V domain (a VL or VH respectively) that pairs with the V domain of the engineered polypeptide to form the antigen binding site of the selected antibody. Advantageously, therefore, the invention provides tetramer, octamer, 12-mer, 16-mer or 20-mer (eg, a tetramer, octamer, 12-mer or 16-mer; or tetramer or octamer)of a binding site of said selected antibody, which beneficially may have improved affinity, avidity and/or efficacy for binding its cognate antigen or for treating or preventing a disease or condition in a human or animal wherein the multimer is administered thereto to bind the cognate antigen in vivo. [0081] For example, the multimer, tetramer, octamer, 12-mer, 16-mer or 20-mer (eg, a tetramer, octamer, 12-mer or 16-mer; or tetramer or octamer) comprises 4 (or said X/4 as described above) copies of an antigen binding site of an antibody, wherein the antibody is adalimumab, sarilumab, dupilumab, bevacizumab (eg, AVASTIN™), cetuximab (eg, ERBITUX™), tocilizumab (eg, ACTEMRA™) or trastuzumab (HERCEPTIN™). In an alternative the antibody is an anti-CD38 antibody, an anti-TNFa antibody, an anti-TNFR antibody, an anti-IL-4Ra antibody, an anti-IL-6R antibody, an anti-IL-6 antibody, an anti-VEGF antibody, an anti-EGFR antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, an anti-PCSK9 antibody, an anti-CD3 antibody, an anti-CD20 antibody, an anti-CD138 antibody, an anti-IL-1 antibody. In an alternative the antibody is selected from the antibodies disclosed in WO2007024715 at page 40, line 23 to page 43, line 23, the disclosure of which is incorporated herein by reference. [0082] A binding site herein may, for example, be a ligand (eg, cytokine or growth factor, eg, VEGF or EGFR) binding site of a receptor (eg, KDR or Flt). A binding site herein may, for example, be a binding site of Eyelea™ , Avastin™ or Lucentis™, eg, for ocular or oncological medical use in a human or animal. When the ligand or antigen is VEGF, the mutlimer, tetramer or octamer may be for treatment or prevention of a caner or ocular condition (eg, wet or dry AMD or diabetic retinopathy) or as an inhibitor of neovascularisation in a human or animal subject. 17. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a TCR binding site, insulin peptide, incretin peptide or peptide hormone; or a plurality of said tetramers, octamers, dodecamers, hexadecamers or 20-mers. [0083] Several important peptide hormones are secreted from the pituitary gland. The anterior pituitary secretes three hormones: prolactin, which acts on the mammary gland; adrenocorticotropic hormone (ACTH), which acts on the adrenal cortex to regulate the secretion of glucocorticoids; and growth hormone, which acts on bone, muscle, and the liver. The posterior pituitary gland secretes antidiuretic hormone, also called vasopressin, and oxytocin. Peptide hormones are produced by many different organs and tissues, however, including the heart (atrial-natriuretic peptide (ANP) or atrial natriuretic factor (ANF)) and pancreas (glucagon, insulin and somatostatin), the gastrointestinal tract (cholecystokinin, gastrin), and adipose tissue stores (leptin). In an example, the peptide hormone of the invention is selected from prolactin, ACTH, growth hormone (somatotropin), vasopressin, oxytocin, glucagon, insulin, somatostatin, cholecystokinin, gastrin and leptin (eg, selected from human prolactin, ACTH, growth hormone, vasopressin, oxytocin, glucagon, insulin, somatostatin, cholecystokinin, gastrin and leptin). [0084] In an example, the incretin is a GLP-1, GIP or exendin-4 peptide. [0085] The invention provides, in embodiments, the following engineered multimers:- An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an incretin. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an insulin peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a GLP-1 (glucagon-like peptide-1 (GLP-1) peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a GIP (glucose-dependent insulinotropic polypeptide) peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an exendin (eg, exendin-4) peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a peptide hormone. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a prolactin or prolactin peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a ACTH or ACTH peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a growth hormone or growth hormone peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a vasopressin or vasopressin peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an oxytocin or oxytocin peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a glucagon or glucagon peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a insulin or insulin peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a somatostatin or somatostatin peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a cholecystokinin or cholecystokinin peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a gastrin or gastrin peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a leptin or leptin peptide. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an antibody binding site (eg, a scFv or Fab). An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a TCR binding site (eg, a scTCR). An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a TCR Vα/Vβ binding site. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a TCR Vγ/Vδ binding site. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an antibody single variable domain binding site. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of an FcAb binding site. [0086] In an example of any of these tetramer, octamer, dodecamer, hexadecamer or 20-mers, the domain or peptide is human. In an example of any of these tetramer, octamer, dodecamer, hexadecamer or 20-mers, the tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises a NHR2 TD (eg, a human NHR2). In an example of any of these tetramer, octamer, dodecamer, hexadecamer or 20-mers, the tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises a p53 TD (eg, a human p53 TD). In an example of any of these tetramer, octamer, dodecamer, hexadecamer or 20-mers, the tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises a p63 TD (eg, a human p63 TD). In an example of any of these tetramer, octamer, dodecamer, hexadecamer or 20- mers, the tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises a p73 TD (eg, a human p73 TD). In an example of any of these tetramer, octamer, dodecamer, hexadecamer or 20-mers, the tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises a tetramer of TDs (eg, human NHR2 TDs), whereby the domains or peptides form a multimer of 4 or 8 domains or peptides. [0087] In an example, the plurality is pure, eg, is not in mixture with multimers of said binding site or peptide wherein the multimers comprise more than one type of polypeptide monomer. 18. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of any preceding Aspect, wherein the mulitmer, tetramer, octamer, dodecamer, hexadecamer or 20-mer is (a) soluble in aqueous solution (eg, an aqueous eukaryotic cell growth medium or buffer); (b) secretable from a eukaryotic cell; and/or (c) an expression product of a eukaryotic cell. [0088] In an example the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer is secretable from a HEK293T (or other eukaryotic, mammalian, CHO or Cos) cell in stable form as indicated by a single band at the molecular weight expected for said multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer on a PAGE gel using a sample of supernatant from such cells and detected using Western Blot. 19. A tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, atetramer or octamer) of (a) TCR V domains or TCR binding sites, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is soluble in aqueous solution (eg, an aqueous eukaryotic cell growth medium or buffer); (b) antibody single variable domains, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is soluble in aqueous solution (eg, an aqueous eukaryotic cell growth medium or buffer); (c) TCR V domains or TCR binding sites, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is capable of being intracellularly and/or extracellularly expressed by HEK293 cells; or (d) antibody variable domains (eg, antibody single variable domains), wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is capable of being intracellularly and/or extracellularly expressed by HEK293 cells. [0089] An example of the medium is SFMII growth medium supplemented with L-glutamine (eg, complete SFMII growth medium supplemented with 4 mM L-glutamine). In an example, the medium is serum-free HEK293 cell culture medium. In an example, the medium is serum-free CHO cell culture medium. [0090] For example, a cell herein is a human cell, eg, a HEK293 cell (such as a HEK293T cell). 20. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of any preceding Aspect, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is bi-specific for antigen or pMHC binding. 21. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of any preceding Aspect, wherein the domains are identical. 22. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of any preceding Aspect, wherein the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises eukaryotic cell glycosylation. [0091] For example, the glycosylation is CHO cell glycosylation. For example, the glycosylation is HEK (eg, HEK293, such as HEK293T) cell glycosylation. For example, the glycosylation is Cos cell glycosylation. For example, the glycosylation is Picchia cell glycosylation. For example, the glycosylation is Sacchaaromyces cell glycosylation. 23. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of Aspect 22, wherein the cell is a HEK293 cell. 24. A plurality of multimers, tetramer, octamer, dodecamer, hexadecamer or 20-mer of any preceding Aspect. 25. A pharmaceutical composition comprising the multimer(s), tetramer(s), octamer(s), dodecamer(s), hexadecamer(s) or 20-mer(s) of any preceding Aspect and a pharmaceutically acceptable carrier, diluent or excipient. 26. A cosmetic, foodstuff, beverage, cleaning product, detergent comprising the multimer(s), tetramer(s), octamer(s), dodecamer(s), hexadecamer(s) or 20-mer(s) of any one of Aspects 1 to 24. 27. A said engineered (and optionally isolated) polypeptide or a monomer (optionally isolated) of a multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of any preceding Aspect. [0092] The monomer is an engineered polypeptide as disclosed herein, comprising a said protein domain or peptide and further comprising a TD. [0093] Optionally, the engineered polypeptide comprises (in N- to C-terminal direction) a variable domain (V1) – a constant domain (C) (eg, a CH1 or Fc) – optional linker – TD. 28. An engineered (and optionally isolated) engineered polypeptide (P1) which comprises (in N- to C-terminal direction):- (a) TCR V1 –TCR C1 – antibody C (eg, CH, CH1 (such as IgG CH1) or CL (such as Cλ or a Cκ)) – optional linker – TD, wherein (i) V1 is a Vα and C1 is a Cα; (ii) V1 is a Vβ and C1 is a Cβ; (iii) V1 is a Vγ and C1 is a Cγ; or (iv) V1 is a Vδ and C1 is a Cδ; or (b) TCR V1 – antibody C (eg, CH, CH1 (such as IgG CH1) or CL (such as Cλ or a Cκ)) – optional linker – TD, wherein (i) V1 is a Vα; (ii) V1 is a Vβ; (iii) V1 is a Vγ; or (iv) V1 is a Vδ; or (c) antibody V1 – antibody C (eg, CH, CH1 (such as IgG CH1) or CL (such as Cλ or a Cκ)) – optional linker – TD, wherein (i) V1 is a VH; or (ii) V1 is a VL (eg, a Vλ or a Vκ); or (d) antibody V1 – optional antibody C (eg, CH, CH1 (such as IgG CH1) or CL (such as Cλ or a Cκ)) – antibody Fc (eg, an IgG Fc) – optional linker – TD, wherein (i) V1 is a VH; or (ii) V1 is a VL (eg, a Vλ or a Vκ); or (e) antibody V1 – antibody CL (eg, a Cλ or a Cκ) – optional linker – TD, wherein (i) V1 is a VH; or (ii) V1 is a VL (eg, a Vλ or a Vκ); or (f) TCR V1 –TCR C1 – optional linker – TD, wherein (i) V1 is a Vα and C1 is a Cα; (ii) V1 is a Vβ and C1 is a Cβ; (iii) V1 is a Vγ and C1 is a Cγ; or (iv) V1 is a Vδ and C1 is a Cδ. [0094] In (a) or (b), in an example, the TCR V is comprised by an single chain TCR binding site (scTCR) that specifically binds to a pMHC , wherein the binding site comprises TCR V-linker - TCRV. In an example, the engineered polypeptide comprises (in N- to C-terminal direction) (i) V1 – linker – V - optional C - optional linker – TD, or (ii) Va – linker – V1 - optional C - optional linker – TD, wherein Va is a TCR V domain and C is an antibody C domain (eg, a CH1 or CL) or a TCR C. [0095] Preferably, the antibody C is CH1 (eg, IgG CH1). [0096] In an example the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer has a size of no more than 155 kDa, eg, wherein said protein domain is an antibody variable domain comprising a CDR3 of at least 16, 17, 18, 19, 20, 21 or 22 amino acids, such as a Camelid CDR3 or bovine CDR3. [0097] In an example, the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises TCR binding sites and antibody binding sites. For example, each polypeptide comprises a TCR V (eg, comprised by a scTCR that specifically binds a pMHC) and an antibody V (eg, comprised by a scFv or paired with a second V domain comprised by a said second polypeptide to form a V/V paired binding site that specifically binds to an antigen). In an example, the pMHC comprises a RAS peptide. In an example the antigen is selected from the group consisting of PD-1, PD-L1 or any other antigen disclosed herein. For example, the antigen is PD-1 and the pMHC comprises a RAS peptide. 29. The polypeptide of Aspect 28, wherein the engineered polypeptide P1 is paired with a further polypeptide (P2), wherein P2 comprises (in N- to C-terminal direction):- (g) TCR V2 –TCR C2 – antibody CL (eg, a Cλ or a Cκ), wherein P1 is according to (a) recited in Aspect 28 and (i) V2 is a Vα and C2 is a Cα when P1 is according to (a)(ii); (ii) V2 is a Vβ and C2 is a Cβ when P1 is according to (a)(i); (iii) V2 is a Vγ and C2 is a Cγ when P1 is according to (a)(iv); or (iv) V2 is a Vδ and C2 is a Cδ when P1 is according to (a)(iii); or (h) TCR V2 – antibody CL (eg, a Cλ or a Cκ), wherein P1 is according to (b) recited in Aspect 28 and (i) V2 is a Vα when P1 is according to (b)(ii); (ii) V2 is a Vβ when P1 is according to (b)(i); (iii) V2 is a Vγ when P1 is according to (b)(iv); or (iv) V2 is a Vδ when P1 is according to (b)(iiii); or (i) Antibody V2 – CL (eg, a Cλ or a Cκ), wherein P1 is according to (c) recited in Aspect 28 and (i) V2 is a VH when P1 is according to (c)(ii); or (ii) V2 is a VL (eg, a Vλ or a Vκ) when P1 is according to (c)(i); or (j) Antibody V2 – optional CL (eg, a Cλ or a Cκ), wherein P1 is according to (d) recited in Aspect 28 and (i) V2 is a VH when P1 is according to (d)(ii); or (ii) V2 is a VL (eg, a Vλ or a Vκ) when P1 is according to (d)(i); or (k) Antibody V2 – CH1 (eg, IgG CH1), wherein P1 is according to (e) recited in Aspect 28 and (i) V2 is a VH when P1 is according to (e)(ii); or (ii) V2 is a VL (eg, a Vλ or a Vκ) when P1 is according to (e)(i); or (l) TCR V2 –TCR C2, wherein P1 is according to (f) recited in Aspect 28 and (i) V2 is a Vα and C2 is a Cα when P1 is according to (f)(ii); (ii) V2 is a Vβ and C2 is a Cβ when P1 is according to (f)(i); (iii) V2 is a Vγ and C2 is a Cγ when P1 is according to (f)(iii); or (iv) V2 is a Vδ and C2 is a Cδ when P1 is according to (f)(iv). [0098] Optionally, V1 and V2 form a paired variable domain binding site that is capable of specifically binding to an antigen or pMHC. In an example, V1 and V2 are variable domains of an antibody, eg, selected from the group consisting of ReoPro™; Abciximab; Rituxan™; Rituximab; Zenapax™; Daclizumab; Simulect™; Basiliximab; Synagis™; Palivizumab; Remicade™; Infliximab; Herceptin™; Mylotarg™; Gemtuzumab; Campath™; Alemtuzumab; Zevalin™; Ibritumomab; Humira™; Adalimumab; Xolair™; Omalizumab; Bexxar™; Tositumomab; Raptiva™; Efalizumab; Erbitux™; Cetuximab; Avastin™; Bevacizumab; Tysabri™; Natalizumab; Actemra™; Tocilizumab; Vectibix™; Panitumumab; Lucentis™; Ranibizumab; Soliris™; Eculizumab; Cimzia™; Certolizumab; Simponi™; Golimumab, Ilaris™; Canakinumab; Stelara™; Ustekinumab; Arzerra™; Ofatumumab; Prolia™; Denosumab; Numax™; Motavizumab; ABThrax™; Raxibacumab; Benlysta™; Belimumab; Yervoy™; Ipilimumab; Adcetris™; Brentuximab; Vedotin™; Perjeta™; Pertuzumab; Kadcyla™; Ado-trastuzumab; Keytruda™, Opdivo™, Gazyva™ and Obinutuzumab. Optionally, the binding site of the polypeptide of the multimer comprises a VH of the binding site of the antibody and also the CH1 of the antibody (ie, in N- to C-terminal direction the VH-CH1 and SAM). In an embodiment, the polypeptide may be paired with a further polypeptide comprising (in N- to C-terminal direction a VL-CL, eg, wherein the CL is the CL of the antibody). [0099] In one embodiment, the antibody is Avastin. [00100] In one embodiment, the antibody is Actemra. [00101] In one embodiment, the antibody is Erbitux. [00102] In one embodiment, the antibody is Lucentis. [00103] In one embodiment, the antibody is sarilumab. [00104] In one embodiment, the antibody is dupilumab. [00105] In one embodiment, the antibody is alirocumab. [00106] In one embodiment, the antibody is bococizumab. [00107] In one embodiment, the antibody is evolocumab. [00108] In one embodiment, the antibody is pembrolizumab. [00109] In one embodiment, the antibody is nivolumab. [00110] In one embodiment, the antibody is ipilimumab. [00111] In one embodiment, the antibody is remicade. [00112] In one embodiment, the antibody is golimumab. [00113] In one embodiment, the antibody is ofatumumab. [00114] In one embodiment, the antibody is Benlysta. [00115] In one embodiment, the antibody is Campath. [00116] In one embodiment, the antibody is rituximab. [00117] In one embodiment, the antibody is Herceptin. [00118] In one embodiment, the antibody is durvalumab. [00119] In one embodiment, the antibody is daratumumab. [00120] In an example, any binding domain herein (eg, a dAb or scFv or Fab) or V1 is capable (itself when a single variable domain, or when paired with V2) of specifically binding to an antigen selected from the group consisting of ABCF1; ACVR1; ACVR1B; ACVR2; ACVR2B; ACVRL1; ADORA2A; Aggrecan; AGR2; AICDA; AWI; AIG1; AKAP1; AKAP2; AIYIH; AMHR2; ANGPT1; ANGPT2; ANGPTL3; ANGPTL4; ANPEP; APC; APOC1; AR; AZGP1 (zinc-a-glycoprotein); B7.1; B7.2; BAD; BAFF; BAG1; BAI1; BCL2; BCL6; BDNF; BLNK; BLRl (MDR15); BlyS; BM Pl; BMP2; BMP3B (GDFIO); BMP4; BMP6; BM P8; BMPRIA; BMPRIB; BM PR2; BPAG1 (plectin); BRCA1; CI9orflO (IL27w); C3; C4A; C5; C5R1; CANT1; CASP1; CASP4; CAV1; CCBP2 (D6 / JAB61); CCL1 (1-309); CCL11 (eotaxin); CCL13 (MCP-4); CCL15 (MIP-id); CCL16 (HCC-4); CCL17 (TARC); CCL18 (PARC); CCL19 (M IP-3b); CCL2 (MCP-1); MCAF; CCL20 (MIP-3a); CCL21 (MIP-2); SLC; exodus-2; CCL22 (MDC / STC-1); CCL23 (M PIF-1); CCL24 (MPIF-2 I eotaxin-2); CCL25 (TECK); CCL26 (eotaxin-3); CCL27 (CTACK /ILC) ; CCL28; CCL3 (MIP-la); CCL4 (M IP-lb); CCL5 (RANTES); CCL7 (MCP-3); CCL8 (mcp-2); CCNA1; CCNA2; CCND1; CCNE1; CCNE2; CCR1 (CKR1 / HM145); CCR2 (mcp-1RB / RA);CCR3 (CKR3 / CMKBR3); CCR4; CCR5 (CM KBR5 / ChemR13); CCR6 (CMKBR6 / CKR-L3 / STRL22 / DRY6); CCR7 (CKR7 / EBI1); CCR8 (CM KBR8 / TER1 / CKR-L1); CCR9 (GPR-9-6); CCRL1 (VSHK1); CCRL2 (L-CCR); CD164; CD19; CD1C; CD20; CD200; CD-22; CD24; CD28; CD3; CD37; CD38; CD3E; CD3G; CD3Z; CD4; CD40; CD40L; CD44; CD45RB; CD52; CD69; CD72; CD74; CD79A; CD79B; CD8; CD80; CD81; CD83; CD86; CDH1 (E-cadherin); CDH10; CDH12; CDH13; CDH18; CDH19; CDH20; CDH5; CDH7; CDH8; CDH9; CDK2; CDK3; CDK4; CDK5; CDK6; CDK7; CDK9; CDKN1A (p2IWapl/Cipl); CDKN1B (p27Kipl); CDKNIC; CDKN2A (pl6INK4a); CDKN2B; CDKN2C; CDKN3; CEBPB; CER1; CHGA; CHGB; Chitinase; CHST10; CKLFSF2; CKLFSF3; CKLFSF4; CKLFSF5; CKLFSF6; CKLFSF7; CKLFSF8; CLDN3; CLDN7 (claudin-7); CLN3; CLU (clusterin); CMKLR1; CMKOR1 (RDC1); CNR1; COL18A1; COL1A1; COL4A3; COL6A1; CR2; CRP; CSFl (M-CSF); CSF2 (GM-CSF); CSF3 (GCSF); CTLA4; CTNNBl (b-catenin); CTSB (cathepsin B); CX3CL1 (SCYDi) ; CX3CR1 (V28); CXCL1 (GROl); CXCLIO (IP-10); CXCL11 (l- TAC / IP-9); CXCL12 (SDF1); CXCL13; CXCL14; CXCL16; CXCL2 (GR02); CXCL3 (GR03); CXCL5 (ENA-78 I LIX); CXCL6 (GCP-2); CXCL9 (MIG); CXCR3 (GPR9/CKR-L2); CXCR4; CXCR6 (TYMSTR ISTRL33 I Bonzo); CYB5; CYC1; CYSLTR1; DAB2IP; DES; DKFZp451J0118; DNCL1; DPP4; E2F1; ECGF1; EDG1; EFNAI; EFNA3; EFNB2; EGF; EGFR; ELAC2; ENG; EN01; EN02; EN03; EPHB4; EPO; ERBB2 (Her-2); EREG; ERK8; ESR1; ESR2; F3 (TF); FADD; FasL; FASN; FCER1A; FCER2; FCGR3A; FGF; FGF1 (aFGF); FGF10; FGF11; FGF12; FGF12B; FGF13; FGF14; FGF16; FGF17; FGF18; FGF19; FGF2 (bFGF); FGF20; FGF21; FGF22; FGF23; FGF3 (int- 2); FGF4 (HST); FGF5; FGF6 (HST-2); FGF7 (KGF); FGF8; FGF9; FGFR3; FIGF (VEGFD); FILl (EPSILON); FILl (ZETA); FU12584; FU25530; FLRTl (fibronectin); FLTl; FOS; FOSLl (FRA-I); FY (DARC); GABRP (GABAa); GAGEB1; GAGEC1; GALNAC4S-65T; GATA3; GDF5; GFI1; GGT1; GM-CSF; GNAS1; GNRHl; GPR2 (CCRIO); GPR31; GPR44; GPR81 (FKSG80); GRCCIO (CIO); GRP; GSN (Gelsolin); GSTPl; HAVCR2; HDAC4; EDAC5; HDAC7A; HDAC9; HGF; HIF1A; HIP1; histamine and histamine receptors; HLA-A; HLA-DRA; HM74; HMOX1; HUMCYT2A; ICEBERG; ICOSL; 1D2; IFN-a; IFNA1; IFNA2; IFNA4; IFNA5; IFNA6; IFNA7; IFNB1; IFNgamma; TFNW1; IGBP1; IGF1; IGF1R; IGF2; IGFBP2; IGFBP3; IGFBP6; IL-1; IL10; IL10RA; IL10RB; IL11; IL11RA; IL-12; IL12A; IL12B; IL12RB1; IL12RB2; 1L13; IL13RA1; IL13RA2; 1L14; 1L15; IL15RA; IL16; 1L17; IL17B; IL17C; IL17R; 1L18; IL18BP; IL18R1; IL18RAP; 1L19; ILIA; IL1B; IL1F10; IL1F5; IL1F6; IL1F7; IL1F8; IL1F9; IL1HY1; IL1R1; IL1R2; IL1RAP; IL1RAPL1; IL1RAPL2; IL1RL1;IL1RL2 IL1RN; 1L2; 1L20; IL20RA; IL21R; 1L22; 1L22R; 1L22RA2; 1L23; 1L24; 1L25; 1L26; 1L27; 1L28A; 1L28B; 1L29; IL2RA; IL2RB; IL2RG; 1L3; 1L30; IL3RA; 1L4; IL4R; 1L5; IL5RA; 1L6; IL6R; IL6ST (glycoprotein 130); 1L7; TL7R; 1L8; IL8RA; IL8RB; IL8RB; 1L9; IL9R; ILK; INHA; INHBA; INSL3; INSL4; IRAKI; IRAK2; ITGA1; ITGA2; 1TGA3; ITGA6 (a6 integrin); ITGAV; ITGB3; ITGB4 (b 4 integrin); JAG1; JAK1; JAK3; JUN; K6HF; KAI1; KDR; MTLG; KLF5 (GC Box BP); KLF6; KLK10; KLK12; KLK13; KLK14; KLK15; KLK3; KLK4; KLK5; KLK6; KLK9; KRT1; KRT19 (Keratin 19); KRT2A; KRTHB6 (hair- specific type II keratin); LAMA5; LEP (leptin); Lingo-p75; Lingo-Troy; LPS; LTA (TNF-b); LTB; LTB4R (GPR16); LTB4R2; LTBR; MACMARCKS; MAG or Omgp; MAP2K7 (c-Jun); MDK; M IB1; midkine; M IF; M IP-2; MK167 (Ki-67); MMP2; M MP9; MS4A1; MSMB; MT3 (metallothionectin-ifi); MTSS 1; M UC 1 (mucin); MYC; MYD88; NCK2; neurocan; NFKB 1; NFKB2; NGFB (NGF); NGFR; NgR-Lingo; NgR-Nogo66 (Nogo); NgR-p75; NgR-Troy; NM E1 (NM23A); NOX5; NPPB; NROB1; NROB2; NR1D1; NR1D2; NR1H2; NR1H3; NR1H4; NR1I2; NR1I3; NR2C1; NR2C2; NR2E1; NR2E3; NR2F1; NR2F2; NR2F6; NR3C1; NR3C2; NR4A1; NR4A2; NR4A3; NR5A1; NR5A2; NR6A1; NRP1; NRP2; NT5E; NTN4; ODZ1; OPRD1; P2RX7; PAP; PARTI; PATE; PAWR; PCA3; PCNA; PDGFA; PDGFB; PECAM1; PF4 (CXCL4); PGF; PGR; phosphacan; PIAS2; PIK3CG; PLAU (uPA); PLG; PLXDC1; PPBP (CXCL7); PPID; PR1; PRKCQ; PRKD1; PRL; PROC; PROK2; PSAP; PSCA; PTAFR; PTEN; PTGS2 (COX-2); PTN; RAC2 (p2IRac2); RARB; RGS1; RGS13; RGS3; RNF110 (ZNF144); ROB02; S100A2; SCGB1D2 (lipophilin B); SCGB2A1 (mammaglobin 2); SCGB2A2 (mammaglobin 1); SCYE1 (endothelial Monocyte-activating cytokine); SDF2; SERPINA1; SERPINIA3; SERPINB5 (maspin); SERPINE1 (PAT-i); SERPINF1; SHBG; SLA2; SLC2A2; SLC33A1; SLC43A1; SLIT2; SPPl; SPRRIB (Spri); ST6GAL1; STABl; STAT6; STEAP; STEAP2; TB4R2; TBX21; TCPIO; TDGF1; TEK; TGFA; TGFB1; TGFB1I1; TGFB2; TGFB3; TGFBI; TGFBR1; TGFBR2; TGFBR3; TH1L; THBS1(thrombospondin-1); THBS2; THBS4; THPO; TIE (Tie-i); T]MP3; tissue factor; TLRIO; TLR2; TLR3; TLR4; TLR5; TLR6; TLR7; TLR8; TLR9; TNF; TNF-a (also referred to herein as TNF alpha or TNFα); TNFAIP2 (B94); TNFAIP3; TNFRSF11A; TNFRSF1A; TNFRSF1B; TNFRSF21; TNFRSF5; TNFRSF6 (Fas); TNFRSF7; TNFRSF8; TNFRSF9; TNFSFIO (TRAIL); TNFSF11 (TRANCE); TNFSF12 (AP03L); TNFSF13 (April); TNFSF13B; TNFSF14 (HVEM-L); TNFSF15 (VEGI); TNFSF18; TNFSF4 (0X40 ligand); TNFSF5 (CD40 ligand); TNFSF6 (FasL); TNFSF7 (CD27 ligand); TNFSF8 (CD30 ligand); TNFSF9 (4-lBB ligand); TOLLIP; Toll-like receptors; TOP2A (topoisomerase lia); TP53; TPM 1; TPM2; TRADD; TRAF1; TRAF2; TRAF3; TRAF4; TRAF5; TRAF6; TREM 1; TREM2; TRPC6; TSLP; TWEAK; VEGF; VEGFB; VEGFC; versican; VHL C5; VLA-4; XCL1 (lymphotactin); XCL2 (SCM-lb); XCR1 (GPR5 / CCXCR1); YY1; and ZFPM2. [00121] For example in any configuration of the invention, the multimer, octamer, dodecamer, hexadecamer or 20-mer specifically binds to first and second (eg, for an octamer, dodecamer, hexadecamer or 20-mer); optionally, first, second and third (eg, for a dodecamer, hexadecamer or 20- mer); or optionally, first, second, third and fourth (eg, for a hexadecamer or 20-mer); or optionally, first, second, third, fourth and fifth (eg, for a 20-mer) epitopes or antigens, each of which is selected from the group consisting of EpCAM and CD3; CD19 and CD3; VEGF and VEGFR2; VEGF and EGFR; CD138 and CD20; CD138 and CD40; CD20 and CD3; CD38 and CD138; CD38 and CD20; CD38 and CD40; CD40 and CD20; CD19 and CD20; CD-8 and IL-6; PDL-1 and CTLA-4; CTLA-4 and BTN02; CSPGs and RGM A; IGF1 and IGF2; IGF1 and/or 2 and Erb2B; IL-12 and IL-18; IL-12 and TWEAK; IL-13 and ADAM8; IL-13 and CL25; IL-13 and IL-lbeta; IL-13 and IL-25; IL-13 and IL-4; IL-13 and IL-5; IL-13 and IL-9; IL-13 and LHR agonist; IL-13 and MDC; IL-13 and MIF; IL- 13 and PED2; IL-13 and SPRR2a; IL-13 and SPRR2b; IL-13 and TARC; IL-13 and TGF-beta; IL-1 alpha and IL-1 beta; MAG and RGM A; NgR and RGM A; NogoA and RGM A; OMGp and RGM A; RGM A and RGM B; Te38 and TNF alpha; TNF alpha and IL-12; TNF alpha and IL-12p40; TNF alpha and IL-13; TNF alpha and IL-15; TNF alpha and IL-17; TNF alpha and IL-18; TNF alpha and IL-1 beta; TNF alpha and IL-23; TNF alpha and M IF; TNF alpha and PEG2; TNF alpha and PGE4; TNF alpha and VEGF; and VEGFR and EGFR; TNF alpha and RANK ligand; TNF alpha and Blys; TNF alpha and GP130; TNF alpha and CD-22; and TNF alpha and CTLA-4 [00122] For example, the first epitope or antigen is selected from the group consisting of CD3; CD16; CD32; CD64; and CD89; and the second epitope or antigen is selected from the group consisting of EGFR; VEGF; IGF-1R; Her2; c-Met (aka HGF); HER3; CEA; CD33; CD79a; CD19; PSA; EpCAM; CD66; CD30; HAS; PSMA; GD2; ANG2; IL-4; IL-13; VEGFR2; and VEGFR3. [00123] In an example, any binding domain herein (eg, a dAb or scFv or Fab) or V1 is capable (itself when a single variable domain, or when paired with V2) of specifically binding to an antigen selected from the group consisting of human IL-1A, IL-1β, IL-1RN, IL-6, BLys, APRIL, activin A, TNF alpha, a BMP, BMP2, BMP7, BMP9, BMP10, GDF8, GDF11, RANKL, TRAIL, VEGFA, VEGFB or PGF; optionally the multimer comprises a cytokine amino acid sequence (eg, C-terminal to a TD), such as IL-2 or an IL2-peptide; and the multimer, octamer, dodecamer, hexadecamer or 20-mer is for treating or preventing a cancer in a human subject. In an example the said effector or protein domain is capable of binding to such an antigen; optionally the multimer comprises a cytokine amino acid sequence (eg, C-terminal to a TD), such as IL-2 or an IL2-peptide; and the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer is for treating or preventing a cancer in a human subject. 30. A multimer (eg, a dimer, trimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer) of P1 as defined in Aspect 28; or of P1 paired with P2 as defined in Aspect 29; or a plurality of said multimers, optionally wherein the multimer is according to any one of aspects 1 to 24. [00124] Preferably the multimer is a tetramer of the engineered polypeptide and/or effector domain. In one example, the plurality of tetramers are not in mixture with monomers, dimers or trimers of the polypeptide, [00125] In one example the multimer, eg, tetramer, is a capable of specifically binding to two different pMHC. 31. A nucleic acid encoding an engineered polypeptide or monomer of any one of Aspects 27 to 29, optionally wherein the nucleic acid is comprised by an expression vector for expressing the polypeptide. [00126] In an example, the nucleic acid is a DNA, optionally operably connected to or comprising a promoter for expression of the polypeptide or monomer. In another example the nucleic acid is a RNA (eg, mRNA). 32. A eukaryotic host cell comprising the nucleic acid or vector of Aspect 31 for intracellular and/or secreted expression of the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer, engineered polypeptide or monomer of any one of Aspects 1 to 24. 33. Use of a nucleic acid or vector according to aspect 31 in a method of manufacture of protein multimers for producing intracellularly expressed and/or secreted multimers, wherein the method comprises expressing the multimers in and/or secreting the multimers from eukaryotic cells comprising the nucleic acid or vector. 34. Use of a nucleic acid or vector according to aspect 31 in a method of manufacture of protein multimers for producing glycosylated multimers in eukaryotic cells comprising the nucleic acid or vector. [00127] Mammalian glycosylation of the invention is useful for producing medicines comprising or consisting of the multimers, tetramer, octamer, dodecamer, hexadecamer or 20-merof the invention for medical treatment or prevention of a disease or condition in a mammal, eg, a human. The invention thus provides such a method of use as well as the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-merof the invention for this purpose. Similarly, intracellular and/or secreted expression in one or more host cells (or cell lines thereof) that are mammalian according to the invention is useful for producing such medicines. Particularly useful is such expression in HEK293, CHO or Cos cells as these are commonly used for production of medicaments. [00128] In an embodiment, the invention comprises a detergent or personal healthcare product comprising a multimer, tetramer, octamer, dodecamer, hexadecamer or 20-merof the invention. In an embodiment, the invention comprises a foodstuff or beverage comprising a multimer, tetramer, octamer, dodecamer, hexadecamer or 20-merof the invention. [00129] In an example, the multimer, monomer, dimer, trimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer, polypeptide, composition, mixture, use or method of the present invention is for an industrial or domestic use, or is used in a method for such use. For example, it is for or used in agriculture, oil or petroleum industry, food or drink industry, clothing industry, packaging industry, electronics industry, computer industry, environmental industry, chemical industry, aeorspace industry, automotive industry, biotechnology industry, medical industry, healthcare industry, dentistry industry, energy industry, consumer products industry, pharmaceutical industry, mining industry, cleaning industry, forestry industry, fishing industry, leisure industry, recycling industry, cosmetics industry, plastics industry, pulp or paper industry, textile industry, clothing industry, leather or suede or animal hide industry, tobacco industry or steel industry. 35. A mixture comprising (i) a eukaryotic cell line encoding an engineered polypeptide according to any one of Aspects 27 to 29; and (ii) multimers, tetramers, octamers, dodecamers, hexadecamers or 20-mersas defined in any one of Aspects 1 to 24. 36. The mixture of Aspect 35, wherein the cell line is in a medium comprising secretion products of the cells, wherein the secretion products comprise said multimers, tetramers, octamers, dodecamers, hexadecamers or 20-mers. 37. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-merof any one of aspects 1 to 24 for medical use. 38. A method producing (a) TCR V domain multimers, the method comprising the soluble and/or intracellular expression of TCR V-NHR2 TD or TCR V- p53 TD fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers; (b) antibody V domain multimers, the method comprising the soluble and/or intracellular expression of antibody V (eg, a single variable domain)-NHR2 TD or V- p53 TD fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers; (c) incretin peptide (eg, GLP-1, GIP or insulin) multimers, the method comprising the soluble and/or intracellular expression of incretin peptide-NHR2 TD or incretin peptide-p53 TD fusion proteins expressed in eukaryotic cells, such as HEK293T cells; the method optionally comprising isolating a plurality of said multimers; or (d) peptide hormone multimers, the method comprising the soluble and/or intracellular expression of peptide hormone-NHR2 TD or peptide hormone- p53 TD fusion proteins expressed in eukaryotic cells, such as HEK293T cells; the method optionally comprising isolating a plurality of said multimers. 39. Use of self-associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue thereof) in a method of the manufacture of a tetramer of polypeptides, for producing a higher yield of tetramers versus monomer and/or dimer polypeptides. 40. Use of an engineered polypeptide in a method of the manufacture of a tetramer of a polypeptide comprising multiple copies of a protein domain or peptide, for producing a higher yield of tetramers versus monomer and/or dimer polypeptides, wherein the engineered polypeptide comprises one or more copies of said protein domain or peptide and further comprises a self- associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue). 41. Use of self-associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue thereof) in a method of the manufacture of a tetramer of a polypeptide, for producing a plurality of tetramers that are not in mixture with monomers, dimers or trimers. 42. Use of an engineered polypeptide in a method of the manufacture of a tetramer of a polypeptide comprising multiple copies of a protein domain or peptide, for producing a plurality of tetramers that are not in mixture with monomers, dimers or trimers, wherein the engineered polypeptide comprises one or more copies of said protein domain or peptide and further comprises a self-associating tetramerisation domains (TD) (eg, NHR2 TD, p53 TD, p63 TD or p73 TD or a homologue or orthologue). 43. The use of any one of Aspects 39 to 42, wherein the yield of tetramers is at least 10, 20, 30, 40 or 50x the yield of monomers and/or dimers. 44. The use of any one of Aspects 39 to 43, wherein the ratio of tetramers produced : monomers and/or dimers produced in the method is at least 90:10 (eg, at least 95:5 or 98:2, or 99:1). 45. The use of any one of Aspects 39 to 44, wherein each monomer has a size of no more than 40, 35, 30, 25 or 20 kDa. 46. The use of any one of Aspects 39 to 45, wherein each tetramer has a size of no more than 200, 160, 155 or 150 kDa. 47. The use of any one of Aspects 39 to 46, wherein the method comprises expressing the tetramers from a eukaryotic cell line. 48. A multivalent heterodimeric soluble T cell receptor capable of binding pMHC complex comprising: (i) TCR extracellular domains; (ii) immunoglobulin constant domains; and (iii) an NHR2 multimerisation domain of ETO. 49. A multimeric immunoglobulin, comprising (i) immunoglobulin variable domains; and (ii) an NHR2 multimerisation domain of ETO. 50. A method for assembling a soluble, multimeric polypeptide, comprising: (a) providing a monomer of the said multimeric polypeptide, fused to an NHR2 domain of ETO; (b) causing multiple copies of said monomer to associate, thereby obtaining a multimeric, soluble polypeptide. [00130] The invention further provides (i) A monomer as shown in Fig 1; (ii) A homodimer as shown in Fig 1; (iii) A homotetramer as shown in Fig 1; (iv) A monomer2 as shown in Fig 2; (v) A homodimer2 as shown in Fig 2; (vi) A homotetramer2 as shown in Fig 2; (vii) A monomer as shown in Fig 11a; (viii) A homodimer as shown in Fig 11a; (ix) A homotetramer as shown in Fig 11a; (x) A monomer as shown in Fig 12a; (xi) A homodimer as shown in Fig 12a; (xii) A homotetramer as shown in Fig 12a; (xiii) A monomer2 as shown in Fig 13a; (xiv) A homodimer2 as shown in Fig 13a; (xv) A homotetramer2 as shown in Fig 13a; or (xvi) A multimeric protein comprising any one of (i) to (xv) (eg, any one of Quads 3, 4, 12, 13, 14, 15, 16 and 17) or a multimer of any protein shown in Figure 21 (excluding any leader or tag); (xvii) A plurality of multimers of (xvi); or (xviii) A pharmaceutical composition comprising any one of (i) to (xvii) and a pharmaceutically acceptable carrier, diluent or excipient. [00131] The invention also provides (i) A tetravalent or octavalent antibody V molecule; (ii) A tetravalent or octavalent antibody Fab molecule; (iii) A tetravalent or octavalent antibody dAb molecule; (iv) A tetravalent or octavalent antibody scFv molecule; (v) A tetravalent or octavalent antibody TCR V molecule; or (vi) A tetravalent or octavalent antibody scFv molecule; Wherein the molecule is (a) soluble in aqueous solution (eg, a solution or cell culture medium disclosed herein) and/or; (b) capable of being intracellularly and/or extracellularly expressed by HEK293 cells. [00132] The invention provides a claim multimer (eg, tetramer) of NHR2 or p53 (or another TD disclosed herein) fused at its N- and/or C-terminus to an amino acid sequence (eg, a peptide, protein domain or protein) that is not an NHR2 sequence. For example, sequence is selected from a TCR (eg, TCRα, TCRβ, Cα or Cβ), cytokine (eg, interleukin, eg, IL-2, IL-12, IL-12 and IFN), antibody fragments (eg, scFv, dAb or Fab) and a antibody domain (eg, V or C domain, eg, VH, VL, Vκ, Vλ, CH, CH1, CH2, CH3, hinge, Cκ or Cλ domain). Optionally, the multimer is the molecule is a) soluble in aqueous solution (eg, a solution or cell culture medium disclosed herein) and/or; b) capable of being intracellularly and/or extracellularly expressed by HEK293 cells. [00133] The invention provides:- (i) Use of NHR2 or p53 (or another TD disclosed herein) for the manufacture of a polypeptide for soluble expression of a multimer of the polypeptide from a cell, eg, a eukaryotic cell, eg, a mammalian, HEK293, CHO or Cos cell. (ii) Use of NHR2 or p53 (or another TD disclosed herein) for the manufacture of a polypeptide for intracellular expression of a multimer of the polypeptide in a cell, eg, a eukaryotic cell, eg, a mammalian, HEK293, CHO or Cos cell. (iii) A cell comprising an intracelllular expression product, wherein the product comprises a multimer of a polypeptide comprising NHR2 or p53 (or another TD disclosed herein) fused at its N- and/or C-terminus to an amino acid sequence (eg, a peptide, protein domain or protein) that is not an NHR2 sequence. (iv) Use of NHR2 as a promiscuous tetramerisation domain for tetramerising peptides, protein domains, polypeptides or proteins in tha manufacture of multimers that are intracellularly and/or solubly expressed from host cell. [00134] Optionally, the amino acid is an amino acid sequence of a human peptide, protein domain or protein,eg, a TCR (eg, TCRα, TCRβ, Cα or Cβ), cytokine (eg, interleukin, eg, IL-2, IL-12, IL-12 and IFN), antibody fragments (eg, scFv, dAb or Fab), or an antibody domain (eg, V or C domain, eg, VH, VL, Vκ, Vλ, CH, CH1, CH2, CH3, hnige, Cκ or Cλ domain). [00135] Optionally, the or each polypeptide comprises a polypeptide selected from the group consisting of Quad 1-46 (ie, a polypeptide as shown in Figure 21 but excluding any leader or tag sequence). Optionally, the invention provides a multimer (eg, a dimer, trimer, tetramer, pentamer, hexamer, septamer or octamer, preferably a tetramer or octamer) of a polypeptide selected from the group consisting of such Quad 1-46 (ie, 2, 3, 4, 5, 6, 7 or 8 copies of such a polypeptide), eg, for medical or diagnostic use, eg, medical use for treating or preventing a disease or condition in a human or animal (eg, a human). [00136] Optionally, the or each polypeptide comprises a polypeptide (excluding any leader or tag sequence) that is encoded by a nucleotide sequence selected from the group consisting of SEQ IDs: 1*13-1*50. Optionally, the or each polypeptide comprises a polypeptide (excluding any leader or tag sequence) that comprises an amino acid sequence selected from the group consisting of SEQ IDs: 1*83-1*115. Optionally, the invention provides a multimer (eg, a dimer, trimer, tetramer, pentamer, hexamer, septamer or octamer, preferably a tetramer or octamer) of such a polypeptide, eg, for medical or diagnostic use, eg, medical use for treating or preventing a disease or condition in a human or animal (eg, a human). [00137] In an example, the TD is a TD comprised by any one of SEQ IDs: 1*1-1*9. In an example, the TD is a TD comprising SEQ ID: 1*10 or 1*126. In an example, the TD is encoded by SEQ ID: 1*124 or 1*125. In an example, the amino acid sequence of each TD is SEQ ID: 1*10 or 1*126 or is at least 80, 85, 90, 95, 96m 97, 98 or 99% identical to SEQ ID: 1*10 or 1*126. [00138] In an example, the TD is a TD comprising SEQ ID: 1*120 or 123. In an example, the TD is encoded by SEQ ID: 1*116 or 1*119. In an example, the amino acid sequence of each TD is SEQ ID: 1*120 or 1*123 or is at least 80, 85, 90, 95, 96m 97, 98 or 99% identical to the SEQ ID: 1*120 or 1*123. [00139] Optionally, the domain or peptide comprised by the engineered polypeptide or monomer comprises an amino acid selected from SEQ ID NOs: 1*51-1*82. [00140] HIGH PURITY TETRAMERS As exemplified herein, the invention in one configuration is based on the surprising realization that tetramerisation domains (TD), eg, p53 tetramerisation domain (p53 TD), can be used to preferentially produce tetramers of effector domains over the production of lower-order structures such as dimers and monomers. This is particularly useful for secretion of tetramers is desirable yields from mammalian expression cell lines, such as CHO, HEK293 and Cos cell lines. The invention is also particularly useful for the production of tetramers no more than 200, 160, 155 or 150 kDa in size. [00141] Thus, the invention provides the following Concepts:- CONCEPTS The following Concepts are not to be interpreted as Claims. The Claims start after the Examples section. 1. Use of a tetramerisation domain (TD) (eg, p53 tetramerisation domain (p53 TD) or NHR2 TD) or a homologue or orthologue thereof in a method of the manufacture of a tetramer of polypeptides, for producing a higher yield of tetramers versus monomer and/or dimer polypeptides. [00142] The monomers and dimers comprise one or two copies of the TD, homologue or orthologue respectively [00143] In an example, the TD, orthologue or homologue is a human domain. [00144] Herein, the TD is a human TD or a homologue, eg, a TD selected from any of the p53 TD sequences disclosed in UniProt (www.uniprot.org), for example the p53 TD is a TD disclosed in Table 13. In an example, the homologue is a p53TD of a non-human animal species, eg, a mouse, rat, horse cat or dog p53TD. See Figure 32, which shows the high level of conservation between p53 TDs of different species, which supports the use of non-human p53 TDs as an alternative to human p53 TDs. In an example, the homologue is a p53TD of a non-human mammalian species. In an example, the homologue is identical to human p53 TD with the exception of up to 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid change(s). [00145] In an example, the yield of tetramers is higher than the yield of monomers; In an example, the yield of tetramers is higher than the yield of dimers; In an example, the yield of tetramers is higher than the yield of trimers; In an example, the yield of tetramers is higher than the yield of monomers and dimers; In an example, the yield of tetramers is higher than the yield of monomers and trimers; In an example, the yield of tetramers is higher than the yield of monomers, dimers and trimers [00146] For example, the TD is the TD of p53 isoform 1. In an example, the TD comprises or consists of an amino acid sequence that is identical to positions 325 to 356 (or 319-360; or 321-359) of human p53 (eg, isoform 1). Optionally, the TD, orthologue or homologue comprises or consists of an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*10, 1*126, 1*11 or 1*12. For example the sequence is identical to said selected sequence. Optionally, the TD, orthologue or homologue comprises or consists of an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*120, 1*121, 1*122 or 1*123. For example, the sequence is identical to said selected sequence. 2. The use of Concept 1, wherein first, second, third and fourth copies of an identical TD or homologue or orthologue thereof is used. 3. The use of any preceding Concept, wherein the TD is a NHR2, p53, p63 or p73 tetramerisation domain. For example, the TD is a p53 TD. In an example, the TD is an orthologue or homologue of a p53 TD, eg, a human p53 TD. 4. The use of any preceding Concept, wherein the yield of tetramers is at least 10x the yield of monomers and/or dimers. [00147] Optionally, the yield is at least 2x 3x, 4x, 5x, 6x, 7x, 8x, 9x, or 10x the yield of monomers and/or dimers. Optionally, the ratio of tetramers produced : monomers and/or dimers is at least 90:10, eg, at least 95:5; or 96:4; or 97:3; or 98:2; or 99:1. Optionally only tetramers are produced. [00148] In an embodiment, each domain comprised by each monomer, dimer or tetramer is a human domain; and optionally the monomer, dimer or tetramer does not comprise non-human amino acid sequences or linkers. 5. The use of any preceding Concept, wherein the ratio of tetramers produced : monomers and/or dimers produced in the method is at least 90:10 (ie, 9x the amount of monomers; 9x the amount of dimers; or 9x the amount of the combination of monomers and dimers). 6. The use of Concept 4 or 5, wherein the yield or ratio is determinable or determined by obtaining a sample of the product of the tetramer manufacture method, using a protein separation technique on the sample to resolve tetramers, monomers and dimers and comparing the amount of tetramers with the amount of monomers and dimers. [00149] Amounts of tetramers, monomers, dimers and trimers can be determined, for example, using Western Blot analysis of a gel described herein, eg, a native gel, ie, a gel not under denatured conditions, such as in the absence of SDS. 7. The use of Concept 4 or 5, wherein the yield or ratio is determinable or determined by (a) Obtaining a sample of the product of the tetramer manufacture method; (b) Carrying out polyacrylamide gel electrophoresis (PAGE) under non-reducing conditions to resolve the sample into a band corresponding to said tetramers and a band corresponding to said monomers and/or a band corresponding to said dimers; and (c) Comparing the tetramer band with the monomer and/or dimer band(s) to determine said yield or ratio, eg, by comparing the relative band intensities and/or band sizes. 8. The use of Concept 4 or 5, wherein the yield or ratio is determinable or determined by (d) Obtaining a sample of the product of the tetramer manufacture method; (e) Carrying out polyacrylamide gel electrophoresis (PAGE) under non-reducing conditions to resolve the sample into a band corresponding to said tetramers, eg, wherein the gel is under non- denatured conditions (eg, in the absence of sodium dodecylsuphate (SDS); (f) Determining that there is no band corresponding to said monomers and/or no band corresponding to said dimers. 9. The use of Concept 7 or 8, comprising (g) Obtaining a second sample of the product of the tetramer manufacture method; (h) Carrying out polyacrylamide gel electrophoresis (PAGE) under reducing conditions to resolve the second sample into a band corresponding to said monomers and/or a band corresponding to said dimers, eg, wherein the gel is under non-denatured conditions (eg, in the absence of sodium dodecylsuphate (SDS); and (i) Comparing the gel produced by step (h) with the gel of step (b) or (e) to determine the position of monomer and/or dimer band(s) in the gel of step (b) or where such gels would be expected in the gel of step (e). 10. The use of any preceding Concept, wherein each monomer has a size of no more than 40 kDa. [00150] For example, the monomer has a size of no more than 35, 30, 25, 24, 23, 22, 21 or 20 kDa 11. The use of any preceding Concept, wherein each tetramer has a size of no more than 150 kDa. [00151] For example, the tetramer has a size of no more than 80, 90, 100, 110, 120, 130 or 140 kDa. 12. The use of any preceding Concept, wherein the method comprises expressing the tetramers from a mammalian cell line, eg, a HEK293, CHO or Cos cell line. [00152] For example, the cell line is a HEK293 (eg, HEK293T) cell line. In the alternative, the cell line is a yeast (eg, Saccharomyces or Pichia, eg, P pastoris) or bacterial cell line. 13. The use of any preceding Concept, wherein the method comprises secreting the tetramers from a mammalian cell line, eg, a HEK293, CHO or Cos cell line. [00153] Thus, advantageously in an example, the use or tetramer is for expression from a mammalian cell line (eg, a HEK293, CHO or Cos cell line) or a eukaryotic cell line. This is useful for large-scale manufacture of the products, eg, tetramers, of the invention. [00154] For example, the cell line is a HEK293 (eg, HEK293T) cell line. In the alternative, the cell line is a yeast (eg, Saccharomyces or Pichia, eg, P pastoris) or bacterial cell line. 14. The use of any preceding Concept, wherein each polypeptide or monomer comprises a said TD, homologue or orthologue and one or more protein effector domains, such as one or more antibody domains, eg, one or more antibody domains forming an antigen binding site. 15. The use of Concept 14, wherein the polypeptide comprises one or more of (i) an antibody single variable domain (dAb or VHH or Nanobody™) that is capable of specifically binding an antigen; (ii) an scFv that is capable of binding an antigen or an scTCR that is capable of binding pMHC; (iii) a Fab that is capable of binding an antigen; or (iv) a TCR variable domain or pMHC binding site. 16. The use of any preceding Concept, wherein each polypeptide or monomer comprises a said TD, homologue or orthologue and one or more incretin, insulin, GLP-1 or Exendin-4 domains. 17. The use of any preceding Concept, wherein each polypeptide or monomer comprises a said TD, homologue or orthologue; and first and second antigen binding sites. 18. The use of Concept 17, wherein each binding site is provided by (i) an antibody single variable domain (dAb or VHH or Nanobody™) that is capable of specifically binding an antigen; (ii) an scFv that is capable of binding an antigen or an scTCR that is capable of binding pMHC; (iii) a Fab that is capable of binding an antigen; or (iv) a TCR variable domain or pMHC binding site. 19. The use of Concept 18, wherein each binding site is provided by an antibody single variable domain. 20. The use of any one of Concepts 14 to 18, wherein the TD, homologue or orthologue is directly fused to said further domain(s). 21. The use of Concept 20, wherein each monomer or polypeptide comprises the TD, homologue or orthologue fused directly or via a peptide linker to the C-terminal of a said further domain. 22. A tetramer of polypeptides, wherein each polypeptide comprises (i) a tetramerisation domain (TD) (eg, a p53 TD or a NHR2 TD) or a homologue or orthologue thereof; (ii) one or more protein effector domains; and (iii) optionally a linker linking (i) to (ii) (eg, linking the C-terminus of (ii) to the N-terminus of (i)); wherein optionally each tetramer has a size of no more than 150 or 200 kDa. [00155] For example, the tetramer has a size of no more than 80, 90, 100, 110, 120, 130 or 140 kDa. In an example, any multimer, dimer, trimer, tetramer, octamer, dodecamer, hexadecamer or 20- merherein has a size of at least 60 or 80 kDa; this may be useful for example to increase half -life in a human or animal subject administered with the multimer, dimer, trimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, to treat or prevent a disease or condition in the subject). Sizes in these ranges may be above the renal filtration size. [00156] In an alternative, the invention provides a monomer, dimer, octamer, dodecamer, hexadecamer or 20-merinstead of a tetramer. 23. The tetramer of Concept 22, wherein each polypeptide comprises one or more of (i) an antibody single variable domain (dAb or VHH or Nanobody™) that is capable of specifically binding an antigen; (ii) an scFv that is capable of binding an antigen or an scTCR that is capable of binding pMHC; (iii) a Fab that is capable of binding an antigen; or (iv) a TCR variable domain or pMHC binding site. 24. The tetramer of Concept 22 or 23, wherein each polypeptide comprises a said TD, homologue or orthologue and one or more incretin, insulin, GLP-1 or Exendin-4 domains. 25. The tetramer of Concept 22 or 23, wherein each polypeptide comprises a said TD, homologue or orthologue; and first and second antigen binding sites. 26. The tetramer of Concept 25, wherein each binding site is provided by (i) an antibody single variable domain (dAb or VHH or Nanobody™) that is capable of specifically binding an antigen; (ii) an scFv that is capable of binding an antigen or an scTCR that is capable of binding pMHC; (iii) a Fab that is capable of binding an antigen; or (iv) a TCR variable domain or pMHC binding site. 27. The tetramer of Concept 26, wherein each binding site is provided by an antibody single variable domain. 28. The tetramer of any one of Concepts 22 to 27, wherein the TD, homologue or orthologue is directly fused to said effector domain(s). 29. The tetramer of any one of Concepts 22 to 27, wherein each polypeptide comprises the TD, homologue or orthologue fused directly or via a peptide linker to the C-terminal of a said effector domain. [00157] In an embodiment, each polypeptide comprises only 2 (ie, only a first and a second, but not a third) effector domains or only 2 dAbs, VHH, scFvs, scTCRs, Fabs or antigen binding sites. 30. A pharmaceutical composition comprising a tetramer of any one of Concepts 22 to 29 and a pharmaceutically acceptable carrier, diluent or excipient. [00158] Optionally the composition is comprised by a sterile medical container or device, eg, a syringe, vial, inhaler or injection device. 31. A cosmetic, foodstuff, beverage, cleaning product, detergent comprising a tetramer of any one of Concepts 22 to 29. 32. A mixture comprising a cell line (eg, a mammalian cell line, eg, a HEK293, CHO or Cos cell line) encoding a polypeptide as recited in any preceding Concept; and tetramers as defined in any preceding Concept. [00159] Optionally, the mixture is comprised by a sterile container. 33. The mixture of Concept 32, wherein the cell line is in a medium comprising secretion products of the cells, wherein the secretion products comprise said tetramers. 34. The mixture of Concept 33, wherein the secretion products do not comprise monomers and/or dimers as defined in any one of Concepts 1 to 31. 35. The mixture of Concept 33, wherein the secretion products comprise said tetramers in an amount of at least 10x the amount of monomers and/or dimers. 36. The mixture of Concept 33, wherein the secretion products comprise said tetramers in a ratio of tetramers : monomers and/or dimers of at least 90:10. 37. A method for enhancing the yield of tetramers of an protein effector domain (eg, an antibody variable domain or binding site), the method comprising expressing from a cell line (eg, a mammalian cell, CHO, HEK293 or Cos cell line) tetramers of a polypeptide, wherein the polypeptide is as defined in any preceding Concept and comprises one or more effector domains; and optionally isolating said expressed tetramers. [00160] The homologue, orthologue or equivalent has multimerisation or tetramerisation function. [00161] Homologue: A gene, nucleotide or protein sequence related to a second gene, nucleotide or protein sequence by descent from a common ancestral DNA or protein sequence. The term, homologue, may apply to the relationship between genes separated by the event of or to the relationship between genes separated by the event of genetic duplication. [00162] Orthologue: Orthologues are genes, nucleotide or protein sequences in different species that evolved from a common ancestral gene, nucleotide or protein sequence by speciation. Normally, orthologues retain the same function in the course of evolution. [00163] In an example, the TD, orthologue or homologue is a TD of any one of proteins 1 to 119 listed in Table 2. In an example, the orthologue or homologue is an orthologue or homologue of a TD of any one of proteins 1 to 119 listed in Table 2. In an embodiment, instead of the use of a p53 tetramerisation domain (p53-TD) or a homologue or orthologue thereof, all aspects of the invention herein instead can be read to relate to the use or inclusion in a polypeptide, monomer, dimer, trimer or tetramer of aTD of any one of proteins 1 to 119 listed in Table 2 or a homologue or orthologue thereof. The TD may be a NHR2 (eg, a human NHR2) TD or an orthologue or homologue thereof. The TD may be a p63 (eg, a human p63) TD or an orthologue or homologue thereof. The TD may be a p73 (eg, a human p73) TD or an orthologue or homologue thereof. This may have one or more advantages as follows:- - secretion of tetramers from mammalian or other eukaryotic cells, eg, a mammalian cell disclosed herein such as CHO, HEK293 or Cos; - enhanced yield of secreted tetramers versus monomers; - enhanced yield of secreted tetramers versus dimers; - enhanced yield of secreted tetramers versus trimers; - enhanced yield of secreted tetramers versus monomers and dimers combined; - enhanced yield of secreted tetramers versus monomers, dimers and trimers combined; - enhanced affinity or avidity of antigen binding in tetramers comprising antigen binding sites; - enhanced tetramer production and/or expression, wherein the tetramer is no more than 200 or no more than 160 or 150 kDa in size. In an embodiment, each polypeptide or monomer comprises one or more VH, VL or VH/VL binding sites of an antibody selected from ReoPro™; Abciximab; Rituxan™; Rituximab; Zenapax™; Daclizumab; Simulect™; Basiliximab; Synagis™; Palivizumab; Remicade™; Infliximab; Herceptin™; Trastuzumab; Mylotarg™; Gemtuzumab; Campath™; Alemtuzumab; Zevalin™; Ibritumomab; Humira™; Adalimumab; Xolair™; Omalizumab; Bexxar™; Tositumomab; Raptiva™; Efalizumab; Erbitux™; Cetuximab; Avastin™; Bevacizumab; Tysabri™; Natalizumab; Actemra™; Tocilizumab; Vectibix™; Panitumumab; Lucentis™; Ranibizumab; Soliris™; Eculizumab; Cimzia™; Certolizumab; Simponi™; Golimumab, Ilaris™; Canakinumab; Stelara™; Ustekinumab; Arzerra™; Ofatumumab; Prolia™; Denosumab; Numax™; Motavizumab; ABThrax™; Raxibacumab; Benlysta™; Belimumab; Yervoy™; Ipilimumab; Adcetris™; Brentuximab; Vedotin™; Perjeta™; Pertuzumab; Kadcyla™; Ado-trastuzumab; Gazyva™ and Obinutuzumab. In an alternative, (eg, for treating or preventing a cancer in a human) each polypeptide or monomer comprise one or more VH, VL or VH/VL binding sites of an antibody selected from ipilimumab (or YERVOYTM), tremelimumab, nivolumab (or OPDIVOTM), pembrolizumab (or KEYTRUDATM), pidilizumab, BMS-936559, durvalumab and atezolizumab. Optionally, the binding site of the polypeptide of the multimer comprises a VH of the binding site of the antibody and also the CH1 of the antibody (ie, in N- to C-terminal direction the VH-CH1 and SAM). In an embodiment, the polypeptide may be paired with a further polypeptide comprising (in N- to C-terminal direction a VL-CL, eg, wherein the CL is the CL of the antibody). [00164] In an example, the tetramer comprises 4 copies of the antigen binding site of a first antibody selected from the group consisting of ipilimumab (or YERVOYTM), tremelimumab, nivolumab (or OPDIVOTM), pembrolizumab (or KEYTRUDATM), pidilizumab, BMS-936559, durvalumab and atezolizumab and optionally 4 copies of the antigen binding site of a second antibody selected from said group, wherein the first and second antibodies are different. For example, the first antibody is ipilimumab (or YERVOYTM) and optionally the second antibody is nivolumab (or OPDIVOTM) or pembrolizumab (or KEYTRUDATM). This is useful for treating or preventing a cancer in a human. [00165] In an example, the tetramer comprises 4 copies of the antigen binding site of Avastin. In an example, the tetramer comprises 4 copies of the antigen binding site of Humira. In an example, the tetramer comprises 4 copies of the antigen binding site of Erbitux. In an example, the tetramer comprises 4 copies of the antigen binding site of Actemra™. In an example, the tetramer comprises 4 copies of the antigen binding site of sarilumab. In an example, the tetramer comprises 4 copies of the antigen binding site of dupilumab. In an example, the tetramer comprises 4 copies of the antigen binding site of alirocumab or evolocumab. In an example, the tetramer comprises 4 copies of the antigen binding site of In an example, the tetramer comprises 4 copies of the antigen binding site of Remicade. In an example, the tetramer comprises 4 copies of the antigen binding site of Lucentis. In an example, the tetramer comprises 4 copies of the antigen binding site of Eylea™. Such tetramers are useful for administering to a human to treat or prevent a cancer. Such tetramers are useful for administering to a human to treat or prevent an ocular condition (eg, wet AMD or diabetic retinopathy, eg, when the binding site is an Avastin, Lucentis or Eylea site). Such tetramers are useful for administering to a human to treat or prevent angiogenesis. [00166] In an example, the tetramer comprises 4 copies of insulin. In an example, the tetramer comprises 4 copies of GLP-1. In an example, the tetramer comprises 4 copies of GIP. In an example, the tetramer comprises 4 copies of Exendin-4. In an example, the tetramer comprises 4 copies of insulin and 4 copies of GLP-1. In an example, the tetramer comprises 4 copies of insulin and 4 copies of GIP. In an example, the tetramer comprises 4 copies of insulin and 4 copies of Exendin-4. In an example, the tetramer comprises 4 copies of GLP-1 and 4 copies of Exendin-4. Such tetramers are useful for administering to a human to treat or prevent diabetes (eg, Type II diabetes) or obesity. EXAMPLE ANTIGENS [00167] The polypeptide, multimer may bind to one or more antigens or epitopes, or each of the binding sites herein (eg, dAb or scFv binding sites) herein may bind to an antigen or epitope. In an example, an (or each) antigen herein is selected from the following list. In an example, an (or each) epitope herein is an epitope of an antigen selected from the following list. [00168] Activin type-II receptor; Activin type-IIB receptor; ADAM11; ADAM12; ADAM15; ADAM17; ADAM18; ADAM19; ADAM1A; ADAM1B; ADAM2; ADAM20; ADAM21; ADAM22; ADAM23; ADAM24P; ADAM28; ADAM29; ADAM30; ADAM32; ADAM33; ADAM3A; ADAM3B; ADAM5; ADAM6; ADAM7; ADAM8; ADAM9; ADORA2A; AKT; ALK; alpa-4 integrin; alpha synuclein; anthrax protective antigen; BACE1; BCMA; beta amyloid; BRAF; BTLA; BTNL2; CCR4; CCR5; CD126; CD151; CD16; CD160; CD19; CD20; CD22; CD226; CD244; CD27; CD274 (PDL1); CD276; CD28; CD3; CD30; CD300A; CD300C; CD300E; CD300LB; CD300LF; CD33; CD38; CD3; CD3 epsilon; CD3 delta; CD3 gamma; CD40; CD40L; CD47; CD48; CD5; CD52; CD59; CD6; CD70; CD72; CD73; CD80; CD81; CD84; CD86; CD96; CDK4/6; CEA; CEACAM1; CEACAM3; CGRP receptor; CLEC12A; CLEC1B; CLEC4A; CLEC5A; CLEC7A; Clostridium difficile toxin ; cMET; Complement C5 factor; Complement factor D; CSF1R; CSF2RA; CTAG1B; CTLA4; CXCL12; CXCR2; CXCR4; DR4; DR5; EDA; EDA2R; EGFR; EGFRvIII; EMR1; ENTPD1; EpCAM; Factor IX; Factor X; Factor VII; FAP; FAS; FCAR; FCER1G; FCER2 ; TFR2; 4-1BB; FCGR2A; FCGR2B; FCGR3A; FCGR3B; FCRL1; FCRL3; FCRL4; FCRL6; FGRF1/2/3; FLT3; GAL; GEM; GITR; GITRL; GM-CSF; GM-CSF receptor; GP IIb IIIa; gpNMB; TIM3; HDAC1; HER-2; HER3; HFE; HHLA2; Histone H1 modulator; HLA-C; HLA-G; HMGB1; HMMR; HVEM; ICAM-1; ICOS; ICOSL; IDO1; IFNG; IL-1 beta; IL-12; IL-13; IL-2; IL-22R; IL- 23; IL-23a; IL-24; IL-2R; IL-34; IL-8; IL10; IL11; IL13; IL17A; IL17D; IL22; IL2RA; IL36G; IL4; IL4a; IL5; IL6; Immunoglobulin E; Immunoglobulin E; Immunoglobulin G; INHBA; INHBB; Interferon type I receptor; INF-a-2a/2b; INF-b-1a/1b; ITGA2B; ITGB3; KIR; KIR2DL1; KIR2DL2; KIR2DL3; KIR2DL4; KIR2DL5A; KIR3DL1; KIR3DL3 ;KIR3DS1; KIT; KLRC1; KLRC2; KLRF1; KLRG1 ;KLRK1 ;KRAS; LAG3; LAIR1; LAIR2; LFA-1; LIGHT; LILRA1; LILRA2; LILRA3; LILRA4; LILRA5; LILRA6; LILRB1; LILRB2; LILRB3; LILRB4; LILRB5 ;LILRP1; LILRP2; LTA; LTBR; LY9; MadCam; MAGE-C1; MAGE-C2; MARCO; MEK-1/2; MIA3; MIC; MICA; MICB; MMP9; MS4A1; MS4A2; mTOR; MUC1; MUCIN-1; Nav1.7; Nav1.8; NCR1; NCR2; NCR3; NGF; NGFR; NT5E; NY-ESO-1; OX40; OX40L; p53; PARP; PCSK9; PD-1; PDCD1LG2; PDCD6; PDGF receptor alpha; PECAM1; PI3K delta; PILRA; PPP1R1B; PSMA; PTPN6; PVR; PVRL2; PVRL3; RANKL; Respiratory syncytial virus protein; SIGLEC10; SIGLEC12; SIGLEC15; SIGLEC5; SIGLEC6; SIGLEC7; SIGLEC9; SIRPA; SIRPB1; SLAMF1; SLAMF6; SLAMF7; SLAMF8; SNCA; SOD1; STAT3; STING; SURVIVIN; TARM1; Tau; TDP43; TfR1; TGF-b; TGM2; TIGIT; TIM-3; TLR-4; TLR03; TMEM30a; TMIGD2; TNFa; TNFRSF10A; TNFRSF10B; TNFRSF10C; TNFRSF10D; TNFRSF11A; TNFRSF11B; TNFRSF12A; TNFRSF13B; TNFRSF13C; TNFRSF14; TNFRSF17; TNFRSF18; TNFRSF19; TNFRSF21; TNFRSF4; TNFRSF6B; TNFRSF8; TNFRSF9; TNFSF10; TNFSF11; TNFSF12; TNFSF13; TNFSF13B; TNFSF14; TNFSF15; TNFSF18; TNFSF4; TNFSF8; TNFSF9; Transmembrane glycoprotein NMB modulator; TREML1; TREML2; TSLP; VEGF; VEGF-2R; VEGF1; VEGFA; VEGFL; VEGFR; Viral envelope glycoprotein; Viral protein haemagglutinin; VISTA; VSIG4; VSTM1; VTCN1; and WEE-1. In an example, an antigen herein is a PCSK9, eg, human PCSK9; optionally the multimer has 4, 8, 12 or 16 copies an anti- PCSK9 binding site (eg, a dAbs). [00169] An example antigen is a toxin, such as a snake venom toxin, eg, wherein a multimer of the invention is administered (such as systemically or by IV injection) to a human or animal subject and the antigen binding sites comprised by the multimer specifically bind to the toxin in the subject. Preferably, each binding site or domain of the multimer is a dAb (eg, a Nanobody™). For example, each snake venom toxin antigen binding site of the multimer of the invention is a C33 single domain VH as disclosed in Figure 4 of PLoS One.2013 Jul 22;8(7):e69495. doi: 10.1371/journal.pone.0069495; “In vivo neutralization of α-cobratoxin with high-affinity llama single-domain antibodies (VHHs) and a VHH-Fc antibody”, Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. For example, each snake venom toxin antigen binding site of the multimer of the invention is a C15 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. For example, each snake venom toxin antigen binding site of the multimer of the invention is a C7 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. For example, each snake venom toxin antigen binding site of the multimer of the invention is a C13 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. For example, each snake venom toxin antigen binding site of the multimer of the invention is a C19 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. For example, each snake venom toxin antigen binding site of the multimer of the invention is a C34 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. For example, each snake venom toxin antigen binding site of the multimer of the invention is a C31 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. For example, each snake venom toxin antigen binding site of the multimer of the invention is a C20 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. For example, each snake venom toxin antigen binding site of the multimer of the invention is a C2 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. For example, each snake venom toxin antigen binding site of the multimer of the invention is a C29 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. For example, each snake venom toxin antigen binding site of the multimer of the invention is a C42 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. For example, each snake venom toxin antigen binding site of the multimer of the invention is a C43 single domain VH as disclosed in Figure 4 of Richard et al, the amino acid of which as discloed in said Figure 4 is incorporated herein in its entirety by reference for possible use in the present invention as a binding site or domain or dAb or Nanobody or VHH or VH. An example of a snake venom toxin is 3FTx, dendrotoxin or PLA2 toxin. Optionally, the toxin is an alpha-neurotoxin, eg, from Cobra. [00170] Another example of a toxin is a blood toxin, eg, wherein a multimer of the invention is administered (such as systemically or by IV injection) to a human or animal subject and the antigen binding sites comprised by the multimer specifically bind to the toxin in the blood of the subject. These examples are useful for sequestering the toxin or for reducing the toxic effect of the toxin to the subject or to promote excretion or metabolism of the toxin. [00171] In an example, the antigen is a viral antigen, each a capsid protein or carbohydrate (eg, a sugar). In an example, a multimer of the invention binds to a virus or virus antigen, eg, a virus selected from Table 19 wherein the virus comprises a surface antigen that is bound by the multimer; or the multimer of the invention binds to a cell or virus antigen, eg, selected from an antigen disclosed in Table 20. Binding to the virus may, for example, reduce or inhibit attachment of the virus to its host cell or infection of the cell by the virus. For example, the invention provides a method of treating or preventing (eg, reducing the risk of) a viral or cell infection in a human or animal or plant subject (eg, in a human subject), the method comprising administering a multimer of the invention to the subject wherein the multimer binds to a surface antigen of the virus, thereby inhibiting the virus from attaching to a host cell; inhibiting infection of a host cell by the virus and/or sequestering the virus in the subject (eg, to mark the bound virus for clearance from the systemic circulation or a tissue of the subject). In an alternative, For example, the invention provides a method of treating or preventing (eg, reducing the risk of) a bacterial or archaeal cell infection in a human or animal or plant subject (eg, in a human subject), the method comprising administering a multimer of the invention to the subject wherein the multimer binds to a surface antigen of the cell, thereby inhibiting infection of the subject by the cell and/or sequestering the cell in the subject (eg, to mark the bound cell for clearance from the systemic circulation or a tissue of the subject). In an alternative, For example, the invention provides a method of treating or preventing (eg, reducing the risk of) a cancer in a human or animal subject (eg, in a human subject), the method comprising administering a multimer of the invention to the subject wherein the multimer binds to a surface antigen of a tumour cell, thereby sequestering the cell in the subject (eg, to mark the bound cell for clearance from the systemic circulation or a tissue of the subject) or marking the cell for targeting by the immune sytem or another therapy (eg, immune checkpoint therapy or CAR-T therapy) administered to the subject. [00172] In an example, the antigen is selected from CXCR2, CXCR4, GM-CSF, ICAM-1, IFN-g, IL- 1, IL-10, IL-12, IL-1R1, IL-1R2, IL-1Ra, IL-1 β , IL-4, IL-6, IL-8, MIF, TGF- β , TNF- α , TNFR1, TNFR2 and VCAM-1. Targeting one or more of these antigens may be useful for treating or preventing sepsis in a subject. Thus, in an example the multimer of the invention comprises one or more antigen binding sites (eg, each one provided by a dAb), wherein the multimer is for use in a method of treating or preventing sepsis in a human or animal subject, wherein the multimer is administered to the subject (eg, systemically or intravenously). Optionally, the multimer is monospecific, bispecific, trispecific or tetraspecific for antigen binding. For example, the multimer is bispecific, trispecific or tetraspecific for an antigen selected from CXCR2, CXCR4, GM-CSF, ICAM- 1, IFN-g, IL-1, IL-10, IL-12, IL-1R1, IL-1R2, IL-1Ra, IL-1 β , IL-4, IL-6, IL-8, MIF, TGF- β , TNF- α , TNFR1, TNFR2 and VCAM-1. There is also provided a pharmaceutical composition comprising such a multimer and a pharmaceutically acceptable diluent, carrier or excipient. There is also provided a method of treating or preventing sepsis in a human or animal subject, the method comprising administering the multimer to the subject, eg, systemically or intravenously. DISEASES AND CONDITIONS [00173] The polypeptide monomer or multimer (eg, dimer, trimer, tetramer or octamer) of the invention can be used in a method for administration to a human or animal subject to treat or prevent a disease or condition in the subject.  [00174] Optionally, the disease or condition is selected from  (a) A neurodegenerative disease or condition; (b) A brain disease or condition; (c) A CNS disease or condition; (d) Memory loss or impairment; (e) A heart or cardiovascular disease or condition, eg, heart attack, stroke or atrial fibrillation; (f) A liver disease or condition; (g) A kidney disease or condition, eg, chronic kidney disease (CKD); (h) A pancreas disease or condition; (i) A lung disease or condition, eg, cystic fibrosis or COPD; (j) A gastrointestinal disease or condition; (k) A throat or oral cavity disease or condition; (l) An ocular disease or condition; (m) A genital disease or condition, eg, a vaginal, labial, penile or scrotal disease or condition; (n) A sexually-transmissible disease or condition, eg, gonorrhea, HIV infection, syphilis or Chlamydia infection; (o) An ear disease or condition; (p) A skin disease or condition; (q) A heart disease or condition; (r) A nasal disease or condition (s) A haematological disease or condition, eg, anaemia, eg, anaemia of chronic disease or cancer; (t) A viral infection; (u) A pathogenic bacterial infection; (v) A cancer; (w) An autoimmune disease or condition, eg, SLE; (x) An inflammatory disease or condition, eg, rheumatoid arthritis, psoriasis, eczema, asthma, ulcerative colitis, colitis, Crohn’s disease or IBD; (y) Autism; (z) ADHD; (aa) Bipolar disorder; (bb) ALS [Amyotrophic Lateral Sclerosis]; (cc) Osteoarthritis; (dd) A congenital or development defect or condition; (ee) Miscarriage; (ff) A blood clotting condition; (gg) Bronchitis; (hh) Dry or wet AMD; (ii) Neovascularisation (eg, of a tumour or in the eye); (jj) Common cold; (kk) Epilepsy; (ll) Fibrosis, eg, liver or lung fibrosis; (mm) A fungal disease or condition, eg, thrush; (nn) A metabolic disease or condition, eg, obesity, anorexia, diabetes, Type I or Type II diabetes. (oo) Ulcer(s), eg, gastric ulceration or skin ulceration; (pp) Dry skin; (qq) Sjogren’s syndrome; (rr) Cytokine storm; (ss) Deafness, hearing loss or impairment; (tt) Slow or fast metabolism (ie, slower or faster than average for the weight, sex and age of the subject); (uu) Conception disorder, eg, infertility or low fertility; (vv) Jaundice; (ww) Skin rash; (xx) Kawasaki Disease; (yy) Lyme Disease; (zz) An allergy, eg, a nut, grass, pollen, dust mite, cat or dog fur or dander allergy; (aaa) Malaria, typhoid fever, tuberculosis or cholera; (bbb) Depression; (ccc) Mental retardation; (ddd) Microcephaly; (eee) Malnutrition; (fff) Conjunctivitis; (ggg) Pneumonia; (hhh) Pulmonary embolism; (iii) Pulmonary hypertension; (jjj) A bone disorder; (kkk) Sepsis or septic shock; (lll) Sinusitus; (mmm) Stress (eg, occupational stress); (nnn) Thalassaemia, anaemia, von Willebrand Disease, or haemophilia; (ooo) Shingles or cold sore; (ppp) Menstruation; (qqq) Low sperm count. NEURODEGENERATIVE OR CNS DISEASES OR CONDITIONS FOR TREATMENT OR PREVENTION [00175] In an example, the neurodegenerative or CNS disease or condition is selected from the group consisting of Alzheimer disease , geriopsychosis, Down syndrome, Parkinson's disease, Creutzfeldt- jakob disease, diabetic neuropathy, Parkinson syndrome, Huntington's disease, Machado-Joseph disease, amyotrophic lateral sclerosis, diabetic neuropathy, and Creutzfeldt Creutzfeldt- Jakob disease. For example, the disease is Alzheimer disease. For example, the disease is Parkinson syndrome. [00176] In an example, wherein the method of the invention is practised on a human or animal subject for treating a CNS or neurodegenerative disease or condition, the method causes downregulation of Treg cells in the subject, thereby promoting entry of systemic monocyte-derived macrophages and/or Treg cells across the choroid plexus into the brain of the subject, whereby the disease or condition (eg, Alzheimer’s disease) is treated, prevented or progression thereof is reduced. In an embodiment the method causes an increase of IFN-gamma in the CNS system (eg, in the brain and/or CSF) of the subject. In an example, the method restores nerve fibre and//or reduces the progression of nerve fibre damage. In an example, the method restores nerve myelin and//or reduces the progression of nerve myelin damage. In an example, the method of the invention treats or prevents a disease or condition disclosed in WO2015136541 and/or the method can be used with any method disclosed in WO2015136541 (the disclosure of this document is incorporated by reference herein in its entirety, eg, for providing disclosure of such methods, diseases, conditions and potential therapeutic agents that can be administered to the subject for effecting treatement and/or prevention of CNS and neurodegenerative diseases and conditions, eg, agents such as immune checkpoint inhibitors, eg, anti- PD-1, anti-PD-L1, anti-TIM3 or other antibodies disclosed therein). CANCERS FOR TREATMENT OR PREVENTION [00177] Cancers that may be treated include tumours that are not vascularized, or not substantially vascularized, as well as vascularized tumours. The cancers may comprise non-solid tumours (such as haematological tumours, for example, leukaemias and lymphomas) or may comprise solid tumours. Types of cancers to be treated with the invention include, but are not limited to, carcinoma, blastoma, and sarcoma, and certain leukaemia or lymphoid malignancies, benign and malignant tumours, and malignancies e.g., sarcomas, carcinomas, and melanomas. Adult tumours/cancers and paediatric tumours/cancers are also included. [00178] Haematologic cancers are cancers of the blood or bone marrow. Examples of haematological (or haematogenous) cancers include leukaemias, including acute leukaemias (such as acute lymphocytic leukaemia, acute myelocytic leukaemia, acute myelogenous leukaemia and myeloblasts, promyeiocytic, myelomonocytic, monocytic and erythroleukaemia), chronic leukaemias (such as chronic myelocytic (granulocytic) leukaemia, chronic myelogenous leukaemia, and chronic lymphocytic leukaemia), polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (indolent and high grade forms), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myeiodysplastic syndrome, hairy cell leukaemia and myelodysplasia. [00179] Solid tumours are abnormal masses of tissue that usually do not contain cysts or liquid areas. Solid tumours can be benign or malignant. Different types of solid tumours are named for the type of cells that form them (such as sarcomas, carcinomas, and lymphomas). Examples of solid tumours, such as sarcomas and carcinomas, include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumour, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer, lung cancers, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous eel! carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, pheochromocytomas sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, Wilms' tumour, cervical cancer, testicular tumour, seminoma, bladder carcinoma, melanoma, and CNS tumours (such as a glioma (such as brainstem glioma and mixed gliomas), glioblastoma (also known as glioblastoma multiforme) astrocytoma, CNS lymphoma, germinoma, medu!loblastoma, Schwannoma craniopharyogioma, ependymoma, pineaioma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, neuroblastoma, retinoblastoma and brain metastases). [00180] AUTOIMMUNE DISEASES FOR TREATMENT OR PREVENTION . Acute Disseminated Encephalomyelitis (ADEM) . Acute necrotizing hemorrhagic leukoencephalitis . Addison’s disease . Agammaglobulinemia . Alopecia areata . Amyloidosis . Ankylosing spondylitis . Anti-GBM/Anti-TBM nephritis . Antiphospholipid syndrome (APS) . Autoimmune angioedema . Autoimmune aplastic anemia . Autoimmune dysautonomia . Autoimmune hepatitis . Autoimmune hyperlipidemia . Autoimmune immunodeficiency . Autoimmune inner ear disease (AIED) . Autoimmune myocarditis . Autoimmune oophoritis . Autoimmune pancreatitis . Autoimmune retinopathy . Autoimmune thrombocytopenic purpura (ATP) . Autoimmune thyroid disease . Autoimmune urticaria . Axonal & neuronal neuropathies . Balo disease . Behcet’s disease . Bullous pemphigoid . Cardiomyopathy . Castleman disease . Celiac disease . Chagas disease . Chronic fatigue syndrome . Chronic inflammatory demyelinating polyneuropathy (CIDP) . Chronic recurrent multifocal ostomyelitis (CRMO) . Churg-Strauss syndrome . Cicatricial pemphigoid/benign mucosal pemphigoid . Crohn’s disease . Cogans syndrome . Cold agglutinin disease . Congenital heart block . Coxsackie myocarditis . CREST disease . Essential mixed cryoglobulinemia . Demyelinating neuropathies . Dermatitis herpetiformis . Dermatomyositis . Devic’s disease (neuromyelitis optica) . Discoid lupus . Dressler’s syndrome . Endometriosis . Eosinophilic esophagitis . Eosinophilic fasciitis . Erythema nodosum . Experimental allergic encephalomyelitis . Evans syndrome . Fibromyalgia . Fibrosing alveolitis . Giant cell arteritis (temporal arteritis) . Giant cell myocarditis . Glomerulonephritis . Goodpasture’s syndrome . Granulomatosis with Polyangiitis (GPA) (formerly called Wegener’s Granulomatosis) . Graves’ disease . Guillain-Barre syndrome . Hashimoto’s encephalitis . Hashimoto’s thyroiditis . Hemolytic anemia . Henoch-Schonlein purpura . Herpes gestationis . Hypogammaglobulinemia . Idiopathic thrombocytopenic purpura (ITP) . IgA nephropathy . IgG4-related sclerosing disease . Immunoregulatory lipoproteins . Inclusion body myositis . Interstitial cystitis . Juvenile arthritis . Juvenile diabetes (Type 1 diabetes) . Juvenile myositis . Kawasaki syndrome . Lambert-Eaton syndrome . Leukocytoclastic vasculitis . Lichen planus . Lichen sclerosus . Ligneous conjunctivitis . Linear IgA disease (LAD) . Lupus (SLE) . Lyme disease, chronic . Meniere’s disease . Microscopic polyangiitis . Mixed connective tissue disease (MCTD) . Mooren’s ulcer . Mucha-Habermann disease . Multiple sclerosis . Myasthenia gravis . Myositis . Narcolepsy . Neuromyelitis optica (Devic’s) . Neutropenia . Ocular cicatricial pemphigoid . Optic neuritis . Palindromic rheumatism . PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus) . Paraneoplastic cerebellar degeneration . Paroxysmal nocturnal hemoglobinuria (PNH) . Parry Romberg syndrome . Parsonnage-Turner syndrome . Pars planitis (peripheral uveitis) . Pemphigus . Peripheral neuropathy . Perivenous encephalomyelitis . Pernicious anemia . POEMS syndrome . Polyarteritis nodosa . Type I, II, & III autoimmune polyglandular syndromes . Polymyalgia rheumatica . Polymyositis . Postmyocardial infarction syndrome . Postpericardiotomy syndrome . Progesterone dermatitis . Primary biliary cirrhosis . Primary sclerosing cholangitis . Psoriasis . Psoriatic arthritis . Idiopathic pulmonary fibrosis . Pyoderma gangrenosum . Pure red cell aplasia . Raynauds phenomenon . Reactive Arthritis . Reflex sympathetic dystrophy . Reiter’s syndrome . Relapsing polychondritis . Restless legs syndrome . Retroperitoneal fibrosis . Rheumatic fever . Rheumatoid arthritis . Sarcoidosis . Schmidt syndrome . Scleritis . Scleroderma . Sjogren’s syndrome . Sperm & testicular autoimmunity . Stiff person syndrome . Subacute bacterial endocarditis (SBE) . Susac’s syndrome . Sympathetic ophthalmia . Takayasu’s arteritis . Temporal arteritis/Giant cell arteritis . Thrombocytopenic purpura (TTP) . Tolosa-Hunt syndrome . Transverse myelitis . Type 1 diabetes . Ulcerative colitis . Undifferentiated connective tissue disease (UCTD) . Uveitis . Vasculitis . Vesiculobullous dermatosis . Vitiligo . Wegener’s granulomatosis (now termed Granulomatosis with Polyangiitis (GPA). [00181] INFLAMMATORY DISEASES FOR TREATMENT OR PREVENTION . Alzheimer's . ankylosing spondylitis . arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis) . asthma . atherosclerosis . Crohn's disease . colitis . dermatitis . diverticulitis . fibromyalgia . hepatitis . irritable bowel syndrome (IBS) . systemic lupus erythematous (SLE) . nephritis . Parkinson's disease . ulcerative colitis. MULTIVALENT SOLUBLE TCR [00182] The present configuration relates to a multivalent soluble TCR protein. In one aspect, the invention relates to tetravalent and octavalent soluble TCR analogues. The TCR proteins of the invention are capable of self-assembly from monomers and are entirely of human origin. The proteins are multimers which comprise an ETO NHR2 multimerisation domain. The invention also relates to methods of constructing multimeric soluble TCRs, and methods of using such proteins. [00183] Attempts to exploit alternative soluble TCR formats as therapeutic molecules have lagged far behind compared to the plethora of antibody formats. This is largely due to TCR, a heterodimeric transmembrane protein having the intrinsic problem of solubility once the extracellular TCR α/β chains are dissociated from their transmembrane and cytoplasmic domain. Secondly the intrinsic low affinity and avidity of these molecules for their cognate ligand at the target site has to a large degree hampered their development as a therapeutic molecule. [00184] In order to overcome these drawbacks, the present configuration of the invention provides a TCR protein which is both multivalent and soluble. Multivalency increases the avidity of the TCR for cognate pMHC, and solubility allows the TCR to be used outside of a transmembrane environment. Accordingly, in a first aspect there is provided a multivalent heterodimeric soluble T cell receptor capable of binding pMHC complex comprising: (i) TCR extracellular domains; (ii) (ii) immunoglobulin constant domains; and (iii) (iii) an NHR2 multimerisation domain of ETO. [00185] The use of Ig constant domains provides the TCR extracellular domains with stability and solubility; multimerisation via the NHR2 domains provides multivalency and increased avidity. Advantageously, all of the domains are of human origin or conform to human protein sequences. [00186] Using the Ig constant domain to stabilise and render soluble the TCR avoids the use of non- native disulphide bonds. Advantageously, therefore, the TCR of the invention does not comprise a non-native disulphide bond. [00187] In one embodiment, said complex comprises a heavy chain and a light chain, and each light chain comprises a TCR Vα domain and an immunoglobulin Cα domain, and each heavy chain comprises a TCR Vβ domain and an immunoglobulin CH1 domain. [00188] In one embodiment, each light chain additionally comprises a TCR Cα domain, and each heavy chain additionally comprises a TCR Cβ domain. [00189] In embodiments, the TCR and immunoglobulin domains can be separated by a flexible linker. [00190] The NHR2 multimerisation domain is advantageously attached to the C-terminus of an immunoglobulin domain. Thus, each dimer of heavy and light chains will be attached to one multimerisation domain, so that the heavy chain-light chain dimers associate into multivalent oligomers. [00191] In embodiments, the multimerisation domain and the immunoglobulin domain are separated by a flexible linker. In certain embodiments, this allows the multimerisation domain to multimerise without hindrance from the immunoglobulin domain(s). [00192] In embodiments, the TCR protein may further comprise an immunoglobulin hinge domain. Hinge domains allow dimerization of heavy chain-light chain dimers; this allows further multimerisation of the TCR proteins. For example, a multimerisation domain which forms polypeptide tetramers can, using an immunoglobulin hinge domain, form multimers up to polypeptide octamers. Likewise, a dimerising multimerisation domain can form tetramers in the presence of a hinge domain. [00193] In embodiments, the TCR protein of the invention is tetravalent. [00194] In embodiments, the TCR protein of the invention is octavalent [00195] The present invention provides a soluble TCR where it is stably assembled in a tetravalent heterodimeric format using the nervy homology region 2 (NHR2) domain found in the ETO family protein in humans (Liu et al.2006). The NHR2 domain is found naturally to form homotetramer, which is formed from pairing of two NHR2 homodimers. NHR2 linked operably to the extracellular TCRα or TCRβ chain will preferentially form tetravalent heterodimeric soluble TCR protein molecules sequentially self-assembled from a monomer followed by a homodimer (Figure 1). [00196] TCR proteins assembling into octamers can be created using the NHR2 domain, by employing immunoglobulin hinge domains. [00197] In a further aspect, the TCR proteins of the invention can be coupled to biologically active polypeptides/effector molecules. Examples of such polypeptides can include immunologically active moieties such as cytokines, binding proteins such as antibodies or targeted polypeptides, and the like. [00198] The invention further relates to methods for making tetravalent and octavalent heterodimeric soluble TCR, the DNA vectors encoding the proteins used for transfecting host cells of interests and the use of these novel highly sensitive multivalent soluble TCR protein molecules. Applications for use could include but not limited to, therapeutics, diagnostics and drug discovery. [00199] In a further aspect, the invention provides a method for constructing multivalent immunoglobulin molecules in an efficient manner, without employing non-human construct components. [00200] Accordingly, there is provided a multimeric immunoglobulin comprising (i) immunoglobulin variable domains; and (ii) an NHR2 multimerisation domain of ETO. [00201] The immunoglobulin variable domains are preferably antibody variable domains. Such domains are fused to the ETO NHR2 multimerisation domain, which provides means for forming tetramers of the immunoglobulin variable domains. [00202] The ETO NHR2 domain is more efficient than p53 and similar multimerisation domains in the production of immunoglobulin multimers, and permits the production of multimeric immunoglobulin molecules without the use of non-human components in the construct. [00203] Also provided is a method for producing a multimeric immunoglobulin, comprising expressing immunoglobulin variable domains in fusion with an NHR2 domain of ETO, and allowing the variable domains to assemble into multimers. [00204] Preferably, the immunoglobulin variable domains are attached to one or more immunoglobulin constant domains. [00205] Advantageously, the immunoglobulin domains are antibody domains. For example, the variable domains can be VH and VL antibody domains. For example, the constant domains are antibody CH1 domains. [00206] In one embodiment, the multimeric immunoglobulin molecules according to the invention, both TCR and non-TCR immunoglobulins, are produced for screening by phage display or another display technology. For example, therefore, the multivalent immunoglobulins are produced as fusions with a phage coat protein. For each immunoglobulin produced fused to a coat protein, other immunoglobulin molecules are produced without a coat protein, such that they can assemble on the phage surface as a result of NHR2 multimerisation. [00207] The present configuration of the invention as detailed above relates to the nucleic acid sequences and methods for producing novel multivalent, for example tetravalent and octavalent, soluble proteins. In one aspect in particular the soluble protein is a TCR assembled into a tetravalent heterodimeric format that can bind four pMHC with high sensitivity, affinity and specificity. The soluble tetravalent heterodimeric TCR is a unique protein molecule composed from either the entire or in part the extracellular TCR α/β chains. The extracellular TCR α/β chains are linked to immunoglobulin CH1 and CL (either Cκ or Cλ) domains. This linkage allows stable formation of heterodimeric TCR α/β. In the context of soluble tetravalent TCR the unique feature is the NHR2 homotetramer domain of the ETO family of proteins, which is operably linked to the C-terminus of CH1 or the C-terminus of CL. Linkage of the NHR2 domain to the heterodimeric α/βTCR in this manner allows it to self-assemble into a tetravalent format inside cells and be subsequently secreted into the supernatant as a soluble protein. TCR Extracellular domains [00208] TCR extracellular domains are composed of variable and constant regions. These domains are present in T-cell receptors in the same way as they are present in antibodies and other immunoglobulin domains. The TCR repertoire has extensive diversity created by the same gene rearrangement mechanisms used in antibody heavy and light chain genes (Tonegawa, S. (1988) Biosci. Rep.8:3-26). Most of the diversity is generated at the junctions of variable (V) and joining (J) (or diversity, D) regions that encode the complementarity determining region 3 (CDR3) of the α and β chains (Davis and Bjorkman (1988) Nature 334:395-402). Databases of TCR genes are available, such as the IMGT LIGM database, and methods for cloning TCRs are known in the art – for example, see Bentley and Mariuzza (1996) Ann. Rev. Immunol.14:563-590; Moysey et al., Anal Biochem. 2004 Mar 15;326(2):284-6; Wälchli, et al. (2011) A Practical Approach to T-Cell Receptor Cloning and Expression. PLoS ONE 6(11): e27930. Immunoglobulin variable domains [00209] Antibody variable domains are known in the art and available from a wide variety of sources. Databases of sequences of antibody variable domains exist, such as IMGT and Kabat, and variable domains can be produced by cloning and expression of natural sequences, or synthesis of artificial nucleic acids according to established techniques. [00210] Methods for the construction of bacteriophage antibody display libraries and lambda phage expression libraries are well known in the art (McCafferty et al. (1990) Nature, 348: 552; Kang et al. (1991) Proc. Natl. Acad. Sci. USA., 88: 4363; Clackson et al. (1991) Nature, 352: 624; Lowman et al. (1991) Biochemistry, 30: 10832; Burton et al. (1991) Proc. Natl. Acad Sci USA., 88: 10134; Hoogenboom et al. (1991) Nucleic Acids Res., 19: 4133; Chang et al. (1991) J Immunol., 147: 3610; Breitling et al. (1991) Gene, 104: 147; Marks et al. (1991) supra; Barbas et al. (1992) supra; Hawkins and Winter (1992) J Immunol., 22: 867; Marks et al., 1992, J Bioi. Chem., 267: 16007; Lerner et al. (1992) Science, 258: 1313, incorporated herein by reference). [00211] One particularly advantageous approach has been the use of scFv phage-libraries (Huston et al., 1988, Proc. Natl. Acad. Sci U.S.A., 85: 5879-5883; Chaudhary et al. (1990) Proc. Natl. Acad. Sci U.S.A., 87: 1066-1070; McCafferty et al. (1990) supra; Clackson et al. (1991) Nature, 352: 624; Marks et al. (1991) J Mol. Bioi., 222: 581; Chiswell et al. (1992) Trends Biotech., 10: 80; Marks et al. (1992) J Bioi. Chem., 267). Various embodiments of scFv libraries displayed on bacteriophage coat proteins have been described. Refinements of phage display approaches are also known, for example as described in W096/06213 and W092/01047 (Medical Research Council et al.) and W097/08320 (Morphosys), which are incorporated herein by reference. [00212] Such techniques can be adapted for the production of multimeric immunoglobulins by the fusion of NHR2 multimerisation domains to the antibody variable domains Immunoglobulin constant domains [00213] An immunoglobulin constant domain, as referred to herein, is preferably an antibody constant domain. Constant domains do vary in sequence between antibody subtypes; preferably, the constant domains are IgG constant domains. Preferably, the constant domains are CH1 constant domains. Antibody constant domains are well known in the art and available from a number of sources and databases, including the IMGT and Kabat databases. [00214] The fusion of antibody constant domains to immunoglobulin variable domains is also known in the art, for example in the construction of engineered Fab antibody fragments. Linkers [00215] Flexible linkers can be used to connect TCR variable domain – Ig constant domain to the NHR2 multimerisation domain. This allows the TCR domains and the multimerisation domain to function without steric hindrance from each other or other molecules in the multimeric complex. Suitable linkers comprise, for example, glycine repeats, glycine-alanine repeats, Gly(4)Ser linkers, or flexible polypeptide linkers as set forth in Reddy Chichili et al., 2012 Protein Science 22:153-167. Immunoglobulin Hinge domain [00216] The Ig Hinge domain, herein preferably an antibody hinge domain, is the domain which links antibody constant regions in a natural antibody. This domain therefore provides for natural dimerization of molecules which include an antibody constant domain. It is present, for example, in a F(ab)2 antibody fragment, as well as whole antibodies such as IgG. This region comprises two natural interchain disulphide bonds, which connect the two CH1 constant domains together. [00217] The multimerisation domain, in one embodiment, may be attached to the Ig constant domain or to the hinge domain. If a hinge domain is present, the multimerisation domain will form a TRC octamer, comprising four dimers of TCR variable-Ig Constant domains joined at a hinge region. Without the hinge region, the multimerisation domain will lead to the formation of a tetramer. Preferably, the multimerisation domain is attached to the C-terminal end of the constant domain or the hinge region. Biologically Active Molecule [00218] One or more biologically active molecules or effector molecules (EM) can be attached to the multimer, eg, multimeric TCR proteins, of the present invention. Such molecules may be, for example, antibodies, especially antibodies which may assist in immune recognition and functioning of the TCR, such as anti-CD3 antibodies or antibody fragments. [00219] In some aspects, the biologically active molecule can be a cytotoxic drug, toxin or a biologically active molecule such as a cytokine, as described in more detail below. Examples of biologically active molecules include chemokines such as MIP-1b, cytokines such as IL-2, growth factors such as GM-CSF or G-CSF, toxins such as ricin, cytotoxic agents, such as doxorubicin or taxanes, labels including radioactive and fluorescent labels, and the like. For examples of biologically active molecules conjugatable to TCRs, see US20110071919. [00220] In other aspects, the biologically active molecule is, for example, selected from the group consisting of: a group capable of binding to a molecule which extends the half-life of the polypeptide ligand in vivo, and a molecule which extends the half-life of the polypeptide ligand in vivo. Such a molecule can be, for instance, HSA or a cell matrix protein, and the group capable of binding to a molecule which extends the half-life of the TCR molecule in vivo is an antibody or antibody fragment specific for HSA or a cell matrix protein. [00221] In one embodiment, the biologically active molecule is a binding molecule, for example an antibody fragment. 2, 3, 4, 5 or more antibody fragments may be joined together using suitable linkers. The specificities of any two or more of these antibody fragments may be the same or different; if they are the same, a multivalent binding structure will be formed, which has increased avidity for the target compared to univalent antibody fragments. [00222] The biologically active molecule can moreover be an effector group, for example an antibody Fc region. [00223] Attachments to the N or C terminus may be made prior to assembly of the TCR molecule or engineered polypeptide into multimers, or afterwards. Thus, the TCR fusion with an Ig Constant domain may be produced (synthetically, or by expression of nucleic acid) with an N or C terminal biologically active molecule already in place. In certain aspects, however, the addition to the N or C terminus takes place after the TCR fusion has been produced. For example, Fluorenylmethyloxycarbonyl chloride can be used to introduce the Fmoc protective group at the N- terminus of the TCR fusion. Fmoc binds to serum albumins including HSA with high affinity, and Fmoc-Trp or FMOC-Lys bind with an increased affinity. The peptide can be synthesised with the Fmoc protecting group left on, and then coupled with the scaffold through the cysteines. An alternative is the palmitoyl moiety which also binds HSA and has, for example been used in Liraglutide to extend the half-life of this GLP-1 analogue. [00224] Alternatively, the TCR fusinon can be modified at the N-terminus, for example with the amine- and sulfhydryl-reactive linker N-e-maleimidocaproyloxy)succinimide ester (EMCS). Via this linker the TCR can be linked to other polypeptides, for example an antibody Fc fragment. The NHR2 domain [00225] AML1/ETO is the fusion protein resulting from the t(8;21) found in acute myeloid leukemia (AML) of the M2 subtype. AML1/ETO contains the N-terminal 177 amino acids of RUNX1 fused in frame with most (575 aa) of ETO. The nervy homology domain 2 of ETO is responsible for many of the biological activities associated with AML1/ETO, including oligomerisation and protein-protein interactions. This domain is characterised in detail in Liu et al (2006). See Genbank accession number NG_023272.2. [00226] In one aspect of the present invention, the protein assembled into a soluble multivalent format is a TCR composed of either in part or all of the extracellular domains of the TCR α and β chains. The TCR α and β chains are stabilized by immunoglobulin CH1 and CL domains and could be arranged in the following configurations: 1. Vα-CL and VβCH1 2. Vα-CH1 and Vβ-CL 3. VαCα-CL and VβCβ-CH1 4. VαCαCH1 and VβCβCL [00227] In one aspect of this invention, the extracellular TCR domains are linked to immunoglobulin CH1 and CL domains via an optional peptide linker (L) to promote protein flexibility and facilitate optimal protein folding. 1. Vα-(L)-CL and Vβ-(L)-CH1 2. Vα-(L)-CH1 and Vβ-(L)-CL 3. VαCα-(L)-CL and VβCβ-(L)-CH1 4. VαCα-(L)-CH1 and VβCβ-(L)-CL [00228] In another aspect of this invention, a tetramerisation domain (TD) such as NHR2 homotetramer domain is linked to the C-terminus of either the immunoglobulin CH1 or CL domain, which is linked to the extracellular TCR α and β chain. The NHR2 domain could be optionally linked to CH1 or CL domain via a peptide linker. The resulting tetravalent heterodimeric TCR protein could be arranged in the following configurations where (L) is an optional peptide linker: 1. Vα-(L)-CL and Vβ-(L)-CH1-(L)-TD 2. Vα-(L)-CH1 -(L)-TD and Vβ-(L)-CL 3. VαCα-(L)-CL and VβCβ-(L)-CH1-(L)-TD 4. VαCα-(L)-CH1-(L)-TD and VβCβ-(L)-CL 5. Vα-(L)-CL-(L)-TD and Vβ-(L)-CH1 6. Vα-(L)-CH1 and Vβ-(L)-CL-(L)-TD 7. VαCα-(L)-CL-(L)-TD and VβCβ-(L)-CH1 8. VαCα-(L)-CH1and VβCβ-(L)-CL-(L)-TD [00229] The sensitivity of the soluble TCR for its cognate pMHC can be enhanced by increasing the avidity effect. This is achieved by increasing the number of antigen binding sites, facilitated by the tetramerisation domain. This in turn also increases the molecular weight of the protein molecule compared to a monovalent soluble TCR and thus extends serum retention in circulation. Increasing the serum half-life also enhances the likelihood of these molecules interacting with their cognate target antigens. [00230] The tetravalent heterodimeric soluble TCR protein molecule is capable of binding simultaneously to one, two, three or four pMHC displayed on a single cell or bind simultaneously to one, two, three or four different cells displaying its cognate pMHC. [00231] TCR α and β chain sequences used in this invention could be from a known TCR specific for a particular pMHC or identified de novo by screening using techniques known in the art, such as phage display. Furthermore, TCR sequences are not limited to α and β chain in this invention but can also incorporate TCRδ and γ or ε chain and sequence variations thereof either directly cloned from human T cells or identified by directed evolution using recombinant DNA technology. [00232] In another aspect to this invention, the tetravalent heterodimeric soluble TCR protein molecules are preferentially produced in mammalian cells for optimal production of soluble, stable and correctly folded protein molecules. [00233] Multimer (eg, tetramer or octamer), or multivalent TCR according to the present invention may be expressed in cells, such as mammalian cells, using any suitable vector system. The pTT5 expression vector is one example of an expression system is used to express multivalent soluble TCR. The pTT5 expression system allows for high-level transient production of recombinant proteins in suspension-adapted HEK293 EBNA cells (Zhang et al.2009). It contains origin of replication (oriP) that is recognized by the viral protein Epstein-Barr Nuclear Antigen 1 (EBNA-1), which together with the host cell replication factor mediates episomal replication of the DNA plasmid allowing enhanced expression of recombinant protein. Other suitable vector system for mammalian cell expression known in the art and commercially available can be used with this invention. [00234] The tetravalent heterodimeric soluble TCR protein molecules or other multimers can be produced by transiently expressing genes from an expression vector. [00235] In another embodiment, tetravalent heterodimeric soluble TCR protein molecules or other multimers can be produced from an engineered stable cell line. Cell lines can be engineered to produce the protein molecule using genome-engineering techniques known in the art where the gene(s) encoding for the protein molecule is integrated into the genome of the host cells either as a single copy or multiple copies. The site of DNA integration can be a defined location within the host genome or randomly integrated to yield maximum expression of the desired protein molecule. Genome engineering techniques could include but not limited to, homologous recombination, transposon mediated gene transfer such as PiggyBac transposon system, site specific recombinases including recombinase-mediated cassette exchange, endonuclease mediated gene targeting such as CRISPR/Cas9, TALENs, Zinc-finger nuclease, meganuclease and virus mediated gene transfer such as Lentivirus. [00236] Also, in another aspect to the invention, the tetravalent heterodimeric soluble TCR protein molecule or other multimer is produced by overexpression in the cytoplasm of E. coli as inclusion bodies and refolded in vitro after purification by affinity chromatography to produce functional protein molecules capable of correctly binding to its cognate pMHC or antigen. [00237] In another aspect to the invention, expression of the tetravalent heterodimeric soluble TCR protein molecule or other multimer is not limited to mammalian or bacterial cells but can also be expressed and produced in insect cells, plant cells and lower eukaryotic cells such as yeast cells. [00238] In another aspect to this invention, the heterodimeric soluble TCR molecule or other multimer is produced as an octavalent protein complex, eg, having up to eight binding sites for its cognate pMHC (Figure 2). The multiple antigen binding sites allow this molecule to bind up to eight pMHC displayed on one cell or bind pMHC displayed on up to eight different cells thus creating a highly sensitive soluble TCR. [00239] The heterodimeric soluble TCR portion of the molecule is made into a bivalent molecule by fusing the immunoglobulin hinge domain to the C-terminus of either the CH1 or CL domain, which is linked itself either to TCR α or β chain. The hinge domain allows for the connection of two heavy chains giving a structure similar to IgG. To the C-terminus of the hinge domain, a tetramerisation domain such as NHR2 is linked via an optional peptide linker. By joining immunoglobulin hinge to C- and N-terminus of Ig CH1 or CL domain and NHR2 domain respectively, it allows for the assembly of two NHR2 monomers referred to as monomer2. In this conformation we predict the two NHR2 domains will most likely not form a homodimer by an antiparallel association due to structural constraints unless a long flexible linker is provided between the hinge and NHR2 domain. Linkage of the tetramerisation and the hinge domain to the to the heterodimeric soluble TCR via immunoglobulin CH1 or CL domain allows for the stepwise self- assembly of an octavalent soluble TCR formed through a NHR2 homotetramer2. The self-assembly of the octavalent soluble TCR is via NHR2 monomer2 and homodimer2 intermediate protein complexes (Figure 2). The resulting octavalent heterodimeric soluble TCR protein molecule will have superior sensitivity for its cognate pMHC thus giving it a distinctive advantage of identifying unknown antigen or pMHC without having to affinity mature the TCR for its pMHC ligand much beyond affinities seen naturally. In particular it would be useful for identifying pMHC recognized by uncharacterized tumour-specific T cells and T cells involved in other diseases such as autoimmune diseases. A number of different configurations of the octavalent heterodimeric soluble TCR protein molecules can be produced. Some examples are shown below. 1. Vα-(L)-CL and Vβ-(L)-CH1-Hinge-(L)-TD 2. Vα-(L)-CH1-Hinge-(L)-TD and Vβ-(L)-CL 3. Vα-Cα-(L)-CL and Vβ-Cβ-(L)-CH1-Hinge-(L)-TD 4. VαCα(L)-CH1-Hinge-(L)-TD and VβCβ-(L)-CL 5. Vα-(L)-CL-(L)-TD and Vβ-(L)-CH1-Hinge 6. Vα-(L)-CH1-Hinge and Vβ-(L)-CL-(L)-TD 7. Vα-Cα-(L)-CL-(L)-TD and Vβ-Cβ(L)-CH1-Hinge 8. Vα-Cα-(L)-CH1-Hinge and Vβ-Cβ-(L)-CL-(L)-TD [00240] In another aspect to this invention, the self-assembled multivalent protein preferentially tetravalent and octavalent heterodimeric soluble TCR are fused or conjugated to biologically active agent/effector molecule thus allowing these molecules to be guided to the desired cell population such as cancers cells and exert their therapeutic effect specifically. The tumour targeting ability of monoclonal antibodies to guide an effector molecule such as a cytotoxic drug, toxins or a biologically active molecule such as cytokines is well established (Perez et al.2014; Young et al.2014). In a similar manner the multivalent soluble TCR molecules outlined in this invention can also be fused with effector proteins and polypeptide or conjugated to cytotoxic agents. Examples of effector protein molecules suitable for use as a fusion protein with the multivalent protein complexes outlined in this invention include but are not limited to, IFNα, IFNβ, IFNγ, IL-2, IL-11, IL-13, granulocyte colony- stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], and tumor necrosis factor [TNF]α, IL-7, IL-10, IL-12, IL-15, IL-21, CD40L, and TRAIL, the costimulatory ligand is B7.1 or B7.2, the chemokines DC-CK1, SDF-1, fractalkine, lyphotactin, IP-10, Mig, MCAF, MlP-lα, MIP-1/3, IL-8, NAP-2, PF-4, and RANTES or an active fragment thereof. Examples of toxic agent suitable for use as a fusion protein or conjugated to the multivalent protein complexes described in this invention include but not limited to, toxins such as diphtheria toxin, ricin, Pseudomonas exotoxin, cytotoxic drugs such as auristatin, maytansines, calicheamicin, anthracyclines, duocarmycins, pyrrolobenzodiazepines. The cytotoxic drug can be conjugated by a select linker, which is either non-cleavable or cleavable by protease or is acid-labile. [00241] To eliminate heterogeneity and improve conjugate stability the cytotoxic drug can be conjugated in a site-specific manner. By engineering specific cysteine residues or using enzymatic conjugation through glycotransferases and transglutaminases can achieve this (Panowski et al.2014). [00242] In another aspect of the invention, the multivalent protein complex is covalently linked to molecules allowing detection, such as fluorescent, radioactive or electron transfer agents. [00243] In another aspect of the invention, an effector molecule (EM) is fused to the multivalent protein complex via the C-terminus of the tetramerisation domain such as NHR2 via an optional peptide linker. Fusion via the NHR2 domain can be arranged to produce multivalent protein complexes in a number of different configurations. Examples of some of the protein configurations that can be produced using the tetravalent heterodimeric soluble TCR is shown below: 1. Vα-(L)-CL and Vβ-(L)-CH1-(L)-TD-(L)-EM 2. Vα-(L)-CH1-(L)-TD-(L)-EM and Vβ-(L)-CL 3. Vα-Cα-(L)-CL and Vβ-Cβ-(L)-CH1-(L)-TD-(L)-EM 4. Vα-Cα-(L)-CH1-(L)-TD-(L)-EM and Vβ-Cβ-(L)-CL 5. Vα- (L)-CL-(L)-TD-(L)-EM and Vβ-(L)-CH1 6. Vα-(L)-CH1 and Vβ-(L)-CL-(L)-TD-(L)-EM 7. Vα-Cα-(L)-CL-(L)-TD-(L)-EM and Vβ-Cβ-(L)-CH1 8. Vα-Cα-(L)-CH1 and Vβ-Cβ-(L)-CL-(L)-TD-(L)-EM [00244] In another aspect of the invention, the effector molecule (EM) is fused to the multivalent protein complex at the C-terminus of either the immunoglobulin CH1 or CL1 domain via an optional peptide linker. Fusion of the EM via the immunoglobulin domain can be arranged to produce multivalent protein complexes in a number of different configurations. Examples of some of the protein configurations that can be produced using the tetravalent heterodimeric soluble TCR is shown below: 9. Vα- (L)-CL-(L)-EM and Vβ-(L)-CH1-(L)-TD 10. Vα- (L)-CH1-(L)-TD and Vβ-(L)-CL-(L)-EM 11. Vα-Cα-(L)-CL-(L)-EM and Vαβ-Cβ-(L)-CH1-(L)-TD 12. Vα-Cα-(L)-CH1-(L)-TD and Vβ-Cβ-(L)-CL-(L)-EM 13. Vα-(L)-CL-(L)-TD and Vβ-(L)-CH1-(L)-EM 14. Vα-(L)-CH1-(L)-EM and Vβ-(L)-CL-(L)-TD 15. Vα-Cα-(L)-CL-(L)-TD and Vβ-Cβ-(L)-CH1-(L)-EM 16. Vα-Cα-(L)-CH1-(L)-EM and Vβ-Cβ-(L)-CL-(L)-TD [00245] In another aspect of the invention, effector molecules (EM) are fused to the multivalent protein complex at the C-terminus of either the immunoglobulin CH1 or CL1 domain and also the C- terminus of the tetramerisation domain (e.g. NHR2) via an optional peptide linkers. This approach allows for the fusion of two effector molecules to be fused per TCR heterodimer complex. Fusion of the EM via the immunoglobulin domain and the tetramerisation domain can be arranged to produce multivalent protein complexes in a number of different configurations. Examples of some of the protein configurations that can be produced using the tetravalent heterodimeric soluble TCR is shown below: 17. Vα- (L)-CL-(L)-EM and Vβ-(L)-CH1-(L)-TD-(L)-EM 18. Vα-(L)-CH1-(L)-TD-(L)-EM and Vβ-(L)-CL-(L)-EM 19. Vα-Cα-(L)-CL-(L)-EM and VβCβ-(L)-CH1-(L)-TD-(L)-EM 20. Vα-Cα-(L)-CH1-(L)-TD-(L)-EM and Vβ-Cβ-(L)-CL-(L)-EM 21. Vα-(L)-CL-(L)-TD-(L)-EM and Vβ-(L)-CH1-(L)-EM 22. Vα-(L)-CH1-(L)-EM and Vβ-(L)-CL-(L-)TD-(L)-EM 23. Vα-Cα-(L)-CL-(L)-TD-(L)-EM and Vβ-Cβ-(L)-CH1-(L)-EM 24. Vα-(L)-CH1-(L)-EM and Vβ-Cβ-(L)-CL-(L)-TD-(L)-EM [00246] In another aspect of the invention, the multivalent protein complex is fused to a protein tag to facilitate purification. Purification tags are known in the art and they include, without being limited to, the following tags: His, GST, TEV, MBP, Strep, FLAG. NON-TCR MULTIMERS [00247] The present invention provides a unique method for assembling proteins in a soluble multivalent format with potential to bind multiple interacting domains or antigens. The protein can be a monomer, homodimer, heterodimer or oligomer preferentially involved either directly or indirectly in the immune system, or having the potential to regulate immune responses. Examples include, but not limited to, TCR, peptide MHC class I and class II, antibodies or antigen-binding portions thereof and binding proteins having alternative non-antibody protein scaffolds. [00248] In another aspect of the invention, the interacting domains or antigens could be any cell surface expressed or secreted proteins, peptide-associated with MHC Class I or II or any proteins associated with pathogens including viral and bacterial proteins. [00249] Non-TCR multimers may be multimers of antibodies or antibody fragments, such as dAbs of Fabs. Examples of dAbs and Fabs in accordance with the invention include the following: [00250] Examples of multivalent dAbs 25. VH-(L)-NHR2 26. VL(λ or κ)-(L)-NHR2 27. VH-(L)-NHR2-(L)-EM 28. VL(λ or κ)-(L)-NHR2-(L)-EM 29. VH-CH1-(L)-NHR2 30. VL(λ or κ)-CL-(L)-NHR2 31. VH-CH1-(L)-NHR2-(L)-EM 32. VL(λ or κ)-CL-(L)-NHR2-(L)-EM [00251] Examples of multivalent Fabs 33. VH-CH1-(L)-NHR2 and VL(λ or κ)-CL 34. VL(λ or κ)-CL-(L)-NHR2 and VH-CH1 35. VH-CH1-Hinge-(L)-NHR2 and VL(λ or κ)-CL 36. VL(λ or κ)-CL-Hinge-(L)-NHR2 and VH-CH1 37. VH-CH1-(L)-NHR2-(L)-EM and VL(λ or κ)-CL 38. VL(λ or κ)-CL-(L)-NHR2-(L)-EM and VH-CH1 39. VH-CH1-Hinge-(L)-NHR2-(L)-EM and VL(λ or κ)-CL 40. VL(λ or κ)-CL-Hinge-(L)-NHR2-(L)-EM and VH-CH1 41. VH-CH1-(L)-NHR2 and VL(λ or κ)-CL-(L)-EM 42. VL(λ or κ)-CL-(L)-NHR2 and VH-CH1-(L)-EM 43. VH-CH1-Hinge-(L)-NHR2 and VL(λ or κ)-CL-(L)-EM 44. VL(λ or κ)-CL-Hinge-(L)-NHR2 and VH-CH1-(L)-EM [00252] In the examples above, (L) denotes an optional peptide linker, whilst EM denotes a biologically active agent or effector molecule such as toxins, drugs or cytokines, and including binding molecules such as antibodies, Fabs and ScFv. [00253] The variable light chain can be either Vλ or Vκ. [00254] In one aspect of the invention, the assembled tetramerized protein molecule in one example could be a human pMHC for the application in drug discovery using animal drug discovery platforms (e.g. mice, rats, rabbits, chicken). In such a context, the tetramerisation domain is preferentially expressed and produced from genes originating from the animal species it is intended for. One example of such drug discovery applications would be the use of the tetramerized human pMHC as an antigen for immunization in rats for example. Once rats are immunized with pMHC the immune response is directed specifically towards the human pMHC and not the tetramerisation domain of the protein complex. [00255] Multivalent antibodies can be produced, for example using single domain antibody sequences, fused to the NHR2 multimerisation domain. [00256] In a related aspect to the invention, the tetravalent protein can be a peptide used as a probe for molecular imaging of tumour antigens. The multivalent binding of such a probe will have distinctive advantage over monovalent molecular probes as it will have enhanced affinity, avidity and retention time in vivo and this in turn will enhance in vivo tumour targeting. [00257] The multimerisation domain is the NHR2 domain set forth above. Preferably, polypeptides are stabilized and/or rendered soluble by the use of Ig constant domains fused to the polypeptides, such that the fusions provide tetramers of polypeptides. Ig hinge domains can be used to provide octamers. USES OF MULTIMERS [00258] Multimeric TCR proteins according to the invention are useful in any application in which soluble TCR proteins are indicated. Particular advantages of the TCR proteins of the invention include increased avidity for the selected target, and/or the ability to bind a plurality of targets. [00259] Thus, in one aspect, the multivalent heterodimeric soluble TCR protein molecules of the invention can be used for selectively inhibiting immune responses, for example suppression of an autoimmune response. The multivalent, for example tetravalent, nature of these soluble protein molecules gives it exquisite sensitivity and binding affinity to compete antigen-specific interactions between T cells and antigen presenting cells. This kind of neutralization effect can be therapeutically beneficial in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, inflammatory bowel diseases, graves disease, vasculitis and type 1 diabetes. [00260] Similarly, the tetravalent heterodimeric soluble TCR protein molecules can be used to prevent tissue transplant rejection by selectively suppressing T cell recognition of specific transplantation antigen and self antigens binding to target molecule and thus inhibiting cell-to-cell interaction. [00261] In another aspect of the invention, the tetravalent heterodimeric soluble TCR protein molecules can be used in clinical studies such as toxicity, infectious disease studies, neurological studies, behavior and cognition studies, reproduction, genetics and xenotransplantation studies. [00262] The tetravalent heterodimeric soluble TCR protein molecules with enhanced sensitivity for cognate pMHC can be used for the purpose of diagnostics using biological samples obtained directly from human patients. The enhanced sensitivity of the tetravalent heterodimeric soluble TCRs allows detection of potential disease-associated peptides displayed on MHC, which are naturally found to be expressed at low density. These molecules can also be used for patient stratification for enrolling patient onto relevant clinical trials. [00263] In another aspect of the invention, octavalent heterodimeric soluble TCR protein molecules can be used in pharmaceutical preparations for the treatment of various diseases. [00264] In another related aspect to this invention, octavalent heterodimeric soluble TCR protein molecules can be used as a probe for tumour molecular imaging or prepared as a therapeutic protein. [00265] Optionally, the polypeptide (first polypeptide) comprises or consists of a polypeptide disclosed in Table 8. In an example the invention provides a multimer (eg, a dimer, trimer or tetramer, preferably a tetramer) of such a polypeptide. In an example, in Table 8, the multimerization domain (SAM) is a p53 domain (eg, a human p53 domain). In an example, in Table 8, the multimerization domain (SAM) is an orthologue or homologue of a p53 domain (eg, a human p53 domain). [00266] Optionally, the invention provides a polypeptide (eg, said polypeptide or said first polypeptide), wherein the polypeptide comprises or consists of (in N- to C-terminal direction*); A. A dAb and a self-associating multimersiation domain (SAM) B. A first dAb, a SAM and a second dAb C. A first scFv and a SAM; D. A first scFv, a SAM and a second scFv; E. A first scFv, a SAM and a first dAb; F. A first dAb, a CH2, a CH3 and a SAM; G. A first scFv, a CH2, a CH3 and a SAM; H. A VH, a CH1, a CH2 a CH3 and a SAM; I. A VL, a CL, a CH2, a CH3 and a SAM; J. A dAb; a SAM, a CH2 and a CH3; K. A scFv; a SAM, a CH2 and a CH3; L. A VH, a CH1, a SAM, a CH2 and a CH3; M. A VL, a CL, a SAM, a CH2 and a CH3; N. A first dAb, a second dAb and a SAM; O. A VH, a CH1 and a SAM; P. A VL, a CL and a SAM; Q. A VH, a CH1, a SAM and a first dAb; R. A VL, a CL, a SAM and a first dAb; S. A first dAb, a second dAb, a SAM and a third dAb; T. A first dAb, a second dAb, a SAM and a first scFv; U. A first dAb, a second dAb, a SAM, a third dAb and a fourth dAb; V. A first dAb, a CH2, a CH3, a SAM and a second dAb; W. A first dAb, a CH2, a CH3, a SAM and a first scFv; X. A first dAb, a second dAb, a CH2, a CH3 and a SAM; Y. A first dAb, a second dAb, a CH2, a CH3, a SAM and a third dAb; Z. A first dAb, a second dAb, a CH2, a CH3, a SAM and a first scFv; or AA. A first dAb, a second dAb, a CH2, a CH3, a SAM, a third dAb and a fourth dAb. *In an alternative the components are written in the C- to N-terminal direction. [00267] In an embodiment, polypeptide H, L, O or Q is associated with a second polypeptide, wherein the second polypeptide comprises (in N- to C-terminal direction) VL and CL, wherein the CL is associated with the CH1 of the first polypeptide. [00268] In an embodiment, polypeptide I, M, P or R is associated with a second polypeptide, wherein the second polypeptide comprises (in N- to C-terminal direction) VH and CH1, wherein the CH1 is associated with the CL of the first polypeptide. [00269] In an example, the polypeptide is encoded by a nucleotide sequence disclosed in Table 9. In an example, the polypeptide comprises or consists of an amino acid sequence disclosed in Table 10. [00270] In an example (i) the polypeptide comprises (in N- to C-terminal direction); A. A dAb and a self-associating multimersiation domain (SAM) B. A first dAb, a SAM and a second dAb C. A first scFv and a SAM; D. A first scFv, a SAM and a second scFv; E. A first scFv, a SAM and a first dAb; F. A first dAb, a CH2, a CH3 and a SAM; G. A first scFv, a CH2, a CH3 and a SAM; H. A VH, a CH1, a CH2 a CH3 and a SAM; I. A VL, a CL, a CH2, a CH3 and a SAM; J. A dAb; a SAM, a CH2 and a CH3; K. A scFv; a SAM, a CH2 and a CH3; L. A VH, a CH1, a SAM, a CH2 and a CH3; M. A VL, a CL, a SAM, a CH2 and a CH3; N. A first dAb, a second dAb and a SAM; O. A VH, a CH1 and a SAM; P. A VL, a CL and a SAM; Q. A VH, a CH1, a SAM and a first dAb; R. A VL, a CL, a SAM and a first dAb; S. A first dAb, a second dAb, a SAM and a third dAb; T. A first dAb, a second dAb, a SAM and a first scFv; U. A first dAb, a second dAb, a SAM, a third dAb and a fourth dAb; V. A first dAb, a CH2, a CH3, a SAM and a second dAb; W. A first dAb, a CH2, a CH3, a SAM and a first scFv; X. A first dAb, a second dAb, a CH2, a CH3 and a SAM; Y. A first dAb, a second dAb, a CH2, a CH3, a SAM and a third dAb; Z. A first dAb, a second dAb, a CH2, a CH3, a SAM and a first scFv; or AA. A first dAb, a second dAb, a CH2, a CH3, a SAM, a third dAb and a fourth dAb. Or (ii) the polypeptide comprises (in C- to N-terminal direction); A. A dAb and a self-associating multimersiation domain (SAM) B. A first dAb, a SAM and a second dAb C. A first scFv and a SAM; D. A first scFv, a SAM and a second scFv; E. A first scFv, a SAM and a first dAb; F. A first dAb, a CH2, a CH3 and a SAM; G. A first scFv, a CH2, a CH3 and a SAM; H. A VH, a CH1, a CH2 a CH3 and a SAM; I. A VL, a CL, a CH2, a CH3 and a SAM; J. A dAb; a SAM, a CH2 and a CH3; K. A scFv; a SAM, a CH2 and a CH3; L. A VH, a CH1, a SAM, a CH2 and a CH3; M. A VL, a CL, a SAM, a CH2 and a CH3; N. A first dAb, a second dAb and a SAM; O. A VH, a CH1 and a SAM; P. A VL, a CL and a SAM; Q. A VH, a CH1, a SAM and a first dAb; R. A VL, a CL, a SAM and a first dAb; S. A first dAb, a second dAb, a SAM and a third dAb; T. A first dAb, a second dAb, a SAM and a first scFv; U. A first dAb, a second dAb, a SAM, a third dAb and a fourth dAb; V. A first dAb, a CH2, a CH3, a SAM and a second dAb; W. A first dAb, a CH2, a CH3, a SAM and a first scFv; X. A first dAb, a second dAb, a CH2, a CH3 and a SAM; Y. A first dAb, a second dAb, a CH2, a CH3, a SAM and a third dAb; Z. A first dAb, a second dAb, a CH2, a CH3, a SAM and a first scFv; or AA. A first dAb, a second dAb, a CH2, a CH3, a SAM, a third dAb and a fourth dAb. [00271] Optionally, the SAM is a tetramerisation domain, eg, a p53 TD. [00272] In an example the first, second, third (when present) and fourth (when present) dAbs have the same antigen binding specificity. In an example the first, second, third (when present) and fourth (when present) dAbs have the same different binding specificity. [00273] In an example the first and second scFvs have the same antigen binding specificity. In an example the first and second scFvs have the same different antigen binding specificity. [00274] In an example the first dAb, second dAb and first scFv have the same antigen binding specificity. In an example the first dAb, second dAb and first scFv have the same different antigen binding specificity. [00275] Herein, where a dAb is provided in the polypeptide, in an alternative there may be provided instead any different type of antigen binding domain, such as a scFv or Fab or non-Ig binding domain (eg, an affibody, avimer or fibronectin domain). [00276] Herein, where a scFv is provided in the polypeptide, in an alternative there may be provided instead any different type of antigen binding domain, such as a dAb or Fab or non-Ig binding domain (eg, an affibody, avimer or fibronectin domain). [00277] Herein, where a Fab is provided in the polypeptide, in an alternative there may be provided instead any different type of antigen binding domain, such as a scFv or dAb or non-Ig binding domain (eg, an affibody, avimer or fibronectin domain). [00278] Each antigen may be any antigen disclosed herein. [00279] In an example, the CH1 (when present), CH2 and CH3 are a human Ig CH1, a CH2 a CH3, eg, a IgG1 CH1, CH2 and CH3. In an example, the CH2 comprises a CH2 domain, the CH3 comprises a CH3 domain and the CH2 comprises a hinge amino acid sequence. In this example, the CH2 comprises (in N- to C-terminal direction) the hinge amino acid sequence and the CH2 domain. In an example the hinge amino acid sequence (i) is a complete hinge; (ii) is a hinge amino acid sequence that is non-functional to dimerise the polypeptide with another such polypeptide; (iii) a hinge amino acid sequence devoid of a hinge core comprising the amino acid motif CXXC (and optionally also devoid of an upper hinge amino acid sequence); or (iv) an upper hinge fused to a lower hinge, but devoid of a hinge core comprising the amino acid motif CXXC; or (v) a lower hinge, but devoid of a hinge core comprising the amino acid motif CXXC (and optionally also devoid of an upper hinge amino acid sequence). Examples of upper, core and lower hinge sequences are disclosed in Table 12. In an example, the CH2 is devoid of a functional hinge region, ie, wherein the hinge region is non-functional to dimerise the polypeptide with another such polypeptide. In an example, the CH2 is devoid of a hinge region. In an example, the CH2 is devoid of a complete hinge region sequence. In an example, the CH2 is devoid of a core hinge region sequence. [00280] In an example, the CH2 comprises (in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and wherein the CH2 (and the polypeptide) is devoid of a core hinge region that is functional to dimerise the polypeptide with another said polypeptide. [00281] In an example, the CH2 comprises in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S). [00282] In an example, the CH2 comprises in N- to C- terminal direction) an amino acid selected from SEQ IDs: 1*163-1*178 and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S). [00283] In an embodiment, the core hinge region amino acid sequence is selected from SEQ IDs: 1*180-1*182. In an embodiment, the CH2 (an the polyeptide) is devoid of amino acid sequences SEQ IDs: 1*183-1*187. [00284] In an embodiment, the CH2 domain is a human IgG1 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180. Optionally, any CH1 and CH3 present in the polypeptide are human IgG1 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CPPC (SEQ ID: 1*180). Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDKTHT (SEQ ID: 1*183) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180). [00285] In an embodiment, the CH2 domain is a human IgG2 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180. Optionally, any CH1 and CH3 present in the polypeptide are human IgG2 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ERKCCVE (SEQ ID: 1*184) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180). [00286] In an embodiment, the CH2 domain is a human IgG3 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*181. Optionally, any CH1 and CH3 present in the polypeptide are human IgG3 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ELKTPLGDTTHT (SEQ ID: 1*185) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181). Optionally, alternatively the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDTPPP (SEQ ID: 1*186) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181). [00287] In an embodiment, the CH2 domain is a human IgG4 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*182. Optionally, any CH1 and CH3 present in the polypeptide are human IgG4 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ESKYGPP (SEQ ID: 1*187) and core hinge region amino acid sequence CPSC (SEQ ID: 1*182). [00288] In an example, the CH2 of a polypeptide herein is devoid of a core hinge (and optionally also an upper hinge) amino acid sequence. In an example, the CH2 of a polypeptide herein is devoid of a core hinge CXXC amino acid sequence, wherein X is any amino acid, preferably P, R or S, most preferably P. In an example, the CH2 comprises an APELLGGPSV amino acid sequence, or an PAPELLGGPSV amino acid sequence. In an example, the CH2 comprises an APPVAGPSV amino acid sequence, or an PAPPVAGPSV amino acid sequence. In an example, the CH2 comprises an APEFLGGPSV amino acid sequence, or an PAPEFLGGPSV amino acid sequence. [00289] In an example, the CH2 and CH3 of a polypeptide herein are human IgG1 CH2 and CH3 domains, wherein the CH2 is devoid of a core hinge (and optionally also an upper hinge) amino acid sequence, eg, wherein the CH2 is devoid of a CPPC sequence. In an example, the CH2 comprises an APELLGGPSV amino acid sequence, or an EPKSCDKTHT[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional. [00290] In an example, the CH2 and CH3 of a polypeptide herein are human IgG2 CH2 and CH3 domains, wherein the CH2 is devoid of a core hinge (and optionally also an upper hinge) amino acid sequence, eg, wherein the CH2 is devoid of a CPPC sequence. In an example, the CH2 comprises an APPVAGPSV amino acid sequence, or an ERKCCVE[P]APPVAGPSV amino acid sequence, wherein the bracketed P is optional. [00291] In an example, the CH2 and CH3 of a polypeptide herein are human IgG3 CH2 and CH3 domains, wherein the CH2 is devoid of a core hinge (and optionally also an upper hinge) amino acid sequence, eg, wherein the CH2 is devoid of a CPRC sequence. In an example, the CH2 comprises an APELLGGPSV amino acid sequence, or an ELKTPLGDTTHT[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional. In an example, the CH2 comprises an EPKSCDTPPP[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional. [00292] In an example, the CH2 and CH3 of a polypeptide herein are human IgG4 CH2 and CH3 domains, wherein the CH2 is devoid of a core hinge (and optionally also an upper hinge) amino acid sequence, eg, wherein the CH2 is devoid of a CPSC sequence. In an example, the CH2 comprises an APEFLGGPSV amino acid sequence, or an ESKYGPP[P]APEFLGGPSV amino acid sequence, wherein the bracketed P is optional. [00293] When the polypeptide comprises a V-CH1, a CH2 may also be present, but in this case optionally lacking the core hinge region (or at least a sequence selected from CXXC as disclosed herein and SEQ IDs: 1*180-1*182) and optionally lacking the upper and/or the lower hinge region to prevent F(ab')2 formation. [00294] ASPECTS: By way of example the invention provides the following Aspects, some of which have been exemplified herein. The following Aspects are not to be interpreted as Claims. The Claims start after the Examples section. 1. A polypeptide comprising (in N- to C-terminal direction; or in C- to N-terminal direction) (a) An immunoglobulin superfamily domain; (b) An optional linker; and (c) A self-associating multimerisation domain (SAM) (optionally a self-associating tetramerisation domain (TD)). In an example, each linker is a peptide linker comprising (or comprising up to, or consisting of) 40, 30, 25, 20, 19, 18, 17, 16, 1514, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4 or amino acids. In an alternative, the domain of (a) is a non-Ig domain or comprises a non-Ig scaffold. [00260] In an alternative herein, instead of using a TD or copies of a TD, in an embodiment any other self-associating multimerization domain (SAM) may be used. In an example, the SAM (eg, TD) is a human, dog, cat, horse, monkey (eg, cynomolgus monkey), rodent (eg, mouse or rat), rabbit, bird (eg, chicken) or fish SAM (or TD). [00261] Optionally, the domain of (a) is capable of specifically binding to an antigen selected from PD-L1, PD-1, 4-1BB, CTLA-4, 4-1BB, CD28, TNF alpha, IL17 (eg, IL17A), CD38, VEGF-A, EGFR, IL-6, IL-4, IL-6R, IL-4R (eg, IL-4Ra), OX40, OX40L, TIM-3, CD20, GITR, VISTA, ICOS, Death Receptor 5 (DR5), LAG-3, CD40, CD40L, CD27, HVEM, KRAS, haemagglutinin, transferrin receptor 1, amyloid beta, BACE1, Tau, TDP43, SOD1, Alpha Synculein and CD3. [00262] In an example, the antigen is a peptide-MHC. [00263] In some embodiments (eg, some embodiments of Aspect 16 below or 17 below), the polypeptide comprises at least two binding moieties, eg, two dAbs, two scFvs, or a dAb and a scFv. In an example, these binding moieties bind to the same antigen (eg, an antigen disclosed herein or in the immediately preceding paragraph herein). In another example, the moieties bind to different antigens (eg, an antigen disclosed herein or in the immediately preceding paragraph herein). For example, in Aspect 16B, D, E or F the variable domains or scFvs are capable of specifically binding to the same or different antigens selected from TNF alpha, CD38, IL17a, CD20, PD-1, PD-L1, CTLA-4 and 4-1BB. For example, one of the moieties binds to TNF alpha and the other binds to IL17a; one of the moieties binds to PD-1 and the other binds to 4-1BB; or one of the moieties binds to PD-L1 and the other binds to 4-1BB; one of the moieties binds to PD- 1 and the other binds to CTLA-4; or one of the moieties binds to PD-L1 and the other binds to CTLA-4. 2. The polypeptide of any preceding Aspect, wherein the domain of (a) is an antibody variable domain. [00261] For example, a variable domain herein is a VH (eg, comprised by a scFv or a Fab polypeptide chain). In another example, it is a VHH (eg, comprised by a scFv or a Fab polypeptide chain). In another example, it is a humanised VH, humanised VHH or a human VH (eg, comprised by a scFv or a Fab polypeptide chain). In another example, it is a VL (eg, comprised by a scFv or a Fab polypeptide chain). In another example, it is a Vκ. In another example, it is a Vλ. [00262] In another example, the domain of (a) is a TCR variable domain (eg, a TCRα, TCRβ, TCRγ or TCRδ). [00263] In an example the immunoglobulin superfamily domain is an antibody single variable domain (dAb). 3. The polypeptide of any preceding Aspect, wherein the domain of (a) is selected from an antibody single variable domain, a VH and a VL; or wherein the domain is comprised by an scFv. [00264] In an example, a single variable domain herein is a human or humanised dAb or nanobody; or is a camelid VHH domain. [00265] In an example, the domain of (a) is comprised by a single-chain TCR (scTCR). 4. The polypeptide of any preceding Aspect, wherein (a) is joined directly to (c); or wherein (b) is joined directly to (a) and (c). 5. The polypeptide of any preceding Aspect, comprising (in N- to C-terminal direction) the SAM, (d) an optional second linker and (e) a second immunoglobulin superfamily domain. 6. The polypeptide of Aspect 5, wherein the second domain is selected from an antibody single variable domain, a VH and a VL; or wherein the domain is comprised by an scFv. [00266] In an example, the single variable domain is a human or humanised dAb or nanobody; or is a camelid VHH domain. 7. The polypeptide of Aspect 5, wherein the second domain is an antibody single variable domain or an antibody constant domain. 8. The polypeptide of Aspect 7, wherein the constant domain is comprised by an antibody Fc region. 9. The polypeptide of any one of Aspects 5 to 8, wherein (c) is joined directly to (e); or wherein (d) is joined directly to (c) and (e). 10. The polypeptide of any preceding Aspect, wherein the TD is a p53, p63 or p73 TD or a homologue or orthologue thereof; or wherein the TD is a NHR2 TD or a homologue or orthologue thereof. [00267] Optionally, the TD herein is a TD of a protein disclosed in Table 2. 11. The polypeptide of any preceding Aspect, wherein the TD comprises an amino acid sequence that is at least 80% identical to SEQ ID: 1*10 or 1*126. 12. The polypeptide of any preceding Aspect, comprising (f) an antibody variable domain, an antibody constant region or an antibody Fc region between (a) and (c). 13. The polypeptide of Aspect 12, wherein (f) comprises (i) an antibody CH1 constant domain; or (ii) an antibody Fc region (ie, comprising a CH2-CH3). 14. The polypeptide of Aspect 13, wherein the polypeptide is associated with a second polypeptide, wherein (iii) the second polypeptide comprises an antibody CL constant domain that is paired with the CH1 domain of (i); or (iv) the second polypeptide comprises a second antibody Fc region that is paired with the Fc region of (ii). 15. The polypeptide of Aspect 12, wherein the variable domain of (f) is an antibody single variable domain. 16. The polypeptide of any preceding Aspect, wherein the polypeptide (first polypeptide) comprises or consists of (in N- to C-terminal direction); A. A first antibody single variable domain (dAb), an optional linker and said SAM; B. A first antibody single variable domain, an optional linker, said SAM and a second antibody single variable domain; C. A first scFv, an optional linker and said SAM; D. A first scFv, an optional linker, said SAM and a second scFv; E. A first antibody single variable domain, an optional linker, said SAM and a first scFv; F. A first scFv, an optional linker, said SAM and a first antibody single variable domain; G. A first antibody variable domain, an optional first linker, a first antibody constant domain, a second optional linker and said SAM; H. Said SAM, an optional linker and a first antibody single variable domain; I. Said SAM, an optional linker and a first scFv; J. Said SAM, an optional linker, a first antibody constant domain, a second optional linker and a first antibody variable domain; or K. Said SAM, an optional linker, a first antibody variable domain, a second optional linker and a first antibody constant domain. [00268] Optionally, each variable domain is a VH or a VL (eg, a Vκ or a Vλ). [00269] Optionally, each domain of the polypeptide herein is a human domain. Optionally, each domain of the polypeptide herein is a human or humanised domain. 17. The polypeptide of any of Aspects 1 to 15, wherein (i) the polypeptide comprises (in N- to C-terminal direction); A. A dAb and a self-associating multimersiation domain (SAM) B. A first dAb, a SAM and a second dAb C. A first scFv and a SAM; D. A first scFv, a SAM and a second scFv; E. A first scFv, a SAM and a first dAb; F. A first dAb, a CH2, a CH3 and a SAM; G. A first scFv, a CH2, a CH3 and a SAM; H. A VH, a CH1, a CH2 a CH3 and a SAM; I. A VL, a CL, a CH2, a CH3 and a SAM; J. A dAb; a SAM, a CH2 and a CH3; K. A scFv; a SAM, a CH2 and a CH3; L. A VH, a CH1, a SAM, a CH2 and a CH3; M. A VL, a CL, a SAM, a CH2 and a CH3; N. A first dAb, a second dAb and a SAM; O. A VH, a CH1 and a SAM; P. A VL, a CL and a SAM; Q. A VH, a CH1, a SAM and a first dAb; R. A VL, a CL, a SAM and a first dAb; S. A first dAb, a second dAb, a SAM and a third dAb; T. A first dAb, a second dAb, a SAM and a first scFv; U. A first dAb, a second dAb, a SAM, a third dAb and a fourth dAb; V. A first dAb, a CH2, a CH3, a SAM and a second dAb; W. A first dAb, a CH2, a CH3, a SAM and a first scFv; X. A first dAb, a second dAb, a CH2, a CH3 and a SAM; Y. A first dAb, a second dAb, a CH2, a CH3, a SAM and a third dAb; Z. A first dAb, a second dAb, a CH2, a CH3, a SAM and a first scFv; or AA. A first dAb, a second dAb, a CH2, a CH3, a SAM, a third dAb and a fourth dAb; Or (ii) the polypeptide comprises (in C- to N-terminal direction); A. A dAb and a self-associating multimersiation domain (SAM) B. A first dAb, a SAM and a second dAb C. A first scFv and a SAM; D. A first scFv, a SAM and a second scFv; E. A first scFv, a SAM and a first dAb; F. A first dAb, a CH2, a CH3 and a SAM; G. A first scFv, a CH2, a CH3 and a SAM; H. A VH, a CH1, a CH2 a CH3 and a SAM; I. A VL, a CL, a CH2, a CH3 and a SAM; J. A dAb; a SAM, a CH2 and a CH3; K. A scFv; a SAM, a CH2 and a CH3; L. A VH, a CH1, a SAM, a CH2 and a CH3; M. A VL, a CL, a SAM, a CH2 and a CH3; N. A first dAb, a second dAb and a SAM; O. A VH, a CH1 and a SAM; P. A VL, a CL and a SAM; Q. A VH, a CH1, a SAM and a first dAb; R. A VL, a CL, a SAM and a first dAb; S. A first dAb, a second dAb, a SAM and a third dAb; T. A first dAb, a second dAb, a SAM and a first scFv; U. A first dAb, a second dAb, a SAM, a third dAb and a fourth dAb; V. A first dAb, a CH2, a CH3, a SAM and a second dAb; W. A first dAb, a CH2, a CH3, a SAM and a first scFv; X. A first dAb, a second dAb, a CH2, a CH3 and a SAM; Y. A first dAb, a second dAb, a CH2, a CH3, a SAM and a third dAb; Z. A first dAb, a second dAb, a CH2, a CH3, a SAM and a first scFv; or AA. A first dAb, a second dAb, a CH2, a CH3, a SAM, a third dAb and a fourth dAb. [00270] Thus, in some embodiments the polypeptide comprises an antibody Fc region, wherein the Fc comprises the CH2 and CH3 domains. 18. The polypeptide of Aspect 16B, 16D, (i) 17B, (i) 17D, (i) 17N, (i) 17S, (i) 17T, (i) 17U, (i) 17X, (i) 17Y, (i) 17Z, (i) 17AA, (ii) 17B, (ii) 17D, (ii) 17N, (ii) 17S, (ii) 17T, (ii) 17U, (ii) 17X, (ii) 17Y, (ii) 17Z or (ii) 17AA wherein the single variable domains (dAbs) are identical; or wherein the scFvs are identical. 19. The polypeptide of Aspect 16B, 16D, (i) 17B, (i) 17D, (i) 17N, (i) 17S, (i) 17T, (i) 17U, (i) 17X, (i) 17Y, (i) 17Z, (i) 17AA, (ii) 17B, (ii) 17D, (ii) 17N, (ii) 17S, (ii) 17T, (ii) 17U, (ii) 17X, (ii) 17Y, (ii) 17Z or (ii) 17AA wherein the single variable domains are different; or wherein the scFvs are different. 20. The polypeptide of Aspect 16G, 16J, 16K, (i) 17H, (i) 17I, (i) 17L, (i) 17M, (i) 17O, (i) 17P, (i) 17Q, (i) 17R, (ii) 17H, (ii) 17I, (ii) 17L, (ii) 17M, (ii) 17O, (ii) 17P, (ii) 17Q or (ii) 17R wherein (i) the first variable domain is a VH domain and the first constant domain is a CH1 domain, and optionally the polypeptide is associated with a second polypeptide, wherein the second polypeptide comprises an antibody CL constant domain that is paired with the CH1 domain; (ii) the first variable domain is a VH domain and the first constant domain is a CL domain, and optionally the polypeptide is associated with a second polypeptide, wherein the second polypeptide comprises an antibody CH1 constant domain that is paired with the CL domain; (iii) the first variable domain is a VL domain and the first constant domain is a CH1 domain, and optionally the polypeptide is associated with a second polypeptide, wherein the second polypeptide comprises an antibody CL constant domain that is paired with the CH1 domain; or (iv) the first variable domain is a VL domain and the first constant domain is a CL domain, and optionally the polypeptide is associated with a second polypeptide, wherein the second polypeptide comprises an antibody CH1 constant domain that is paired with the CL domain. 21. The polypeptide of any one of Aspects 16 to 20, comprising an antibody Fc region or a further antibody single variable domain between (v) the first variable domain or scFv and (vi) the SAM, wherein the Fc comprises a CH2 and a CH3. [00271] This further variable domain may be different from the first single variable domain or may have a target binding specificity that is different from the target binding specificity of the first single variable domain or scFv. 22. The polypeptide of any one of Aspects 16 to 21, comprising an antibody Fc region or an antibody single variable domain between (vii) the SAM and (viii) the most C-terminal variable domain, wherein the Fc comprises a CH2 and a CH3. 23. The polypeptide of any one of Aspects 16 to 22, comprising in N- to C-terminal direction an antibody Fc region and the most N-terminal variable domain or scFv, wherein the Fc comprises a CH2 and a CH3. 24. The polypeptide of any one of Aspects 16 to 23, comprising in N- to C-terminal direction the SAM and an antibody Fc region, wherein the Fc comprises a CH2 and a CH3. 25. The polypeptide of any one of Aspects 17 to 24, wherein the CH2 is devoid of an amino acid sequence CXXC or an amino acid sequence selected from SEQ IDs: 1*180-1*182; and optionally is devoid of amino acid sequences SEQ IDs: 1*183-1*187. [00272] In an example, the CH2 is a CH2’ disclosed herein. Optionally, the CH2 comprises (in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and wherein the CH2 (and the polypeptide) is devoid of a core hinge region that is functional to dimerise the polypeptide with another said polypeptide. Optionally, the CH2 comprises in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S). Optionally, the CH2 comprises in N- to C- terminal direction) an amino acid selected from SEQ IDs: 1*163-1*178 and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S). In an embodiment, the core hinge region amino acid sequence is selected from SEQ IDs: 1*180-1*182. In an embodiment, the CH2 (an the polyeptide) is devoid of amino acid sequences SEQ IDs: 1*183-1*187. In an embodiment, the CH2 domain is a human IgG1 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180. Optionally, any CH1 and CH3 present in the polypeptide are human IgG1 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CPPC (SEQ ID: 1*180). Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDKTHT (SEQ ID: 1*183) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180). In an embodiment, the CH2 domain is a human IgG2 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180. Optionally, any CH1 and CH3 present in the polypeptide are human IgG2 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ERKCCVE (SEQ ID: 1*184) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180). In an embodiment, the CH2 domain is a human IgG3 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*181. Optionally, any CH1 and CH3 present in the polypeptide are human IgG3 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ELKTPLGDTTHT (SEQ ID: 1*185) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181). Optionally, alternatively the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDTPPP (SEQ ID: 1*186) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181). In an embodiment, the CH2 domain is a human IgG4 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*182. Optionally, any CH1 and CH3 present in the polypeptide are human IgG4 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ESKYGPP (SEQ ID: 1*187) and core hinge region amino acid sequence CPSC (SEQ ID: 1*182). 26. The polypeptide of any preceding Aspect, wherein the first or each linker is a (G4S)n linker, wherein n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. [00273] In an example, n is 3. In an example, n is 4. In an example, n is 5. 27. The polypeptide of any preceding Aspect, wherein each domain and SAM is a human domain and SAM respectively. 28. The polypeptide of any preceding Aspect, wherein each variable domain or scFv is capable of binding to an antigen. [00274] In an example, the binding antagonises the antigen. In another example, the binding agonises the antigen. 29. The polypeptide of any preceding Aspect, wherein the polypeptide comprises binding specificity for more than one antigen, optionally 2, 3 or 4 different antigens. [00275] For example, the polypeptide comprises at least one anti-CTLA-4 binding domain (eg, dAb or scFv) and at least one anti-4-1BB binding domain. For example, the polypeptide comprises at least one anti-CTLA-4 binding domain (eg, dAb or scFv) and at least one anti-PD-L1 binding domain. For example, the polypeptide comprises at least one anti-CTLA-4 binding domain (eg, dAb or scFv) and at least one anti-PD-1 binding domain. For example, the polypeptide comprises at least one anti-TNF alpha binding domain (eg, dAb or scFv) and at least one anti-IL-17A binding domain. [00276] For example, the polypeptide comprises a first antigen binding domain (eg, a said VH, VL, VHH, dAb, scFv or Fab variable region) that is N-terminal of the SAM and a second antigen binding domain (eg, a said VH, VL, VHH, dAb, scFv or Fab variable region) that is C-terminal of the SAM. In an example, the polypeptide comprises a third antigen binding domain (eg, a said VH, VL, VHH, dAb, scFv or Fab variable region) that is N-terminal of the SAM (eg, and also N-terminal of the first domain; or between the first domain and the SAM); and optionally the polypeptide a fourth antigen binding domain (eg, a said VH, VL, VHH, dAb, scFv or Fab variable region) that is C-terminal of the SAM (eg, and also C-terminal of the second domain; or between the second domain and the SAM). [00277] In an embodiment, the first domain is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3) and the second binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3). In an example, the domains have the same antigen binding specificity. In an example, the domains have the same epitope binding specificity. In an example, the domains have different antigen binding specificity. In an example, the domains have different epitope binding specificity on the same antigen. In an example, the domains bind TNF alpha. In an example, the domains bind CD20. In an example, the domains bind PD-1. In an example, the domains bind PD- L1. In an example, the domains bind CTLA-4. [00278] In an embodiment, the first domain is capable of specifically binding to 4-1BB, PD-1 or PD- L1 and the second binding site is capable of specifically binding to CTLA-4. In an embodiment, the second domain is capable of specifically binding to 4-1BB, PD-1 or PD-L1 and the first binding site is capable of specifically binding to CTLA-4. In an example, the first domain is capable of specifically binding to 4-1BB, the second binding site is capable of specifically binding to CTLA-4, the third binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3) and the fourth binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3). In an example, the first domain is capable of specifically binding to PD-1, the second binding site is capable of specifically binding to CTLA-4, the third binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3) and the fourth binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3). In an example, the first domain is capable of specifically binding to PD-L1, the second binding site is capable of specifically binding to CTLA-4, the third binding site is capable of specifically binding to CTLA-4, PD-L1, CD3 or CD28 and the fourth binding site is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3). [00279] In an embodiment, the first domain is capable of specifically binding to TNF alpha and the second binding site is capable of specifically binding to IL-17 (eg, IL-17A). In an embodiment, the second domain is capable of specifically binding to TNF alpha and the first binding site is capable of specifically binding to IL-17 (eg, IL-17A). [00280] In an example, the polypeptide comprises a cytokine, eg, an IL-2, IL-15 or IL-21. In an example, the cytokine is a truncated cytokine, eg, a truncated IL-2, IL-15 or IL-21. In an example, the cytokine is C-terminal of the SAM (eg, C-terminal of the C-terminal most antigen binding domain). In an example, the cytokine is N-terminal of the SAM (eg, N-terminal of the N-terminal most antigen binding domain). In an embodiment of these examples, the first domain is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3). In an embodiment of these examples, the first domain is capable of specifically binding to 4-1BB, PD-1, PD-L1 or CTLA-4. In an embodiment of these examples, the second domain is capable of specifically binding to an immune checkpoint or T-cell co- stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3). In an embodiment of these examples, the second domain is capable of specifically binding to 4-1BB, PD-1, PD-L1 or CTLA-4. In an embodiment of these examples, the third domain is capable of specifically binding to an immune checkpoint or T-cell co-stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3). In an embodiment of these examples, the third domain is capable of specifically binding to 4-1BB, PD-1, PD-L1 or CTLA-4. In an embodiment of these examples, the fourth domain is capable of specifically binding to an immune checkpoint or T-cell co- stimulatory antigen (eg, selected from OX40, GITR, VISTA, CD40, CD28, LAG3 and TIM-3). In an embodiment of these examples, the fourth domain is capable of specifically binding to 4-1BB, PD-1, PD-L1 or CTLA-4. 30. A multimer (optionally a tetramer) of a polypeptide according to any preceding Aspect. [00281] In an example, the multimer is a polypeptide dimer. [00282] In an example, the multimer is a polypeptide trimer. [00283] In an example, the multimer is a polypeptide tetramer. 31. The polypeptide or multimer of any preceding Aspect, comprising eukaryotic cell glycosylation. 32. The polypeptide or multimer of Aspect 31, wherein the cell is a HEK293, CHO or Cos cell. 33. The polypeptide or multimer of any preceding Aspect for medical use. 34. A pharmaceutical composition comprising the polypeptide or multimer of any preceding Aspect. 35. A nucleic acid encoding a polypeptide of any one of Aspects 1 to 29 and 31 to 33. 36. A eukaryotic cell or vector comprising the nucleic acid of Aspect 35. 37. A method of binding multiple copies of an antigen, the method comprising combining the copies with a multimer of any one of Aspects 30 to 33, wherein the copies are bound by polypeptides of the multimer, and optionally the method comprising isolating the multimer bound to the antigen copies. 38. The method of Aspect 37 wherein the method is a diagnostic method for detecting the presence of a substance in a sample, wherein the substance comprises the antigen, the method comprising providing the sample (eg, a bodily fluid, food, food ingredient, beverage, beverage ingredient, soil or forensic sample), mixing the sample with multimers according to any one of Aspects 30 to 33 and detecting the binding of multimers to the antigen in the sample. [00284] In an example the bodily fluid is a blood, saliva, semen or urine sample. [00285] In an example, the method is for pregnancy testing or diagnosing a disease or condition in a subject from which the sample has been previously obtained. 39. A method of treating or reducing the risk of a disease or condition in a human or animal subject, the method comprising administering the composition of Aspect 34 to the subject, wherein multimers comprised by the composition specifically bind to a target antigen in the subject, wherein said binding mediates the treatment or reduction in risk. 40. The method of Aspect 39, wherein the antigen is an immune checkpoint or T-cell co- stimulatory antigen (eg, PD-L1, PD-1 or CTLA4); or wherein the antigen is TNF alpha or IL-17A. 41. The method of Aspect 39, wherein the antigen mediates the disease or condition in the subject; and optionally wherein the binding antagonises the antigen. [00286] In another embodiment, the binding agonises the antigen. 42. A composition comprising a plurality of polypeptides according to any one of Aspects 1 to 29 and 31 to 33, wherein at least 90% of the polypeptides are comprised by tetramers of said polypeptides. [00287] Optionally, at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% of the polypeptides are comprised by tetramers of said polypeptides. 43. The composition of Aspect 42, wherein at least 98% of the polypeptides are comprised by tetramers of said polypeptides. 44. The composition of Aspect 42 or 43, wherein the remaining (ie, the balance to 100% of polypeptide) polypeptides are selected from one or more of polypeptide monomers, dimers and trimers. 45. A method of producing a composition (optionally a composition according to any one of Aspects 42 to 44) comprising a plurality of polypeptides according to any one of Aspects 1 to 29 and 31 to 33, the method comprising providing eukaryotic host cells according to Aspect 34, culturing the host cells, and allowing expression and secretion from the cells of tetramers of the polypeptides, and optionally isolating or purifying the tetramers. Any of these Aspects is combinable with any other disclosure herein, eg, any of the Clauses or Paragraphs. POLYPEPTIDES & MULTIMERS COMPRISING FC [00288] The invention also provides polypeptides and multimers comprising antibody Fc region(s). This is useful, for example, to harness FcRn recycling when administered to a subject, such as a human or animal, which may contribute to a desirable half-life in vivo. Fc regions are also useful for providing Fc effector functions. For example, an IgG1 Fc may be useful when the multimer is used to treat a cancer or where cell killing is desired, eg, by ADCC. [00289] To this end, the invention provides the following: A polypeptide comprising an antibody Fc region, wherein the Fc region comprises an antibody CH2 and an antibody CH3; and a self-associating multimerisation domain (SAM); wherein the CH2 comprises an antibody hinge sequence and is devoid of a core hinge region. [00290] In an embodiment, the polypeptide comprises an epitope binding site, eg, an antibody VH single variable domain or an antibody VH/VL pair that binds to an epitope. Additionally or alternatively, the polypeptide comprises an epitope which is cognate to an antibody. This is useful, for example, as the polypeptide can form a multimer that binds copies of the antibodies, such as when the multimer is contacted with a sample comprising the antibodies (eg, for medical use as disclosed herein). In this way, for example, the multimer can be used in a method of diagnosis or testing to determine the presence and/or quantity (or relative amount) of the antibody in the sample. As the multimer provides multiple copies of the epitope (at least one for each polypeptide comprised by the multimer), this can be useful to bind many copies of the antibody, which may be present in relatively small amounts in the sample, thereby having the effect of enhancing the chances of detecting (or amplifying) a positive signal denoting presence of the antibody. Thus, assay sensitivity may be enhanced so that relatively rare antibodies in samples can be detected. [00291] Optionally, the CH2 is devoid of (i) a core hinge CXXC amino acid sequence, wherein X is any amino acid or wherein each amino acid X is selected from a P, R and S; and/or (ii) an upper hinge amino acid sequence. For the CH2 is devoid of (i) a core hinge CXXC amino acid sequence, wherein X is any amino acid or wherein each amino acid X is selected from a P, R and S and the Fc does not directly pair with another Fc. [00292] Optionally, the CXXC sequence is selected from SEQ IDs: 1*180-1*182; or the CH2 is devoid of amino acid sequences SEQ IDs: 1*183-1*187. [00293] Optionally, the CH2 comprises A. amino acid sequence APELLGGPSV (SEQ ID: 1*163), or PAPELLGGPSV (SEQ ID: 1*164); B. amino acid sequence APPVAGPSV (SEQ ID: 1*165), or PAPPVAGPSV (SEQ ID: 1*166); C. amino acid sequence APEFLGGPSV (SEQ ID: 1*175), or PAPEFLGGPSV (SEQ ID: 1*176); D. amino acid sequence EPKSCDKTHT[P]APELLGGPSV (SEQ ID: 1*167 or 1*168), wherein the bracketed P is optional; E. amino acid sequence ERKCCVE[P]APPVAGPSV (SEQ ID: 1*169 or 1*170), wherein the bracketed P is optional; F. amino acid sequence ELKTPLGDTTHT[P]APELLGGPSV (SEQ ID: 1*171 or 1*172), wherein the bracketed P is optional; G. amino acid sequence EPKSCDTPPP[P]APELLGGPSV (SEQ ID: 1*173 or 1*174), wherein the bracketed P is optional; or H. amino acid sequence ESKYGPP[P]APEFLGGPSV (SEQ ID: 1*177 or 1*178), wherein the bracketed P is optional. [00294] Optionally, the CH2 comprises (in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and wherein the CH2 (and the polypeptide) is devoid of a core hinge region that is functional to dimerise the polypeptide with another said polypeptide. Optionally, the CH2 comprises in N- to C- terminal direction) an optional upper hinge region, a lower hinge region and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S). Optionally, the CH2 comprises in N- to C- terminal direction) an amino acid selected from SEQ IDs: 1*163-1*178 and a CH2 domain and the wherein the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CXXC, wherein X is any amino acid (optionally wherein each amino acid X is selected from a P, R and S). In an embodiment, the core hinge region amino acid sequence is selected from SEQ IDS: 1*180-1*182. In an embodiment, the CH2 (an the polyeptide) is devoid of amino acid sequences SEQ IDs: 1*183- 1*187. In an embodiment, the CH2 domain is a human IgG1 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180. Optionally, any CH1 and CH3 present in the polypeptide are human IgG1 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of a core hinge region amino acid sequence CPPC (SEQ ID: 1*180). Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDKTHT (SEQ ID: 1*183) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180). In an embodiment, the CH2 domain is a human IgG2 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180. Optionally, any CH1 and CH3 present in the polypeptide are human IgG2 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ERKCCVE (SEQ ID: 1*184) and core hinge region amino acid sequence CPPC (SEQ ID: 1*180). In an embodiment, the CH2 domain is a human IgG3 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*181. Optionally, any CH1 and CH3 present in the polypeptide are human IgG3 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ELKTPLGDTTHT (SEQ ID: 1*185) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181). Optionally, alternatively the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence EPKSCDTPPP (SEQ ID: 1*186) and core hinge region amino acid sequence CPRC (SEQ ID: 1*181). In an embodiment, the CH2 domain is a human IgG4 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*182. Optionally, any CH1 and CH3 present in the polypeptide are human IgG4 CH1 and CH3 respectively. Optionally, the CH2 (and the polypeptide) is devoid of upper hinge region amino acid sequence ESKYGPP (SEQ ID: 1*187) and core hinge region amino acid sequence CPSC (SEQ ID: 1*182). [00295] Optionally, the polypeptide comprises an antibody CH1-hinge sequence devoid of core region-CH2-CH3. [00296] Optionally, the CH2 and CH3 comprise A. human IgG1 CH2 and CH3 domains; B. human IgG2 CH2 and CH3 domains; C. human IgG3 CH2 and CH3 domains; or D. human IgG4 CH2 and CH3 domains. [00297] Optionally, the CH2 and CH3 comprise (a) human IgG1 CH2 and CH3 domains and the hinge sequence and core hinge region is a human IgG1 hinge sequence and hinge region; (b) human IgG2 CH2 and CH3 domains and the hinge sequence and core hinge region is a human IgG2 hinge sequence and hinge region; (c) human IgG3 CH2 and CH3 domains and the hinge sequence and core hinge region is a human IgG31 hinge sequence and hinge region; or (d) human IgG4 CH2 and CH3 domains and the hinge sequence and core hinge region is a human IgG4 hinge sequence and hinge region [00298] Optionally, A. the CH2 domain comprises a human IgG1 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180, optionally wherein the CH2 is devoid of upper hinge region amino acid sequence EPKSCDKTHT (SEQ ID: 1*183); B. the CH2 domain comprises a human IgG2 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*180, optionally wherein the CH2 is devoid of upper hinge region amino acid sequence ERKCCVE (SEQ ID: 1*184); C. the CH2 domain comprises a human IgG3 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*181, optionally wherein the CH2is devoid of upper hinge region amino acid sequence ELKTPLGDTTHT (SEQ ID: 1*185) or upper hinge region amino acid sequence EPKSCDTPPP (SEQ ID: 1*186); or D. the CH2 domain comprises a human IgG4 CH2 domain and the core hinge region amino acid sequence is SEQ ID: 1*182, and optionally wherein the CH2 is devoid of upper hinge region amino acid sequence ESKYGPP (SEQ ID: 1*187). [00299] Optionally, the polypeptide comprises (in N- to C-terminal direction) the Fc region and the SAM, the Fc region comprising (in N- to C-terminal direction) the hinge sequence, a CH2 domain and a CH3 domain. [00300] Optionally, the polypeptide comprises one or more epitope binding sites, eg, an antibody variable domain that is capable of specifically binding to a first epitope. Optionally, the first epitope is comprised by an antigen (eg, a human antigen) selected from the group consisting of ABCF1; ACVR1; ACVR1B; ACVR2; ACVR2B; ACVRL1; ADORA2A; Aggrecan; AGR2; AICDA; AWI; AIG1; AKAP1; AKAP2; AIYIH; AMHR2; ANGPT1; ANGPT2; ANGPTL3; ANGPTL4; ANPEP; APC; APOC1; AR; AZGP1 (zinc-a-glycoprotein); B7.1; B7.2; BAD; BAFF; BAG1; BAI1; BCL2; BCL6; BDNF; BLNK; BLRl (MDR15); BlyS; BM Pl; BMP2; BMP3B (GDFIO); BMP4; BMP6; BM P8; BMPRIA; BMPRIB; BM PR2; BPAG1 (plectin); BRCA1; CI9orflO (IL27w); C3; C4A; C5; C5R1; CANT1; CASP1; CASP4; CAV1; CCBP2 (D6 / JAB61); CCL1 (1-309); CCL11 (eotaxin); CCL13 (MCP-4); CCL15 (MIP-id); CCL16 (HCC-4); CCL17 (TARC); CCL18 (PARC); CCL19 (M IP-3b); CCL2 (MCP-1); MCAF; CCL20 (MIP-3a); CCL21 (MIP-2); SLC; exodus-2; CCL22 (MDC / STC-1); CCL23 (M PIF-1); CCL24 (MPIF-2 I eotaxin-2); CCL25 (TECK); CCL26 (eotaxin-3); CCL27 (CTACK /ILC) ; CCL28; CCL3 (MIP-la); CCL4 (M IP-lb); CCL5 (RANTES); CCL7 (MCP- 3); CCL8 (mcp-2); CCNA1; CCNA2; CCND1; CCNE1; CCNE2; CCR1 (CKR1 / HM145); CCR2 (mcp-1RB / RA);CCR3 (CKR3 / CMKBR3); CCR4; CCR5 (CM KBR5 / ChemR13); CCR6 (CMKBR6 / CKR-L3 / STRL22 / DRY6); CCR7 (CKR7 / EBI1); CCR8 (CM KBR8 / TER1 / CKR- L1); CCR9 (GPR-9-6); CCRL1 (VSHK1); CCRL2 (L-CCR); CD164; CD19; CD1C; CD20; CD200; CD-22; CD24; CD28; CD3; CD37; CD38; CD3E; CD3G; CD3Z; CD4; CD40; CD40L; CD44; CD45RB; CD52; CD69; CD72; CD74; CD79A; CD79B; CD8; CD80; CD81; CD83; CD86; CDH1 (E-cadherin); CDH10; CDH12; CDH13; CDH18; CDH19; CDH20; CDH5; CDH7; CDH8; CDH9; CDK2; CDK3; CDK4; CDK5; CDK6; CDK7; CDK9; CDKN1A (p2IWapl/Cipl); CDKN1B (p27Kipl); CDKNIC; CDKN2A (pl6INK4a); CDKN2B; CDKN2C; CDKN3; CEBPB; CER1; CHGA; CHGB; Chitinase; CHST10; CKLFSF2; CKLFSF3; CKLFSF4; CKLFSF5; CKLFSF6; CKLFSF7; CKLFSF8; CLDN3; CLDN7 (claudin-7); CLN3; CLU (clusterin); CMKLR1; CMKOR1 (RDC1); CNR1; COL18A1; COL1A1; COL4A3; COL6A1; CR2; CRP; CSFl (M-CSF); CSF2 (GM- CSF); CSF3 (GCSF); CTLA4; CTNNBl (b-catenin); CTSB (cathepsin B); CX3CL1 (SCYDi) ; CX3CR1 (V28); CXCL1 (GROl); CXCLIO (IP-10); CXCL11 (l-TAC / IP-9); CXCL12 (SDF1); CXCL13; CXCL14; CXCL16; CXCL2 (GR02); CXCL3 (GR03); CXCL5 (ENA-78 I LIX); CXCL6 (GCP-2); CXCL9 (MIG); CXCR3 (GPR9/CKR-L2); CXCR4; CXCR6 (TYMSTR ISTRL33 I Bonzo); CYB5; CYC1; CYSLTR1; DAB2IP; DES; DKFZp451J0118; DNCL1; DPP4; E2F1; ECGF1; EDG1; EFNAI; EFNA3; EFNB2; EGF; EGFR; ELAC2; ENG; EN01; EN02; EN03; EPHB4; EPO; ERBB2 (Her-2); EREG; ERK8; ESR1; ESR2; F3 (TF); FADD; FasL; FASN; FCER1A; FCER2; FCGR3A; FGF; FGF1 (aFGF); FGF10; FGF11; FGF12; FGF12B; FGF13; FGF14; FGF16; FGF17; FGF18; FGF19; FGF2 (bFGF); FGF20; FGF21; FGF22; FGF23; FGF3 (int-2); FGF4 (HST); FGF5; FGF6 (HST-2); FGF7 (KGF); FGF8; FGF9; FGFR3; FIGF (VEGFD); FILl (EPSILON); FILl (ZETA); FU12584; FU25530; FLRTl (fibronectin); FLTl; FOS; FOSLl (FRA-I); FY (DARC); GABRP (GABAa); GAGEB1; GAGEC1; GALNAC4S-65T; GATA3; GDF5; GFI1; GGT1; GM- CSF; GNAS1; GNRHl; GPR2 (CCRIO); GPR31; GPR44; GPR81 (FKSG80); GRCCIO (CIO); GRP; GSN (Gelsolin); GSTPl; HAVCR2; HDAC4; EDAC5; HDAC7A; HDAC9; HGF; HIF1A; HIP1; histamine and histamine receptors; HLA-A; HLA-DRA; HM74; HMOX1; HUMCYT2A; ICEBERG; ICOSL; 1D2; IFN-a; IFNA1; IFNA2; IFNA4; IFNA5; IFNA6; IFNA7; IFNB1; IFNgamma; TFNW1; IGBP1; IGF1; IGF1R; IGF2; IGFBP2; IGFBP3; IGFBP6; IL-1; IL10; IL10RA; IL10RB; IL11; IL11RA; IL-12; IL12A; IL12B; IL12RB1; IL12RB2; 1L13; IL13RA1; IL13RA2; 1L14; 1L15; IL15RA; IL16; 1L17; IL17B; IL17C; IL17R; 1L18; IL18BP; IL18R1; IL18RAP; 1L19; ILIA; IL1B; IL1F10; IL1F5; IL1F6; IL1F7; IL1F8; IL1F9; IL1HY1; IL1R1; IL1R2; IL1RAP; IL1RAPL1; IL1RAPL2; IL1RL1;IL1RL2 IL1RN; 1L2; 1L20; IL20RA; IL21R; 1L22; 1L22R; 1L22RA2; 1L23; 1L24; 1L25; 1L26; 1L27; 1L28A; 1L28B; 1L29; IL2RA; IL2RB; IL2RG; 1L3; 1L30; IL3RA; 1L4; IL4R; 1L5; IL5RA; 1L6; IL6R; IL6ST (glycoprotein 130); 1L7; TL7R; 1L8; IL8RA; IL8RB; IL8RB; 1L9; IL9R; ILK; INHA; INHBA; INSL3; INSL4; IRAKI; IRAK2; ITGA1; ITGA2; 1TGA3; ITGA6 (a6 integrin); ITGAV; ITGB3; ITGB4 (b 4 integrin); JAG1; JAK1; JAK3; JUN; K6HF; KAI1; KDR; MTLG; KLF5 (GC Box BP); KLF6; KLK10; KLK12; KLK13; KLK14; KLK15; KLK3; KLK4; KLK5; KLK6; KLK9; KRT1; KRT19 (Keratin 19); KRT2A; KRTHB6 (hair-specific type II keratin); LAMA5; LEP (leptin); Lingo-p75; Lingo-Troy; LPS; LTA (TNF-b); LTB; LTB4R (GPR16); LTB4R2; LTBR; MACMARCKS; MAG or Omgp; MAP2K7 (c-Jun); MDK; M IB1; midkine; M IF; M IP-2; MK167 (Ki-67); MMP2; M MP9; MS4A1; MSMB; MT3 (metallothionectin-ifi); MTSS 1; M UC 1 (mucin); MYC; MYD88; NCK2; neurocan; NFKB 1; NFKB2; NGFB (NGF); NGFR; NgR- Lingo; NgR-Nogo66 (Nogo); NgR-p75; NgR-Troy; NM E1 (NM23A); NOX5; NPPB; NROB1; NROB2; NR1D1; NR1D2; NR1H2; NR1H3; NR1H4; NR1I2; NR1I3; NR2C1; NR2C2; NR2E1; NR2E3; NR2F1; NR2F2; NR2F6; NR3C1; NR3C2; NR4A1; NR4A2; NR4A3; NR5A1; NR5A2; NR6A1; NRP1; NRP2; NT5E; NTN4; ODZ1; OPRD1; P2RX7; PAP; PARTI; PATE; PAWR; PCA3; PCNA; PDGFA; PDGFB; PECAM1; PF4 (CXCL4); PGF; PGR; phosphacan; PIAS2; PIK3CG; PLAU (uPA); PLG; PLXDC1; PPBP (CXCL7); PPID; PR1; PRKCQ; PRKD1; PRL; PROC; PROK2; PSAP; PSCA; PTAFR; PTEN; PTGS2 (COX-2); PTN; RAC2 (p2IRac2); RARB; RGS1; RGS13; RGS3; RNF110 (ZNF144); ROB02; S100A2; SCGB1D2 (lipophilin B); SCGB2A1 (mammaglobin 2); SCGB2A2 (mammaglobin 1); SCYE1 (endothelial Monocyte-activating cytokine); SDF2; SERPINA1; SERPINIA3; SERPINB5 (maspin); SERPINE1 (PAT-i); SERPINF1; SHBG; SLA2; SLC2A2; SLC33A1; SLC43A1; SLIT2; SPPl; SPRRIB (Spri); ST6GAL1; STABl; STAT6; STEAP; STEAP2; TB4R2; TBX21; TCPIO; TDGF1; TEK; TGFA; TGFB1; TGFB1I1; TGFB2; TGFB3; TGFBI; TGFBR1; TGFBR2; TGFBR3; TH1L; THBS1(thrombospondin-1); THBS2; THBS4; THPO; TIE (Tie-i); T]MP3; tissue factor; TLRIO; TLR2; TLR3; TLR4; TLR5; TLR6; TLR7; TLR8; TLR9; TNF; TNF-a; TNFAIP2 (B94); TNFAIP3; TNFRSF11A; TNFRSF1A; TNFRSF1B; TNFRSF21; TNFRSF5; TNFRSF6 (Fas); TNFRSF7; TNFRSF8; TNFRSF9; TNFSFIO (TRAIL); TNFSF11 (TRANCE); TNFSF12 (AP03L); TNFSF13 (April); TNFSF13B; TNFSF14 (HVEM-L); TNFSF15 (VEGI); TNFSF18; TNFSF4 (0X40 ligand); TNFSF5 (CD40 ligand); TNFSF6 (FasL); TNFSF7 (CD27 ligand); TNFSF8 (CD30 ligand); TNFSF9 (4-lBB ligand); TOLLIP; Toll-like receptors; TOP2A (topoisomerase lia); TP53; TPM 1; TPM2; TRADD; TRAF1; TRAF2; TRAF3; TRAF4; TRAF5; TRAF6; TREM 1; TREM2; TRPC6; TSLP; TWEAK; VEGF; VEGFB; VEGFC; versican; VHL C5; VLA-4; XCL1 (lymphotactin); XCL2 (SCM-lb); XCR1 (GPR5 / CCXCR1); YY1; and ZFPM2. Optionally, the second epitope (as discussed below) is comprised by the same antigen as the first epitope (eg, comprised by the same antigen molecule). In another example, the second antigen is comprised by said group. In an example, the first and second epitopes are comprised by different antigens selected from said group. [00301] For example, the polypeptide has 1, 2, 3, 4 or 5 epitope binding sites (optionally wherein the polypeptide comprises 2 or more binding sites (eg, single variable domains) that bind to different epitopes, or wherein the polypeptide binding sites are identical). In an embodiment, the SAM is a TD (eg, a p53 TD, such as a human p53 TD) and the polypeptide has 2, 3 or 4 binding sites, such as 3 sites or such as 4 sites. Preferably, the polypeptide has 3 binding sites. Preferably, the polypeptide has 4 binding sites. For example, the binding sites each binds TNF alpha (eg, wherein the binding sites are identical, eg, identical antibody single variable domains). [00302] In an example, the multimer is an octavalent bispecific multimer comprising 4 copies of an anti-PD-L1binding site (eg, dAb) and 4 copies of an anti-4-1BB binding site (eg, dAb). [00303] In an example, the multimer is a tetravalent multimer comprising copies of an anti-PD-L1 binding site (eg, dAb). In an example, the multimer is an octavalent multimer comprising copies of an anti-PD-L1 binding site (eg, dAb). In an example, the multimer is a 12-valent multimer comprising copies of an anti-PD-L1 binding site (eg, dAb). In an example, the multimer is a 16- valent multimer comprising copies of an anti-PD-L1 binding site (eg, dAb). In an example, the anti- PD-L1 binding site comprises an avelumab or atezolizumab binding site that specifically binds to PD- L1. Preferably, in these examples the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD. For the tetramer, each polypeptide comprises one copy of the binding site. For the octamer each polypeptide comprises 2 copies of the binding site. For the 12-mer each polypeptide comprises 3 copies of the binding site. For the 16-mer each polypeptide comprises 4 copies of the binding site. [00304] In an example, the multimer is a tetravalent multimer comprising copies of an anti-PD-1 binding site (eg, dAb). In an example, the multimer is an octavalent multimer comprising copies of an anti-PD-1 binding site (eg, dAb). In an example, the multimer is a 12-valent multimer comprising copies of an anti-PD-1 binding site (eg, dAb). In an example, the multimer is a 16-valent multimer comprising copies of an anti-PD-1 binding site (eg, dAb). In an example, the anti- PD-1 binding site comprises a nivolumab or pembrolizumab binding site that specifically binds to PD-1. Preferably, in these examples the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD. For the tetramer, each polypeptide comprises one copy of the binding site. For the octamer each polypeptide comprises 2 copies of the binding site. For the 12-mer each polypeptide comprises 3 copies of the binding site. For the 16-mer each polypeptide comprises 4 copies of the binding site. [00305] In an example, the multimer is a tetravalent multimer comprising copies of an anti-DR5 (Death Receptor 5) binding site (eg, dAb). In an example, the multimer is an octavalent multimer comprising copies of an anti-DR5 binding site (eg, dAb). In an example, the multimer is a 12-valent multimer comprising copies of an anti-DR5 binding site (eg, dAb). In an example, the multimer is a 16-valent multimer comprising copies of an anti-DR5 binding site (eg, dAb). Preferably, in these examples the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD. For the tetramer, each polypeptide comprises one copy of the binding site. For the octamer each polypeptide comprises 2 copies of the binding site. For the 12-mer each polypeptide comprises 3 copies of the binding site. For the 16-mer each polypeptide comprises 4 copies of the binding site. [00306] In an example, the multimer is a tetravalent multimer comprising copies of an anti-OX40 or OX40L binding site (eg, dAb). In an example, the multimer is an octavalent multimer comprising copies of an anti-OX40 or OX40L binding site (eg, dAb). In an example, the multimer is a 12-valent multimer comprising copies of an anti- OX40 or OX40L binding site (eg, dAb). In an example, the multimer is a 16-valent multimer comprising copies of an anti- OX40 or OX40L binding site (eg, dAb). Preferably, in these examples the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD. For the tetramer, each polypeptide comprises one copy of the binding site. For the octamer each polypeptide comprises 2 copies of the binding site. For the 12-mer each polypeptide comprises 3 copies of the binding site. For the 16-mer each polypeptide comprises 4 copies of the binding site. [00307] In an example, the multimer is a tetravalent multimer comprising copies of an anti-  glucocorticoid-induced tumor necrosis factor receptor (GITR) binding site (eg, dAb). In an example, the multimer is an octavalent multimer comprising copies of an anti-GITR binding site (eg, dAb). In an example, the multimer is a 12-valent multimer comprising copies of an anti-GITR binding site (eg, dAb). In an example, the multimer is a 16-valent multimer comprising copies of an anti-GITR binding site (eg, dAb). Preferably, in these examples the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD. For the tetramer, each polypeptide comprises one copy of the binding site. For the octamer each polypeptide comprises 2 copies of the binding site. For the 12-mer each polypeptide comprises 3 copies of the binding site. For the 16-mer each polypeptide comprises 4 copies of the binding site. [00308] In an example, the multimer is a tetravalent multimer comprising copies of an anti-antibody kappa light chain (KLC) binding site (eg, dAb). In an example, the multimer is an octavalent multimer comprising copies of an anti-KLC binding site (eg, dAb). In an example, the multimer is a 12-valent multimer comprising copies of an anti-KLC binding site (eg, dAb). In an example, the multimer is a 16-valent multimer comprising copies of an anti-KLC binding site (eg, dAb). Preferably, in these examples the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD. For the tetramer, each polypeptide comprises one copy of the binding site. For the octamer each polypeptide comprises 2 copies of the binding site. For the 12-mer each polypeptide comprises 3 copies of the binding site. For the 16-mer each polypeptide comprises 4 copies of the binding site. [00309] In an example, the multimer is a tetravalent multimer comprising copies of an anti-VEGF binding site (eg, dAb). In an example, the multimer is an octavalent multimer comprising copies of an anti-VEGF binding site (eg, dAb). In an example, the multimer is a 12-valent multimer comprising copies of an anti-VEGF binding site (eg, dAb). In an example, the multimer is a 16-valent multimer comprising copies of an anti-VEGF binding site (eg, dAb). In an example, the anti-VEGF binding site comprises a VEGF receptor domain that specifically binds to VEGF (eg, a VEGF binding site of human flt (eg, flt-1) or KDR, eg, Ig domain 2 from VEGFR1 or Ig domain 3 from VEGFR2)). In an example, the anti-VEGF binding site comprises an aflibercept, bevacizumab or ranibizumab binding site that specifically binds to VEGF. Preferably, in these examples the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD. For the tetramer, each polypeptide comprises one copy of the binding site. For the octamer each polypeptide comprises 2 copies of the binding site. For the 12-mer each polypeptide comprises 3 copies of the binding site. For the 16-mer each polypeptide comprises 4 copies of the binding site. [00310] In an example, the multimer is a tetravalent multimer comprising copies of an anti-TNF alpha binding site (eg, dAb). In an example, the multimer is a tetravalent multimer comprising copies of an anti-TNF alpha binding site (eg, dAb). In an example, the multimer is an octavalent multimer comprising copies of an anti-TNF alpha binding site (eg, dAb). In an example, the multimer is a 12- valent multimer comprising copies of an anti-TNF alpha binding site (eg, dAb). In an example, the multimer is a 16-valent multimer comprising copies of an anti-TNF alpha binding site (eg, dAb). Preferably, in these examples the SAM domain is a TD, eg, a p53 TD, such as a human p53 TD. For the tetramer, each polypeptide comprises one copy of the binding site. For the octamer each polypeptide comprises 2 copies of the binding site. For the 12-mer each polypeptide comprises 3 copies of the binding site. For the 16-mer each polypeptide comprises 4 copies of the binding site. [00311] Optionally, the variable domain is selected from an antibody single variable domain, a VH and a VL; or wherein the domain is comprised by an scFv. Optionally, the domain is comprised by an antibody VH/VL pair that binds to said first epitope. In an example, epitope binding herein is specific binding as herein defined. [00312] Optionally, the polypeptide comprises (in N- to C-terminal direction) A. the variable domain, the SAM and the Fc region; B. the Fc region, the SAM and the variable domain; C. the variable domain, the Fc region and the SAM; D. the SAM, the variable domain and the Fc region; or E. the SAM, the Fc region and the variable domain. [00313] Optionally, the polypepide comprises a second antibody variable domain N- or C-terminal to the SAM, wherein the second variable domain is capable of specifically binding to a second epitope, wherein the first and second epitopes are identical or different. [00314] Optionally, the SAM is a self-associating tetramerisation domain (TD); optionally wherein the TD is a p53, p63 or p73 TD or a homologue or orthologue thereof; or wherein the TD is a NHR2 TD or a homologue or orthologue thereof; or wherein the TD comprises an amino acid sequence that is at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*10 or 1*126. [00315] Optionally, (i) the polypeptide comprises (in N- to C-terminal direction); A. A first antibody single variable domain (dAb), an optional linker and said SAM; B. A first antibody single variable domain, an optional linker, said SAM and a second antibody single variable domain; C. A first scFv, an optional linker and said SAM; D. A first scFv, an optional linker, said SAM and a second scFv; E. A first antibody single variable domain, an optional linker, said SAM and a first scFv; F. A first scFv, an optional linker, said SAM and a first antibody single variable domain; G. A first antibody variable domain, an optional first linker, a first antibody constant domain, a second optional linker and said SAM; H. Said SAM, an optional linker and a first antibody single variable domain; I. Said SAM, an optional linker and a first scFv; J. Said SAM, an optional linker, a first antibody constant domain, a second optional linker and a first antibody variable domain; or K. Said SAM, an optional linker, a first antibody variable domain, a second optional linker and a first antibody constant domain; Or (ii) the polypeptide comprises (in N- to C-terminal direction); A. A dAb and the SAM; B. A first dAb, the SAM and a second dAb; C. A first scFv and the SAM; D. A first scFv, the SAM and a second scFv; E. A first scFv, the SAM and a first dAb; F. A first dAb, the Fc region and the SAM; G. A first scFv, the Fc region and the SAM; H. A VH, a CH1, the Fc region and the SAM; I. A VL, a CL, the Fc region and the SAM; J. A dAb; the SAM and the Fc region; K. A scFv; the SAM and the Fc region; L. A VH, a CH1, the SAM and the Fc region; M. A VL, a CL, the SAM and the Fc region; N. A first dAb, a second dAb and the SAM; O. A VH, a CH1 and the SAM; P. A VL, a CL and the SAM; Q. A VH, a CH1, the SAM and a first dAb; R. A VL, a CL, the SAM and a first dAb; S. A first dAb, a second dAb, the SAM and a third dAb; T. A first dAb, a second dAb, the SAM and a first scFv; U. A first dAb, a second dAb, the SAM, a third dAb and a fourth dAb; V. A first dAb, the Fc region, the SAM and a second dAb; W. A first dAb, the Fc region, the SAM and a first scFv; X. A first dAb, a second dAb, the Fc region and the SAM; Y. A first dAb, a second dAb, the Fc region, the SAM and a third dAb; Z. A first dAb, a second dAb, the Fc region, the SAM and a first scFv; or AA. A first dAb, a second dAb, the Fc region, the SAM, a third dAb and a fourth dAb; Or (iii) the polypeptide comprises (in C- to N-terminal direction); A. A dAb and the SAM; B. A first dAb, the SAM and a second dAb; C. A first scFv and the SAM; D. A first scFv, the SAM and a second scFv; E. A first scFv, the SAM and a first dAb; F. A first dAb, the Fc region and the SAM; G. A first scFv, the Fc region and the SAM; H. A VH, a CH1, the Fc regionand the SAM; I. A VL, a CL, the Fc region and the SAM; J. A dAb; the SAM and the Fc region; K. A scFv; the SAM and the Fc region; L. A VH, a CH1, the SAM and the Fc region; M. A VL, a CL, the SAM and the Fc region; N. A first dAb, a second dAb and the SAM; O. A VH, a CH1 and the SAM; P. A VL, a CL and the SAM; Q. A VH, a CH1, the SAM and a first dAb; R. A VL, a CL, the SAM and a first dAb; S. A first dAb, a second dAb, the SAM and a third dAb; T. A first dAb, a second dAb, the SAM and a first scFv; U. A first dAb, a second dAb, the SAM, a third dAb and a fourth dAb; V. A first dAb, the Fc region, the SAM and a second dAb; W. A first dAb, the Fc region, the SAM and a first scFv; X. A first dAb, a second dAb, the Fc region and the SAM; Y. A first dAb, a second dAb, the Fc region, the SAM and a third dAb; Z. A first dAb, a second dAb, the Fc region, the SAM and a first scFv; or AA. A first dAb, a second dAb, the Fc region, the SAM, a third dAb and a fourth dAb. [00264] Optionally, any single variable domain or dAb herein is a Nanobody™ or a Camelid VHH (eg, a humanised Camelid VHH). For example, a variable domain, such as a dAb (AKA antibody single variable domain) herein is a VH (eg, comprised by a scFv or a Fab polypeptide chain). In another example, it is a VHH (eg, comprised by a scFv or a Fab polypeptide chain). In another example, it is a humanised VH, humanised VHH or a human VH (eg, comprised by a scFv or a Fab polypeptide chain). In another example, it is a VL (eg, comprised by a scFv or a Fab polypeptide chain). In another example, it is a Vκ. In another example, it is a Vλ. [00316] In an embodiment, each polypeptide of the multimer is paired with a copy of a further polypeptide, wherein the further polypeptide comprises an antibody light chain constant region (eg, a Cκ or a Cλ) that pairs with the Fc of the first polypeptide. In an example, the first polypeptide comprises an antibody VH domain, the further polypeptide comprises an antibody VL domain (eg, a Vκ or a Vλ), wherein the VH and VL form an epitope binding site. In this way, the multimer may be a multimer of Fab-like structures, such as comprising multiple copies of an adalimumab (Humira) or avelumab (Bavencio) binding site as exemplified in the Examples below. All of the antibody domains in such a multimer may, for example, be human, and optionally the SAM is a human domain. When the SAM is a TD (eg a p53 TD) the multimer comprises a tetramer of the VH/VL epitope binding sites. The first polypeptide or the further polypetide may comprise a second epitope binding site, for example, wherein the multimer is octavalent. When the 8 binding sites may bind the same antigen; alternatively the 4 VH/VL binding sites bind a first antigen and the other 4 binding sites bind to a second antigen, wherein the antigens are different. Thus, the multimer may be octavalent and bispecific. If the first or further polypetide comprises yet another antigen binding site, the multimer may be 12-valent (and, eg, monospecific, bispecific or trispecific for antigen binding). If the first or further polypetide comprises yet another antigen binding site, the multimer may be 16-valent (and, eg, monospecific, bispecific, trispecific or tetraspecific for antigen binding). [00317] The invention further provides:- A multimer (optionally a tetramer) of a polypeptide according to the invention; optionally wherein the multimer is for medical use. In an example, the medical use herein is the treatment or prevention of a cancer, autoimmune disease or condition or any other disease or condition disclosed herein. A multimer of a plurality of antibody Fc regions, wherein each Fc is comprised by a respective polypeptide and is unpaired with another Fc region; optionally wherein the multimer is for medical use. Optionally, each polypeptide comprises an epitope binding domain or site as disclosed herein. A pharmaceutical composition comprising the polypeptide or multimer of the invention. A nucleic acid encoding a polypeptide of the invention; optionally wherein the nucleic acid is comprised by a eukaryotic cell or a vector. A method of binding multiple copies of an antigen, the method comprising combining the copies with a multimer of or the composition of the invention, wherein the copies are bound by polypeptides of the multimer, and optionally the method comprising isolating the multimer bound to the antigen copies. In an example, the multimer is contacted with a sample comprising the copies of the antigen and copies of the antigen are sequestered in the sample by binding to the multimer. For example, the multimer is administered to a human or animal patient (or an environment is exposed to the multimer) and antigen copies are sequestered in the human (eg, for said medical use), animal (eg, for said medical use) or environment. For example, the environment is comprised by a soil, water source, waterway or industrial fluid, eg, for environmental remediation, such as where the antigen is comprised by an environmental pollutant or contaminant. In an example, the method is for purifying the sample or for isolating antigen comprised by the sample. A method of treating or reducing the risk of a disease or condition in a human or animal subject, the method comprising administering the composition of the invention to the subject, wherein multimers comprised by the composition specifically bind to a target antigen in the subject, wherein said binding mediates the treatment or reduction in risk of the disease or condition. A method of producing a composition comprising a plurality of polypeptides according to the invention, wherein the SAM is a self-associating tetramerisation domain (TD), the method comprising providing eukaryotic host cells according to the invention, culturing the host cells, and allowing expression and secretion from the cells of tetramers of the polypeptides, and optionally isolating or purifying the tetramers. [00318] PARAGRAPHS: The invention provides the following Paragraphs. The following Paragraphs are not to be interpreted as Claims. The Claims start after the Examples section. 1. A polypeptide (optionally according any polypeptide herein) comprising (a) An antibody Fc region, wherein the Fc region comprises an antibody CH2 domain and an antibody CH3 domain; and (b) A self-associating multimerisation domain (SAM); wherein the CH2 is devoid of a core hinge CXXC amino acid sequence, wherein X is any amino acid. 2. The polypeptide of Paragraph 1, wherein each amino acid X is selected from a P, R and S. 3. The polypeptide of Paragraph 1 or 2, wherein the CH2 is devoid of a complete upper hinge sequence. 4. The polypeptide of any preceding Paragraph, wherein the CH2 comprises (a) an APELLGGPSV amino acid sequence, or an PAPELLGGPSV amino acid sequence; (b) an APPVAGPSV amino acid sequence, or an PAPPVAGPSV amino acid sequence; or (c) an APEFLGGPSV amino acid sequence, or an PAPEFLGGPSV amino acid sequence. 5. The polypeptide of any preceding Paragraph, wherein the CH2 and CH3 are (a) human IgG1 CH2 and CH3 domains; (b) human IgG2 CH2 and CH3 domains; (c) human IgG3 CH2 and CH3 domains; or (d) human IgG4 CH2 and CH3 domains. 6. The polypeptide of Paragraph 5(a) or (b), wherein CH2 is devoid of a CPPC sequence; or the polypeptide of Paragraph 5(c) wherein the CH2 is devoid of a CPRC sequence; or the polypeptide of Paragraph 5(d) wherein the CH2 is devoid of a CPSC sequence. 7. The polypeptide of any one of Paragraphs 1 to 4, wherein the CH2 comprises (a) an APELLGGPSV amino acid sequence; (b) an EPKSCDKTHT[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional; (c) an APPVAGPSV amino acid sequence; (d) an ERKCCVE[P]APPVAGPSV amino acid sequence, wherein the bracketed P is optional; (e) an ELKTPLGDTTHT[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional; (f) an EPKSCDTPPP[P]APELLGGPSV amino acid sequence, wherein the bracketed P is optional; or (g) an APEFLGGPSV amino acid sequence; or (h) an ESKYGPP[P]APEFLGGPSV amino acid sequence, wherein the bracketed P is optional. 8. The polypeptide of any preceding Paragraph, wherein the CH2 is devoid of a sequence selected from CXXC disclosed herein and SEQ IDs: 1*180-1*182. 9. The polypeptide of any preceding Paragraph, wherein the polypeptide comprises an antibody variable domain that is capable of specifically binding to a first epitope. 10. The polypeptide of Paragraph 9, wherein the variable domain selected from an antibody single variable domain, a VH and a VL; or wherein the domain is comprised by an scFv. 11. The polypeptide of any preceding Paragraph, wherein the Fc region is 3’ of the SAM. 12. The polypeptide of Paragraph 9, 10 or 11, wherein (a) the variable domain is 5’ of the SAM and the Fc region is 3’ of the SAM; (b) the variable domain is 3’ of the SAM and the Fc region is 5’ of the SAM; (c) the variable domain and Fc are 5’ of the SAM; or (d) the variable domain and Fc are 3’ of the SAM. 13. The polypeptide of Paragraph 12 comprising a second variable domain 5’ or 3’ of the SAM, wherein the second variable domain is capable of specifically binding to a second epitope, wherein the first and second epitopes are identical or different. 14. The polypeptide of paragraph 13, wherein the epitopes are different epitopes of the same antigen, or are epitopes of different antigens. 15. The polypeptide of Paragraph 13 or 14, wherein the second variable domain is selected from an antibody single variable domain, a VH and a VL; or wherein the domain is comprised by an scFv. 16. The polypeptide of Paragraph 15, wherein the second variable domain is an antibody single variable domain or an antibody constant domain. 17. The polypeptide of any preceding Paragraph, wherein the SAM is a self-associating tetramerisation domain (TD). 18. The polypeptide of Paragraph 17, wherein the TD is a p53, p63 or p73 TD or a homologue or orthologue thereof; or wherein the TD is a NHR2 TD or a homologue or orthologue thereof. 19. The polypeptide of Paragraph 17 or 18, wherein the TD comprises an amino acid sequence that is at least 80% identical to SEQ ID: 1*10 or 1*126. 20. The polypeptide of any preceding Paragraph, comprising an antibody CH1 constant domain, optionally a CH1-CH2-CH3, wherein the CH2 and CH3 are comprised by said Fc region. 21. The polypeptide of any preceding Paragraph, wherein the polypeptide (first polypeptide) comprises or consists of (in N- to C-terminal direction); A. A first antibody single variable domain (dAb), an optional linker and said SAM; B. A first antibody single variable domain, an optional linker, said SAM and a second antibody single variable domain; C. A first scFv, an optional linker and said SAM; D. A first scFv, an optional linker, said SAM and a second scFv; E. A first antibody single variable domain, an optional linker, said SAM and a first scFv; F. A first scFv, an optional linker, said SAM and a first antibody single variable domain; G. A first antibody variable domain, an optional first linker, a first antibody constant domain, a second optional linker and said SAM; H. Said SAM, an optional linker and a first antibody single variable domain; I. Said SAM, an optional linker and a first scFv; J. Said SAM, an optional linker, a first antibody constant domain, a second optional linker and a first antibody variable domain; or K. Said SAM, an optional linker, a first antibody variable domain, a second optional linker and a first antibody constant domain. 22. The polypeptide of any of Paragraphs 1 to 20, wherein (i) the polypeptide comprises (in N- to C-terminal direction); A. A dAb and the self-associating multimersiation domain (SAM); B. A first dAb, the SAM and a second dAb; C. A first scFv and the SAM; D. A first scFv, the SAM and a second scFv; E. A first scFv, the SAM and a first dAb; F. A first dAb, the Fc region and the SAM; G. A first scFv, the Fc region and the SAM; H. A VH, a CH1, the Fc region and the SAM; I. A VL, a CL, the Fc region and the SAM; J. A dAb; the SAM and the Fc region; K. A scFv; the SAM and the Fc region; L. A VH, a CH1, the SAM and the Fc region; M. A VL, a CL, the SAM and the Fc region; N. A first dAb, a second dAb and the SAM; O. A VH, a CH1 and the SAM; P. A VL, a CL and the SAM; Q. A VH, a CH1, the SAM and a first dAb; R. A VL, a CL, the SAM and a first dAb; S. A first dAb, a second dAb, the SAM and a third dAb; T. A first dAb, a second dAb, the SAM and a first scFv; U. A first dAb, a second dAb, the SAM, a third dAb and a fourth dAb; V. A first dAb, the Fc region, the SAM and a second dAb; W. A first dAb, the Fc region, the SAM and a first scFv; X. A first dAb, a second dAb, the Fc region and the SAM; Y. A first dAb, a second dAb, the Fc region, the SAM and a third dAb; Z. A first dAb, a second dAb, the Fc region, the SAM and a first scFv; or AA. A first dAb, a second dAb, the Fc region, the SAM, a third dAb and a fourth dAb; Or (ii) the polypeptide comprises (in C- to N-terminal direction); A. A dAb and a self-associating multimersiation domain (SAM); B. A first dAb, the SAM and a second dAb; C. A first scFv and the SAM; D. A first scFv, the SAM and a second scFv; E. A first scFv, the SAM and a first dAb; F. A first dAb, the Fc region and the SAM; G. A first scFv, the Fc region and the SAM; H. A VH, a CH1, the Fc regionand the SAM; I. A VL, a CL, the Fc region and the SAM; J. A dAb; the SAM and the Fc region; K. A scFv; the SAM and the Fc region; L. A VH, a CH1, the SAM and the Fc region; M. A VL, a CL, the SAM and the Fc region; N. A first dAb, a second dAb and the SAM; O. A VH, a CH1 and the SAM; P. A VL, a CL and the SAM; Q. A VH, a CH1, the SAM and a first dAb; R. A VL, a CL, the SAM and a first dAb; S. A first dAb, a second dAb, the SAM and a third dAb; T. A first dAb, a second dAb, the SAM and a first scFv; U. A first dAb, a second dAb, the SAM, a third dAb and a fourth dAb; V. A first dAb, the Fc region, the SAM and a second dAb; W. A first dAb, the Fc region, the SAM and a first scFv; X. A first dAb, a second dAb, the Fc region and the SAM; Y. A first dAb, a second dAb, the Fc region, the SAM and a third dAb; Z. A first dAb, a second dAb, the Fc region, the SAM and a first scFv; or AA. A first dAb, a second dAb, the Fc region, the SAM, a third dAb and a fourth dAb. 23. The polypeptide of Paragraph 21B, 21D, (i) 22B, (i) 22D, (i) 22N, (i) 22S, (i) 22T, (i) 22U, (i) 22X, (i) 22Y, (i) 22Z, (i) 22AA, (ii) 22B, (ii) 22D, (ii) 22N, (ii) 22S, (ii) 22T, (ii) 22U, (ii) 22X, (ii) 22Y, (ii) 22Z or (ii) 22AA wherein the single variable domains (dAbs) are identical; or wherein the scFvs are identical. 24. The polypeptide of Paragraph 21B, 21D, (i) 22B, (i) 22D, (i) 22N, (i) 22S, (i) 22T, (i) 22U, (i) 22X, (i) 22Y, (i) 22Z, (i) 22AA, (ii) 22B, (ii) 22D, (ii) 22N, (ii) 22S, (ii) 22T, (ii) 22U, (ii) 22X, (ii) 22Y, (ii) 22Z or (ii) 22AA wherein the single variable domains are different; or wherein the scFvs are different. 25. The polypeptide of Paragraph 21G, 21J, 21K, (i) 22H, (i) 22I, (i) 22L, (i) 22M, (i) 22O, (i) 22P, (i) 22Q, (i) 22R, (ii) 22H, (ii) 22I, (ii) 22L, (ii) 22M, (ii) 22O, (ii) 22P, (ii) 22Q or (ii) 22R wherein (i) the first variable domain is a VH domain and the first constant domain is a CH1 domain, and optionally the polypeptide is associated with a second polypeptide, wherein the second polypeptide comprises an antibody CL constant domain that is paired with the CH1 domain; (ii) the first variable domain is a VH domain and the first constant domain is a CL domain, and optionally the polypeptide is associated with a second polypeptide, wherein the second polypeptide comprises an antibody CH1 constant domain that is paired with the CL domain; (iii) the first variable domain is a VL domain and the first constant domain is a CH1 domain, and optionally the polypeptide is associated with a second polypeptide, wherein the second polypeptide comprises an antibody CL constant domain that is paired with the CH1 domain; or (iv) the first variable domain is a VL domain and the first constant domain is a CL domain, and optionally the polypeptide is associated with a second polypeptide, wherein the second polypeptide comprises an antibody CH1 constant domain that is paired with the CL domain. 26. The polypeptide of any one of Paragraphs 21 to 25, comprising an antibody Fc region or antibody single variable domain between (v) the first variable domain or scFv and (vi) the SAM, wherein the Fc comprises a CH2 and a CH3. 27. The polypeptide of any one of Paragraphs 21 to 26, comprising the Fc region or an antibody single variable domain between (i) the SAM and (ii) the most C-terminal variable domain. 28. The polypeptide of any one of Paragraphs 21 to 27, comprising in N- to C-terminal direction the antibody Fc region and the most N-terminal variable domain or scFv. 29. The polypeptide of any one of Paragraphs 21 to 28, comprising in N- to C-terminal direction the SAM and the antibody Fc region. 30. The polypeptide of any one of Paragraphs 21 to 29, wherein the first or each linker is a (G4S)n linker, wherein n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. 31. The polypeptide of any preceding Paragraph, wherein each domain and SAM is a human domain and SAM respectively. 32. The polypeptide of any preceding Paragraph, wherein the polypeptide comprises binding specificity for more than one antigen, optionally 2, 3 or 4 different antigens. 33. A multimer (optionally a tetramer) of a polypeptide according to any preceding Paragraph. 34. A multimer of a plurality of antibody Fc regions, wherein each Fc is comprised by a respective polypeptide and is unpaired with another Fc region. 35. The multimer of Paragraph 34, wherein the multimer is a polypeptide tetramer comprising at least 4 Fc regions. 36. The multimer of Paragraph 34 or 35, wherein each Fc region is identical. 37. The multimer of any one of Paragraphs, wherein each Fc comprise a CH2 and a CH3, wherein each CH2 is a CH2 as recited in any one of Paragraphs 1 to 32. 38. The polypeptide or multimer of any preceding Paragraph, comprising eukaryotic cell glycosylation. 39. The polypeptide or multimer of Paragraph 38, wherein the cell is a HEK293, CHO or Cos cell. 40. The polypeptide or multimer of any preceding Paragraph for medical use. 41. A pharmaceutical composition comprising the polypeptide or multimer of any preceding Paragraph. 42. A nucleic acid encoding a polypeptide of any one of Paragraphs 1 to 32 and 38 to 40. 43. A eukaryotic cell or vector comprising the nucleic acid of Paragraph 42. 44. A method of binding multiple copies of an antigen, the method comprising combining the copies with a multimer of any one of Paragraphs 33 to 40, wherein the copies are bound by polypeptides of the multimer, and optionally the method comprising isolating the multimer bound to the antigen copies. 45. The method of Paragraph 37 wherein the method is a diagnostic method for detecting the presence of a substance in a sample, wherein the substance comprises the antigen, the method comprising providing the sample (eg, a bodily fluid, food, food ingredient, beverage, beverage ingredient, soil or forensic sample), mixing the sample with multimers according to any one of Paragraphs 33 to 40 and detecting the binding of multimers to the antigen in the sample. 46. A method of treating or reducing the risk of a disease or condition in a human or animal subject, the method comprising administering the composition of Paragraph 41 to the subject, wherein multimers comprised by the composition specifically bind to a target antigen in the subject, wherein said binding mediates the treatment or reduction in risk. 47. The method of Paragraph 46, wherein the antigen is an immune checkpoint antigen (eg, PD- L1, PD-1 or CTLA4); or wherein the antigen is TNF alpha or IL-17A. 48. The method of Paragraph 46, wherein the antigen mediates the disease or condition in the subject; and optionally wherein the binding antagonises the antigen. 49. A composition comprising a plurality of polypeptides according to any one of Paragraphs 1 to 32 and 38 to 40, wherein at least 90% of the polypeptides are comprised by tetramers of said polypeptides. 50. The composition of Paragraph 49, wherein at least 98% of the polypeptides are comprised by tetramers of said polypeptides. 51. The composition of Paragraph 49 or 50, wherein the remaining polypeptides are selected from one or more of polypeptide monomers, dimers and trimers. 52. A method of producing a composition (optionally a composition according to any one of Paragraphs 49 to 51) comprising a plurality of polypeptides according to any one of Paragraphs 1 to 32 and 38 to 40, the method comprising providing eukaryotic host cells according to Paragraph 34, culturing the host cells, and allowing expression and secretion from the cells of tetramers of the polypeptides, and optionally isolating or purifying the tetramers.  [00319] CONCEPTS: In certain embodiments, the invention is useful for providing multimers for treating cancer in humans or animals. In this respect, it may be useful to use the multimers to target tumours by binding to tumour-associated antigen and/or to bind to T-cells to modulate their activity. For example the multimers may bind to an antigen on T regulatory cells (Tregs) to downregulate their activity. Additionally or alternatively, the multimers may bind to T effector (Teff) cells to upregulate their activity. The provision of an antibody Fc region in the polypeptides of multimers may be advantageous for providing Fc effector functions and/or cytotoxicity for killing tumour cells. In one advantageous configuration, the invention exploits the ability to provide multiple identical antigen or epitope binding sites that can be used to bind to several copies of the same antigen or epitope on tumour cells, thereby providing for an avidity affect wherein the multimers bind preferentially to tumour cells over any non-target or normal cells, since the former surface-express more copies of the antigen than normal cells. In one configuration, when the multimer also comprises binding sites for an immune checkpoint regulator. In one example the regulator is an immune checkpoint inhibitor and the binding sites antagonise the inhibitor. This is useful, for example when the inhibitor is expressed by Teff cells, for upregulating Teff activity in the vicinity of tumour cells that are targeted by the multimer (eg, by binding TAA on the tumour cells). In another example the regulator is an immune checkpoint stimulator and the binding sites agonise the inhibitor. This is useful, for example when the inhibitor is expressed by Teff cells, for upregulating Teff activity in the vicinity of tumour cells that are targeted by the multimer (eg, by binding TAA on the tumour cells). Thus, upregulation of T-cell activity may be stimulated in the vicinity of tumour cells, rather in the vicinity of non-target (eg, normal or non-cancerous) cells. To this end, the invention provides the following Concepts. The following Concepts are not to be interpreted as Claims. The Claims start after the Examples section. 1. A polypeptide comprising a self-associating multimerisation domain (SAM), a first antigen binding site and a second antigen binding site, wherein the first site specifically binds to a first antigen or epitope, and the second binding site specifically binds to a second antigen or epitope, wherein each antigen or epitope is a tumour-associated antigen (TAA) or epitope, or an immune checkpoint regulator (eg, inhibitor) antigen or epitope. 2. The polypeptide of Concept 1, wherein the first antigen is a TAA and the second antigen is an immune checkpoint regulator (eg, inhibitor). 3. The polypeptide of Concept 1, wherein the first antigen is a TAA and the second antigen is a TAA. 4. The polypeptide of Concept 1, wherein the first antigen is an immune checkpoint inhibitor and the second antigen is an immune checkpoint regulator (eg, inhibitor). 5. The polypeptide of Concept 3 or 4, wherein the binding sites are capable of specifically binding to the same epitope of the same antigen. 6. The polypeptide of Concept 3 or 4, wherein the binding sites are capable of specifically binding to different epitopes of the same antigen. 7. The polypeptide of any preceding Concept, wherein the first antigen is selected from 4-1BB, 4-1BBL, CD28, OX40, OX40L, ICOS, ICOSL, GITR, CD40, CD27, CD27L, CD40L, LIGHT, CD70, CD80, CD86, HER2, HER3, PSMA, WT1, MUC1, LMP2, EGFRvIII, MAGE A3, GD2, CEA, Melan a/MART1, Bcr-Abl, Survivin, PSA, hTERT, EphA2, PAP, EpCAM, ERG, PAX3, ALK, Androgen receptor, Cyclin B1, RhoC, GD3, PSCA, PAX5, LCK, VEGFR2, MAD CT-1, FAP, MAD CT-2, PDGFR-beta, Fos related antigen 1, NY-BR-1, ETV6-AML, RGS5, SART3, SSX2, XAGE-1, STn, PAP and BCMA. 8. The polypeptide of any preceding Concept, wherein the second antigen is selected from PDL1, PD1, CTLA4, BTLA, KIR, LAG3, TIM3, A2aR, HVEM, GAL9, VISTA, SIRPa, CD47, CD160, CD155, IDO, CEACAM1, 2B4, CD48 and TIGIT. 9. The polypeptide of any preceding Concept, wherein the polypeptide comprises a third antigen binding site that is capable of specifically binding to a third antigen or epitope. 10. The polypeptide of Concept 9, wherein the third antigen is a TAA. 11. The polypeptide of Concept 9, wherein the third antigen is an immune checkpoint regulator (eg, inhibitor). 12. The polypeptide of any one of Concepts 9 to 11, wherein the third antigen is the same as the first or second antigen. 13. The polypeptide of any one of Concepts 9 to 12, wherein the third antigen is CD3 (eg, CD3e) or CD28. 14. The polypeptide of any one of Concepts 9 to 13, wherein the polypeptide comprises a fourth antigen binding site that is capable of specifically binding to a fourth antigen or epitope. 15. The polypeptide of Concept 14, wherein the fourth antigen is a TAA. 16. The polypeptide of Concept 14, wherein the fourth antigen is an immune checkpoint regulator (eg, inhibitor). 17. The polypeptide of any preceding Concept, wherein the polypeptide is according to any polypeptide disclosed herein. [00290] In an example, said first dAb or first scFv of the polypeptide herein is the first antigen binding site of these Concepts; and optionally when a further dAb or scFv binding site is present this is the second antigen binding site of the Concepts. [00291] In an example, said first dAb or first scFv of the polypeptide herein is the second antigen binding site of these Concepts; and optionally when a further dAb or scFv binding site is present this is the first antigen binding site of the Concepts. 18. A multimer of a polypeptide of any preceding Concept. 19. The multimer of Concept 18 for administration to a human or animal subject for targeting of an immune checkpoint inhibitor and an immune co-stimulatory molecule for the treatment of cancer. 20. A method of treating a cancer in a human or animal subject, the method comprising administering the multimer of claim 18 to the subject. [00291] CLAUSES: In a configuration, the invention provides the following Clauses. The following Clauses are not to be interpreted as Claims. The Claims start after the Examples section. 1. A protein multimer of at least first, second, third and fourth copies of an effector domain (eg, a protein domain) or a peptide, wherein the multimer is multimerised by first, second, third and fourth self-associating tetramerisation domains (TDs) which are associated together, wherein each tetramerisation domain is comprised by a respective engineered polypeptide comprising one or morecopies of said protein domain or peptide. 2. The multimer of Clause 1, wherein the multimer is a tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer or an octamer) of said domain or peptide. 3. The multimer of any Clause 1 or 2, comprising a tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer or an octamer) of an immunoglobulin superfamily binding site. 4. The multimer of Clause 3, wherein the binding site comprises a first variable domain paired with a second variable domain. 5. The multimer of any preceding Clause, wherein each polypeptide comprises first and second copies of said protein domain or peptide, wherein the polypeptide comprises in (N- to C-terminal direction) (i) a first of said copies – TD – the second of said copies; (ii) TD – and the first and second copies; or (iii) said first and second copies – TD. 6. The multimer of any preceding Clause, wherein the TDs are NHR2 TDs and the domain or peptide is not a NHR2 domain or peptide; or wherein the TDs are p53 TDs and the domain or peptide is not a p53 domain or peptide. 7. The multimer of any preceding Clause, wherein the engineered polypeptide comprises one or more copies of a second type of protein domain or peptide, wherein the second type of protein domain or peptide is different from the first protein domain or peptide. 8. The multimer of any preceding Clause, wherein the domains are immunoglobulin superfamily domains. 9. The multimer of any preceding Clause, wherein the domain or peptide is an antibody variable or constant domain, a TCR variable or constant domain, an incretin, an insulin peptide, or a hormone peptide. 10. The multimer of any preceding Clause, wherein the multimer comprises first, second, third and fourth identical copies of a said engineered polypeptide, the polypeptide comprising a TD and one (but no more than one), two (but no more than two) or more copies of the said protein domain or peptide. 11. The multimer of any preceding Clause, wherein the engineered polypeptide comprises an antibody or TCR variable domain (V1) and a NHR2 TD. 12. The multimer of Clause 11, wherein the polypeptide comprises (in N- to C-terminal direction) (i) V1-an optional linker-NHR2 TD; (ii) V1-an optional linker-NHR2 TD-optional linker-V2; or (iii) V1-an optional linker-V2 – optional linker - NHR2 TD, wherein V1 and V2 are TCR variable domains and are the same or different, or wherein V1 and V2 are antibody variable domains and are the same or different. 13. The multimer of Clause 12, wherein V1 and V2 are antibody single variable domains. 14. The multimer of Clause 11, wherein each engineered polypeptide comprises (in N- to C- terminal direction) V1-an optional linker- TD, wherein V1 is an antibody or TCR variable domain and each engineered polypeptide is paired with a respective second engineered polypeptide that comprises V2, wherein V2 is a an antibody or TCR variable domain respectively that pairs with V1 to form an antigen or pMHC binding site, and optionally one polypeptide comprises an antibody Fc, or comprises antibody CH1 and the other polypeptide comprises an antibody CL that pairs with the CH1. 15. The multimer of any preceding Clause, wherein the TD comprises (i) an amino acid sequence identical to SEQ ID: 1*10 or 1*126 or at least 80% identical thereto; or (ii) an amino acid sequence identical to SEQ ID: 1*120 or 1*123 or at least 80% identical thereto. 16. The multimer of any preceding Clause, wherein the multimer comprises a tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer or an octamer) of an antigen binding site of an antibody selected from the group consisting of ReoPro™; Abciximab; Rituxan™; Rituximab; Zenapax™; Daclizumab; Simulect™; Basiliximab; Synagis™; Palivizumab; Remicade™; Infliximab; Herceptin™; Mylotarg™; Gemtuzumab; Campath™; Alemtuzumab; Zevalin™; Ibritumomab; Humira™; Adalimumab; Xolair™; Omalizumab; Bexxar™; Tositumomab; Raptiva™; Efalizumab; Erbitux™; Cetuximab; Avastin™; Bevacizumab; Tysabri™; Natalizumab; Actemra™; Tocilizumab; Vectibix™; Panitumumab; Lucentis™; Ranibizumab; Soliris™; Eculizumab; Cimzia™; Certolizumab; Simponi™; Golimumab, Ilaris™; Canakinumab; Stelara™; Ustekinumab; Arzerra™; Ofatumumab; Prolia™; Denosumab; Numax™; Motavizumab; ABThrax™; Raxibacumab; Benlysta™; Belimumab; Yervoy™; Ipilimumab; Adcetris™; Brentuximab; Vedotin™; Perjeta™; Pertuzumab; Kadcyla™; Ado-trastuzumab; Keytruda™, Opdivo™, Gazyva™ and Obinutuzumab. 17. An isolated tetramer, octamer, dodecamer, hexadecamer or 20-mer of a TCR binding site, insulin peptide, incretin peptide or peptide hormone; or a plurality of said tetramers or octamers. 18. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer or an octamer) of any preceding Clause, wherein the mulitmer, tetramer, octamer, dodecamer, hexadecamer or 20-mer is (a) soluble in aqueous solution; (b) secretable from a eukaryotic cell; and/or (c) an expression product of a eukaryotic cell. 19. A tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer or an octamer) of (a) TCR V domains or TCR binding sites, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is soluble in aqueous solution; (b) antibody single variable domains, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is soluble in aqueous solution; (c) TCR V domains or TCR binding sites, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is capable of being intracellularly and/or extracellularly expressed by HEK293 cells; or (d) antibody variable domains, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is capable of being intracellularly and/or extracellularly expressed by HEK293 cells. 20. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of any preceding Clause, wherein the tetramer, octamer, dodecamer, hexadecamer or 20-mer is bi-specific for antigen or pMHC binding. 21. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of any preceding Clause, wherein the domains are identical. 22. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of any preceding Clause, wherein the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer comprises eukaryotic cell glycosylation. 23. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of Clause 22, wherein the cell is a HEK293 cell. 24. A plurality of multimers, tetramers, octamers, dodecamesr, hexadecamers or 20-mers (eg, tetramers or octamers) of any preceding Clause. 25. A pharmaceutical composition comprising the multimer(s), tetramer(s), octamer(s), dodecamer(s), hexadecamer(s) or 20-mer(s) (eg, tetramer(s) or octamer(s)) of any preceding Clause and a pharmaceutically acceptable carrier, diluent or excipient. 26. A cosmetic, foodstuff, beverage, cleaning product, detergent comprising the multimer(s), tetramer(s), octamer(s), dodecamer(s), hexadecamer(s) or 20-mer(s) (eg, tetramer(s) or octamer(s)) of any one of Clauses 1 to 24. 27. A said engineered (and optionally isolated) polypeptide or a monomer (optionally isolated) of a multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer of any preceding Clause. 28. An engineered (and optionally isolated) polypeptide (P1) which comprises (in N- to C- terminal direction):- (a) TCR V1 –TCR C1 – antibody CH1 – optional linker – TD, wherein (i)V1 is a Vα and C1 is a Cα; (ii)V1 is a Vβ and C1 is a Cβ; (iii)V1 is a Vγ and C1 is a Cγ; or (iv) V1 is a Vδ and C1 is a Cδ; or (b) TCR V1 – antibody CH1– optional linker – TD, wherein (i)V1 is a Vα; (ii)V1 is a Vβ; (iii)V1 is a Vγ; or (iv) V1 is a Vδ; or (c) antibody V1 – antibody CH1– optional linker – TD, wherein (i)V1 is a VH; or (ii)V1 is a VL; or (d) antibody V1 – optional antibody CH1– antibody Fc – optional linker – TD, wherein (i)V1 is a VH; or (ii)V1 is a VL; or (e) antibody V1 – antibody CL – optional linker – TD, wherein (i)V1 is a VH; or (ii)V1 is a VL; or (f) TCR V1 –TCR C1 – optional linker – TD, wherein (i)V1 is a Vα and C1 is a Cα; (ii)V1 is a Vβ and C1 is a Cβ; (iii)V1 is a Vγ and C1 is a Cγ; or (iv)V1 is a Vδ and C1 is a Cδ. 29. The polypeptide of Clause 28, wherein the engineered polypeptide P1 is paired with a further polypeptide (P2), wherein P2 comprises (in N- to C-terminal direction):- (g) TCR V2 –TCR C2 – antibody CL, wherein P1 is according to (a) recited in Clause 28 and (i)V2 is a Vα and C2 is a Cα when P1 is according to (a)(ii); (ii)V2 is a Vβ and C2 is a Cβ when P1 is according to (a)(i); (iii)V2 is a Vγ and C2 is a Cγ when P1 is according to (a)(iv); or (iv)V2 is a Vδ and C2 is a Cδ when P1 is according to (a)(iii); or (h) TCR V2 – antibody CL, wherein P1 is according to (b) recited in Clause 28 and (i)V2 is a Vα when P1 is according to (b)(ii); (ii)V2 is a Vβ when P1 is according to (b)(i); (iii)V2 is a Vγ when P1 is according to (b)(iv); or (iv)V2 is a Vδ when P1 is according to (b)(iii); or (i) Antibody V2 – CL, wherein P1 is according to (c) recited in Clause 28 and (i)V2 is a VH when P1 is according to (c)(ii); or (ii)V2 is a VL when P1 is according to (c)(i); or (j) Antibody V2 – optional CL, wherein P1 is according to (d) recited in Clause 28 and (i)V2 is a VH when P1 is according to (d)(ii); or (ii)V2 is a VL when P1 is according to (d)(i); or (k) Antibody V2 – CH1, wherein P1 is according to (e) recited in Clause 28 and (i)V2 is a VH when P1 is according to (e)(ii); or (ii)V2 is a VL when P1 is according to (e)(i); or (l) TCR V2 –TCR C2, wherein P1 is according to (f) recited in Clause 28 and (i)V2 is a Vα and C2 is a Cα when P1 is according to (f)(ii); (ii)V2 is a Vβ and C2 is a Cβ when P1 is according to (f)(i); (iii)V2 is a Vγ and C2 is a Cγ when P1 is according to (f)(iii); or (iv)V2 is a Vδ and C2 is a Cδ when P1 is according to (f)(iv). 30. A multimer of P1 as defined in Clause 28; or of P1 paired with P2 as defined in Clause 29; or a plurality of said multimers, optionally wherein the multimer is according to any one of Clauses 1 to 24. 31. A nucleic acid encoding an engineered polypeptide or monomer of any one of Clauses 27 to 29, optionally wherein the nucleic acid is comprised by an expression vector for expressing the polypeptide. 32. A eukaryotic host cell comprising the nucleic acid or vector of Clause 31 for intracellular and/or secreted expression of the multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer, octamer), engineered polypeptide or monomer of any one of Clauses 1 to 24. 33. Use of a nucleic acid or vector according to Clause 31 in a method of manufacture of protein multimers for producing intracellularly expressed and/or secreted multimers, wherein the method comprises expressing the multimers in and/or secreting the multimers from eukaryotic cells comprising the nucleic acid or vector. 34. Use of a nucleic acid or vector according to Clause 31 in a method of manufacture of protein multimers for producing glycosylated multimers in eukaryotic cells comprising the nucleic acid or vector. 35. A mixture comprising (i) a eukaryotic cell line encoding an engineered polypeptide according to any one of Clauses 27 to 29; and (ii) multimers, tetramers, octamers, dodecamers, hexadecamers or 20-mers (eg, tetramers or octamers)as defined in any one of Clauses 1 to 24. 36. The mixture of Clause 35, wherein the cell line is in a medium comprising secretion products of the cells, wherein the secretion products comprise said multimers, tetramers, octamers, dodecamers, hexadecamers or 20-mers (eg, tetramers or octamers). 37. The multimer, tetramer, octamer, dodecamer, hexadecamer or 20-mer (eg, tetramer, octamer) of any one of Clauses 1 to 24 for medical use. 38. A method producing (a) TCR V domain multimers, the method comprising the soluble and/or intracellular expression of TCR V-NHR2 TD or TCR V- p53 TD fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers; (b) antibody V domain multimers, the method comprising the soluble and/or intracellular expression of antibody V -NHR2 TD or V- p53 TD fusion proteins expressed in eukaryotic cells, the method optionally comprising isolating a plurality of said multimers; (c) incretin peptide multimers, the method comprising the soluble and/or intracellular expression of incretin peptide-NHR2 TD or incretin peptide-p53 TD fusion proteins expressed in eukaryotic cells, such as HEK293T cells; the method optionally comprising isolating a plurality of said multimers; or (d) peptide hormone multimers, the method comprising the soluble and/or intracellular expression of peptide hormone-NHR2 TD or peptide hormone- p53 TD fusion proteins expressed in eukaryotic cells, such as HEK293T cells; the method optionally comprising isolating a plurality of said multimers. 39. Use of self-associating tetramerisation domains (TD) in a method of the manufacture of a tetramer of polypeptides, for producing a higher yield of tetramers versus monomer and/or dimer polypeptides. 40. Use of an engineered polypeptide in a method of the manufacture of a tetramer of a polypeptide comprising multiple copies of a protein domain or peptide, for producing a higher yield of tetramers versus monomer and/or dimer polypeptides, wherein the engineered polypeptide comprises one or more copies of said protein domain or peptide and further comprises a self- associating tetramerisation domains (TD). 41. Use of self-associating tetramerisation domains (TD) in a method of the manufacture of a tetramer of a polypeptide, for producing a plurality of tetramers that are not in mixture with monomers, dimers or trimers. 42. Use of an engineered polypeptide in a method of the manufacture of a tetramer of a polypeptide comprising multiple copies of a protein domain or peptide, for producing a plurality of tetramers that are not in mixture with monomers, dimers or trimers, wherein the engineered polypeptide comprises one or more copies of said protein domain or peptide and further comprises a self-associating tetramerisation domains (TD). 43. The use of any one of Clauses 39 to 42, wherein the yield of tetramers is at least 10x the yield of monomers and/or dimers. 44. The use of any one of Clauses 39 to 43, wherein the ratio of tetramers produced : monomers and/or dimers produced in the method is at least 90:10. 45. The use of any one of Clauses 39 to 44, wherein each monomer has a size of no more than 40 kDa. 46. The use of any one of Clauses 39 to 45, wherein each tetramer has a size of no more than 150 kDa 47. The use of any one of Clauses 39 to 46, wherein the method comprises expressing the tetramers from a eukaryotic cell line. 48. A multivalent heterodimeric soluble T cell receptor capable of binding pMHC complex comprising: (a) TCR extracellular domains; (b) immunoglobulin constant domains; and (c) an NHR2 multimerisation domain of ETO. 49. A multimeric immunoglobulin, comprising (i) immunoglobulin variable domains; and (ii) an NHR2 multimerisation domain of ETO. 50. A method for assembling a soluble, multimeric polypeptide, comprising: (a) providing a monomer of the said multimeric polypeptide, fused to an NHR2 domain of ETO; and (b) causing multiple copies of said monomer to associate, thereby obtaining a multimeric, soluble polypeptide. [00292] In any disclosure herein, the or each constant region or domain, the CH2, the CH3, the CH2 and CH3 or the Fc is respectively a constant region or domain, the CH2, the CH3, the CH2 and CH3 or the Fc of a human constant region. For example, the constant region is selected from the group IGHA1*01, IGHA1*02, IGHA1*03, IGHA2*01, IGHA2*02, IGHA2*03, IGHD*01, IGHD*02, IGHE*01, IGHE*02, IGHE*03, IGHE*04, IGHEP1*01, IGHEP1*02, IGHEP1*03, IGHEP1*04, IGHG1*01, IGHG1*02, IGHG1*03, IGHG1*04, IGHG1*05, IGHG1*06, IGHG1*07, IGHG1*08, IGHG1*09, IGHG1*10, IGHG1*11, IGHG1*12, IGHG1*13, IGHG1*14, IGHG2*01, IGHG2*02, IGHG2*03, IGHG2*04, IGHG2*05, IGHG2*06, IGHG2*07, IGHG2*08, IGHG2*09, IGHG2*10, IGHG2*11, IGHG2*12, IGHG2*13, IGHG2*14, IGHG2*15, IGHG2*16, IGHG2*17, IGHG3*01, IGHG3*02, IGHG3*03, IGHG3*04, IGHG3*05, IGHG3*06, IGHG3*07, IGHG3*08, IGHG3*09, IGHG3*10, IGHG3*11, IGHG3*12, IGHG3*13, IGHG3*14, IGHG3*15, IGHG3*16, IGHG3*17, IGHG3*18, IGHG3*19, IGHG3*20, IGHG3*21, IGHG3*22, IGHG3*23, IGHG3*24, IGHG3*25, IGHG3*26, IGHG3*27, IGHG3*28, IGHG3*29, IGHG4*01, IGHG4*02, IGHG4*03, IGHG4*04, IGHG4*05, IGHG4*06, IGHG4*07, IGHG4*08, IGHGP*01, IGHGP*02, IGHGP*03, IGHM*01, IGHM*02, IGHM*03 and IGHM*04 (eg, the constant region is a *01 allele listed in said group, preferably the constant region is a human IGHG1*01 or IGHM*01 constant region). In an alternative, the constant region is a non-human (eg, mammal, rodent, mouse, rat, dog, cat or horse) constant region, such as a homologue of a human constant region listed in said group. [00293] The polypeptide, in one embodiment, comprises (in N- to C-terminal direction) a first antigen binding site (eg, a dAb), an antibody CH1 (eg, human IgG1 CH1), a hinge sequence comprising a lower hinge and devoid of a core hinge region (and optionally devoid of an upper hinge region), an antibody Fc region and a SAM (eg, a TD, such as a p53 TD). For example, the core hinge region sequence is a CXXC amino acid sequence. The polypeptide may comprise another antigen binding site (eg a dAb or scFv) between the first binding site and the CH1, between the Fc and SAM and/or C- terminal to the SAM. Optionally, the multimer comprises a plurality (eg, 4 copies) of such polypeptide, for example wherein each polypeptide is paired with a further polypeptide comprising (in N- to C-terminal direction) a second antigen binding site (eg, a dAb), an antibody CL (eg, a human Cκ) and optionally a third antigen binding site. Optionally the binding sites have the same antigen specificity (eg, all bind TNF alpha). In another option, the first and second (and optionally said another binding site) bind to different antigens. The or each binding site can bind any antigen disclosed herein, eg, each binding site binds TNF alpha (as shown in Example 17). In another example, the first antigen binding site is a VH of an antigen binding site of a predetermined antibody that specifically binds to the antigen (and the CH1 is optionally the CH1 of the antibody), and the second binding site of the further polypeptide is a VL of the antigen binding site of the predetermined antibody (and the CL is optionally the CL of the antibody), wherein the VH and VL pair to form a VH/VL binding site which has binding specificity for the antigen. The predetermined antibody may be a marketed antibody, for example, as shown in Example 19. For example, the VH/VL binding site specifically binds to CTLA-4, eg, wherein the predetermined antibody is ipilimumab (or Yervoy™). For example, the VH/VL binding site specifically binds to TNF alpha, eg, wherein the predetermined antibody is adalimumab, golimumab, infliximab (or Humira™, Simponi™ or Remicade™). For example, the VH/VL binding site specifically binds to PD-L1, eg, wherein the predetermined antibody is avelumab (or Bavencio™) or atezolizumab (or Tecentriq™). For example, the VH/VL binding site specifically binds to PD-1, eg, wherein the predetermined antibody is nivolumab (or Opdivo™) or pembrolizumab (or Keytruda™). For example, the VH/VL binding site specifically binds to VEGF, eg, wherein the predetermined antibody is bevacizumab (or Avastin™) or ranibizumab (or Lucentis™). In another example, the polypeptide comprises (in N- to C-terminal direction) a first VEGF binding site, an optional second VEGF binding site, an antibody CH1 (eg, human IgG1 CH1), a hinge sequence comprising a lower hinge and devoid of a core hinge region (and optionally devoid of an upper hinge region), an antibody Fc region and a SAM (eg, a TD, such as a p53 TD). In an example, the first binding site is a Ig domain 2 from VEGFR1 and the second binding site is Ig domain 3 from VEGFR2 (as shown in Example 20). In another example, the first binding site is a Ig domain 3 from VEGFR2 and the second binding site is Ig domain 2 from VEGFR2. In an example, the first and second binding domains are (in N- to C-terminal direction) the first and second VEGF binding sites of aflibercept (or Eylea™). [00294] Suitable predetermined antibodies are ReoPro™; Abciximab; Rituxanh™; Rituximab; Zenapaxh™; Daclizumab; Simulecth™; Basiliximab; Synagis™; Palivizumab; Remicadeh™; Infliximab; Herceptinh™; Trastuzumab; Mylotargh™; Gemtuzumab; Campathh™; Alemtuzumab; Zevalinh™; Ibritumomab; Humirah™; Adalimumab; Xolair™; Omalizumab; Bexxarh™; Tositumomab; Raptivah™; Efalizumab; Erbituxh™; Cetuximab; Avastinh™; Bevacizumab; Tysabrih™; Natalizumab; Actemrah™; Tocilizumab; Vectibixh™; Panitumumab; Lucentish™; Ranibizumab; Solirish™; Eculizumab; Cimziah™; Certolizumab; Simponih™; Golimumab, Ilaris™; Canakinumab; Stelara™; Ustekinumab; Arzerrah™; Ofatumumab; Prolie™; Denosumab; Numaxh™; Motavizumab; ABThraxh™; Raxibacumab; Benlystah™; Belimumab; Yervoyh™; Ipilimumab; Adcetrish™; Brentuximab; Vedotin™; Perjeta™; Pertuzumab; Kadcyla™; Ado-trastuzumab; Gazyva™ and Obinutuzumab. Also disclosed are the generic versions of these and the corresponding INN names – each of which is a suitable predetermined antibody for use as a source of antigen binding sites for use in the present invention. Suitable sequences of VH and VL domains of predetermined antibodies are disclosed in Table 4. Thus, for example, the multimer of the invention comprises a plurality (eg, 4, 8, 12, 16 or 20) copies of the VH/VL antigen binding site of any of these antibodies, eg, wherein the VH of the binding site is comprised by a polypeptide of the invention that comprises a SAM (eg, a TD) and each polypeptide is paired with a further polypeptide comprising the VL that pairs with the VH, thus forming an antigen binding site. In an example, the polypeptide comprising the SAM also comprises a CH1 which pairs with a CL of the further polypeptide. Optionally, the binding site of the polypeptide of the multimer comprises a VH of the binding site of the antibody and also the CH1 of the antibody (ie, in N- to C-terminal direction the VH-CH1 and SAM). In an embodiment, the polypeptide may be paired with a further polypeptide comprising (in N- to C-terminal direction a VL-CL, eg, wherein the CL is the CL of the antibody). [00295] In one embodiment, the predetermined antibody is Avastin. [00296] In one embodiment, the predetermined antibody is Actemra. [00297] In one embodiment, the predetermined antibody is Erbitux. [00298] In one embodiment, the predetermined antibody is Lucentis. [00299] In one embodiment, the predetermined antibody is sarilumab. [00300] In one embodiment, the predetermined antibody is dupilumab. [00301] In one embodiment, the predetermined antibody is alirocumab. [00302] In one embodiment, the predetermined antibody is evolocumab. [00303] In one embodiment, the predetermined antibody is pembrolizumab. [00304] In one embodiment, the predetermined antibody is nivolumab. [00305] In one embodiment, the predetermined antibody is ipilimumab. [00306] In one embodiment, the predetermined antibody is remicade. [00307] In one embodiment, the predetermined antibody is golimumab. [00308] In one embodiment, the predetermined antibody is ofatumumab. [00309] In one embodiment, the predetermined antibody is Benlysta. [00310] In one embodiment, the predetermined antibody is Campath. [00311] In one embodiment, the predetermined antibody is rituximab. [00312] In one embodiment, the predetermined antibody is Herceptin. [00313] In one embodiment, the predetermined antibody is durvalumab. [00314] In one embodiment, the predetermined antibody is daratumumab. [00315] In another embodiment, the polypeptide comprises (in N- to C-terminal direction) a first antigen binding site, an optional linker (eg, a G4Sn, wherein n=1, 2, 3, 4, 5, 6, 7, ot 8, preferably 3), a second antigen binding site, a hinge sequence comprising a lower hinge and devoid of a core hinge region (and optionally devoid of an upper hinge region), an antibody Fc (eg, an IgG1 Fc) and a SAM (eg, a TD, such as a p53 TD). For example, the core hinge region sequence is a CXXC amino acid sequence. The polypeptide may comprise another antigen binding site (eg a dAb or scFv) between the Fc and SAM and/or C-terminal to the SAM. Optionally, the multimer comprises a plurality (eg, 4 copies) of such polypeptide. Optionally the binding sites have the same antigen specificity (eg, all bind TNF alpha). In another option, the first and second (and optionally said another binding site) bind to different antigens. The or each binding site can bind any antigen disclosed herein, eg, each binding site binds PD-L1, or the first binding site binds PD-L1 and the second binding site binds 41- BB, or the first binding site binds 4-1BB and the second binding site binds PD-L1 (as shown in Example 18). [00316] The polypeptide, in one embodiment, comprises (in N- to C-terminal direction) a first antigen binding site (eg, a dAb), an optional linker (eg, a G4Sn, wherein n=1, 2, 3, 4, 5, 6, 7, ot 8, preferably 3), a second antigen binding site (eg, a dAb), an antibody CH1 (eg, human IgG1 CH1) and a SAM (eg, a TD, such as a p53 TD). The polypeptide may comprise another antigen binding site (eg a dAb or scFv) C-terminal to the SAM. Optionally, the multimer comprises a plurality (eg, 4 copies) of such polypeptide, for example wherein each polypeptide is paired with a further polypeptide comprising (in N- to C-terminal direction) a third antigen binding site (eg, a dAb), an optionaly fourth antigen binding site (eg, a dAb), an antibody CL (eg, a human Cκ or Cλ) and optionally a furhter antigen binding site. For example, the fourth and further binding sites are omitted. In another example, the third and fourth binding sites, but not the further binding site, are present. In another example, the third and further (but not the fourth) binding sites are present. Optionally the binding sites have the same antigen specificity (eg, all bind TNF alpha). In another option, the first and second (and optionally said another said binding site) bind to different antigens. The or each binding site can bind any antigen disclosed herein, eg, each binding site binds TNF alpha (as shown in Examples 21 and 22). In an example, the first and third, or the second and third binding sites pair to form a VH/VL pair that is identical to the VH/VL binding site of an anti-TNF alpha antibody, such as adalimumab, golimumab, infliximab (or Humira™, Simponi™ or Remicade™). In an example, the first and third, or the second and third binding sites pair to form a VH/VL pair that is identical to the VH/VL binding site of an anti-PD-L1 antibody, such as avelumab (or Bavencio™) or atezolizumab (or Tecentriq™). In an example, the first and third, or the second and third binding sites pair to form a VH/VL pair that is identical to the VH/VL binding site of an anti-PD-1 antibody, such as nivolumab (or Opdivo™) or pembrolizumab (or Keytruda™). In an example, the first and third, or the second and third binding sites pair to form a VH/VL pair that is identical to the VH/VL binding site of an anti-VEGF antibody, such as bevacizumab (or Avastin™) or ranibizumab (or Lucentis™). Predetermined antibodies as discussed above can be used as the source of the VH/VL pairs. [00317] In an example, the polypeptide of the invention is any Quad polypeptide disclosed herein, eg, comprising the Quad amino acid shown in any of the Tables herein (eg, any one of SEQ IDs: 1*81- 1*115, 1*151-1*162, 1*190, 1*191, 1*209-1*224 and 1*179) or encoded by any of the Quad nucleotide sequences in any of the Tables herein (eg, Table 9, 14 or 17), or having the structure of a polypeptide shown in Table 8. The SAM may be any SAM disclosed herein, eg, any p53 or homologue TD disclosed in any Table herein (eg, as shown in Table 7 or comprised by a protein in Table 13). [00318] Where amino acid sequences are shown with plural histidines at their C-terminus (eg, “HHHHHH” optionally followed by “..AAA”), such histidines and the optional ..AAA are in one embodiment omitted and the corresponding nucleotides encoding this are omitted from the nucleic acid encoding the amino acid sequence. Where amino acid sequences are shown with a DYKDDDDK motif (eg, a DYKDDDDKHHHHHH or DYKDDDDKHHHHHH..AAA), such a motif is in one embodiment omitted and the corresponding nucleotides encoding this are omitted from the nucleic acid encoding the amino acid sequence. FURTHER CONFIGURATIONS [00319] As discussed herein, the invention provides configurations in which the polypeptide a self- associating multimerisation domain (SAM, eg, a TD) and a peptide, domain or an epitope or antigen binding site (eg, a dAb or an antibody variable domain). In an embodiment, the SAM is a TD, such a p53 TD as disclosed herein. Anti-Virus Examples, Surprising Expansion of Antigen Specificity etc: [00320] In an example, the polypeptide comprises (eg, in N- to C-terminal direction) at least an extracellular domain (ECD) of a cell-surface protein that is a receptor for a virus or required for virus activation. For example, the protein poteolytically cleaves and activates a spike glycoprotein of the virus (eg, Coronoavirus or any other virus disclosed herein, such as in Table 19). Optionally, the entire cell-surface portion of the receptor is comprised by the polypeptide of the invention. In an example, the virus is capable of infecting human cells and the receptor is a cell-surface protein found on human cells (such as lung cells). In an example, the virus is capable of infecting non-human animal cells and the receptor is a cell-surface protein found on cells of such animal (such as lung cells). In an example, the virus is capable of infecting plant cells and the receptor is a cell-surface protein found on cells of such plant (such as a crop, wheat, corn, barley, tobacco, grass, fruiting plant or tree). By forming multimers using copies of the polypeptide according to the invention, multimers of the invention comprising copies of all or portions of such cell-surface proteins may act as sinks for binding several virus particles per copy of multimer. Advantageously, this will prevent the bound viruses from infecting cells of the human, animal, plant or other subject or environment in which the cells are present. So, for example, the invention provides a method of treating a viral infection in a human or animal subject, the method comprising administering a composition comprising a plurality of the multimers to a human or animal subject (eg, intravenously or by inhalation), wherein the subject is suffering from a virus infection and copies of the multimer bind to copies of the virus, thereby reducing the severity of the infection and/or reducing progression of the infection and/or reducing one or more symptoms of the infection (such as a inflammatory response). In another example, the composition can be used prophylactically; thus the invention provides a method of preventing or reducing the risk of a viral infection or a symptom thereof in a human or animal subject, the method comprising administering a composition comprising a plurality of the multimers to a human or animal subject (eg, intravenously or by inhalation), wherein the subject is at risk of suffering from a virus infection, thereby preventing or reducing the risk of the viral infection and/or preventing or reducing one or more symptoms of the infection (such as a inflammatory response). In an example, the virus is a Coronavirus. [00321] In an example, the virus is a virus selected from Table 19. [00322] For example, the virus is a Coronavirus, a MERS-Cov, a SARS-Cov, SARS-Cov-1 or preferably SARS-Cov-2. In this example, the receptor may be ACE2. In an alternative, the cell- surface protein is a TMPRSS protein, preferably a TMPRSS2 protein. Optionally, the polypeptide of the invention in this example comprises an ACE2 extracellular domain and a TMPRSS protein extracellular domain, optionally wherein the domains are human domains and the polypeptides (or multimers according to the invention comprising copies of such a polypeptide) are for treating or preventing a Coronavirus infection in a human. In an embodiment in this example, the SAM is a TD, such a p53 TD as disclosed herein. [00323] An example of a protein required for virus activation is TMPRSS2 protein, eg, human TMPRSS2 protein (UniProtKB - O15393 (TMPS2_HUMAN), the sequence with of which with identifier O15393-1 is explicitly incorporated herein for use in the invention and possible inclusion in one or more claims herein). In an example, the polypeptide of the invention comprises amino acids of human TMPRSS2 protein from amino acid 106 to 492. [00324] In an alternative, the virus is selected from Coronavirus 229E (HCoV-229E), Coronavirus EMC (HCoV-EMC), Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV), and influenza A virus (eg, strains H1N1, H3N2 and H7N9). [00325] In an embodiment, the polypeptide comprises an angiotensin converting enzyme 2 (ACE2) protein as disclosed in any of US9,561,263; US 8,586,319; or EP2089715, EP2047867, EP2108695, EP2543724, EP2155871, EP2274005, EP3375872, EP2222330, EP2943216, EP2332582 or any US counterpart patent application or patent of any of these that shares a common priority. The disclosures of such proteins and their sequences as disclosed in these European and US patents and applications are explicitly incorporated herein for possible use in the invention, such as in polypepides or multimers of the invention. For example, the peptide or domain of the polypeptide of the invention comprises an ECD of entire ACE2 protein as disclosed in any one of these European and US patents and applications. Each such protein and sequence is also individually and explicitly incorporated herein such that any one of such proteins or sequences can be included in any claim herein as a component of a polypeptide or multimer of the invention. Also explicitly incorporated herein are the uses and medical diseases and conditions disclosed in any of such European and US patents and applications and the polypeptide or multimer or method or use of the present invention may be for treating, preventing or reducing the risk of any of such diseases or conditions and may be included in any claim herein. [00326] As discussed, a polypeptide of the invention may comprises amino acid sequence from an ACE2 protein. In an embodiment, there is provided a polypeptide comprising an amino acid sequence selected from SEQ IDs: 1*229-1*231. In an embodiment, there is provided a polypeptide comprising an amino acid sequence selected from SEQ IDs: 1*229-1*231 with the exception that the polypeptide comprises an alternative SAM other than the p53 TD disclosed in such sequence. For example, the SAM is a p63, p73 or homologue TD as disclosed herein. In an embodiment, there is provided a polypeptide comprising an ACE2 amino acid sequence as comprised by any one of SEQ IDs: 1*229- 1*231. The invention also provides a tetramer of the invention comprising 4 copies of such a polypeptide, as well as a composition of the invention comprising such a tetramer. Such a multimer or composition may preferably be for use in a method of treating, preventing or reducing the risk of a viral infection (eg, a Coronavirus, or preferably SARS-Cov-2 infection), hypertension or a lung condition (eg, an acute lung injury or inflammation) in a human. [00327] For example, a polypeptide of the invention (eg, for treating or preventing a viral infection, preferably a Coronavirus, a MERS-Cov, a SARS-Cov, SARS-Cov-1 or SARS-Cov-2 infection) comprises the amino acid sequence from amino acid 18 to 615; or from 18 to 656 of SEQ ID NO: 1 disclosed in US9,561,263, which sequences are explicitly incorporated herein by reference for use in the present invention and for possible inclusion in one or more claims herein. Optionally, the polypeptide comprises the amino acid sequence from amino acid 18 to 615; or from 18 to 656; or from 18 to 740 of SEQ ID NO: 1 disclosed in US9,561,263, but does not comprise any other amino acids from such SEQ ID NO: 1. Optionally, the polypeptide comprises the amino acid sequence of SEQ ID NO: 2 disclosed in EP2332582, or an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% homologous thereto, which sequences are explicitly and individually incorporated herein by reference for use in the invention and possible inclusion in one or more claims herein. Optionally, N-glycosylation sites of Asn53, Asn90, Asn103, Asn322, Asn432, Asn546 and Asn690 of SEQ ID NO:1 are sialyzed, eg, as disclosed in US8,568,319, which disclosure of sialyzation is explicitly incorporated herein for use in the invention. [00328] In an alternative to treating, preventing or reducing the risk of a viral infection as discussed above, the invention instead provides polypeptides, multimers, methods and uses for treating, preventing or reducing the risk of inflammation in the subject (eg, in a human suffering from lung inflammation or at risk of such). [00329] In an alternative to treating, preventing or reducing the risk of a viral infection as discussed above, the invention instead provides polypeptides, multimers, methods and uses for treating, preventing or reducing the risk of hypertension, heart failure (eg, congestive heart failure or chronic heart failure or acute heart failure), myocardial infarction, atherosclerosis, renal failure or insufficiency, polycystic kidney disease (PKD), or a pulmonary disease. Examples are disclosed in EP2543724, the disclosure of which are explicitly incorporated herein for use in the invention. [00330] In an alternative to treating, preventing or reducing the risk of a viral infection as discussed above, the invention instead provides polypeptides, multimers, methods and uses for treating, preventing or reducing the risk of an acute lung injury (ALI), eg, ARDS (Adult Respiratory Distress Syndrome), SARS (Severe Acute Respiratory Syndrome) or MERS (Middle East Respiratory Syndrome). [00331] Optionally, the polypeptide of the invention comprises eukaryotic cell, mammalian or human cell glycosylation eg, CHO or HEK293 or Cos cell glycosylation. [00332] Optionally, the invention provides a composition (eg, for medical use as described herein, such as for treating, preventing or reducing the risk of a viral infection) comprising a plurality of polypeptides of the invention, wherein less than 15, 10, 5, 4, 3, 2, or 1% of all the polypeptides are comprised by the group consisting of polypeptide monomers, dimers and trimers. Additionally or alternatively, at least 80, 85, 90, 95, 96, 97, 98 or 99% of all of the polypeptides are comprised by multimers comprising 4 copies of the SAM (eg, p53 TD). [00333] In an alternative to treating, preventing or reducing the risk of a viral infection as discussed above, the invention instead provides polypeptides, multimers, methods and uses for treating, preventing or reducing the risk of hypertension in the subject (eg, in a human suffering from a lung or cardiovascular condition or at risk of such). [00334] In a configuration, the polypeptide of the invention comprises one or more binding sites for an antigen comprised by the extracellular part of a cell-surface protein that is a receptor (eg, ACE2 or a homologue or orthologue) for a virus or a protein (eg, TMPRSS2 protein) required for virus activation. In an embodiment, 1, 2, 3, 4 or 5 such binding sites are comprised by the polypeptide or by a multimer of the invention comprising copies of the polypeptide. In an example, each binding site is comprised by a dAb, Fv or scFv. In an example, the multimer comprises a plurality (eg, 4 and no more and no less than 4) copies of a polypepide of the invention comprising a SAM (eg, a TD) and each polypeptide as paired with a respective copy of a further polypeptide, wherein each polypeptide pair comprises a VH/VL antigen binding site. In an example, the binding site specifically binds to a spike glycoprotein of the virus, eg, any virus disclosed herein, preferably a Coronavirus, more preferably SARS-Cov-2. In an example, the binding site binds to 2 or more different Coronaviruses, eg, SARS-Cov-1 and SARS-Cov-2. Advantageously, multimers comprising 4 (and no more or less than 4) copies of a heavy chain polypeptide comprising an amino acid sequence selected from SEQ IDs: 1*225-1*227, wherein each copy is paired with a copy of a polypeptide comprising the amino acid of SEQ ID: 1*228 will bind to a virus, such as a Coronavirus (eg, SAR-Cov-1 and/or SARS-Cov- 2) and preferably SAR-Cov-1 and SARS-Cov-2. In an example, the binding site is a VH/VL antigen binding site of a SAR-Cov antibody, such as antibody CR3022, CR3006, CR3013 or CR3014 disclosed in PLoS Med.2006 Jul;3(7):e237; “Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants”, ter Meulen J et al and J Virol.2005 Feb; 79(3): 1635–1644; doi: 10.1128/JVI.79.3.1635-1644.2005; PMCID: PMC544131; PMID: 15650189, “Molecular and Biological Characterization of Human Monoclonal Antibodies Binding to the Spike and Nucleocapsid Proteins of Severe Acute Respiratory Syndrome Coronavirus”, Edward N. van den Brink et al, the sequences of these antibodies and all anti-virus antibodies in these papers and individually of their VH and VL domains are incorporated herein by reference for use in the invention and possible inclusion in one or more claims herein. In an example, the polypeptide of the invention comprises a first SAR-Cov antigen binding site and a second SAR-Cov antigen binding site wherein the first site comprises a VH/VL binding site of CR3022 and the second site compriss a VH/VL binding site of an antibody selected from CR3006, CR3013 and CR3014 (eg, CR3022/3014; CR3022/3006; CR3022/3013 or CR3022/3014). In an example, the multimer of the invention comprises a first SAR-Cov antigen binding site and a second SAR-Cov antigen binding site wherein the first site comprises a VH/VL binding site of CR3022 and the second site compriss a VH/VL binding site of an antibody selected from CR3006, CR3013 and CR3014 (eg, CR3022/3014; CR3022/3006; CR3022/3013 or CR3022/3014). [00335] In a configuration, the polypeptide of the invention comprises one or more binding sites for human TMPRSS2 protein, for example, the polypeptide comprises a binding site for TMPRSS2 protein as disclosed in US20190300625, eg, the VH/VL pair of any anti-TMPRSS2 antibody disclosed in US20190300625, eg wherein the binding site comprises SEQ ID NOs: 17 and 18 disclosed in US20190300625; all of these sequences and binding site disclosures are incorporated herein by reference for use in the present invention and for possible inclusion in one or more claims herein. In a configuration, the polypeptide of the invention comprises one or more binding sites for human IL-6R, for example, the polypeptide comprises the VH/VL pair of sarilumab. In a configuration, the polypeptide of the invention comprises one or more binding sites for human IL-4R, for example, the polypeptide comprises the VH/VL pair of dupilumab. In a configuration, the polypeptide of the invention comprises one or more binding sites for human OX40L or OX40, eg, the VH/VL pair of oxelumab. [00336] In a configuration, the multimer of the invention comprises binding sites for human TMPRSS2 protein, for example, the multimer comprises a plurality of copies of a binding site for TMPRSS2 protein as disclosed in US20190300625, eg, the VH/VL pair of any anti-TMPRSS2 antibody disclosed in US20190300625, eg wherein the binding site comprises SEQ ID NOs: 17 and 18 disclosed in US20190300625; all of these sequences and binding site disclosures are incorporated herein by reference for use in the present invention and for possible inclusion in one or more claims herein. In a configuration, the multimer of the invention comprises a plurality of copies of a binding sites for human IL-6R, for example, the VH/VL pair of sarilumab. In a configuration, the multimer of the invention comprises a plurality of copies of a binding sites for human IL-4R, for example, the VH/VL pair of dupilumab. In a configuration, the multimer of the invention comprises binding sites for human OX40L or OX40, eg, a plurality of clpies of the VH/VL pair of oxelumab. [00337] Thus, generally multimers of the invention may advantageously be cross-reactive to more than one antigen (ie, bind to more than one antigen, such as first and second antigens which are different from each other); or may be capable of binding to an antigen using binding sites of the multimer, wherein the binding site as a monomer or dimer is not capable of binding to the antigen. For example, the binding by the multimer and by the monomer or dimer form are tested under identical conditions (eg, of temperature, pH, time and antigen concentration). For example, the binding site as a monomer or dimer means that one or two copies (but no more than one or two respectively) of the binding site when comprised by a protein are not capable of binding to the antigen (first antigen). Thus, in that example the protein is monovalent or bivalent for the antigen. For example, the binding site is a VH/VL binding site of a 4-chain antibody having 2 copies (but no more than 2) of the antigen binding site, wherein the antibody is not capable of binding to the antigen (eg, TACI); optionally the antigen is an antigen that is cognate to a receptor or ligand (eg, APRIL when the antigen is TACI; eg, the antigen is a ligand is cognate to a receptor (or another, second ligand); or the antigen is a receptor and is cognate to a ligand) wherein the receptor or first ligand is capable of binding to a second antigen and the antibody is capable of binding to the second antigen (eg, BCMA when the first antigen is TACI), and wherein a multimer of the invention is capable of binding to the first and second antigens. Thus, in an example, the first antigen is TACI and the second antigen is BCMA, and the multimer of the invention is capable of binding to TACI and BCMA. In another example, the first antigen is a SARS-Cov-2 antigen (eg, spike protein antigen) and the second antigen is a SARS-Cov-1 antigen (eg, spike protein antigen), and optionally the multimer of the invention is capable of binding to the first and second antigens. In another example, the first antigen is an antigen (eg, spike protein) of a first virus and the second antigen is an antigen (eg, spike protein) of a second virus, and optionally the multimer of the invention is capable of binding to the first and second antigens. The viruses are different, eg, the viruses are Coronaviruses; eg, the viruses are different strains of influenza viruses. For example, the first and second antigens are HIV antigens (eg, for the treatment or prevention of HIV infection or a symptom thereof); or P. falciparum antigens, such first and second CSP epitopes (eg, for the treatment or prevention of malaria or a symptom thereof); or Salmonella typhimurium antigens (eg, for the treatment or prevention of Salmonella infection or a symptom thereof. In an example, a multimer of the invention specifically binds to human BCMA and human TACI, and optionally the multimer comprises a plurality (eg, 4 and no more or less than 4) of a polypeptide of the invention wherein the polypeptide comprises a BCMA binding site as disclosed herein, such as in the next paragraph. Multimers that bind in these ways can be used in any method or use disclosed herein. [00338] The invention, thus, provides: A method of expanding the antigen binding specificity of a binding site, wherein the binding site binds a first antigen, but not a second antigen (eg, when administered to humans) when the binding site is comprised in monovalent or bivalent form by a protein that specifically binds to the first antigen, the method comprising providing a plurality of copies of a polypeptide of the invention, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens. In another example, the invention provides: Use of a polyepeptide of the invention in a method of manufacturing a multimer for expanding the antigen binding specificity of a binding site, wherein the binding site binds a first antigen, but not a second antigen (eg, when administered to humans) when the binding site is comprised in monovalent or bivalent form by a protein that specifically binds to the first antigen, wherein the method comprises providing a plurality of copies of a polypeptide of the invention, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens. For this method and use: Optionally, the polypeptide comprises a SAM which is a TD, eg, a p53 TD. Optionally, the polypeptide comprises one (and no more than one) copy of the binding site. Optionally, the polypeptide comprises two (and no more or less than two) copies of the binding site. I an example the binding site is a VH/VL binding site or a dAb. In an example, each antigen is a cell surface receptor or ligand, eg, a human cell surface receptor or ligand. In an example, each antigen is a cell surface receptor for a common ligand. [00339] A “4-chain antibody”, as the skilled addressee will understand, is a conventional antibody format having 2 copies of a heavy chain and 2 copies of a light chain, wherein each heavy chain is paired with a respective light chain and the heavy chain Fc regions pair to form heavy chain dimers. [00340] The invention, by providing the ability to create multimers with broadened antigen specificity, provides useful multimers, compositions, methods and uses to target viruses whose antigens evolve through mutation during the natural history of a viral infection. In this respect, the invention may provide broadly-antigen-neutralising multimers, which can be useful for treatment or prevention of HIV infections, CoV (eg Cov-1 or Cov-2) infections or malaria. [00341] Thus, the invention may find application to shift antigen-binding specificity of a predetermined binding site against a first antigen so that the multimer additionally or alternatively binds to a second antigen. For example, this can be demonstrated where the predetermined binding site specifically binds to BCMA, wherein the multimer of the invention binds to BCMA and TACI. For example, the predetermined binding site is the BCMA binding site of JNJ64007957 (Johnson & Johnson), AMG420 (Amgen), AMG701 (Amgen), CC-93269 (Cellgene), RGN5458, (Regeneron), PF-06863135 (Pfizer), SEA-BCMA (Seattle Genetics), MEDI2228 (AstraZeneca), belantamab (GlaxoSmithKline), idecabtagene vicleucel (Celgene), JNJ-4528 (Johnson & Johnson, Nanjing Legend Biotech), P-BCMA-01 (Poseidon Therapeutics), bb21217 (Bluebird Bio), JCARH125 (Celgene, Juno) or ALLO-715 (Allogene). Preferably, the binding site is the BCMA binding site of JNJ64007957. Preferably, the binding site is the BCMA binding site of JNJ-4528. Preferably, the binding site is the BCMA binding site of RGN5458. In an example, the multimer in this paragraph is for treating a cancer, eg, multiple myeloma. [00342] In any aspect of the invention herein, the polypeptide of the invention optionally comprises A: one or more epitope binding sites, optionally wherein the binding site binds to (i) a SARS- Cov-2 antigen (eg, a SARS-Cov-1 antigen and a SARS-Cov-2 antigen); (ii) BCMA (B-cell maturation antigen) and TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor); (iii) first and second Coronovirus antigens; (iv) first and second HIV antigens; (v) first and second P falciparum antigens; (vi) first and second Salmonella antigens; (vii) a TMPRSS protein (eg, a TMPRSS2 antigen); or (viii) a ACE2 antigen; or B: one, two or more copies of an ACE2 peptide (eg, an ACE2 extracellular domain) and/or a TMPRSS2 peptide (eg, a TMPRSS protein extracellular domain); or C: a first binding site that binds to a Coronavirus antigen (eg, a SARS-Covantigen, preferably a SARS-Cov-1 or -2 antigen) and one or more copies of an ACE2 peptide (eg, an ACE2 extracellular domain) and/or a TMPRSS2 peptide (eg, a TMPRSS protein extracellular domain); or D: a first binding site that binds to a ACE2 extracellular domain; and one or more copies of an ACE2 peptide (eg, an ACE2 extracellular domain) and/or a TMPRSS2 peptide (eg, a TMPRSS protein extracellular domain); or E: a first binding site that binds to a TMPRSS2 peptide extracellular domain; and one or more copies of an ACE2 peptide (eg, an ACE2 extracellular domain) and/or a TMPRSS2 peptide (eg, a TMPRSS protein extracellular domain). Such a polypeptide may be useful for producing multimers of the invention, and such multimers may be used for any method or use disclosed herein, such as for cancer (eg, multiple myeloma) treatment when the polypepide is according to option A(ii); or for treatment or prevention of a viral (eg, Covidvirus) infection when the polypepide is according to option A ((i), (iii), (vi) or (viii) or option B, C, D or E. [00343] In one embodiment, the multimer is useful for binding to a first epitope and a second epitope which is a mutant of the first epitope, ie, wherein the second epitope differs from the first epitope by one or more amino acids or one or more sugar residues. For example, the epitopes differ by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids or sugar residues. As shown in Example 25, multimerization of polypeptides described herein may produce multimers that can use the same binding site to bind more than one (eg, 2) different epitopes or antigens. Thus, in an example, the first epitope is comprised by a first antigen and the second epitope is comprised by a second antigen, eg, the antigens are different receptors (such as cell-surface receptors), or different ligands (such as different forms of spike protein of a virus). Optionally, the virus is a SARS virus (eg, SARS-Cov, SARS-Cov-2 or MERS-Cov), HIV or influenza virus. Optionally, the virus is HIV and the epitope is an Env epitope, gp41 epitope or gp120 epitope. Optionally, the virus is influenza virus and the epitope is an epitope of haemagglutinin or matrix protein 2. By providing a multimer that is capable of binding to different forms of a spike protein of such a virus, the multimer is useful for treating or preventing or reducing a seasonal viral infection in humans or animals. For example, the multimer is useful for treating, preventing or reducing infection by a virus comprising a first form of spike protein, and the multimer is useful for treating, preventing or reducing infection by a virus comprising a second form of the spike protein. Thus, in this way the multimer is useful for treating or preventing viral infection in a first and second season wherein humans are infected in the first season by the virus comprising the first spike form and humans are infected in the second season by the virus comprising the second spike form. Instead of a spike protein, the epitope may be a different virus antigen, such as a capsid or tail protein. The multimer, therefore, is capable of binding to different strains of a virus and preferably neutralises the virus (eg, renders it non-infective and/or reduces proliferation of the virus). Thus, in an embodiment the invention provides a seasonal virus treatment or prophylaxis medicament for administration to a human or animal subject, wherein the medicament comprises a plurality of multimers of the invention, such as multimers according to this paragraph, wherein the medicament comprises a pharmaceutically acceptable diluent, carrier or excipient. Such diluents, carriers and excipients are well known to the skilled person. Administration is, eg, intravenous, inhaled, oral or intranasal administration. The invention therefore provides in an embodiment: a multi-seasonal (eg, 2-seasonal or 3-seasonal) anti-viral medicament comprising a plurality of multimers of the invention which are capable of binding to first and second strains of the virus, wherein the strains differ in a surface-exposed antigen to which the multimers can bind. In an example, the seasons are a first year and a second year (eg, two consecutive years or two consecutive winters thereof, or two consecutive summers thereof, or two consecutive springs thereof, or two consecutive falls/autumns thereof). Optionally in any embodiment herein, the virus is a SARS virus (eg, SARS-Cov, SARS-Cov-2, MERS-Cov), HIV, ebola virus, zika virus, norovirus, rotovirus, respiratory synctial virus (RSV), an exanthematous virus, papilloma virus, hepatitis (eg, A, B, C, D or E) virus, Lassa fever virus, dengue fever virus, yellow fever virus, Marburg fever virus, Crimean- Congo fever virus, polio virus, viral meningitis virus, viral encephalitis virus, rabies virus, smallpox virus, hantavirus or influenza virus. When the multimer is useful or used in a method for reducing the virus in an animal, this is advantageous for reducing a zoonotic population of viruses that are transmissible to humans, wherein the viruses are capable of causing a disease or condition (or death) in humans. In this respect, the animal may be a livestock animal, such as a pig, poultry (eg, chicken, duck or turkey), sheep, cow, goat, fish or shellfish. In an example, the animal is a bat, racoon dog, dog, cat, palm civet or camelid (eg, a camel or dromedary). In an example, the animal is a bird. [00344] By presenting multiple copies of the epitope(s) multimers of the invention are believed to provide useful means for vaccination and for stimulating strong immune responses in a human or animal. Thus, in an alternative, the multimers comprise a plurality (eg, 4, 8, 12, 16 or 20) of copies of a peptide, wherein the peptide comprises an epitope of a pathogen, such as a surface-exposed epitope of a virus or bacterium. For example, the peptide comprises a first and/or second epitope as described in the immediately preceding paragraph. In this way, there is provided a vaccine composition for administration to a human or animal for preventing or reducing an infection by the virus or bacterium. In an example, each polypeptide of the multimer comprises a first peptide comprising a first said epitope of the pathogen and a second peptide comprising a second said epitope of the pathogen. Optionally, the polypeptide comprises 2, 3, 4, 5, 6, 7, 8, 9 or 10 (eg, 2 or 3) said epitopes of the pathogen. Optionally, the polypeptide comprises 2, 3, 4, 5, 6, 7, 8, 9 or 10 (eg, 2 or 3) different epitopes of the pathogen. [00345] For example, the virus is Coronavirus, eg, SARS-Cov, SARS-Cov-2, a SARS-related coronavirus (a SARSr-Cov), HCoV-OC43, HCoV-HKU1, HCoV-NL63, HCoV-229E. In an example, the virus is SARS-CoV ZXC21, ZC45, RaTG13, CUHK-W1, Urbani, GZ02, A031, A022, WIV16, WIV1, Rp3, Rs672 or HKU4. For example, the virus is Coronavirus is a group 1, group 2 or group 3 Coronavirus. For example, the multimer is a vaccine antigen composition comprising copies of a polypeptide of the invention. In an aspect, the polypeptide comprises one or more S epitopes of said virus. In an aspect, the polypeptide of the invention comprises a S1 and/or S2 epitope of said virus; or a SA and/or SB epitope of said virus (eg, a SARS-Cov-2 SA and/or SB epitope, preferably SARS-Cov-2 SB epitope). In an aspect, the polypeptide comprises a peptide which comprises all or part of the SA domain and/or all or part of the SB domain. In an aspect, the polypeptide comprises a peptide which comprises all or part of the SB domain and all or part of the S2 subunit, and optionally also the S1/ S2 boundary. Additionally or alternatively, the polypeptide comprises a peptide which comprises the virus spike protein S1 subunit/ S2 subunit boundary. Additionally or alternatively, the polypeptide comprises a peptide which comprises the virus spike protein furin cleavage site. In an alternative, the multimer comprises a plurality of binding sites for one or more of the epitopes, wherein the multimer comprises copies of a polypeptide of the invention wherein the polypeptide comprises one or more epitope binding sites, each epitope being an epitope as described in this paragraph. [00346] In an example, the SARS-Cov epitope comprises one or more N-linked glycans, eg, where each N is an N selected from the following table or is a corresponding N in the virus. Conservation of N-Linked Glycosylation Sequons in SARS-CoV-2 S and SARS-CoV S SARS-CoV-2 S SARS-CoV S N17LT T21FD P25PA N29YT N61VT N65VT H69VS N73HT N74GT ... S112KT N109KS N121NA N118NS N122AT N119ST N149KS T146QT N165CT N158CT N234IT N227IT N282GT N269GT N331IT N318IT N343AT N330AT N370SA N357ST N603TS N589AS N616CT N602CT N657NS D643TS N709NS N691NT SARS-CoV-2 S SARS-CoV S N717FT N699FS N801FS N783FS N1074FT N1056FT N1098GT N1080GT N1134NT N1116NT N1158HT N1140HT N1173AS N1155AS N1194ES N1176ES Italic font indicates the absence of a glycosylation sequon and deletions are indicated with periods. Glycans observed in the SARS-CoV-2 S cryo-EM map are underlined. (see Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS- CoV-2 Spike Glycoprotein [published online ahead of print, 2020 Mar 6]. Cell.2020;S0092- 8674(20)30262-2. doi:10.1016/j.cell.2020.02.058, the disclosure of which is incorporated herein by reference. [00347] Position numbers are with reference to SARS-CoV-2 sequence with Accession Number: YP_009724390.1; and SARC-CoV Urbani sequence with Accession Number: AAP13441.1. [00348] In an example, the virus is selected from SARS-CoV-2 (YP_009724390.1), SARSr- CoV RaTG13 (QHR63300.2), SARS-CoV Urbani (AAP13441.1), SARS-CoV CUHK-W1 (AAP13567.1), SARS-CoV GZ02 (AAS00003.1), SARS-CoV A031 (AAV97988.1), SARS-CoV A022 (AAV91631.1), WIV-16 (ALK02457.1), WIV-1 (AGZ48828.1), SARSr-CoV ZXC21 (AVP78042.1), SARSr-CoV ZC45 (AVP78031.1), SARSr-CoV Rp3 (Q3I5J5.1), SARSr-CoV Rs672 (ACU31032.1). Accession numbers are shown in brackets; the sequences thereof are explicitly incorporated herein by reference for use in the present invention, eg, for providing epitope or antigen sequence. [00349] For example, the pathogen is HIV and the polypeptide comprises a gp120 epitope and a gp41 epitope, eg, the polypeptide comprises a SOSIP peptide. [00350] For example, the pathogen is a Coronavirus (eg, SARS-Cov, SARS-Cov-2 or MERS- Cov) and the polypeptide comprises a first spike epitope and a second spike epitope, wherein the epitopes are different from each other. For example, the first epitope and/or second epitope comprises a sugar residue. For example, the first epitope comprises a viral contact residue for ACE2 and/or the second epitope comprises a viral contact reside for TMPRSS2 and optionally the virus is SARS-Cov or SARS-Cov-2. For example, the first epitope comprises a viral contact residue for DPP4 and/or the second epitope comprises a viral contact reside for TMPRSS2 and optionally the virus is MERS-Cov. [00351] For example, the pathogen is influenza and the polypeptide comprises one or more haemagglutinin epitopes. Optionally, any influenza herein is influenza A, B or H1N1. [00352] For example, the pathogen is HIV and the polypeptide comprises a plurality of Env epitopes. [00353] For example, the pathogen is a virus (eg, a Coronavirus) and the polypeptide comprises a plurality of spike epitopes. [00354] For example, the pathogen is a virus and the polypeptide comprises a plurality of capsid or tail epitopes. [00355] In an example, the virus is a bacteriophage that is capable of infecting a host bacterial cell; or the virus is a virus that is capable of infecting an archaeal cell. [00356] In an example, the pathogen is a bacterium selected from . Bacillus anthracis . Bacillus cereus . Bartonella henselae . Bartonella quintana . Bordetella pertussis . Borrelia burgdorferi . Borrelia garinii . Borrelia afzelii . Borrelia recurrentis . Brucella abortus . Brucella canis . Brucella melitensis . Brucella suis . Campylobacter jejuni . Chlamydia pneumoniae . Chlamydia trachomatis . Chlamydophila psittaci . Clostridium botulinum . Clostridium difficile . Clostridium perfringens . Clostridium tetani . Corynebacterium diphtheriae . Enterococcus faecalis . Enterococcus faecium . Escherichia coli . Francisella tularensis . Haemophilus influenzae . Helicobacter pylori . Legionella pneumophila . Leptospira interrogans . Leptospira santarosai . Leptospira weilii . Leptospira noguchii . Listeria monocytogenes . Mycobacterium leprae . Mycobacterium tuberculosis . Mycobacterium ulcerans . Mycoplasma pneumoniae . Neisseria gonorrhoeae . Neisseria meningitidis . Pseudomonas aeruginosa . Rickettsia rickettsii . Salmonella typhi . Salmonella typhimurium . Shigella sonnei . Staphylococcus aureus . Staphylococcus epidermidis . Staphylococcus saprophyticus . Streptococcus agalactiae . Streptococcus pneumoniae . Streptococcus pyogenes . Treponema pallidum . Ureaplasma urealyticum . Vibrio cholerae . Yersinia pestis . Yersinia enterocolitica; and . Yersinia pseudotuberculosis [00357] The invention provides a protein comprising 4, 12, 16, 20, 24, 28 or 32 copies of an epitope disclosed herein, optionally also comprising 4, 12, 16, 20, 24, 28 or 32 copies of a second second epitope disclosed herein. Optionally, the protein is useful as a vaccine for treating or preventing an infection of a virus or bacterium in a human or animal subject, wherein the virus or bacterium comprises the epitope(s). Optionally, the protein is a multimer as disclosed herein, the multimer comprising four copies of a polypeptide, wherein the polypeptide comprises 1, 2, 3, 4, 5, 6, 7, or 8 copies of the first epitope (and optionally comprises 1, 2, 3, 4, 5, 6, 7, or 8 copies of the second epitope). In an alternative, the invention provides a protein comprising 4, 12, 16, 20, 24, 28 or 32 copies of a binding site that is capable of binding to an epitope disclosed herein, optionally also comprising 4, 12, 16, 20, 24, 28 or 32 copies of a second binding site that is capable of binding to a second epitope disclosed herein. Optionally, the protein is useful as a therapy for treating or preventing an infection of a virus or bacterium in a human or animal subject, wherein the virus or bacterium comprises the epitope(s). Optionally, the protein is a multimer as disclosed herein, the multimer comprising four copies of a polypeptide, wherein the polypeptide comprises 1, 2, 3, 4, 5, 6, 7, or 8 copies of the first epitope (and optionally comprises 1, 2, 3, 4, 5, 6, 7, or 8 copies of the second epitope). In an example, the protein is useful as an assay reagent for detecting a virus of bacterium comprising the epitope(s). To this end there is provided a first method of detecting the virus or bacterium in a sample (eg, in vitro), the method comprising contacting the sample with the protein to allow the protein to bind to one or more copies of the virus or bacterium in the sample, and detecting the binding, eg, using a detection reagent that binds to virus or bacteria that have bound to the protein. There is also provided a method of detecting antibodies that are capable of binding (and optionally neutralising) the virus or bacterium in a sample (eg, in vitro), the method comprising contacting the sample with the protein to allow the protein to bind to such antibodies in the sample, and detecting the binding, eg, using a detection reagent that binds to the antibodies that have bound to the protein. The detection reagent may be an anti-virus or bacterium agent (such as a labelled antibody) in the first method; or an anti-antibody (eg, anti-IgG or anti-IgM) agent (such as a labelled antibody) in the second method. The label may, for example, be a fluorescence label, eg, GFP. The sample may be a blood, spit, sputum or cell sample, eg, a patient sample, such as a patient that is suffering from, is suspected of suffering from or has suffered from an infection by the virus or bacterium. In an example, the protein or multimer of the invention is immobilised on a solid surface, eg, a petri dish or test tube surface, or a flow chamber surface. For example, the surface is a particle surface, eg, a bead surface, such a magenetic bead, magnetisable bead, metal or ferrous bead. In an example, the protein or multimer of the invention is comprised by a fluid, eg, a liquid, eg, a liquid in a droplet, such as an emulsion droplet. Thus, the protein or multimer is useful in a microfluidics method of detecting the virus, bacterium or antibody (eg, IgG or IgM that binds the virus or bacterium). [00358] In an example, the polypeptide comprises one or more (eg, 1, 2, 3 or 4) protein G peptides each of which is capable of binding to IgG, or the protein or multimer comprises a plurality of such polypeptides. Such a multimer or protein is useful to capture IgG when the protein or sample is contacted with a sample (eg, blood, sputum, saliva, semen or cell sample), such as wherein the contacting is carried out in vitro, such as in an in vitro assay. The avidity effect of the multimer’s plurality of protein G peptides is useful to enhance IgG detection sensitivity . The invention, therefore, provides such an assay method and a kit comprising the protein or multimer (optionally immobilised on a solid surface, such as on the surface of a container) and a detection reagent. In an example, the reagent comprises an antigen or epitope that is bound (eg, specifically bound) by the captured IgG. Optionally, the epitope is a viral or bacterial epitope, eg, a viral spike, capsid or tail fibre epitope; or eg, a bacterial cell surface epitope. Optionally, the epitope is a virus spike epitope, eg, a Coronavirus spike epitope, such as a SARS-CoV or SARS-Cov-2 or MERS-CoV spike epitope. Optionally, the reagent comprises a label that is detectable, such as a fluorescence marker, eg, GFP or an Alexa fluor marker. Instead of a protein G peptide, additionally or alternatively the polypeptide, multimer or protein comprises one or more protein A peptides that are each capable of binding to an antibody Fc, such as a Fc of an anti-viral or anti-bacterial antibody from a patient sample. Instead of a protein G peptide, additionally or alternatively the polypeptide, multimer or protein comprises one or more protein L peptides that are each capable of binding to an antibody light chain , such as a light chain of an anti-viral or anti-bacterial antibody from a patient sample (eg, an IgG, IgM, IgA, IgE or IgD antibody). [00359] See Fig 45. The invention provides any reagent or combination of reagents disclosed in that figure, such as the reagent of any one of A-E or the configuration of reagents disclosed in any one of F to P. [00360] Optionally, where the protein or multimer comprises binding sites for ACE2, the protein or multimer may be used for treating or preventing hypertension in a human or animal subject. Optionally, the protein or multimer comprises one or more ACE2 epitopes, wherein the protein or multimer may be used for treating or preventing hypertension in a human or animal subject, such as by administration of the protein or multimer to the subject to raise antibodies against ACE2 in the subject. Alternatively, the treatment or prevention is an inflammatory condition (eg, lung inflammation), pneumonia, COPD, asthma or any treatment or prevention of a condition disclosed in US20110020315A1, the disclosure of which is incorporated herein by reference. [00361] Optionally, where the protein or multimer comprises binding sites for TMPRSS2, the protein or multimer may be used for treating or preventing a cancer (eg, prostate cancer) or viral infection (eg, influenza infection) in a human or animal subject. Optionally, the protein or multimer comprises one or more TMPRSS2 epitopes, wherein the protein or multimer may be used for treating or preventing a cancer (eg, prostate cancer) or viral infection (eg, influenza infection) in a human or animal subject, such as by administration of the protein or multimer to the subject to raise antibodies against TMPRSS2in the subject. Alternatively, the treatment or prevention is any treatment or prevention of a condition disclosed in US 9,498,529, the disclosure of which is incorporated herein by reference. For example, the inflammation is local inflammation of a tissue or an organ and/or a systemic inflammation. For example, the inflammation comprises sepsis. For example, the inflammation comprises an autoimmune disease. [00362] Optionally, where the protein or multimer comprises copies of a binding site for a virus spike, the binding site may be the binding site of antibody 80R, CR3014, CR3006, CR3013 or CR3022. The VH and VL domain sequences of these antibodies are incorporated herein by reference for possible inclusion in a protein or multimer of the invention. Optionally, where the protein or multimer comprises copies of a binding site for a virus spike, the binding site is capable of binding to amino acid residues 426-492, 318-510, or 318-510 of S1 subunit of SARS-CoV, and wherein optionally the protein or multimer binds SARS-CoV and SARS-CoV-2. [00363] Optionally, where the protein or multimer herein is for treating or preventing viral pneumonia in a human or animal subject, eg, wherein the subject is suffering from or is at risk of suffering from a Coronavirus infection. Optionally, where the protein or multimer herein is for treating or preventing Coronavirus viral pneumonia in a human or animal subject. Optionally, where the protein or multimer herein is for treating or preventing Coronavirus viral pneumonia in a human or animal subject, wherein the binding sites are capable of binding to a Pseudomonoas aeruginosa epitope, or wherein the protein or multimer comprises Pseudomonoas aeruginosa epitopes. [00364] Optionally, where the protein or multimer herein is for treating or preventing a viral infection or symptom thereof in a human or animal subject, wherein the binding sites are capable of binding to a Cathepsin L epitope, or wherein the protein or multimer comprises Cathepsin L epitopes. In an example, the virus is Ebola virus or a SARS virus or a Coronavirus (eg, SARS-CoV or SARS- CoV-2). [00365] Optionally, where the protein or multimer herein is for treating or preventing a Coronavirus infection or symptom thereof in a human or animal subject, wherein the binding sites are capable of binding SARS-CoV S1 RBD or RBDR, or wherein the protein or multimer comprises SARS-CoV S1 RBD or RBDR. The receptor-binding determining region (RBDR) that recognizes ACE2. For example, the binding sites are capable of binding the peptide S471–503 of the RBD; or the protein or multimer comprises copies of S471–503 of the RBD. [00366] Optionally, where the protein or multimer herein is for treating or preventing a Coronavirus infection or symptom thereof in a human or animal subject, wherein the binding sites are capable of binding SARS-CoV-2 S1 RBD or RBDR, or wherein the protein or multimer comprises SARS-CoV-2 S1 RBD or RBDR. The receptor-binding determining region (RBDR) that recognizes ACE2. For example, the binding sites are capable of binding the peptide S471–503 (ALNCYWPLNDYGFYTTTGIGYQPYRVVVLSFEL) (SEQ ID: 1*500) of the RBD; or the protein or multimer comprises copies of S471–503 of the RBD. In an example, the protein or multimer comprises copies of a peptide comprises by the amino acid sequence from position 318 to 536 of SARS-CoV or the equivalent amino acid sequence of SARS-CoV-2, wherein the peptide comprises the amino acid sequence from position 424 to position 494. Optionally, the peptide is RBD219-N1 (see For example, Chen, W.; Hotez, P.J.; Bottazzi, M.E. Potential for Developing a SARS-CoV Receptor Binding Domain (RBD) Recombinant Protein as a Heterologous Human Vaccine against Coronavirus Infectious Disease (COVID)-19. Preprints 2020, 2020020449, the sequences of (i) RBD219-N1, (ii) the sequence in the blue box (the epitope consisting S343–367, 373–390 and 411– 428 (reported by Bian et al)) and (iii) the sequences in the green box from the first N to QPY for each of RBD219-N1 and SARS-CoV-2 spike shown in Fig 1 each is incorporated herein by reference for possible use in the invention (eg, the protein or multimer of the invention comprises one or more binding sites that binds to a said peptide of (i), (ii) or (iii); or the protein or multimer comprises one or more of peptides (i), (ii) and (iii)). Optionally, the protein or multimer of the invention comprises one or more copies of the antigen binding site of an antibody shown in Table 1 or 2 of Chen, W.; Hotez, P.J.; Bottazzi, M.E., “Potential for Developing a SARS-CoV Receptor Binding Domain (RBD) Recombinant Protein as a Heterologous Human Vaccine against Coronavirus Infectious Disease (COVID)-19”, Preprints 2020, 2020020449; or shown in Table 1 or 2 of Asian Pac J Allergy Immunol.2020 Mar;38(1):10-18. doi: 10.12932/AP-200220-0773, “Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19)”, Shanmugaraj B et al; or shown in Table 1 of Zhou G, Zhao Q. Perspectives on therapeutic neutralizing antibodies against the Novel Coronavirus SARS-CoV-2. Int J Biol Sci. 2020;16(10):1718–1723, Published 2020 Mar 15, doi:10.7150/ijbs.45123; or shown in Table 1 of Trends in Immunology 2020, “Neutralizing Antibodies against SARS-CoV-2 and Other Human Coronaviruses”, Shibo Jiang, Christopher Hillyer, and Lanying Du (https://www.cell.com/trends/immunology/fulltext/S1471-4906(20)30057-0?rss=yes), the disclosures of all of which (including the VH and VL sequences of said antibodies) are incorporated herein by reference for use in the invention. Optionally, the protein or multimer comprises copies of a peptide, wherein the peptide comprises (i) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 amino acids corresponding to amino acids selected from 415T, 439N, 449Y, 453Y, 455L, 486F, 487N, 489Y, 493Q, 498Q, 500T, 501N, 502G and 505Y of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), (ii) amino acids corresponding to amino acids 486F, 487N, 489Y, 493Q, 498Q, 500T, 501N, 502G and 505Y of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), (iii) an amino acid corresponding to amino acid 415T of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), or (iv) amino acids corresponding to amino acids 439N, 449Y, 453Y, 455L of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)). Optionally, the protein or multimer comprises copies of a peptide, wherein the peptide comprises (i) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 amino acids corresponding to amino acids selected from 415T, 439R, 449Y, 453Y, 455Y, 486L, 487N, 489Y, 493N, 498Y, 500T, 501T, 502G and 505Y of SARS-CoV (eg, SARS-CoV Urbani), (ii) amino acids corresponding to amino acids 486L, 487N, 489Y, 493N, 498Y, 500T, 501T, 502G and 505Y of SARS-CoV (eg, SARS-CoV Urbani), (iii) an amino acid corresponding to amino acid 415T of SARS-CoV (eg, SARS-CoV Urbani), or (iv) amino acids corresponding to amino acids 439R, 449Y, 453Y, 455Y of SARS-CoV (eg, SARS-CoV Urbani). Optionally, the protein or multimer comprises copies of binding site that binds to a peptide, wherein the peptide comprises (i) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 amino acids selected from 415T, 439N, 449Y, 453Y, 455L, 486F, 487N, 489Y, 493Q, 498Q, 500T, 501N, 502G and 505Y of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), (ii) amino acids c 486F, 487N, 489Y, 493Q, 498Q, 500T, 501N, 502G and 505Y of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), (iii) amino acid 415T of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)), or (iv) amino acids 439N, 449Y, 453Y, 455L of SARS-CoV-2 (eg, SARS-CoV-2 (YP_009724390.1)). Optionally, the protein or multimer comprises copies of a comprises copies of binding site that binds to a peptide, wherein the peptide comprises (i) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 amino acids selected from 415T, 439R, 449Y, 453Y, 455Y, 486L, 487N, 489Y, 493N, 498Y, 500T, 501T, 502G and 505Y of SARS-CoV (eg, SARS-CoV Urbani), (ii) amino acids 486L, 487N, 489Y, 493N, 498Y, 500T, 501T, 502G and 505Y of SARS-CoV (eg, SARS-CoV Urbani), (iii) amino acid 415T of SARS-CoV (eg, SARS-CoV Urbani), or (iv) amino acids 439R, 449Y, 453Y, 455Y of SARS-CoV (eg, SARS-CoV Urbani). Optionally, the binding sites are capable of binding the P6 peptide (EEQAKTFLDKFNHEAEDLFYQSSGLGKGDFR) (SEQ ID: 1*501) of the RBD; or the protein or multimer comprises copies of the P6 peptide (EEQAKTFLDKFNHEAEDLFYQSSGLGKGDFR) of the RBD. In an example, the binding site is the antigen binding site of an antibody selected from 80R, m396, F26G19, s230, CR3014, and CR3022. See, eg, Shah et al, doi: 10.21203/rs.3.rs-16932/v1, “Sequence variation of SARS-CoV-2 spike protein may facilitate stronger interaction with ACE2 promoting high infectivity” and supplementary materials, which are incorporated herein by reference. The binding site of the invention may, for example, comprise the VH/VL or scFv of antibody A, B, C, D or E in Fig 3 of this reference, the sequence of which is incorporated herein by reference for use in the invention; and optionally the virus is a Coronavirus, such as SARS-CoV or SARS-CoV-2. [00367] Optionally, the protein or multimer of the invention is for treating or preventing HIV and comprises one or more copies of the antigen binding site of an antibody shown in Table 1 or Fig 4 of Annu. Rev. Immunol.2016.34:635–59, doi: 10.1146/annurev-immunol-041015-055515, “Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design”, Dennis R. Burton and Lars Hangartner; the disclosures of all of which (including the VH and VL sequences of said antibodies) are incorporated herein by reference for use in the invention. [00368] In an example, the protein or multimer comprises a plurality of (eg, 4, 8, 12, 12, 16, 20, 24, 28 or 32) copies of a peptide disclosed herein, eg, a peptide disclosed in the immediately preceding paragraph. [00369] Optionally, where the protein or multimer herein is for treating or preventing a RSV infection or symptom thereof in a human or animal subject, wherein the binding sites are palivizumab binding sites. [00370] Optionally, the binding site of the protein, multimer or polypeptide of the invention disclosed herein comprises a binding site for a peptide or epitope disclosed herein, or for a peptide or epitope whose amino acid sequence is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of a peptide or epitope disclosed herein. Alternatively, the protein, multimer or polypeptide binding site competes (eg, in SPR) with a binding site disclosed in the first sentence of this paragraph. [00371] In one configuration, the invention provides a RNA (eg, mRNA or self-amplifying mRNA, or saRNA) that encodes a polypeptide or protein of the invention. In an example, there is provided a medicament (eg, a vaccine) comprising the RNA, wherein the RNA is for administration to a human or animal subject for treating or preventing a disease or condition in the subject, wherein the RNA is expressed in the subject to produce polypeptides, proteins or multimers of the invention. Optionally, the medicament is a vaccine and the condition is a virial or bacterial infection, such as when the encoded polypeptide comprises an epitope of the virus or bacterium or a binding site that is capable of binding to such an epitope. [00372] The polypeptide, protein or multimer can comprise multiple (i.e.2, 3 or 4) different peptides of the target virus or bacterium (eg, peptides of cell-surface proteins) for use as vaccine. In another embodiment, there is provided a composition comprising first and a second multimer or protein of the invention wherein the multimers/proteins comprise peptides of the target virus or bacterium (eg, peptides of cell-surface proteins) for use as vaccine, wherein the peptides of the first multimer or protein differ from the peptides of the second multimer or protein. For example, the proteins or multimers do not comprise a common such peptide. For example, the second multimer or protein comprises a such peptide that is not comprised by the first protein or multimer. Optionally, the composition comprises a third protein or multimer which is different from the first and second proteins/multimers, wherein the third protein or multimer comprises a said peptide that is not comprised by the first and second proteins/multimers. [00373] For a vaccine herein that targets a virus, the peptide or epitope is not limited to a spike epitope (eg, S1 or S2 subunit epitope); the virus epitope could be from any region of the virus, preferably a region that is exposed on the cell surface of the viral host. Multimerizing virus or bacterial peptides or epitopes according to the invention may advantageously enhance immunogenicity in the subject and thus promote generation of anti-viral/bacterial antibodies that are desirably affinity matured and may give rise to antibodies with a broad epitope coverage (ie, more recognising more than one epitope) of the virus/bacterium. PROVIDING NEW SPECIFITY BY MULTIMERISATION & CROSS-REACTIVE MULTIMERS [00374] Through multimerization made possible by the invention, certain aspects advantageously enable provision of new antigen specificities for binding sites; or new cross-reactivity of binding sites (eg, wherein a binding site in a control binds, such as an IgG, a first but not second antigen, but when present as a multimer of the invention binds both antigens – as exemplified herein). The multimerization also or alternatively can greatly enhance binding strength for an antigen, such as a viral antigen, thereby providing multimer format that are useful for human or animal therapy and for highly sensitive assays, eg, to detect antigen or virus in a sample, such as a serum sample of a subject. Again, such highly sensitive assaying is exemplified herein. Thus, the invention may render therapeutically- or prophylactically-useful a binding site that has hitherto been useless for therapy of prophylaxis of a disease or condition (eg, infection by a certain virus) in humans or animals. As exemplified herein, the multimerization of the invention converts binding based on anti-SARS-CoV-2 binding sites from therapeutically- or prophylactically-useless to therapeutically- or prophylactically- useful for administration of the multimer of the invention to a human or animal subject for treating (eg, reducing) or preventing a SARS-CoV-2 infection. Thus, the invention enables re-purposing of pre-existing antigen binding sites to provide for possible new applications for treatement, prevention or detection of a disease, condition or infection. [00375] In a first aspect, the invention provides: A protein multimer (first multimer) comprising more than 2 copies of a binding site, wherein the binding site is capable of binding to a first antigen, optionally wherein the multimer is capable of binding to the first antigen and a second antigen, wherein the antigens are different.  [00376] For example, the multimer comprises from 4 to 32 (eg, from 4 to 24, or from 4 to 20, or from 4 to 16) copies of the binding site, ie, this means that the multimer does not comprise any more or less than said number. In an embodiment, the multimer comprises, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 copies of the binding site. [00377] For example, the multimer contains from 4 to 32 (eg, from 4 to 24, or from 4 to 20, or from 4 to 16) copies of the binding site, ie, this means that the multimer does not have any more or less than said number. In an embodiment, the multimer contains, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 copies of the binding site. For example, the binding site is any binding site mentioned herein, for example, any VH, VL, VHH, dAb, nanobody, VH/VL pair, sybody or scFv. [00378] In an embodiment, a control protein multimer comprising 1 or 2 (but no more than 1 or 2 respectively) of said binding sites is not capable of binding to the first antigen; or is capable of binding to the first antigen, but not to the second antigen. This is exemplified herein in Example 25. Binding may be determined by an ELISA assay, such as by determining OD450, for example in an ELISA assay described herein. In an example, the first antigen is BCMA and the second antigen is TACI. Optionally, the antigens are human antigens. Optionally, the antigens are bacterial, archaeal or fungal antigens. Alternatively, the antigens are different viral antigens, or antigens of first and second viruses which viruses are different from each other, eg, SARS-CoV and SARS-CoV-2. Optionally, the virus antigens are spike proteins. Alternatively, the virus antigens are nucleocapsid (N) proteins. Alternatively, the virus antigens are envelope (E) proteins. Alternatively, the virus antigens are membrane (M) proteins. Optionally, the antigens of first and second viruses are different and the viruses are different strains of the same type of virus (eg, SARS-CoV strains; or SARS-CoV-2 strains; or influenza strains). Optionally, the antigens of first and second viruses are different and the viruses are different types of virus, eg, SARS-CoV and SARS-CoV-2. [00379] The invention also provides multimers of binding sites that bind to virus antigens, as expemplified herein. Thus, the invention provides: A protein multimer (first multimer) comprising more than 2 copies of a binding site, wherein the binding site is capable of binding to a virus protein (eg, a virus spike, E, M or N protein) of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different. This is exemplified herein for 2 different viruses. For example, the multimer comprises 4 copies of the binding site, wherein the binding site is capable of binding to the virus protein (first virus protein) and a second virus protein which is a mutated version of the first virus protein, wherein the second virus protein is found in a second virus that is infectious to humans. For example, the first and second viruses are SARS viruses or coronaviruses, eg, SARS-CoV-2 viruses. For example, the first protein is a SARS-CoV-2 spike protein comprising the amino acid N501 (ie, asparagine at position 501) and the second protein is a a SARS-CoV-2 spike protein comprising the amino acid Y501 (ie, tyrosine at position 501) or T501. Additionally or alternatively, the first protein comprises E484 and the second protein comprises K484; and/or the first protein comprises K417 and the second protein comprises N417 or T417. Additionally or alternatively, compared to the first protein, the second protein comprises deletion ∆HV69-70, ∆Y144 or ∆LLA242- 244. Additionally or alternatively, the first protein comprises A222 and the second protein comprises V222; and/or the first protein comprises N439 and the second protein comprises K439; and/or the first protein comprises S477 and the second protein comprises N477; and/or the first protein comprises Y453 and the second protein comprises F453; and/or the first protein comprises F486 and the second protein comprises L486; and/or the first protein comprises G261 and the second protein comprises D261; and/or the first protein comprises V367 and the second protein comprises F367. Thus, we have discovered that multimers, as per the invention, comprising at least 4 copies of a binding site that binds to SARS-CoV-2 spike protein, such as the RBD (and preferably the inner face of the RBD) are particularly useful as medicaments (or diagnostic agents to idenfity the presence of the virus). As exemplified in Example 37, a multimer that recognises the epitope recognised by QB-GB binding site is capable of binding to several such mutant forms of SARS-CoV-2 spike and is well suited for administration to patients (or a human population) for treating or preventing SARS-CoV-2 infection, such as where some degree of resistance to mutants occurring during the life history of the virus is desired. [00380] Optionally, each virus is a coronavirus. Optionally, one of the viruses is SARS-Cov and the other virus is SARS-Cov-2. For example, the first virus is SARS-CoV and the second virus is SARS- Cov-2. In an alternative, the first virus is SARS-CoV-2 and the second virus is SARS-Cov. [00381] Optionally, the multimer comprises 4 copies of the binding site. Optionally, the multimer comprises 4 (but no more than 4) copies of the binding site. Optionally, the multimer comprises 8 (but no more than 8) copies of the binding site. Optionally, the multimer comprises 12 (but no more than 12) copies of the binding site. Optionally, the multimer comprises 16 (but no more than 16) copies of the binding site. Optionally, the multimer comprises 20 (but no more than 20) copies of the binding site. Optionally, the multimer comprises 24 (but no more than 24) copies of the binding site.Optionally, the multimer comprises 4, 8, 12, 16, 20 or 24 copies of the binding site. [00382] Optionally, (a) the binding of the multimer to the first antigen (or first virus protein) is stronger than the binding of a second multimer (eg, an immunoglobulin, such as an IgG) to the first antigen (or first virus protein), wherein the second multimer comprises 2 (but no more than 2) copies of said binding site; and/or (b) the binding of the multimer to the second antigen (or a protein of the second virus, eg, a spike, E, M or N protein of the second virus) is stronger than the binding of a or said second multimer (eg, an immunoglobulin, such as an IgG) to the second antigen (or second virus protein), wherein the second multimer comprises 2 (but no more than 2) copies of said binding site. [00383] Optionally, (a) the binding of the multimer to the first virus spike protein is stronger than the binding of a second multimer (eg, an immunoglobulin, such as an IgG) to the first antigen (or first virus spike protein), wherein the second multimer comprises 2 (but no more than 2) copies of said binding site; and/or (b) the binding of the multimer to a spike protein of the second virus is stronger than the binding of a or said second multimer (eg, an immunoglobulin, such as an IgG) to the second virus spike protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site. [00384] Optionally, (a) the binding of the multimer to the first virus nucleocapsid (N) protein is stronger than the binding of a second multimer (eg, an immunoglobulin, such as an IgG) to the first virus N protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site; and/or (b) the binding of the multimer to a N protein of the second virus is stronger than the binding of a or said second multimer (eg, an immunoglobulin, such as an IgG) to the second virus N protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site. [00385] Optionally, (a) the binding of the multimer to the first virus membrane (M) protein is stronger than the binding of a second multimer (eg, an immunoglobulin, such as an IgG) to the first virus M protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site; and/or (b) the binding of the multimer to a M protein of the second virus is stronger than the binding of a or said second multimer (eg, an immunoglobulin, such as an IgG) to the second virus M protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site. [00386] Optionally, (a) the binding of the multimer to the first virus envelope (E) protein is stronger than the binding of a second multimer (eg, an immunoglobulin, such as an IgG) to the first virus E protein), wherein the second multimer comprises 2 (but no more than 2) copies of said binding site; and/or (b) the binding of the multimer to a E protein of the second virus is stronger than the binding of a or said second multimer (eg, an immunoglobulin, such as an IgG) to the second virus E protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site. [00387] Preferably, binding or binding strength is determined by ELISA, eg, by determining OD450. An ELISA herein may be carried out at room temperature and pressure (rtp), or preferably at 20 or 25 degrees centigrade and 1 atmosphere. [00388] Optionally, (a) the first multimer binds to the first antigen (or first virus protein, eg, spike protein) with an OD450 from 1 to 3 (such as from 1 to 2 or from 2 to 3) in an ELISA assay in which the first antigen or protein is at a concentration of 1 nM in the assay (and optionally the second multimer binds to the first antigen or protein with an OD450 less than 0.5 in an ELISA assay in which the antigen or protein is at a concentration of 1 nM in the assay); (b) the first multimer (i) binds to a first virus spike protein trimer with an OD450 from 2 to 3 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay and (ii) binds to a first virus spike protein monomer with an OD450 from 1 to 2 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay (optionally wherein the binding site comprises an ACE2 extracellular protein); and/or (c) the first multimer binds to the first antigen (or a first virus protein) with an OD450 from 2 to 3 (optionally from 2.5 to 3) in an ELISA assay in which the first antigen or protein is at a concentration of 10 nM in the assay (and optionally the second multimer binds to the first antigen or protein with an OD450 from 1 to 2 in an ELISA assay in which the antigen or protein is at a concentration of 10 nM in the assay). In an example, the multimer binds according to (a). In an example, the multimer binds according to (b). In an example, the multimer binds according to (c). In an example, the multimer binds according to (a) and (b). In an example, the multimer binds according to (a) and (c). In an example, the multimer binds according to (a), (b) and (c). In an example, the multimer binds according to (b) and (c). These are exemplified herein. Binding of the the first multimer with said OD450 indicates that the first multimer (ie, multimer of the invention) is useful for medical use, ie, therapy or prophylaxis of a disease or condition in a human or animal subject wherein the disease or condition is mediated by the first antigen (or a pathogen comprising the first antigen). Binding of the the second multimer (eg, IgG having only 2 of said binding sites) with said OD450 indicates that the second multimer is not useful for medical use or said therapy or prophylaxis. Binding of the the first multimer with said OD450 indicates that the first multimer (ie, multimer of the invention) is useful for assaying for detecting the presence of the first antigen or antibodies against the first antigen in a bodily fluid sample of a human or animal, eg, a serum, saliva or cell sample obtained from a human or animal, wherein the human or animal (i) is suffering from, has suffered from or is suspected of suffering from a disease or conditionthat is mediated by the first antigen, or (ii) is suffering from, has suffered from or is suspected of suffering from an infection by a pathogen that comprises the first antigen, such as a virus, bacterium or fungus (eg, a yeast). Binding of the the second multimer (eg, IgG having only 2 of said binding sites) with said OD450 indicates that the second multimer is not useful for such assaying or detection. Generally, an Ig (eg, IgG) that binds to its cognate antigen with an affinity (Kd) higher than 1, 10, 100 or 1000 mM are not useful as medicaments. In an example, the binding site of the multimer of the invention is an antigen binding site of an Ig (eg, IgG) Fab fragment that binds to the antigen with an affinity (Kd) higher than 0.1, 1, 10, 100 or 1000 mM (eg, higher than 1 or 10 mM). Optionally, the Ig is said second multimer. In an example, the multimer of the invention binds to the antigen with an apparent affinity (avidity) of lower than 0.1 mM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM, 1 pM or 100 fM. These affinities are amenable to medical use. Affinities are may be determined by any standard method, for example by surface plasmon resonance (SPR) or ELISA, or bilayer interferometry (eg, as per the example below). The method may be carried out at rtp, or optionally at 20 or 25 degrees centrigrade and 1 atm and optionally at a pH from 6.5 to 7.5 (eg, at pH 7). Reference is made to Science.2020 May 8;368(6491):630-633. doi: 10.1126/science.abb7269. Epub 2020 Apr 3, “A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV”, Yuan M et al, which determined binding affinity using a Fab version of CR3022, it can be seen CR3022 binds spike RBD of CoV-2 with at least 100x less affinity than CoV-1. The Kd for CR3022 for CoV- 2 is around 115 nM. A multimer of the invention comprising 4 copies of the CR3022 binding site will have a Kd in the low pM range, thereby greatly improving on the apparent affinity and rendering the multimer useful as a medicament. We expect also a large improvement in affinity (expected to be in the double of single digit pM range or less) for the multimer binding to RBD of the CoV-1 strain. We would expect binding to such RBD with higher affinity again in the low pM range. Example Biolayer interferometry binding assay: Binding assays may performed by biolayer interferometry (BLI) using an Octet Red® instrument (FortéBio). Briefly, His6-tagged antigen (eg, S or RBD protein) at 20 to 100 µg/mL in 1x kinetics buffer (1x PBS, pH 7.4, 0.01% BSA and 830.002% Tween 20) are loaded onto Anti-Penta-HIS™ (HIS1K) biosensors and incubated with the indicated concentrations of Fab or IgG (eg, CR3022 Fab or IgG) or multimer. The assay comprises fivesteps: 1) baseline: 60 s with 1x kinetics buffer; 2) loading: 300 s with his6-tagged proteins; 3) baseline: 60 s with 1x kinetics buffer; 4) association: 120 s with samples (Fab or IgG or multimer); and 5) dissociation: 120 s with 1x kinetics buffer. For estimating the exact Kd, a 1:1 binding model is used. Example ELISA assay: ELISAs are performed in duplicates to compare the binding affinities of the different product formats. Recombinant antigen is diluted to 1 ug/ml in ELISA coating buffer (50 mM carbonate/bicarbonate). One hundred ul of 1 ug/ml antigen is added to each well of an ELISA plate and the plates are incubated overnight at 4°C. The plates are washed three times with PBS containing 0.05% Tween-20 before being blocked with 200 ul 1% bovine serum albumin in PBS for 4 hrs at room temperature. The plates are washed three times as before. Products (multimers or other protein to be tested) are serially diluted in PBS containing 0.05% Tween-20. One hundred ul of sample is added to each well and the plates are incubated overnight at 4°C. The plates are washed four times with PBS containing 0.05% Tween-20. One hundred ul of detection antibody (anti-His-HRP, A7058, Sigma; or anti- Human-IgG HRP, 31410, Thermo Fisher Scientific; or Protein L HRP, M00098, Genscript) diluted in blocking buffer (according to the manufacturers’ recommendations) is added to each well and the plates are incubated at room temperature for 2 h. Following four plate washes, 25 ul of TMB substrate solution (Thermo Fisher Scientific) is added to each well. The reaction is terminated after ~15 min by the addition of 25 ul 3 M HCl. The absorbance at 450 nm is read using a CLARIOstar™ microplate reader (BMG Labtech). Example SPR binding assay: The SPR is carried out at a detergent level of no greater than 0.05% by volume, eg, in the presence of P20 (polysorbate 20; eg, Tween-20™) at 0.05% and EDTA at 3 mM. In one example, the SPR is carried out at 25° C. or 37° C. in a buffer at pH7.6, 150 mM NaCl, 0.05% detergent (eg, P20) and 3 mM EDTA. The buffer can contain 10 mM Hepes. In one example, the SPR is carried out at 25° C. or 37° C. in HBS-EP. HBS-EP is available from Teknova Inc (California; catalogue number H8022). In an example, the affinity (eg, of a VH/VL binding site) is determined using SPR by using any standard SPR apparatus, such as by Biacore™ or using the ProteOn XPR36™ (Bio-Rad®). The binding data can be fitted to 1:1 model inherent using standard techniques, eg, using a model inherent to the ProteOn XPR36™ analysis software. [00389] Optionally, (a) the first multimer binds to the first antigen (or first virus protein, eg, spike protein) with an OD450 from 1 to 3 (such as from 1 to 2 or from 2 to 3) in an ELISA assay in which the antigen or protein is at a concentration of 1 nM in the assay (and optionally the second multimer binds to the first antigen or protein with an OD450 less than 0.5 in an ELISA assay in which the antigen or protein is at a concentration of 1 nM in the assay); (b) the first multimer (i) binds to a first virus spike protein trimer with an OD450 from 2 to 3 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay and (ii) binds to a first virus spike protein monomer with an OD450 from 1 to 2 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay (optionally wherein the binding site comprises an ACE2 extracellular protein); and/or (c) the first multimer binds to the first antigen (or first virus protein, eg, spike protein) with an OD450 from 2 to 3 (optionally from 2.5 to 3) in an ELISA assay in which the antigen or protein is at a concentration of 10 nM in the assay (and optionally the second multimer binds to the first antigen or protein with an OD450 from 1 to 2 in an ELISA assay in which the antigen or protein is at a concentration of 10 nM in the assay). In an example, the multimer binds according to (a). In an example, the multimer binds according to (b). In an example, the multimer binds according to (c). In an example, the multimer binds according to (a) and (b). In an example, the multimer binds according to (a) and (c). In an example, the multimer binds according to (a), (b) and (c). In an example, the multimer binds according to (b) and (c). These are exemplified herein. [00390] Optionally, binding of the first multimer to the first antigen or protein is saturated as determined by OD450 in an ELISA assay in which the antigen or protein is at a concentration between 10 and 100 nM in the assay (and optionally the second multimer binds to the first antigen or protein with an OD450 less than 2.5 (eg, from 2 to 2.5) in an ELISA assay in which the antigen or protein is at a concentration between 10 and 100 nM in the assay). [00391] Optionally, (a) the first multimer binds to the second antigen (or second virus protein, eg, spike protein) with an OD450 from 1 to 2 in an ELISA assay in which the second antigen or protein is at a concentration of 1 nM in the assay (and optionally the second multimer binds to the second antigen or protein with an OD450 less than 0.5 in an ELISA assay in which the antigen or protein is at a concentration of 1 nM in the assay); and/or (b) the first multimer binds to the second antigen (or second virus protein, eg, spike protein) with an OD450 from 2 to 3 (optionally from 2.5 to 3) in an ELISA assay in which the second antigen or protein is at a concentration of 10 nM in the assay (and optionally the second multimer binds to the second antigen or protein with an OD450 from 0.5 to 1.5 (eg, 0.5 to 1) in an ELISA assay in which the antigen or protein is at a concentration of 10 nM in the assay). [00392] Optionally, binding of the first multimer to the second antigen or protein is saturated as determined by OD450 in an ELISA assay in which the antigen or protein is at a concentration between 10 and 100 nM in the assay (and optionally the second multimer binds to the second antigen or protein with an OD450 less than 1.5 (eg, from 1 to 1.5) in an ELISA assay in which the antigen or protein is at a concentration between 10 and 100 nM in the assay). [00393] Optionally, the multimer is capable of detectably binding to antibodies that bind to the first antigen or the second antigen or virus protein (eg, anti-virus protein antibodies, such as anti-SARS- Cov spike antibodies or anti-SARS-Cov-2 spike antibodies or anti-influenza haemagglutinin antibodies) in an ELISA assay, wherein detection of the multimer binding is measured by OD450 and the assay comprises (a) Optionally diluting a serum sample of a mammal between 100 and 106-fold; (b) Contacting the antigen or protein (eg, SARS-Cov-2 spike protein) with the a serum sample of a mammal (which optionally has been diluted in step (a)) whereby anti-antigen or protein antibodies present in the sample bind to the antigen or protein, wherein the antigen or protein is immobilised on a solid surface; (c) Contacting the bound antibodies with copies of the multimer; and (d) Detecting multimer bound to antibody. [00394] ELISA herein may be a sandwich ELISA. [00395] Optionally, the dilution is from 10 to 104, 105 or 106-fold. Optionally, the dilution is from 100 to 104, 105 or 106-fold. Optionally, the dilution is from 1000 to 104, 105 or 106-fold. Preferably, the dilution is 1000 to 1,000,000-fold (such as 1000 to 100,000-fold or 1000 to 10,000-fold). Optionally, dilution is dilution with water or an aqueous solution, eg, PBS, such as PBS containing from 0.1 to 0.05% (eg, either 0.1% or 0.05%) Tween-20. This is exemplified herein, demonstrating the possibility of extremely sensitive assaying using multimers of the invention comprising more than 2 (eg, at least 4) binding site copies. [00396] Optionally, the spike protein is a trimer of polypeptides. [00397] Optionally, the binding site is an antibody VH/VL pair or an antibody single variable domain (such as a nanobody, VHH or a dAb). [00398] Optionally, the binding site is (a) The spike protein binding site of an antibody selected from CR3022, CR3014, or any other anti-coronavirus antibody disclosed herein (eg, an antibody of Table 21); (b) An ACE2 protein which is capable of binding to the first virus spike protein; or (c) A TMPRSS2 protein which is capable of binding to the first virus spike protein. [00399] Optionally, the binding site comprises or consists of an ACE2 extracellular protein. Optionally, the ACE2 protein is human ACE2 protein. For example, an extracellular protein of ACE2 having UNIPROT number Q9BYF1, the sequence of such ACE2 and the extracellular domain thereof being incorporated herein by reference, along with the nucleotide sequence encoding such. In an example, ACE2 extracellular protein comprises or consists of positions 18 to 615 or 18 to 740 of ACE2 having UNIPROT number Q9BYF1, the sequence comprising or consisting of positions 18 to 740 being incorporated herein by reference, along with the nucleotide sequence encoding such. [00400] Optionally, the binding site comprises or consists of an TMPRSS2 extracellular protein. Optionally, the TMPRSS2 protein is human TMPRSS2 protein. For example, an extracellular protein of TMPRSS2 having UNIPROT number O15393, the sequence of such TMPRSS2 and the extracellular domain thereof being incorporated herein by reference, along with the nucleotide sequence encoding such. In an example, TMPRSS2 extracellular protein comprises or consists of positions 106 to 492 of TMPRSS2 having UNIPROT number O15393, the sequence comprising or consisting of positions 106 to 492 being incorporated herein by reference, along with the nucleotide sequence encoding such. [00401] Optionally, the binding site is an antibody VH/VL pair, wherein the VH comprises an amino acid sequence of a VH disclosed in Table 23 and the VL comprises the amino acid sequence of the cognate VL disclosed in Table 23. Optionally, the binding site comprises an scFv disclosed in Table 23. Optionally, the binding site comprises an antibody single variable domain (eg, a VHH, nanobody, dAb, VH or VL) disclosed in Table 23, Table 32 or elsewhere herein. [00402] Optionally, the binding site is an antibody VH/VL pair, wherein the VH comprises an amino acid sequence of a VH disclosed in Table 32 and the VL comprises the amino acid sequence of the cognate VL disclosed in Table 32. Optionally, the binding site comprises an scFv disclosed in Table 32. [00403] Optionally, the multimer comprises a multimer of a polypeptide disclosed in Table 23, optionally wherein the polypeptide is a polypeptide in the Table that comprises a TD. [00404] Optionally, the multimer comprises a multimer of a polypeptide disclosed in Table 32, optionally wherein the polypeptide is a polypeptide in the Table that comprises a TD. [00405] Any amino acid sequence in Table 23, Table 32 or elsewhere herein that ends at its C- terminus in TVS may in the alternative be provided as the indentical sequence except that the alternative ends in TVSS. Any amino acid sequence in Table 23, Table 32 or elsewhere herein that ends at its C-terminus in TVSS may in the alternative be provided as the indentical sequence except that the alternative ends in TVS. [00406] The multimer may be a multimer of any format disclosed herein. The multimer may be a multimer of any polypeptide dislosed herein. [00407] Optionally, the multimer comprises more than 2 (eg, comprises 4) copies of a heavy/light chain pair, wherein each heavy chain comprises (in N- to C-terminal direction) a VH and an antibody constant region (eg, an Fc) and wherein each light chain comprises (in N- to C-terminal direction) a VL and an antibody constant region (eg, a CL), wherein the binding site of the multimer comprises the VH paired with the VL; optionally wherein each heavy chain comprises a self-assembly multimerization domain (such as a tetramerization domain, such as a p53 TD). Optionally, each heavy chain comprises a hinge region as disclosed herein. [00408] Optionally, the multimer comprises more than 2 (eg, comprises 4) copies of a polypeptide, wherein the polypeptide comprises (in N- to C-terminal direction) a single variable domain and a multimerization domain (eg, a tetramerization domain, such as a p53 TD), and optionally an antibody constant region (eg, an Fc or CL) between the single variable domain and the multimerization domain, or the multimersiation domain is between the single variabl domain and the constant region. [00409] In an aspect, the invention provides assays and methods:- A method for detecting the presence of an antigen in a sample, the method comprising combining the sample with a multimer of the invention, allowing antigen in the sample to bind multimers to form antigen/multimer complexes and detecting antigen/multimer complexes. The antigen may be a virus antigen, eg, a spike, M, E or N antigen, or a coronavirus antigen. The antigen may be comprised by an antibody present in the sample, eg, an antibody that is capable of binding do an antigen of an infectious disease pathogen (such as a virus or bacterium) or an antigen that is capable of binding to a human protein. The sample may be a blood sample, serum sample, sputum sample, cell sample, saliva sample, bodily fluid sample of an animal or human subject. Optionally, the sample is diluted before said detection, eg, before said combining. Dilution may be any fold dilution disclosed herein, eg, and dilution by a PBS solution or water. Optionally, the antigen is immobilised on a solid surface before or after said combining. Immobilisation may be carried out by binding the antigen to an anti-antigen immunoglobulin or superantigen that is bound to the solid surface. Examples of superantigens are Proteins A, L and G or antibody-binding fragments thereof. Immobilisation may be carried out by binding the antigen to a multimer of the invention that is bound to the solid surface, wherein the binding sites of the multimer are capable of binding to the antigen, eg wherein the antigen is comprised by an antibody. For example, the binding site is an antibody binding site of Protein G, A or L. Thus, in an example multimers of the invention are bound to a solid surface, the surface is contacted with the sample wherein antigen (eg, antibodies or virus particles) comprised by the sample are bound to multimers of the invention to form antigen/multimer complexes, and complexes are detected thereby determining the presence of the antigen in the sample. In a different example, the antigen is comprised by antibodies that are capable of binding to a second antigen (eg, a human, bacteria, fungal or viral protein, such as a viral spike, M, E or N protein), wherein the second antigen is immobilised on a solid surface, the surface is contacted with the sample, wherein antibodies comprised by the sample bind to the second antigen to form second antigen/antibody complexes, and complexes are contacted with multimers of the invention wherein multimers bind to antibodies whereby second antigen/antibody/multimer complexes are formed, and second antigen/antibody/multimer complexes are detected thereby determining the presence of said antibodies in the sample. For example, the antibodies are IgM, IgG, IgD, IgE or IgA antibodies, preferably IgM, IgG or IgA antibodies. In an example, the method further comprises isolating complexes and optionally obtaining sequence information of antigen (first antigen, eg, antibodies) comprised by complexes. Optionally, the sequence may be inserted into an expression vector and expressed to produce proteins, eg, wherein the proteins are isolated. For example, VH and/or VL domain amino acid sequence of antibodies comprised by complexes is obtained and use to express copies of the VH and/or VL in an expression host, eg, CHO or HEK cell. [00410] Optionally, the method is an ELISA method, eg, a sandwich ELISA. The method is carried out in vitro. [00411] Suitable assay example formats are shown Figures 50-55, as well as reagents and polypeptides for making multimers of the invention that are useful for the methods and assays. The examples show assay formats relating to SARS-CoV and SARS-CoV2, but they are equally applicable mutatis mutandis to detecting pathogens (eg, any virus, bacterium or fungus) other than SARS-CoV and SARS-CoV2 and the disclosures of Figures 50-55can therefore in the alternative be read as relating to any pathogen, any pathogen antigen or protein, any anti-pathogen antibody and any other suitable multimer of the invention. [00412] For example, the invention provides an assay comprising a format shown in any of Figures 50-55 for detecting the presence of a pathogen (eg, any virus, bacterium or fungus), anti-pathogen antibodies or a pathogen protein in a sample (eg, in serum, blood, saliva or any other sample disclosed herein). In an example, the pathogen is a coronavirus, eg, SARS-CoV or SARS-CoV-2, or infuenza virus or HIV, or any other virus disclosed herein. [00413] In an embodiment, there is provided:- A method of detecting the presence of anti-SARS-Cov-2 protein (eg, spike, M, E or N) antibodies in a serum sample, the method comprising carrying out an ELISA assay (eg, an assay disclosed herein), and the assay comprises (a) Optionally diluting the serum sample from 10 to 106-fold; (b) contacting the SARS-Cov-2 protein with the serum sample (which optinally is diluted in step (a)) whereby anti-SARS-Cov-2 protein antibodies present in the sample bind to the virus protein to produce virus protein/antibody complexes; and (c) contacting anti-SARS-Cov-2 virus protein antibodies with copies of the multimer of the invention; and (d) detecting multimer bound to virus protein/antibody complexes, the detecting comprising detection of the multimer binding, optionally by determining optical density (eg, OD450); wherein the steps can be carried out in the order (a) (b) (c) and (d) or (a) (c) (b) and (d), or wherein steps (b) and (c) are carried out simultaneously and between steps (a) and (d). [00414] The method is carried out in vitro. In an alternative, the antibodies are antibodies that bind to a protein of SARS-Cov or a different coronavirus. Optionally, the antibodies are antibodies that bind to a N, M or E proteins of a coronavirus, eg SARS-Cov or SARS-Cov-2. [00415] Optionally, the presence of anti-antigen or protein antibodies (eg, anti-virus protein antibodies, such as anti-SARS-Cov-2 spike antibodies) in the sample is detected when the optical density (eg, OD450) is greater than 0.1 or 0.5 (optionally, greater than 1, 1.5 or 2) in the assay. [00416] Optionally wherein the spike protein is immobilised on a solid surface. Alternatively, the multimers are immobilised on a solid surface. [00417] Optionally, the dilution is 1000 to 1,000,000-fold (such as 1000 to 100,000-fold or 1000 to 10,000-fold) or any other fold dilution disclosed herein. Optionally, the dilution is from 10 to 104, 105 or 106-fold. Optionally, the dilution is from 100 to 104, 105 or 106-fold. Optionally, the dilution is from 1000 to 104, 105 or 106-fold. Optionally, dilution is dilution with water or an aqueous solution, eg, PBS, such as PBS containing from 0.1 to 0.05% (eg, either 0.1% or 0.05%) Tween-20. [00418] Optionally, the spike protein is a trimer of polypeptides. For example, the spike protein is a monomer of either S1 or S2 spike ectodomain, a trimer of the spike, monomer of the spike receptor binding domain (RBD domain); or a RBD multimer, such as a dimer, trimer, tetramer or octamer of the RBD. [00419] In an alternative to binding spike, the multimer of may bind a Nucleocapsid (N protein), membrane protein (M protein) or envelope protein (E protein) and the disclsoures herein referring to spike protein binding can apply mutatis mutandis to those alternatives. [00420] Before carrying the method herein the serum sample may have been obtained by taking a blood sample or other bodily fluid sample from a mammal (eg, a human or animal, such as any animal disclosed herein). In an example, the human is a human suspected of having previously been infected or currently infected by a pathogen, eg a virus, bacterium or fungus comprising the antigen (first antigen), eg, SARS-CoV or SARS-Cov-2. For example, the human is a male, female, adult, teenager, child, baby or a human of at least 10, 20, 30, 40, 50, 60, 70 or 80 years’ of age (preferably over 50). [00421] In embodiments, the binding site of the multimer is (a) The spike protein binding site of an antibody, optionally an antibody selected from CR3022, CR3014, or any other anti-coronavirus antibody disclosed herein (eg, an antibody of Table 21); (b) An ACE2 protein which is capable of binding to the spike protein; or (c) A TMPRSS2 protein which is capable of binding to the spike protein. [00422] Optionally, the multimer is a multimer of a polypeptide disclosed in Table 24, optionally wherein the polypeptide is a polypeptide in the Table that comprise a TD. [00423] Optionally, the multimer comprises a plurality of copies of an Ig binding domain disclosed in Table 25, optionally wherein the multimer further comprises a plurality of copies of a further (ie, different) Ig binding domain disclosed in Table 25, [00424] Optionally, the binding site of the multimer is alternatively capable of binding to an antibody (eg, an antibody that is capable of binding a human antigen, viral antigen, bacterial antigen or fungal antigen, such as an anti-SARS-Cov2 antibody, optionally wherein the binding site is comprised by (a) Protein G or a fragment thereof; (b) Protein A or a fragment thereof; (c) Protein L or a fragment thereof; or (d) An scFv or antibody single variable domain. [00425] Optionally, step (c) is carried out before step (b), wherein the protein A, G, L or fragment, scFv or variable domain binding sites of the multimers bind a plurality of copies of the antibody (eg, anti-SARS-Cov2 antibody). For this option, the multimers may be immobilised on a solid support. [00426] Optionally, the multimers are immobilised on a solid surface. Optionally, in any method or assay herein, the step of determining optical density (eg, OD450) comprises labelling complexes comprising first antigen or protein (eg, spike protein) and multimers with horseradish peroxidase (HRP) and detecting the label (optionally at a wavelength of 450 nm). For example, the HRP is contacted with tetramethyl benzidine and abosorbance is read at 450 nm, whereby OD450 is determined. [00427] The invention also provides:- A pharmaceutical composition or assay reagent comprising a plurality of multimers of the invention, optionally wherein the reagent comprises said multimers immobilised on a solid support. [00428] In an example the following provide the solid support: Beads, petri dish, a laboratory apparatus, flow cell or a swab or dipstick. The support may be sterile or suitable for medical use. [00429] For example, the pharmaceutical composition comprises a pharmaceutically-acceptable carrier, diluent or excipient. [00430] The invention also provides:- A multimer of the invention for administration to a human or animal subject for medical use. A multimer of the invention for administration to a human or animal subject for treatment or prevention of an infection by a pathogen (eg, a virus, bacterium or fungus) that comprises the first antigen or protein, or a symptom of such an infection (eg, an unwanted inflammatory response). A multimer of the invention for administration to a human or animal subject for treatment or prevention of an infection by the first and/or second virus, or a symptom of such an infection (eg, an unwanted inflammatory response). A method of treating a disease, condition or symptom thereof in a human or animal subject, the method comprising administering to the subject a plurality of multimers of the invention. For example, the disease, condition or symptom is caused by the first antigen or protein (or by a pathogen that comprises the first antigen or protein, such as a virus that comprises the antigen or protein). A method of treating a viral infection or symptom thereof in a human or animal subject, the method comprising administering to the subject a plurality of multimers of the invention. The composition or multimers of the invention may be admistered in said use or method to the subject by any means, such as intravenously, orally, by inhalation or any other route disclosed herein. [00431] The invention also provides:- An assay kit comprising a reagent of the invention and an amount of the first antigen or protein (eg, viral spike protein), optionally wherein the reagent and protein are comprised by different containers. EXPANDING UTILITY OF BINDING SITES THROUGH MULTIMERISATION [00432] Examples 23 -26 demonstrate how advantageously multimerization of the invention can repurpose a binding site which otherwise would not be useful or much less useful, such as for medical use (eg, for treatment or prophylaxis of a disease or condition mediated by or associated with an antigen to which the binding site binds), or for assay use (eg, detecting a pathogen or antigen that mediates, causes or is adversely associated with a a disease or condition in a subject). Through multimerization of the invention, very high-order multimers (eg, containing 8-24 copies of a binding site) can easily be achieved in a stable multimer that can be readily expressed, such as in eukaryotic expression systems and host cells (as demonstrated in the exemplification herein). The high-order multimers usefully can repurpose binding sites that individually have relatively low binding strength for an antigen, wherein in the multimers an avidity effect is produced rendering the combined binding strength of copies of the binding site well suited to medical applications or very sensitive assay detection of low levels of antigens in samples. Usefully, for example, we demonstrate this even for very diluted samples where the antigen is at very low concentration. This is advantageous, for example where the antigen is an antigen of a pathogen (eg, a virus, bacterium or fungus that causes disease, such as in humans, animals or plants); or where the antigen is comprised by antibodies produced by a human or animal subject in response to immunisation, such as in response to a pathogen or a human protein in the subject. [00433] Thus, in an embodiment, the invention provides:- A method of expanding a utility of an antigen (eg, a protein) binding site, the method comprising producing a multimer of the invention, wherein the multimer comprises a plurality of copies (eg, at least 4 or 8 copies) of the binding site. [00434] In an example the utility is a medical utility, such as treating or preventing a disesase or condition mediated by the antigen in a human or animal subject (eg, an infection caused by a pathogen comprising the antigen). In an example the utility is an assay or detection method for determining the presence or relative amount of the antigen (or a pathogen comprising the antigen) or antibodies that bind the antigen in a sample (eg, an environmental sample or any sample of a human or animal subject disclosed herein). In an example, the method increases the sensitivity of assaying for the antigen or antibodies in a sample. For example, the sample is a blood or serum or saliva sample which has been diluted, such as diluted with fold dilution disclosed herein. For example, the utlity is a reduced propensity for producing false positive results in assaying for the presence of the antigen or antibodies that bind the antigen in a sample. Exemplary Polypeptides & Multimers [00435] In examples, the invention provides a polypeptide comprising one or more copies of an antigen binding domain (BD), the polypeptide comprising or consisting of, in N- to C-terminal direction (a) BD-TD; (b) TD-BD; (c) BD-BD-TD; (d) TD-BD-BD (e) BD-TD-BD-BD (f) BD-BD-TD-BD (g) BD-BD-TD-BD-BD. [00436] Preferably in these examples, TD is a p53 TD, eg, a human p53TD. [00437] Optionally, the BD is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH, eg, a single variable domain comprising SEQ ID: 1*288, preferably Nb-112). Preferably, BD comprises the amino acid of QB-GB (SEQ ID: 1*307). Preferably, BD comprises the amino acid of QB-BG. Preferably, the BD comprises the amino acid of QB-FE. Preferably, BD comprises the amino acid of SEQ ID: 1*288. For example, the BD comprises an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*288. Preferably, BD comprises the amino acid sequence of a VH or VL disclosed in Table 32 (optionally wherein in the multimer each said VH is paired with the cognate VL shown in Table 32; or optionally wherein in the multimer each said VL is paired with the cognate VH shown in Table 32, eg, the pair comprises the VH and VL of regdanvimab OR REGKINORA™, REGN10987, REGN10933 or CB6). Preferably, BD comprises the VH or VL of REGN10987 (optionally wherein in the multimer each said VH is paired with the VL of REGN10987; or optionally wherein in the multimer each said VL is paired with the VH of REGN10987). Preferably, BD comprises the VH or VL of REGN10933 (optionally wherein in the multimer each said VH is paired with the VL of REGN10933; or optionally wherein in the multimer each said VL is paired with the VH of REGN10933). Preferably, BD comprises the VH or VL of CB6 (optionally wherein in the multimer each said VH is paired with the VL of CB6; or optionally wherein in the multimer each said VL is paired with the VH of CB6). Antibody CB6 is also known as LY-CoV555. [00438] Optionally, example (a) is BD-CH1-TD, where BD= an antibody VH domain and CH1 is an antibody CH1 domain. In an embodiment, this polypeptide is paired with a second polypeptide comprising or consisting of, in N- to C-terminal direction BD2-CL, wherein BD2=an antibody VL domain, wherein the VH and VL form an antigen binding site and the CH1 pairs with the CL. An optional peptide linker may be between the TD and a domain (eg, the CH1) that is immediately N- terminal to the TD in the polypeptide. Multimerisation of 4 copies of the polypeptide using TDs produces a multimer (ie, tetramer) comprising 4 identical antigen binding sites, see, eg, Figure 53A. The invention provides such a multimer. [00439] For example, in the immediately preceding paragraph BD and BD2 respectively comprise the VH and VL of an antibody selected from regdanvimab OR REGKINORA™, REGN10987, REGN10933 and CB6 (see Table 32 for sequences). For example, the multimer comprises the monomer (middle schematic) shown in any of Figs 16-A to 16-C. For example, in the immediately preceding paragraph BD and BD2 respectively comprise the VH and VL of an antibody selected from regdanvimab OR REGKINORA™, REGN10987, REGN10933, CB6, rRBD-15 (ABLINK Biotech Co., Ltd / Chengdu Medical College), B38, H4 (Capital Medical University, Beijing), FYB-207 (Formycon AG), ABP300 (Abpro Corporation), BRII-198 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), BRII-196 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), CT-P59 (Celltrion), HFB-3013, or HFB30132A (HiFiBiO Therapeutics), MW33 (Mabwell), SAB-185 (SAB Biotherapeutics), Etesevimab (Junshi Biosciences), SCTA01 or H014 (University of Chinese Academy of Sciences), STI-1499 or COVI-GUARD (Sorrento Therapeutics), TY027 (Tychan), COVI-AMG™ or STI-2020 (Sorrento Therapeutics), HLX70 (Hengenix Biotech Inc), ADM03820 (Ology Bioservices), an antibody comprised by XAV-19 (Nantes University Hospital), BGB DXP-593 or DXP-604 (BeiGene), VIR-7831 or GSK4182136 (Vir Biotechnology, GSK), AZD8895 or AZD1061 (AstraZeneca), HBM9022 or 47D11 (AbbVie, Harbour BioMed, Utrecht University and Erasmus Medical Center), Ab8 (University of Pittsburgh), MAbCo19 (AchilleS Vaccines Srl), AR-701 or AR-711 (Aridis Pharmaceuticals), DXP-604 (BeiGene), Centi-B9 (Centivax), GIGA-2050 (GigaGen), TATX-03 or TATX-06 or TATX-09 or TATX-13 or TATX-16 (ImmunoPrecise Antibodies), MTX-COVAB (Memo Therapeutics), NOVOAB-20 (NovoAb), COVI-SHIELD (Sorrento Therapeutics), STI-4920 or ACE-MAB or CMAB020 (MabPharm), IDB003 (IDBiologics) and VIR-7832 (Vir Biotechnology, GSK). [00440] For example, the effector domain or binding domain or binding site of a polypeptide herein comprises the VH and/or VL of an antibody selected from regdanvimab OR REGKINORA™, REGN10987, REGN10933, CB6, rRBD-15 (ABLINK Biotech Co., Ltd / Chengdu Medical College), B38, H4 (Capital Medical University, Beijing), FYB-207 (Formycon AG), ABP300 (Abpro Corporation), BRII-198 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), BRII-196 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), CT-P59 (Celltrion), HFB-3013, or HFB30132A (HiFiBiO Therapeutics), MW33 (Mabwell), SAB-185 (SAB Biotherapeutics), Etesevimab (Junshi Biosciences), SCTA01 or H014 (University of Chinese Academy of Sciences), STI-1499 or COVI-GUARD (Sorrento Therapeutics), TY027 (Tychan), COVI-AMG™ or STI-2020 (Sorrento Therapeutics), HLX70 (Hengenix Biotech Inc), ADM03820 (Ology Bioservices), an antibody comprised by XAV-19 (Nantes University Hospital), BGB DXP- 593 or DXP-604 (BeiGene), VIR-7831 or GSK4182136 (Vir Biotechnology, GSK), AZD8895 or AZD1061 (AstraZeneca), HBM9022 or 47D11 (AbbVie, Harbour BioMed, Utrecht University and Erasmus Medical Center), Ab8 (University of Pittsburgh), MAbCo19 (AchilleS Vaccines Srl), AR-701 or AR-711 (Aridis Pharmaceuticals), DXP-604 (BeiGene), Centi-B9 (Centivax), GIGA- 2050 (GigaGen), TATX-03 or TATX-06 or TATX-09 or TATX-13 or TATX-16 (ImmunoPrecise Antibodies), MTX-COVAB (Memo Therapeutics), NOVOAB-20 (NovoAb), COVI-SHIELD (Sorrento Therapeutics), STI-4920 or ACE-MAB or CMAB020 (MabPharm), IDB003 (IDBiologics) and VIR-7832 (Vir Biotechnology, GSK). [00441] For example, the multimer herein comprises at least 4 copies (eg, 4, 8, 12, 16, 20, 24 or 28 copies) of the VH and/or VL of an antibody selected from regdanvimab OR REGKINORA™, REGN10987, REGN10933, CB6, rRBD-15 (ABLINK Biotech Co., Ltd / Chengdu Medical College), B38, H4 (Capital Medical University, Beijing), FYB-207 (Formycon AG), ABP300 (Abpro Corporation), BRII-198 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), BRII- 196 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), CT-P59 (Celltrion), HFB-3013, or HFB30132A (HiFiBiO Therapeutics), MW33 (Mabwell), SAB-185 (SAB Biotherapeutics), Etesevimab (Junshi Biosciences), SCTA01 or H014 (University of Chinese Academy of Sciences), STI-1499 or COVI-GUARD (Sorrento Therapeutics), TY027 (Tychan), COVI-AMG™ or STI- 2020 (Sorrento Therapeutics), HLX70 (Hengenix Biotech Inc), ADM03820 (Ology Bioservices), an antibody comprised by XAV-19 (Nantes University Hospital), BGB DXP-593 or DXP-604 (BeiGene), VIR-7831 or GSK4182136 (Vir Biotechnology, GSK), AZD8895 or AZD1061 (AstraZeneca), HBM9022 or 47D11 (AbbVie, Harbour BioMed, Utrecht University and Erasmus Medical Center), Ab8 (University of Pittsburgh), MAbCo19 (AchilleS Vaccines Srl), AR-701 or AR-711 (Aridis Pharmaceuticals), DXP-604 (BeiGene), Centi-B9 (Centivax), GIGA-2050 (GigaGen), TATX-03 or TATX-06 or TATX-09 or TATX-13 or TATX-16 (ImmunoPrecise Antibodies), MTX-COVAB (Memo Therapeutics), NOVOAB-20 (NovoAb), COVI-SHIELD (Sorrento Therapeutics), STI-4920 or ACE-MAB or CMAB020 (MabPharm), IDB003 (IDBiologics) and VIR-7832 (Vir Biotechnology, GSK). The multimer may comprise no more than said number of copies. [00442] In an example, there is a provided a tetramer of an antibody (or a fragment of an antibody, eg, a Fab of an antibody), wherein the tetramer is tetramersised using tetramerization domains (TDs). For example, the tetramer has the configuration shown in the right-hand-side schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the tetramer that are not shown in said Figure). In an example, there is provided an antibody (or a fragment of an antibody, eg, a Fab of an antibody), wherein the antibody or fragment comprises a TD (eg, a p53 TD), preferably wherein the TD is at the N-terminus of at least one of the polypeptide chains of the antibody or fragment. For example, one or both of the heavy chains of the antibody or fragment comprise a TD at its N-terminus. For example, one or both of the light chains of the antibody or fragment comprise a TD at its N-terminus. For example, the antibody or fragment has the configuration shown in the middle schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the antibody or fragment that are not shown in said Figure). In an embodiment, the antibody is an antibody disclosed in the immediately preceding paragraph. In an embodiment, there is provided a tetramer of said antibody or fragment that comprises a TD. [00443] A multimer or tetramer herein may have the configuration shown in the any one of the Figures herein (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the multimer or tetramer that are not shown in said Figure). A multimer or tetramer herein may have the configuration shown in the right-hand-side schematic of any one of Figures 14A to 14-F, 15-A to 15-L and 16-A to 16-C (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the multimer or tetramer that are not shown in said Figure). A polypeptide or monomer herein may have the configuration shown in any one of the Figures herein (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the polypeptide or monomer that are not shown in said Figure). A polypeptide or monomer herein may have the configuration shown in the middle schematic of any one of Figures 14A to 14-F, 15-A to 15-L and 16-A to 16-C (and there may further be other moieties, such as one or more additional peptides, domains or proteins comprised by the polypeptide or monomer that are not shown in said Figure). In the multimer or tetramer the multimer the multimer or tetramer may comprise 4 VH/VL pairs, such as shown in the right-hand-side schematic of any one of Figures 14A to 14-F, 15-A to 15-L and 16-A to 16-C. For example, each of said VH/VL pairs is a VH/VL antigen binding site comprised by an antibody disclosed herein eg, any antibody selected from regdanvimab OR REGKINORA™, REGN10987, REGN10933, CB6, rRBD-15 (ABLINK Biotech Co., Ltd / Chengdu Medical College), B38, H4 (Capital Medical University, Beijing), FYB-207 (Formycon AG), ABP300 (Abpro Corporation), BRII-198 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), BRII-196 (Brii Biosciences, TSB Therapeutics (Beijing) CO.LTD), CT-P59 (Celltrion), HFB-3013, or HFB30132A (HiFiBiO Therapeutics), MW33 (Mabwell), SAB-185 (SAB Biotherapeutics), Etesevimab (Junshi Biosciences), SCTA01 or H014 (University of Chinese Academy of Sciences), STI-1499 or COVI-GUARD (Sorrento Therapeutics), TY027 (Tychan), COVI-AMG™ or STI-2020 (Sorrento Therapeutics), HLX70 (Hengenix Biotech Inc), ADM03820 (Ology Bioservices), an antibody comprised by XAV-19 (Nantes University Hospital), BGB DXP- 593 or DXP-604 (BeiGene), VIR-7831 or GSK4182136 (Vir Biotechnology, GSK), AZD8895 or AZD1061 (AstraZeneca), HBM9022 or 47D11 (AbbVie, Harbour BioMed, Utrecht University and Erasmus Medical Center), Ab8 (University of Pittsburgh), MAbCo19 (AchilleS Vaccines Srl), AR-701 or AR-711 (Aridis Pharmaceuticals), DXP-604 (BeiGene), Centi-B9 (Centivax), GIGA- 2050 (GigaGen), TATX-03 or TATX-06 or TATX-09 or TATX-13 or TATX-16 (ImmunoPrecise Antibodies), MTX-COVAB (Memo Therapeutics), NOVOAB-20 (NovoAb), COVI-SHIELD (Sorrento Therapeutics), STI-4920 or ACE-MAB or CMAB020 (MabPharm), IDB003 (IDBiologics) and VIR-7832 (Vir Biotechnology, GSK). [00444] There is provided a mixture of at least 2 (eg, 2 or 3) different multimers, wherein each multimer is according to the invention. For example, a first of said multimers comprises 4 copies of an antigen binding site that is capable of binding to a first antigen; and a second of said multimers comprises 4 copies of an antigen binding site that is capable of binding to a second antigen, optionally the antigens are identical and the binding sites bind different epitopes comprised by the antigen, or the antigens are different. For example, the or each antigen is an antigen of a virus, eg, SARS-CoV or SARS-Cov-2 antigen, such as spike antigen, or the virus is influenza virus or any other virus disclosed herein. For example, wherein a first of said multimers comprises 4 copies of the SARS-CoV-2 antigen binding site of REGN10987, and a second of said multimers comprises 4 copies of the SARS-CoV-2 antigen binding site of REGN10933. [00445] For example, the binding site (eg, BD or BD2) of a polypeptide or multimer herein comprises the variable domain of Nb11-59 (Shanghai Novamab Biopharmaceuticals Co., Ltd.), MERS VHH-55, SARS VHH-72 or VHH30372-Fc. For example, the binding site (eg, BD or BD2) of a polypeptide or multimer herein comprises a Darpin of MP0420 or MP0423. [00446] Optionally, example (a) is BD-CH1-hinge-Fc-TD, where BD= an antibody VH domain and CH1 is an antibody CH1 domain, optionally the hinge is devoid of a core hinge region or is any other hinge disclosed herein and Fc is an antibody Fc region (ie, CH2-CH3). In an embodiment, this polypeptide is paired with a second polypeptide comprising or consisting of, in N- to C-terminal direction BD2-CL, wherein BD2=an antibody VL domain, wherein the VH and VL form an antigen binding site and the CH1 pairs with the CL. An optional peptide linker may be between the TD and a domain (eg, the CH3) that is immediately N-terminal to the TD in the polypeptide. Multimerisation of 4 copies of the polypeptide using TDs produces a multimer (ie, tetramer) comprising 4 identical antigen binding sites, see, eg, Figure 53C. The invention provides such a multimer. In an alternative, example (a) is BD-Fc-TD (eg, see Figures 54C, 55C) and multimers thereof are also provided by the invention, such as tetramers of such polypeptide. [00447] In an example, the invention provides a polypeptide comprising an antigen binding domain (BD), the polypeptide comprising or consisting of, in N- to C-terminal direction BD-Fc- Td, wherein Fc is an antibody Fc region. In an embodiment, there is provided a dimer of first and second copies of such a polypeptide, wherein the Fc of the first polypeptide is associated with the Fc of the second polypeptide. In an embodiment there is a dimer of such a dimer, eg, as shown in Fig 12C. Optionally, the BD is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH). Optionally in such a polypeptide, dimer or tetramer BD comprises the amino acid of QB-GB (SEQ ID: 1*307), QB-DD, QB-BG or QB-FE (see Table 23 for sequences). [00448] In an example, the invention provides a provides polypeptide comprising an antigen binding domain (BD), the polypeptide comprising or consisting of, in N- to C-terminal direction BD-CH1-Fc-Td, wherein Fc is an antibody Fc region. In an embodiment, there is provided a dimer of first and second copies of such a polypeptide, wherein the Fc of the first polypeptide is associated with the Fc of the second polypeptide. In an embodiment there is a dimer of such a dimer, eg, as shown in Fig 12E Preferably each polypeptide is paired with a further polypeptide, wherein the further polypeptide comprises, in N- to C-terminal direction, BD2-CL, wherein the CH1 pairs with the CL. Optionally, the BD is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH). Optionally, the BD2 is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH). In an alternative, BD and BD2 are a VH/VL pair that binds an antigen. The CL of said further polypeptide associates with the CH1 of the other polypeptide (see, eg, Fig 12E). Optionally in such a polypeptide, dimer or tetramer BD comprises the amino acid of QB-GB (SEQ ID: 1*307), QB-BG or QB-FE (see Table 23 for sequences). [00449] In an example, the invention provides a provides polypeptide comprising an antigen binding domain (BD), the polypeptide comprising or consisting of, in N- to C-terminal direction BD-CH1-Td, wherein CH1 is an antibody CH1. In an embodiment, there is provided a dimer of first and second copies of such a polypeptide, eg, wherein the TDs of the polypeptides are associated together. In an embodiment there is a dimer of such a dimer, eg, as shown in Fig 12I Preferably each polypeptide is paired with a further polypeptide, wherein the further polypeptide comprises, in N- to C-terminal direction, BD2-CL, wherein the CH1 pairs with the CL. Optionally, the BD is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH). Optionally, the BD2 is a single variable domain (also referred to as a domain antibody or dAb, eg, a nanobody or VHH). In an alternative, BD and BD2 are a VH/VL pair that binds an antigen. The CL of said further polypeptide associates with the CH1 of the other polypeptide (see, eg, Fig 12I. Optionally in such a polypeptide, dimer or tetramer BD comprises the amino acid of QB-GB (SEQ ID: 1*307), QB-DD, QB-BG or QB-FE (see Table 23 for sequences). [00450] BD and BD2 may be a VH/VL pair of an antigen binding site of an antibody selected from the group consisting of regdanvimab OR REGKINORA™, REGN10987, REGN10933 and CB6. [00451] There is also provided: A protein multimer comprising 4 copies of an antigen binding site of an antibody, wherein the antibody is selected from regdanvimab OR REGKINORA™, REGN10987, REGN10933 and CB6. A protein multimer comprising 4 copies of an antigen binding site of an antibody, wherein the multimer comprises a dimer of an antibody or a fragment thereof (eg, a Fab), wherein the antibody is selected from regdanvimab OR REGKINORA™, REGN10987, REGN10933 and CB6. A protein multimer comprising a dimer of an antibody or a fragment thereof (eg, a Fab), wherein the antibody is selected from regdanvimab OR REGKINORA™, REGN10987, REGN10933 and CB6. A protein multimer comprising 4 (and optionally no more than 4) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 4 (and optionally no more than 4) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 8 (and optionally no more than 8) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 8 (and optionally no more than 8) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 12 (and optionally no more than 12) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 12 (and optionally no more than 12) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 16 (and optionally no more than 16) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 16 (and optionally no more than 16) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 20 (and optionally no more than 20) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 20 (and optionally no more than 20) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 24 (and optionally no more than 24) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 24 (and optionally no more than 24) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. A protein multimer comprising 28 (and optionally no more than 28) copies of Nb-112 (SEQ ID: 1*288). A protein multimer comprising 28 (and optionally no more than 28) copies of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288. Instead of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288, the multimer comprises antibody single variable domain Nb11-59 or an antibody single variable domain comprising SEQ ID: 1*293, or an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of Nb11-59 or SEQ ID: 1*293. Reference is made to Koenig et al 2021 (Science, 2021 Feb 12;371(6530):eabe6230. doi: 10.1126/science.abe6230. Epub 2021 Jan 12, “Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape”). Instead of an antibody variable domain comprising the amino acid sequence SEQ ID: 1*288 or Nb11-59, the multimer comprises an antibody single variable domain selected from nanobodies A to W disclosed in Koenig et al, the sequences of which are incorporated in their entirety herein for use in a multimer or polypeptide as described herein. Preferably, the domain is nanobody E, U, V or W. In an alternative, each copy of the variable domain comprises an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*288, wherein the variable domain is capable of binding to a SARS-CoV-2 antigen, eg, spike. In an alternative, each copy of the variable domain is Nb11-59 or an antibody single variable domain comprising SEQ ID: 1*293. Herein, in any part of the disclosure where NB11-59 is mentioned, in an alternative an antibody single variable domain is used wherein the domain comprises a HCDR3 comprising SEQ ID: 1*294. Usefully, the invention provides a pharmaceutical composition for inhaled delivery to a patient (eg, a patient suffering from or at risk of SARS-CoV-2 infection), wherein the composition comprises a multimer of the invention. Preferably, the multimer comprises copies of Nb-112 or a variable domain comprising SEQ ID: 1*288. Preferably, the multimer comprises copies of Nb11-59 or an antibody single variable domain comprising SEQ ID: 1*293, or an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of Nb11-59 or SEQ ID: 1*293. The invention also provides a nebuliser or inhaler device comprising such a composition. There is also provided a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing a lung condition. There is also provided a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing a SARS-CoV-2 infection. There is also provided a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing an inflammatory condition. There is also provided a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing pneumonia. There is also provided a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing a cough. There is also provided a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing loss of smell and/or taste. There is also provided a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing an elevated temperature (eg, a temperature greater than 38, 39 or 40 degrees centrigrade, eg, 37.8 degrees centrigrade or greater). There is also provided a multimer or composition of the invention for inhaled administration to a human or animal patient for treating or preventing COVID or a symptom thereof. Advantageously, the multimer may comprise mammalian cell glycosylation. The multimer may, for example, comprise 8, 12, 16, 20 or 24 copies of the binding site (eg, VHH). The multimer may contain 4 (but no more than 4) copies of the binding site (eg, VHH). The binding site may be anti-SARS-CoV-2 antigen VH/VL pair comprised by the antibody. [00452] Advantageously, as shown in Example 33, a VH or VHH herein may be a VH3 family VH or VHH. As shown in the example, multimerization of such a variable domain can surprisingly produce a multimer of the invention that can be readily purified by binding to protein A. Thus, preferably, the multimer can be devoid of an affinity tag, such as a His tag. [00453] Herein, any Fc may be a human antibody Fc. Herein, an Fc may be a gamma antibody Fc, mu antibody Fc, delta antibody Fc, epsilon antibody Fc or alpha antibody Fc, preferably a gamma (eg, gamma-1, gamma-2, gamma-3 or gamma-4) antibody Fc (preferably a gamma-1 antibody Fc). [00454] Optionally, the invention provides a protein multimer comprising the configuration of ACE2-TD shown in Figure 54B. The multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure. [00455] Optionally, the invention provides a protein multimer comprising the configuration of ACE2 monomeric Ig-TD shown in Figure 54C. The multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure. [00456] Optionally, the invention provides a protein multimer comprising the configuration of ACE2 dimer-TD shown in Figure 54D. The multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure. [00457] Optionally, the invention provides a protein multimer comprising the configuration of ACE2- Ig-TD shown in Figure 54E. The multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure. [00458] Optionally, the invention provides a protein multimer comprising the configuration of BD- Heavy Chain Only -TD shown in Figure 55C. The multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure. [00459] Optionally, the invention provides a protein multimer comprising the configuration of BD- Ig-TD shown in Figure 55B. The multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure. [00460] Optionally, the invention provides a protein multimer comprising the configuration of BD- Fab-like -TD shown in Figure 55B. The multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure. [00461] Optionally, the invention provides a protein multimer comprising the configuration of BD- Fab-like monomeric Ig-TD shown in Figure 55E. The multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure. [00462] Optionally, the invention provides a protein multimer comprising the configuration of Dimeric-TD shown in Figure 55H. The multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure. [00463] Optionally, the invention provides a protein multimer comprising the configuration of BD- Fab’-like -TD shown in Figure 55F. The multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure. [00464] Optionally, the invention provides a protein multimer comprising the configuration of BD- monomeric Ig-TD shown in Figure 55G. The multimer may comprise further moieties, such as protein domains or peptides than are shown in the figure. [00465] Optionally, BD-TD denotes the binding domain directly linked N-terminal to the TD. [00466] Optionally, TD-BD denotes the binding domain directly linked C-terminal to the TD. [00467] Optionally, BD-BD denotes the binding domains directly linked to each other. [00468] Optionally, 2 copies of the polypeptide are associated or joined together so that the N- and C-termini of each polypeptide is not directly joined to the other polypeptide to form a polypeptide dimer (eg, see Figure 54D or 55C). For example, the polypeptides of the dimer are disulphide bonded to each other. For example, Fc dimerisation between 2 copies of the polypeptide produce a dimer, wherein the polypeptide comprises an antibody Fc. The invention, in an embodiment, provides a multimer (ie, tetramer) comprising 2 identical copies of the dimer (ie, comprising 4 copies of the polypeptide), wherein the multimer comprises at least 4 copies of BD. For example, each polyeptide has only one BD, wherein the multimer has 4 copies of BD. In another example, each polyeptide has only 2 copies of BD, wherein the multimer has 8 copies of BD. In another example, each polyeptide has only 3 copies of BD, wherein the multimer has 12 copies of BD. [00469] The BD or binding domain herein may be a binding domain disclosed in Table 23, eg, QB- GB, QB-BG or QB-FE (see Table 23 for sequences), or as disclosed in Table 32. The VH/VL pair may be a VH/VL pair of antibody CR3022: CR3022 VH (ie, QMQLVQSGTEVKKPGESLKISCKGSGYGFITYWIGWVRQMPGKGLEWMGIIYPGDSETR YSPSFQGQVTISADKSINTAYLQWSSLKASDTAIYYCAGGSGISTPMDVWGQGTTVTV) paired with CR3022 VL (ie, DIQLTQSPDSLAVSLGERATINCKSSQSVLYSSINKNYLAWYQQKPGQPPKLLIYWASTRE SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPYTFGQGTKVEIK). [00470] In an alternative, instead of BD, the polypeptide comprises or contains a peptide (eg, an insulin peptide or a superantigen peptide or domain) or a receptor (eg, ACE2 ECD). See, eg, Figure 54C. Exemplary superantigens (eg protein G, A or L) and peptides and domains thereof are disclosed herein. [00471] The invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 copies of a binding domain or a peptide. For example, the binding domain may be any binding domain disclosed herein. [00472] The invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 8 copies of a binding domain or a peptide. For example, the binding domain may be any binding domain disclosed herein. [00473] The invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 16 copies of a binding domain or a peptide. For example, the binding domain may be any binding domain disclosed herein. [00474] The invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 20 copies of a binding domain or a peptide. For example, the binding domain may be any binding domain disclosed herein. [00475] The invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 24 copies of a binding domain or a peptide. For example, the binding domain may be any binding domain disclosed herein. [00476] Herein, by “comprising” said number of copies of the binding domain or peptide, the multimer may, for example, comprise no more than said number of the domain or peptide. For example, the multimer may contain exactly said number of copies of the binding domain or peptide. [00477] The invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 copies of a first binding domain or a peptide; and 4 copies of a second binding domain or a peptide, wherein the first and second binding domains are different (eg, they bind to different antigens of a virus, eg, a coronavirus or HIV or influenza, or immune checkpoint antigens, or cytokine antigens, or growth factor antigens, or venom (eg, snake venom) antigens). For example, the first binding domain may be any binding domain disclosed herein. For example, the second binding domain may be any binding domain disclosed herein. [00478] The invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 or 8 copies of a first binding domain or a peptide; and 4 copies of a second binding domain or a peptide, wherein the first and second binding domains are different (eg, they bind to different antigens of a virus, eg, a coronavirus or HIV or influenza, or immune checkpoint antigens, or cytokine antigens, or growth factor antigens, or venom (eg, snake venom) antigens). For example, the first binding domain may be any binding domain disclosed herein. For example, the second binding domain may be any binding domain disclosed herein. [00479] The invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 or 8 copies of a first binding domain or a peptide; and 8 copies of a second binding domain or a peptide, wherein the first and second binding domains are different (eg, they bind to different antigens of a virus, eg, a coronavirus or HIV or influenza, or immune checkpoint antigens, or cytokine antigens, or growth factor antigens, or venom (eg, snake venom) antigens). For example, the first binding domain may be any binding domain disclosed herein. For example, the second binding domain may be any binding domain disclosed herein. [00480] The invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 copies of a first binding domain or a peptide; 4 copies of a second binding domain or a peptide; and 4 copies of a third binding domain or a peptide, wherein the first, seond and third binding domains are different from each other (eg, they bind to different antigens of a virus, eg, a coronavirus or HIV or influenza, or immune checkpoint antigens, or cytokine antigens, or growth factor antigens, or venom (eg, snake venom) antigens). For example, the first binding domain may be any binding domain disclosed herein. For example, the second binding domain may be any binding domain disclosed herein. For example, the third binding domain may be any binding domain disclosed herein. [00481] The invention comprises a multimer (eg, a multimer described elsewhere herein) comprising 4 copies of a first binding domain or a peptide; 4 copies of a second binding domain or a peptide; 4 copies of a third binding domain or a peptide; and 4 copies of a fourth binding domain or a peptide, wherein the first, second, third and fourth binding domains are different from each other (eg, they bind to different antigens of a virus, eg, a coronavirus or HIV or influenza, or immune checkpoint antigens, or cytokine antigens, or growth factor antigens, or venom (eg, snake venom) antigens). For example, the first binding domain may be any binding domain disclosed herein. For example, the second binding domain may be any binding domain disclosed herein. For example, the third binding domain may be any binding domain disclosed herein. For example, the fourth binding domain may be any binding domain disclosed herein. [00482] Optionally, the multimer comprises said number of first and second binding domains. Optionally, the multimer comprises said number of first and second peptides. [00483] Optionally, the multimer comprises mammalian cell (eg, human cell) glycosylation. [00484] Optionally, the multimer binds to the antigen with an affinity of less than 200, 150, 100, 90, 80, 70, 60, 50, 40, 35, 30, 25, 20, 15 or 10 pM (preferably less than 40 or 20 pM) in an ELISA assay, such as an ELISA assy disclosed herein. Optionally, the multimer binds to the antigen with an affinity of less than 200, 150, 100, 90, 80, 70, 60, 50, 40, 35, 30, 25, 20, 15 or 10 pM (preferably less than 40 or 20 pM) in an SPR assay, such as an SPR assy disclosed herein. In an embodiment of these options, the multimer comprises or contains 16 copies of a binding domain or peptide. [00485] Optionally, the multimer neutralises the antigen with an IC50 of less than 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 nM (preferably from 0.06 to 0.01 nM) in an ELISA assay, such as an ELISA assay disclosed herein. Optionally, the multimer neutralises the antigen with an IC50 of less than 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 nM (preferably from 0.06 to 0.01 nM) in an SPR assay, such as an SPR assay disclosed herein. In an embodiment of these options, the multimer comprises or contains 16 copies of a binding domain or peptide. [00486] In an embodiment, the multimer comprises anti-coronavirus (eg, SARS-Cov-2) spike protein binding sites or receptor peptides, wherein the multimer binds to spike trimer or spike RBD. For example, the binding is with an affinity of less than 200, 150, 100, 90, 80, 70, 60, 50, 40, 35, 30, 25, 20, 15 or 10 pM (preferably less than 40 or 20 pM) in an SPR assay, such as an SPR assay disclosed herein; or in an ELISA assay, such as an ELISA assay disclosed herein (eg, an assay as disclosed in Example 28). See, eg, Example 28. [00487] An antigen binding domain or site comprised by a polypeptide or multimer of the invention may be any binding domain or binding site selected from those disclosed herein (eg, any VH, VL, dAb, VHH or scFv) or may be a binding domain or binding site that comprises an amino acid sequence that is at least 70, 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of said selected domain or site. [00488] An antigen binding domain or site comprised by a polypeptide or multimer of the invention may be any binding domain or binding site selected from those disclosed herein (eg, any VH, VL, dAb, VHH or scFv) or may be a binding domain or binding site that comprises an amino acid sequence that is identical to the amino acid sequence of said selected domain or site except for 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid differences (eg, conseravative amino acid changes). [00489] An antigen binding domain or site comprised by a polypeptide or multimer of the invention may be a domain or site that competes with any binding domain or binding site selected from those disclosed herein (eg, any VH, VL, dAb, VHH or scFv) for binding to the antigen. Competition may be determined by a standard competition assay, such as an SPR competition assay or an ELISA assay. [00490] A polypeptide of the invention may have a configuration shown for a polypeptide in any of the figures herein. A multimer (eg, polyeptide dimer or tetramer) of the invention may have a configuration shown for a multimer in any of the figures herein. [00491] In a configuration, the invention provides: A protein multimer comprising or containing 8 copies of a peptide or an antigen binding site, (optionally wherein the antigen is a virus spike protein of a first virus, optionally wherein the multimer is capable of binding to the first and a second virus, wherein the viruses are different). The term “comprising” is open language wherein more than 8 copies of the peptide or binding site are possible in embodiments of the multimer. The term “containing” is closed language wherein 8 (but not more or less than 8) copies are present in the multimer. The term “comprising or containing” or “comprises or contains” herein is to be construed accordingly. [00492] In an alternative, the multimer comprises or contains 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 copies of the peptide or binding site. Preferably, the multimer comprises or contains 4, 8, 12, 16, 20, 24, 28, 32 or 36 copies of the peptide or binding site. For example, the binding site is a VH/VL pair comprising VH-ICC paired with VL-ICC or VH-IHG paired with VL-IHG. For example, the binding site comprises QB-GB, QB-DD, QB-BG or QB-FE. [00493] Optionally, the multimer comprises or contains 16 copies of the peptide or binding site. [00494] Optionally, the multimer comprises (i) 4 copies of a polypeptide, wherein each polypeptide copy comprises a tetramerization domain and 2 or more (eg, 2, 3 or 4) copies of the peptide or binding site; or (ii) 4 copies of a dimer of a polypeptide, wherein each polypeptide copy comprises a tetramerization domain and 1 or more (eg, 2) copies of the peptide or binding site. [00495] Optionally, the polypeptide comprises a self-assembly multimerization domain (SAM) (preferably a tetramerization domain (TD)) and one or more copies of an antigen binding site (BD), the polypeptide comprising or consisting of, in N- to C-terminal direction BD-TD; TD-BD; BD-BD-TD; TD-BD-BD; BD-TD-BD-BD; BD-BD-TD-BD; or BD-BD-TD-BD-BD. [00496] Optionally, the BD is a single variable domain. [00497] Optionally, the BD comprises the amino acid sequence of QB-GB (SEQ ID: 1*307), QB-DD, QB-BG or QB-FE. [00498] Optionally, the polypeptide comprises, in N- to C-terminal direction, BD-CH1-TD, BD-CL-TD, BD-CH1-Fc-TD or BD-Fc-TD, where BD is an antibody V domain (eg, a VH), Fc is an antibody Fc region, and CH1 is an antibody CH1 domain; and optionally each BD-CH1-TD or BD- CH1-Fc-TD polypeptide of the multimer is paired with a respective second polypeptide, wherein the second polypeptide comprises, in N- to C-terminal direction BD2-CL, wherein BD2 is an antibody V domain (eg, a VL or single variable domain), wherein the CH1 pairs with the CL. [00499] In an example, tandam dAbs are provided N-termial to the TD, preferably at the N- terminus of the polypeptide. For example the polypeptide comprises, in N- to C-terminal direction, BD’-optionaly linker-BD-CH1-TD, BD’-optionaly linker-BD -CL-TD, BD’-optionaly linker-BD - CH1-Fc-TD or BD’-optionaly linker-BD -Fc-TD, wherein each of BD and BD’ is an antibody single variable domain (eg, a nanobody), Fc is an antibody Fc region, and CH1 is an antibody CH1 domain. BD’ and BD may be the same or different (eg, comprising different antigen specificities). [00500] In an example, the dimer comprises a first polypeptide comprising, in N- to C-terminal direction, BD-hinge-TD; BD’-optional linker-BD-Hinge-TD; or BD-optional linker-CH1-Hinge-TD. Optionally the first polypeptide is associated with a second polypeptide. In an embodiment, the second polypeptide comprises, in N- to C-terminal direction, BD’’-optional Linker 1-BD-optional linker 2-CL (kappa or lambda) (eg, BD’’- Linker 1-BD-optional linker 2-CL; BD’’-BD-optional linker-CL; or BD’’-BD-CL), wherein the first polyeptide comprises a CH1 domain that is paired with the CL, and wherein each of BD and BD’ is an antibody single variable domain (eg, a nanobody). [00501] Optionally, (i) each of BD and BD2 is an antibody single variable domain; or (ii) BD1 is an antibody VH domain and BD2 is an antibody VL domain, wherein the VH and VL form a VH/VL pair comprising an antigen binding site. [00502] Optionally, the polypeptide comprises, in N- to C-terminal direction, BD-CH1-Fc-TD or BD-CH1-Linker-Fc-TD (optionally wherein the Linker is an antibody hinge, wherein the hinge is devoid of a core hinge region). [00503] In configuration, the invention further provides:- A protein dimer containing 2 copies of the polypeptide. A protein dimer containing 2 copies of a polypeptide as described herein. A protein dimer comprising first and second polypeptides, wherein each polypeptide is a polypeptide disclosed herein. A 4-chain multimer (eg, an antibody) comprising a dimer of the invention, wherein a first polypeptide of the dimer is associated with a second polypeptide of the dimer, wherein a third polypeptide is associated with the first polypeptide and a fourth polypeptide is associated with the second polypeptide. For example, the first and second polypeptides are antibody heavy chains and the third and fourth polypeptides are light chains. For example, the first and third polypetides are associated together and comprise a first antigen binding site that is capable of binding to a first antigen; and the second and fourth polypeptides are associated together and comprise a second antigen binding site that is capable of binding to a second antigen. Optionally, the first and second antigens are different. Optionally, the first and second binding sites are different. For example, each binding site comprises a VH/VL pair. For example, the first and third polypeptides comprise first and second single variable domains, wherein each single variable domain is capable of binding a respective antigen (eg, different antigens) and/or (i) the second and fourth polypeptides comprise third and fourth single variable domains, wherein each single variable domain is capable of binding a respective antigen (eg, different antigens) or (ii) the second and fourth polypeptides are associated together and comprise a VH/VL pair that is capable of binding to an antigen. Optionally, a multimer herein is multispecific for antigen binding, eg, bispecific, trispecific or tetraspecific. The polypeptides are associated together, eg, a Fc region of a first polypeptide of the dimer is associated with a Fc of a second polypeptide of the dimer. In an example, each polypeptide comprises a TD. [00504] Optionally, the (or the first) polypeptide comprises, in N- to C-terminal direction, BD- TD. [00505] Optionally, the 2 copies of the polypeptide are disulphide bonded together in the dimer. [00506] The invention also provides: A protein dimer containing 2 copies of a polypeptide recited herein, wherein the polypeptide comprises BD-CH1-Fc-TD, wherein the Fc regions of the polypeptides associate with each other to form the dimer. [00507] The invention also provides: A multimer comprising or containing 4 copies of the dimer of the invention. [00508] The invention also provides: [00509] A polypeptide as recited for the multimer or dimer of the invention. Optionally, the polypeptide is isolated or recombinant. [00510] The multimer, dimer or polypeptide may be comprised by a medical or sterile container, eg, a syringe, vial, IV bag, container connected to a needle or a subcutaneous injection administration device. [00511] Optionally, the antigen is a viral antigen, bacterial antigen, fungal antigen, toxin antigen, venom antigen, immune checkpoint protein antigen, cytokine antigen, growth factor antigen, hormone antigen (eg, chorionic gonadotropin), sugar antigen, lipid antigen or protein antigen. [00512] Optionally, BD and BD2 are different from each other and each comprises a binding site for an antigen of a virus, an antigen of a bacterium, an antigen of a fungus, an antigen of a toxin, an antigen of a venom, an antigen of an immune checkpoint protein, an antigen of a cytokine, an antigen of a growth factor antigen or an antigen of a hormone; optionally wherein both BD and B2 comprises a binding site for a virus. [00513] Optionally, the multimer binds to the antigen with an affinity of less than 200 pM in an ELISA assay; and/or the multimer neutralises the antigen with an IC50 of less than 0.2 nM in an ELISA assay. [00514] Optionally, the multimer is capable of detectably binding to anti-first antigen antibodies (optionally anti-SARS-Cov-2 spike antibodies) in an ELISA assay, wherein detection of the multimer binding is measured by OD450 and the assay comprises (a) Diluting a serum sample of a mammal between 100 and 106-fold; (b) Contacting the antigen (eg, SARS-Cov-2 spike protein) with the serum sample (which has been diluted in step (a)) whereby anti-first antigen (eg, anti-SARS-Cov-2 spike) antibodies present in the sample bind to the antigen (eg, spike protein), wherein the antigen protein is immobilised on a solid surface; (c) Contacting the bound antibodies with copies of the multimer of any preceding claim and (d) Detecting multimer bound to antibody. [00515] Optionally, the dilution is 1000 to 1,000,000, 100,000 or 10000-fold (preferably 10,000 to 100,000-fold). [00516] The invention provides: A method of detecting the presence of anti-first antigen antibodies (eg, anti-SARS-Cov-2 spike antibodies) in a bodily fluid sample of a human or animal, the method comprising carrying out an ELISA assay, and the assay comprises (a) Optionally diluting the serum sample from 10 to 106-fold; (b) contacting the first antigen (eg, SARS-Cov-2 spike protein) with the sample (optionally which has been diluted in step (a)) whereby anti-first antigen (eg, anti- SARS-Cov-2 spike) antibodies present in the sample bind to the first antigen (eg, spike protein) to produce antigen/antibody complexes; and (c) contacting and binding the first antigen or anti-first antigen (eg, anti-SARS-Cov-2 spike) antibodies with copies of the multimer of any one of claims 1 to 9, 14 and 16 to 19 and (d) detecting multimer bound to antigen/antibody complexes, the detecting optionally comprising detection of the multimer binding by determining optical density, such as OD450; (e) wherein the steps can be carried out in the order (a) (b) (c) and (d) or (a) (c) (b) and
Figure imgf000189_0001
(d), or wherein steps (b) and (c) are carried out simultaneously and between steps (a) and (d). [00517] Optionally, the presence of anti-first antigen antibodies in the sample is detected when the optical density (eg, OD450) is greater than 0.1 or 0.5 (optionally, greater than 1, 1.5 or 2) in the assay. Optionally, the dilution is 1000 to 1,000,000, 100,000 or 10000-fold (preferably 10,000 to 100,000-fold). [00518] Optionally, the binding site is (a) QB-GB, QB-DD, QB-FE or QB-BG; (b) The spike protein binding site of an antibody selected from 80R, CR3014, CR3006, CR3013 and CR3022; (c) An anti-SARS-Cov-2 antigen binding site of an antibody selected from regdanvimab OR REGKINORA™, REGN10987, REGN10933, CB6, rRBD-15, B38, H4, FYB- 207, ABP300, BRII-198, BRII-196, CT-P59, HFB-3013, HFB30132A, MW33, SAB- 185, Etesevimab, SCTA01, H014, STI-1499, COVI-GUARD™, TY027, COVI- AMG™, STI-2020, HLX70, ADM03820, an XAV-19 antibody, BGB DXP-593, DXP-604, VIR-7831, GSK4182136, AZD8895, AZD1061, HBM9022, 47D11, Ab8, MAbCo19, AR-701, AR-711, DXP-604, Centi-B9, GIGA-2050, TATX-03, TATX- 06, TATX-09, TATX-13, TATX-16, NOVOAB-20, COVI-SHIELD™, STI-4920, ACE-MAB, CMAB020, IDB003 and VIR-78320; or a VH or VL thereof; (d) A viral antigen binding site of an antibody selected from the antibodies of Table 21; (e) A viral antigen binding site disclosed in Table 23 or Table 32; (f) An ACE2 protein which is capable of binding to the first virus spike protein; (g) An ACE2 protein disclosed in Table 24; (h) A TMPRSS2 protein which is capable of binding to the first virus spike protein; (i) Protein G or a fragment thereof; (j) Protein A or a fragment thereof; (k) Protein L or a fragment thereof; (l) an Ig binding domain disclosed herein (eg, as disclosed in Table 25); (m) an antibody VH/VL pair, wherein the VH comprises an amino acid sequence selected from a VH sequence disclosed herein (eg, SEQ ID: O) and the VL comprises an amino acid sequence selected from a respective VL sequence disclosed herein (eg, SEQ ID: P) (optionally wherein the VH is encoded by the DNA sequence of VH-ICC or VH-IHG and the VL is encoded by the DNA sequence of VL-ICC or VL-IHG respectively); (n) an antibody single variable domain comprising the amino acid sequence of SEQ ID: 1*288 or an amino acid sequence that is at least 80% (eg, at least 80, 85, 90, 95, 96, 97, 98 or 99%) identical to SEQ ID: 1*288; (o) antibody single variable domain Nb11-59 or or an antibody single variable domains comprising SEQ ID: 1*203, or an antibody single variable domain comprising amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of Nb11-59 or SEQ ID: 1*293; or (p) the spike protein binding site of regdanvimab or REGKINORA™; or a VH or VL thereof. [00519] Optionally, the multimers are immobilised on a solid surface; or the first antigen is immobilised on a solid surface. [00520] Optionally, determining optical density (eg, OD450) comprises labelling complexes comprising spike protein and multimers with horseradish peroxidase (HRP) and detecting the label (eg, at a wavelength of 450 nm). [00521] For the multimer, dimer, polypeptide or method, each multimer may comprise a polypeptide; or variable domain or binding site amino acid disclosed herein. [00522] The invention provides: A multimer comprising 4 copies of a binding site for an antigen, wherein the multimer comprises a dimer of an antibody or a dimer of an antigen binding fragment (eg, Fab) of an antibody, optionally wherein the multimer is according to any preceding claim. The antibody can be any antibody disclosed herein, eg, an antibody selected from regdanvimab or REGKINORA™, regdanvimab OR REGKINORA™, REGN10987, REGN10933, CB6, rRBD-15, B38, H4, FYB- 207, ABP300, BRII-198, BRII-196, CT-P59, HFB-3013, HFB30132A, MW33, SAB-185, Etesevimab, SCTA01, H014, STI-1499, COVI-GUARD™, TY027, COVI-AMG™, STI-2020, HLX70, ADM03820, an XAV-19 antibody, BGB DXP-593, DXP-604, VIR-7831, GSK4182136, AZD8895, AZD1061, HBM9022, 47D11, Ab8, MAbCo19, AR-701, AR-711, DXP-604, Centi- B9, GIGA-2050, TATX-03, TATX-06, TATX-09, TATX-13, TATX-16, NOVOAB-20, COVI- SHIELD™, STI-4920, ACE-MAB, CMAB020, IDB003 and VIR-7832. [00523] The multimer may be a tetramer having a configuration shown in the right-hand-side schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C (eg, Fig 16A, 16B or 16C, optionally wherein the VH and VL pair is a VH/VL pair of an antigen binding site of an antibody selected from the group consisting of regdanvimab or REGKINORA™, REGN10987, REGN10933 and CB6); or wherein the polypeptdide herein may be a polypeptide having a configuration shown in the middle schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C; or the dimer may be a dimer of any such polypeptide. The multimer may be a tetramer having a configuration shown in the right-hand-side schematic of Figure 62A or 62B. [00524] Optionally, (a) the multimer is a tetramer having a configuration shown in the right-hand-side schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C (eg, Fig 16A, 16B or 16C, optionally wherein the VH and VL pair is a VH/VL pair of an antigen binding site of an antibody selected from the group consisting of regdanvimab or REGKINORA™, REGN10987, REGN10933 and CB6); or wherein the polypeptdide is a polypeptide having a configuration shown in the middle schematic of any one of Figures 14C, 14-D, 15-I, 15-J and 16-A to 16-C; or the dimer is a dimer of any such polypeptide; optionally wherein each VH and each VL is a VH and VL of an antigen binding site of an antibody selected from the group consisting of regdanvimab OR REGKINORA™, REGN10987, REGN10933 and CB6; (b) the multimer is a tetramer of 4 copies of a polypeptide, wherein each polypeptide comprises an amino acid sequence selected from SEQs: 1*232, 1*233, 1*234, 1*235, 1*236, 1*237, 1*238 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*240), 1*239 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*287), 1*241, 1*242, 1*243, 1*244, 1*245 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*240 or 1*286), 1*246 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*240), 1*247 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*287), 1*248 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*240), 1*249 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*287), 1*250 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*253), 1*251 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*253), 1*252 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*253), 1*254 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*257), 1*255 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*257), 1*256 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*257), 1*258 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*261), 1*259 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*261) and 1*260 (optionally wherein the polypeptide is paired with a polypeptide comprising SEQ ID: 1*261); (c) the multimer comprises 4 copies of an antigen binding site, wherein the binding site comprises a VH/VL pair, wherein the VH and VL are respectively encoded by the nucleotide sequences of SEQ IDs: 1*268 and 1*269, 1*270 and 1*271, 1*272 and 1*273, 1*274 and 1*275, 1*276 and 1*277, 1*278 and 1*279, 1*280 and 1*281, 1*282 and 1*283, or 1*284 and 1*285; the polypeptide comprises a copy of such a binding site; or the dimer comprises 2 copies of such a binding site; or (d) wherein the multimer comprises 4 copies of an antigen binding site, wherein the binding site comprises a VH/VL pair, wherein the VH and VL respectively comprise the amino acid sequences of SEQ IDs: 1*262 and 1*263, 1*264 and 1*265, or 1*266 and 1*267; the polypeptide comprises a copy of such a binding site; or the dimer comprises 2 copies of such a binding site. [00525] Optionally, any multimer herein comprises 4 (eg, no more than 4) copies of any antibody variable domain disclosed herein, eg, a variable domain comprising SEQ ID: O or P. [00526] The invention provides: A pharmaceutical composition or assay reagent comprising a plurality of multimers of the invention, optionally wherein the reagent comprises said multimers immobilised on a solid support. A multimer of the invention (or a combination of at least 2 or 3 multimers of the invention claim) for administration to a human or animal subject for medical use. [00527] There is provided a composition comprising a multimer of the invention, eg, for medical use or for use in vitro. [00528] A VH herein may be a VH encoded by a VH DNA sequence shown in Table 21(b) and a VL herein may be a VL encoded by the cognate VL DNA sequence shown in Table 21(b) , wherein the VH and VL form an antigen binding VH/VL pair (eg, that is capable of binding to a SARS-CoV-2 antigen, such as spike antigen). Alternatively, the VH sequence is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VH DNA sequence; and/or the VL sequence is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VL DNA sequence. In an example, the VH DNA sequence is VH-ICC (see Table 21(b)) or a VH sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VH-ICC DNA sequence; and the VL DNA sequence is VL-ICC (see Table 21(b)) or a VL sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VL-ICC DNA sequence. In an example, the VH DNA sequence is VH-IHG (see Table 21(b)) or a VH sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VH-IHG DNA sequence; and the VL DNA sequence is VL-IHG (see Table 21(b)) or a VL sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to said VL-IHG DNA sequence. [00529] A VH herein may comprise the amino acid sequence of SEQ ID: 1*288 or an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: 1*288. Preferably, such a VH is unpaired with a second variable domain (eg, a VL), since the VH in this instance is a single variable domain, it is able to bind to a SARS-Cov-2 antigen (eg, spike) without requirement for pairing. [00530] A VH herein may comprise antibody single variable domain Nb11-59 (Novamab Biopharmaceuticals Co. Ltd) or an antibody single variable domain of ALX-0171 (Ablynx). A VH herein may comprise antibody single variable domain comprising SEQ ID: 1*203, or an antibody single variable domain comprising amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of Nb11-59 or SEQ ID: 1*293. [00531] [00532] Optionally, the combination comprises first and second multimers of the invention, wherein the first multimer comprises a binding site comprising a first VH/VL pair and the second multimer comprises a second VH/VL pair which is different from the first VH/VL pair. In an example, the VH of the first VH/VL pair is encoded by the DNA sequence of VH-ICC and the VL is encoded by the DNA sequence of VL-ICC. In an example, the VH of the first VH/VL pair is encoded by the DNA sequence of VH-IHG and the VL is encoded by the DNA sequence of VL-IHG. [00533] In an example, the VH of the first VH/VL pair is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VH-ICC and the VL is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VL-ICC. In an example, the VH of the first VH/VL pair is encoded by the DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VH-IHG and the VL is encoded by the DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VL-IHG. [00534] Optionally, the multimer comprises first and second antigen binding sites which are different from each other. For example, the first binding site comprises a first VH/VL pair and the second binding site comprises a second VH/VL pair. In an example, the VH of the first VH/VL pair is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to a first VH DNA sequence disclosed in Table 21(b) and the VL is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the cognate VL DNA sequence disclosed in Table 21(b); and the VH of the second VH/VL pair is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to a second VH DNA sequence disclosed in Table 21(b) and the VL is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the cognate VL DNA sequence disclosed in Table 21(b), wherein the first and second VH DNA sequences are different. For example, the first VH DNA sequence is the sequence of VH-IHI (see Table 21(b)), the cognate VH DNA sequence is VL-IHI; and the second VH DNA sequence is the sequence of VH-IHG, VH-ICC, VH-ICD, VH-IGG, VH-IFD, VH-IED, VH-IHD or VH-IHF. For example, the first VH DNA sequence is the sequence of VH-IHG (see Table 21(b)), the cognate VH DNA sequence is VL-IHG; and the second VH DNA sequence is the sequence of VH-IHI, VH-ICC, VH-ICD, VH-IGG, VH-IFD, VH-IED, VH-IHD or VH-IHF. For example, the first VH DNA sequence is the sequence of VH-ICC (see Table 21(b)), the cognate VH DNA sequence is VL-ICC; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHQ, VH-ICD, VH-IGG, VH- IFD, VH-IED, VH-IHD or VH-IHF. For example, the first VH DNA sequence is the sequence of VH-ICD (see Table 21(b)), the cognate VH DNA sequence is VL-ICD; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHI, VH-ICC, VH-IGG, VH-IFD, VH-IED, VH-IHD or VH-IHF. For example, the first VH DNA sequence is the sequence of VH-IGG (see Table 21(b)), the cognate VH DNA sequence is VL-IGG; and the second VH DNA sequence is the sequence of VH- ICC, VH-ICD, VH-IHI, VH-IFD, VH-IED, VH-IHD or VH-IHF. For example, the first VH DNA sequence is the sequence of VH-IFD (see Table 21(b)), the cognate VH DNA sequence is VL-IFD; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHI, VH-ICC, VH-ICD, VH-GG, VH-IED, VH-IHD or VH-IHF. For example, the first VH DNA sequence is the sequence of VH-IED (see Table 21(b)), the cognate VH DNA sequence is VL-IED; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHI, VH-ICC, VH-ICD, VH-IGG, VH-IFD, VH-IHD or VH-IHF. For example, the first VH DNA sequence is the sequence of VH-IHD (see Table 21(b)), the cognate VH DNA sequence is VL-IHD; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHI, VH-ICC, VH-ICD, VH-GG, VH-IFD, VH-IED, or VH-IHF. For example, the first VH DNA sequence is the sequence of VH-IHF (see Table 21(b)), the cognate VH DNA sequence is VL-IHF; and the second VH DNA sequence is the sequence of VH-IHG, VH-IHI, VH-ICC, VH-ICD, VH-GG, VH-IFD, VH-IED or VH-IHD. Preferably, the second VH DNA sequence is VH-ICC or VH-IHG. [00535] Optionally, the multimer comprises first and second antigen binding sites which are different from each other. For example, the first binding site comprises a first VH/VL pair and the second binding site comprises a second VH/VL pair. In an example, the VH of the first VH/VL pair is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VH-ICC and the VL is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VL-ICC; and the VH of the second VH/VL pair is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VH-IHG and the VL is encoded by a DNA sequence that is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical (or 100% identical) to the DNA sequence of VL-IHG. For example, the multimer comprises (i) at least 4, 8, 12, 16, 20, 24 or 28 (optionally no more than 4, 8, 12, 16, 20, 24 or 28 respectively) copies of a further antibody variable domain that is different from the domain of (i). For example, each domain is capable of specifically binding to a SARS-CoV-2 antigen. [00536] In an embodiment, the multimer comprises a tetramer of a polyeptide dimer, wherein the dimer comprises a first polypeptide associated with a second polypeptide, wherein the first polypeptide comprises at least one copy of a first peptide or a first antigen binding site and a teramerisation domain (TD), the second polypeptide comprises at least one copy of a second peptide or a second antigen binding site and a teramerisation domain (TD). [00537] Preferably, the TDs of the first and second polypeptides are identical. Optionally, the TDs are p53 TDs, such as human p53 TDs. In one embodiment, each of the first and second polypeptides comprises a said peptide and the first and second peptides are different. In one embodiment, each of the first and second polypeptides comprises a said peptide and the first and second peptides are the same. In one embodiment, each of the first and second polypeptides comprises a said binding site and the first and second binding sites are different. [00538] In one embodiment, each of the first and second polypeptides comprises a said binding site and the first and second binding sites are the same. In an example, in each dimer the first and second polypeptides are disulphide bonded together. [00539] In an example, in each dimer the first polypeptide comprises an antibody CH3 domain (eg, a CH2-CH3) and the second polypeptide comprises an antibody CH3 domain (eg, a CH2-CH3), wherein the CH3 domains associate together to form said dimer. For example, each of the first and second polypeptides comprises, in N- to C-terminal direction, a peptide or antigen binding site -TD – optional CH2 domain -CH3 domain, wherein the CH3 domains are associated together. For example, each of the first and second polypeptides comprises, in N- to C-terminal direction, a peptide or antigen binding site – optional CH2 domain - CH3 domain - TD, wherein the CH3 domains are associated together. [00540] “Knobs into holes” technology for making bispecific antibodies was described in [1] and in US5,731,168, both incorporated herein by reference. The principle is to engineer paired CH3 domains of heterodimeric heavy chains so that one CH3 domain contains a “knob” and the other CH3 domains contains a “hole” at a sterically opposite position. Knobs are created by replacing small amino acid side chain at the interface between the CH3 domains, while holes are created by replacing large side chains with smaller ones. The knob is designed to insert into the hole, to favour heterodimerisation of the different CH3 domains while destabilising homodimer formation. In in a mixture of antibody heavy and light chains that assemble to form a bispecific antibody, the proportion of IgG molecules having paired heterodimeric heavy chains is thus increased, raising yield and recovery of the active molecule [00541] Mutations Y349C and/or T366W may be included to form “knobs” in an IgG CH3 domain. Mutations E356C, T366S, L368A and/or Y407V may be included to form “holes” in an IgG CH3 domain. Knobs and holes may be introduced into any human IgG CH3 domain, e.g., an IgG1, IgG2, IgG3 or IgG4 CH3 domain. A preferred example is IgG4. The IgG4 may include further modifications such as the “P” and/or “E” mutations. A "P" substitution at position 228 in the hinge (S228P) stabilises the hinge region of the heavy chain. An "E" substitution in the CH2 region at position 235 (L235S) abolishes binding to FcγR. A bispecific antibody of the present invention may contain an IgG4 PE human heavy chain constant region, optionally comprising two such paired   1 Ridgway et al Protein Eng 9:617-6211996 constant regions, optionally wherein one has "knobs" mutations and one has "holes" mutations. [00542] While knobs-into-holes technology involves engineering amino acid side chains to create complementary molecular shapes at the interface of the paired CH3 domains in the bispecific heterodimer, another way to promote heterodimer formation and hinder homodimer formation is to engineer the amino acid side chains to have opposite charges. Association of CH3 domains in the heavy chain heterodimers is favoured by the pairing of oppositely charged residues, while paired positive charges or paired negative charges would make homodimer formation less energetically favourable. WO2006/106905 described a method for producing a heteromultimer composed of more than one type of polypeptide (such a heterodimer of two different antibody heavy chains) comprising a substitution in an amino acid residue forming an interface between said polypeptides such that heteromultimer association will be regulated, the method comprising: (a) modifying a nucleic acid encoding an amino acid residue forming the interface between polypeptides from the original nucleic acid, such that the association between polypeptides forming one or more multimers will be inhibited in a heteromultimer that may form two or more types of multimers; (b) culturing host cells such that a nucleic acid sequence modified by step (a) is expressed; and (c) recovering said heteromultimer from the host cell culture, wherein the modification of step (a) is modifying the original nucleic acid so that one or more amino acid residues are substituted at the interface such that two or more amino acid residues, including the mutated residue(s), forming the interface will carry the same type of positive or negative charge. [00543] An example of this is to suppress association between heavy chains by introducing electrostatic repulsion at the interface of the heavy chain homodimers, for example by modifying amino acid residues that contact each other at the interface of the CH3 domains, including: (a) positions 356 and 439 (b) positions 357 and 370 (c) positions 399 and 409, the residue numbering being according to the EU numbering system. [00544] By modifying one or more of these pairs of residues to have like charges (both positive or both negative) in the CH3 domain of a first heavy chain, the pairing of heavy chain homodimers is inhibited by electrostatic repulsion. By engineering the same pair or pairs of residues in the CH3 domain of a second (different) heavy chain to have an opposite charge compared with the corresponding residues in the first heavy chain, the heterodimeric pairing of the first and second heavy chains is promoted by electrostatic attraction. [00545] In one example, amino acids at the heavy chain constant region CH3 interface of the dimer of the invention are modified to introduce charge pairs, the mutations being listed in Table 1 of WO2006/106905. It was reported that modifying the amino acids at heavy chain positions 356, 357, 370, 399, 409 and 439 to introduce charge-induced molecular repulsion at the CH3 interface had the effect of increasing efficiency of formation of the intended bispecific antibody. WO2006/106905 also exemplified bispecific IgG antibodies in which the CH3 domains of IgG4 were engineered with knobs-into-holes mutations. [00546] Further examples of charge pairs are disclosed in WO2013/157954, which described a method for producing a heterodimeric CH3 domain-comprising molecule from a single cell, the molecule comprising two CH3 domains capable of forming an interface. The method comprised providing in the cell (a) (a) a first nucleic acid molecule encoding a first CH3 domain-comprising polypeptide chain, this chain comprising a K residue at position 366 according to the EU numbering system and (b) (b) a second nucleic acid molecule encoding a second CH3 domain-comprising polypeptide chain, this chain comprising a D residue at position 351 according to the EU numbering system, the method further comprising the step of culturing the host cell, allowing expression of the two nucleic acid molecules and harvesting the heterodimeric CH3 domain-comprising molecule from the culture. [00547] Further methods of engineering electrostatic interactions in polypeptide chains to promote heterodimer formation over homodimer formation were described in WO2011/143545. [00548] Another example of engineering at the CH3-CH3 interface that can be used in the dimer of the invention is strand-exchange engineered domain (SEED) CH3 heterodimers. The CH3 domains are composed of alternating segments of human IgA and IgG CH3 sequences, which form pairs of complementary SEED heterodimers referred to as “SEED-bodies” [2; WO2007/110205]. [00549] Bispecifics have also been produced with heterodimerised heavy chains that are differentially modified in the CH3 domain to alter their affinity for binding to a purification reagent such as Protein A. WO2010/151792 described a heterodimeric bispecific antigen-binding protein comprising (a) a first polypeptide comprising, from N-terminal to C-terminal, a first epitope-binding region that selectively binds a first epitope, an immunoglobulin constant region that comprises a first CH3 region of a human IgG selected from IgG1, IgG2, and IgG4; and (b) a second polypeptide comprising, from N-terminal to C-terminal, a second epitope-   2 Davis JH et al., PEDS 23:195-202) binding region that selectively binds a second epitope, an immunoglobulin constant region that comprises a second CH3 region of a human IgG selected from IgG1, IgG2, and IgG4, wherein the second CH3 region comprises a modification that reduces or eliminates binding of the second CH3 domain to Protein A. [00550] Thus, in the dimer of the present invention, the CH3 of one (but not the other) of the first and second polypeptides comprises a modification that reduces or eliminates binding of the respective CH3 domain to Protein A. [00551] Dimers and antibodies of the present invention may employ any of these techniques and molecular formats as desired. [00552] Optionally, each of the first and second polypeptides comprises an antigen binding site, wherein each binding site is an antibody single variable domain (eg, a VHH or nanobody). [00553] Optionally, the dimer comprises a third polypeptide and a fourth polypeptide, wherein the third polypeptide is associated with the first polypeptide, and the fourth polypeptide is associated with the second polypeptide, wherein each polyeptide comprises an antibody variable domain, wherein (i) the variable domain of the first polypeptide is paired with the variable domain of the third polypepeptide to form a first VH/VL binding site for binding a first antigen; (ii) and the variable domain of the second polypeptide is paired with the variable domain of the fourth polypepeptide to form a second VH/VL binding site for binding a second antigen. Preferably, the first antigen is different from the second antigen. In an alternative, the first and second antigens are the same. In an example, the variable domain of the first polypeptide is a VH and the variable domain of the third polypeptide is a VL. In an example, the variable domain of the first polypeptide is a VL and the variable domain of the third polypeptide is a VH. In an example, the variable domain of the second polypeptide is a VH and the variable domain of the fourth polypeptide is a VL. In an example, the variable domain of the second polypeptide is a VL and the variable domain of the fourthe polypeptide is a VH. [00554] For example, the first polypeptide comprises a CH1 domain that associates with a CL domain that is comprised by the third polypeptide and/or the second polypeptide comprises a CH1 domain that associates with a CL domain that is comprised by the fourth polypeptide. [00555] For example, (i) the first polypeptide comprises, in N- to C-terminal direction, a peptide or a variable domain of a first VH/VL antigen binding site - CH1 domain – optional hinge region -TD – [a Fc region comprising a CH2 domain and aCH3 domain]; and (ii) the second polypeptide comprises, in N- to C-terminal direction, a peptide or a variable domain of a second VH/VL antigen binding site - CH1 domain – optional hinge region -TD – [a Fc region comprising a CH2 domain and a CH3 domain], wherein the CH3 domains of the first and second polypeptides are associated together. In this example, (i) the third polypeptide comprises, in N- to C-terminal direction, a peptide or a variable region of the first antigen binding site – CL; (ii) the fourth polypeptide comprises, in N- to C-terminal direction, a peptide or a variable region of the second antigen binding site – CL, wherein (iii) said variable domains or the first and third polypeptides form the first VH/VL binding site (eg, wherein the variable domain of the first polypeptide is a VH and the variable domain of the third polypeptide is a cognate VL), (iv) said variable domains of the second and fourth polypeptides form the second VH/VL binding site (eg, wherein the variable domain of the second polypeptide is a VH and the variable domain of the fourth polyeptide is a cognate VL), (v) the CH1 of the first polypeptide is associated with the CL of the third polypeptide, (vi) the CH1 of the second polypeptide is associated with the CL of the fourth polypeptide, and (vii) the Fc of the first polyeptide is associated with the Fc of the seond polypeptide (eg, the CH3 domains are associated together). [00556] Optionally, the Fc regions (or CH3 domains) of the first and second polypeptides are associated together using knob-in-hole technology or charge pairing. [00557] The multimer of the invention may be a multimer for administration to a human or animal subject for treatment or prevention of a disease or condition (eg, an infection by the first and/or second virus, or a symptom of such an infection (eg, an unwanted inflammatory response)) in the subject. [00558] The invention provides: A method for the treatment or prevention of a disease or condition (eg, an infection by the first and/or second virus, or a symptom of such an infection (eg, an unwanted inflammatory response)) in a human or animal subject , the method comprising administering to the subject a plurality of multimers of the invention. An assay kit comprising an assay reagent as mentioned above and an amount of the first antigen (eg, viral spike protein), optionally wherein the reagent and protein are comprised by different containers. A method for detecting the presence of an antigen in a sample, the method comprising combining the sample with a multimer of the invention, allowing antigen in the sample to bind multimers to form antigen/multimer complexes and detecting antigen/multimer complexes. A method of expanding a utility of an antigen (eg, a protein) binding site, the method comprising producing a multimer of the invention, wherein the multimer comprises a plurality of copies (eg, at least 8 or 16 copies) of the binding site. [00559] Optionally for the multimer, dimer, polypeptide, method, kit or composition, the multimer comprises a tetramer of a polyeptide dimer, wherein the dimer comprises a first polypeptide associated with a second polypeptide, wherein the first polypeptide comprises at least one copy of a first peptide or a first antigen binding site and a teramerisation domain (TD), the second polypeptide comprises at least one copy of a second peptide or a second antigen binding site and a teramerisation domain (TD). [00560] Optionally, each of the first and second polypeptides comprises a said binding site and the first and second binding sites are different. [00561] Optionally, in each dimer the first polypeptide comprises an antibody CH3 domain (eg, a CH2-CH3) and the second polypeptide comprises an antibody CH3 domain (eg, a CH2-CH3), wherein the CH3 domains associate together to form said dimer. [00562] Optionally, each of the first and second polypeptides comprises, in N- to C-terminal direction, (i) a peptide or antigen binding site -TD – optional CH2 domain -CH3 domain, wherein the CH3 domains of the first and second polypeptides are associated together; or (ii) a peptide or antigen binding site – optional CH2 domain - CH3 domain - TD, wherein the CH3 domains of the first and second polypeptide are associated together. [00563] Optionally, each of the first and second polypeptides comprises an antigen binding site, wherein each binding site is an antibody single variable domain (eg, a VHH or nanobody). [00564] Optionally, the dimer is associated with a third polypeptide and a fourth polypeptide, wherein the third polypeptide is associated with the first polypeptide, and the fourth polypeptide is associated with the second polypeptide, wherein each polyeptide comprises an antibody variable domain, wherein (i) the variable domain of the first polypeptide is paired with the variable domain of the third polypepeptide to form a first VH/VL binding site for binding a first antigen; and (ii) the variable domain of the second polypeptide is paired with the variable domain of the fourth polypepeptide to form a second VH/VL binding site for binding a second antigen. [00565] Optionally, the first and second antigens are different. [00566] Optionally, the variable domain of the first polypeptide is a VH and the variable domain of the third polypeptide is a VL and/or the variable domain of the second polypeptide is a VH and the variable domain of the fourth polypeptide is a VL. [00567] Optionally, (A) (i) the first polypeptide comprises a CH1 domain that associates with a CL domain that is comprised by the third polypeptide and (ii) the second polypeptide comprises a CH1 domain that associates with a CL domain that is comprised by the fourth polypeptide; or (B) (i) the first polypeptide comprises a CH1 domain that associates with a CL domain that is comprised by the third polypeptide and (ii) the second polypeptide comprises a CL domain that associates with a CH1 domain that is comprised by the fourth polypeptide. [00568] In an embodiment of option (A), the third and fourth polypeptides are identical. Thus, a common chain or polypeptide is used. Thus, the common polypeptide associates with each of the first and second polypeptides. This may simplify production by requiring only 3, instead of 4 different polypeptides to be expressed together. [00569] Option (B) is useful to reduce chances of undesirable light chain pairing, ie, the fourth polypeptide pairing with the first polypeptide and/or the third polypeptide pairing with the second polypeptide. Thus, having the CH1 in the first polypeptide and the CL in the third polypeptide, this avoids the risk of the third polypeptide pairing with the second polypeptide, since these two polypeptides comprise CL domains that do not pair with each other. Similarly, the CH domains of the first and fourth polypeptides do not pair with each other. This is advantageous for favouring production of multimers of the invention where there is a first/third polypeptide pair and a second/fourth polypeptide pair comprised by each dimer of the multimer. For example (i) the first/third polypeptide pair comprises the following configuration wherin the first polypeptide comprises in N- to C-terminal direction [VH-CL-Hinge-CH2-CH3-TD] paired with the third polypeptide wherein the third polypeptide comprises in N- to C-terminal direction [VL-CH1]; and (ii) the second/fourth polypeptide pair comprises the following configuration wherein the second polyeptide comprises in N- to C-terminal direction [VH-CH1-Hinge-CH2-CH3-TD] paired with the fourth polypeptide wherein the fourth polypeptide comprises in N- to C-terminal direction [VL-CL]. [00570] Optionally: (A) (i) the first polypeptide comprises, in N- to C-terminal direction, a variable domain of a first VH/VL antigen binding site - CH1 domain – optional hinge region – [a Fc region comprising a CH2 domain and a CH3 domain]; (ii) the second polypeptide comprises, in N- to C-terminal direction, a variable domain of a second VH/VL antigen binding site - CH1 domain – optional hinge region – [a Fc region comprising a CH2 domain and a CH3 domain]; (iii) the third polypeptide comprises, in N- to C-terminal direction, a variable region of the first antigen binding site – CL; (iv) the fourth polypeptide comprises, in N- to C-terminal direction, a variable region of the second antigen binding site – CL; (v) said variable domains or the first and third polypeptides form the first VH/VL binding site (eg, wherein the variable domain of the first polypeptide is a VH and the variable domain of the third polypeptide is a cognate VL); (vi) said variable domains of the second and fourth polypeptides form the second VH/VL binding site (eg, wherein the variable domain of the second polypeptide is a VH and the variable domain of the fourth polyeptide is a cognate VL); (vii) the CH1 of the first polypeptide is associated with the CL of the third polypeptide; (viii) the CH1 of the second polypeptide is associated with the CL of the fourth polypeptide, and (ix) the Fc of the first polyeptide is associated with the Fc of the second polypeptide (eg, the CH3 domains are associated together); or (B) (i) the first polypeptide comprises, in N- to C-terminal direction, a first antibody single variable domain - CH1 domain – optional hinge region – [a Fc region comprising a CH2 domain and a CH3 domain]; (ii) the second polypeptide comprises, in N- to C-terminal direction, a second antibody single variable domain - CH1 domain – optional hinge region – [a Fc region comprising a CH2 domain and a CH3 domain]; and (ix) the Fc of the first polyeptide is associated with the Fc of the second polypeptide (eg, the CH3 domains are associated together). [00571] Optionally, the Fc regions of the first and second polypeptides are associated by knob- in-hole or charge pairing technology. [00572] Optionally: (i) each of the first and second polypeptides comprises a respective TD between the CH1 and the Fc thereof; (ii) each of the first and second polypeptides comprises a hinge reion and each of said polypeptides comprises a respective TD between the hinge region and the Fc thereof; or (iii) each of the first and second polypeptides comprises in N- to C-terminal direction the Fc thereof and a respective TD. [00573] Optionally, (i) the first/third polypeptide pair comprises a configuration wherein the first polypeptide comprises in N- to C-terminal direction [VH-CL-Hinge-CH2-CH3-TD] paired with the third polypeptide comprising in N- to C-terminal direction [VL-CH1]; and (ii) the second/fourth polypeptide pair comprises a wherein the second polyeptide comprises in N- to C-terminal direction [VH-CH1-Hinge-CH2-CH3-TD] paired with the fourth polypeptide wherein the fourth polypeptide comprises in N- to C-terminal direction [VL-CL]. [00574] Optionally, the Fc regions of the first and second polypeptides are associated using knob-in-hole technology, wherein (i) the Fc of the first polypeptide comprises a CH3 domain having a knob that associates with a hole of a CH3 domain of the Fc of the second polypeptide; or (ii) the Fc of the first polypeptide comprises a CH3 domain having a hole that associates with a knob of a CH3 domain of the Fc of the second polypeptide. [00575] Optionally, the Fc regions of the first and second polypeptides are associated using charge pairing technology, wherein (i) the Fc of the first polypeptide comprises a first amino acid positive charge that associates with a second amino acid negative charge of the Fc of the second polypeptide; or (ii) the Fc of the first polypeptide comprises a first amino acid negative charge that associates with a second amino acid positive charge of the Fc of the second polypeptide. [00576] In an alternative, the first, but not the second, polypeptide comprises a TD. In another alternative each of the first and second polypeptides are devoid of a TD. [00577] In an alternative, the dimer of the invention may be devoid of a TD, wherein the Fc regions of the first and second polypeptides are associated together in the dimer. For such an embodiment where the dimer is devoid of a TD, all other features of the dimer disclosed herein (in respect of dimers comprsing a TD) are otherwise applicable mutatis mutandis and combinable with the alternative emobidment that is devoid of a TD. For example, the Fc regions may be associated using any technology described herein, such as using knob-in-hole or charge pairing technology. In an embodiment, the first polyeptide comprises a first antigen binding site (eg, a single variable domain or a variable domain that is paired with a variable domain of the third polypeptide (when present) to form a first VH/VL binding site) and/or the second polyeptide comprises a second antigen binding site (eg, a single variable domain or a variable domain that is paired with a variable domain of the fourth polypeptide (when present) to form a second VH/VL binding site). [00578] Optionally, the dimer is an antibody and the first polypeptide is a first heavy chain, the second polypeptide is a second heavy chain, the third polypeptide is a first light chain and the fourth polypeptide is a second light chain. For example, the first and second heavy chains are identical. In an example, they are different (eg, they comprise different peptides or they comprise different antigen binding sites or V domains). For example, the first and second light chains are identical. In an example, they are different (eg, they comprise different different peptides or they comprise different antigen binding sites or V domains). In an embodiment the dimer is a bispecific antibody wherein the first and second heavy chains comprise different binding sites capable of binding a respective antigen and the light chains are identical; alternatively, the light chains are different (eg, V’-CL and V’’-CL wherein V’=a first variable domain (eg, a VL, VH or dAb) that is capable (alone or paired with a V domain of the associated heavy chain) of binding a first antigen; and V’’= a second variable domain (eg, a VL, VH or dAb) that is capable (alone or paired with a V domain of the associated heavy chain) of binding a second antigen). In an embodiment, a V domain of the first heavy chain is paired with a V domain of the first light chain and is comprised by a first VH/VL binding site that is capable of binding to a first antigen; and/or a V domain of the second heavy chain is paired with a V domain of the second light chain and is comprised by a first VH/VL binding site that is capable of binding to a second antigen. The antigens in this case are different, eg, different antigens of a virus, bacterium or cell. [00579] Optionally each single variable domain is selected from a variable domain disclosed herein. Optionally, each VH/VL binding site is a VH/VL binding site comprised by an antibody disclosed herein (or encoded by VH and VL DNA sequences disclosed herein). Optionally, the antigen is a viral antigen (eg, a coronavirus or SARS-CoV or SARS-Cov-2 antigen, such as RBD or spike antigen) and each single variable domain is an anti-viral antigen variable domain (eg, nanobody or VH or VHH) disclosed herein, such as a variable domain that comprises the amino acid sequence of QB-GB (SEQ ID: 1*307), QB-DD, QB-BG or QB-FE). Optionally, the first and second antigen binding sites are different. Optionally, they are the same. Optionally, the first and second VH/VL sites are different. Optionally, they are the same. Optionally, the first VH/VL site is (i) a VH/VL binding site comprising a VH and a VL encoded by a VH DNA sequence and the cognate VL DNA sequence shown in Table 21(b), or (ii) a VH/VL binding site of any antibody disclosed in Table 21(a). For example, the VH and VL are encoded by VH-ICC and VL-ICC DNA sequences. Optionally, the second VH/VL site is (i) a VH/VL binding site comprising a VH and a VL encoded by a VH DNA sequence and the cognate VL DNA sequence shown in Table 21(b), or (ii) a VH/VL binding site of any antibody disclosed in Table 21(a). For example, the VH and VL are encoded by VH-IHG and VL-IHG DNA sequences. In one embodiment, the first and second VH/VL sites are the same. In another embodiment, they are different. [00580] Optionally, a polypeptide herein (eg, a first; second; third; fourth; first and second; third and fourth; or first, second, third and fourth polypeptide) comprises in N-to C-terminal direction (i) a first antibody single variable domain, a second antibody single variable domain and TD; or a first antibody single variable domain, a second antibody single variable domain and Fc; or (iii) a first antibody single variable domain, a second antibody single variable domain and CH1. Each single variable domain is capable of binding to a respective antigen. Preferably, the antigens are different, although they may be the same. Optionally, the single variable domains are connected by a peptide linker (eg, a (G4S)n linker, wherein n=1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 2 or 3). Optionally, the single variable domains are directly connected together. [00581] Optionally, when the first and second polypeptides of the dimer are associated with the third and fourth polypeptides respectively, the first and third polypeptides comprise a respective variable domain, wherein the variable domains are comprised by a VH/VL pair that is capable of binding a first antigen; and wherein the second polypeptide comprises a first antibody single variable domain that is capable of binding a second antigen; and the fourth polypeptide comprises a second antibody variable domain that is capable of binding a third antigen. In an example, the first antigen is different from the second and third antigens. In an example, the second and third antigens are the same, or they may be different. Each single variable domain (dAb) may, for example, be a nanobody. Each single variable domain (dAb) may, for example, be a human dAb. In an embodiment, (i) the first polypeptide comprises a configuration of, in N- to C-terminal direction, V1-CH1-Hinge-CH2- CH3(with optional knob or first charged amino acid)-TD which is paired with the third polypeptide, wherein the third polypeptide comprises a configuration of, in N- to C-terminal direction, V2-CL, wherein V1 and V2 comprise a first VH/VL pair that is capable of binding to the first antigen (eg, wherein V1=VH and V2=VL; or V1=VL and V2=VH); and (ii) the second polypeptide comprises a configuration of, in N- to C-terminal direction, V3-CH1-Hinge-CH2-CH3(with optional hole that pairs with the knob; or optionally a second charged amino acid that pairs with the first charged amino acid)-TD, wherein the fourth polypeptide comprises a configuration of, in N- to C-terminal direction, V4-CL, wherein each of V3 and V4 is an antibody single variable domain that is capable of binding to a second and third antigen respectively. In an alternatiave, hinge is absent from the first and second polypeptides. Optionally, the first charge is a positive charge and the second charge is a negative charge. Optionally, the second charge is a positive charge and the first charge is a negative charge. [00582] Optionally, wherein the dimer comprises the first and second polypeptides and a third (but not fourth) polypeptide, wherein the first polypeptide is associated with the third polypeptide, the first and third polypeptides comprise a respective variable domain, wherein the variable domains are comprised by a VH/VL pair that is capable of binding a first antigen; and wherein the second polypeptide comprises a first antibody single variable domain that is capable of binding a second antigen. In an example, the first antigen is different from the second antigen. Preferably, the second polypeptide is devoid of a CH1 domain. In an example, the first and second antigens are the same, or they may be different. The single variable domain (dAb) may, for example, be a nanobody. The single variable domain (dAb) may, for example, be a human dAb. In an embodiment, (i) the first polypeptide comprises a configuration of, in N- to C-terminal direction, V1-CH1-Hinge-CH2- CH3(with optional knob or first charged amino acid)-TD which is paired with the third polypeptide, wherein the third polypeptide comprises a configuration of, in N- to C-terminal direction, V2-CL, wherein V1 and V2 comprise a first VH/VL pair that is capable of binding to the first antigen (eg, wherein V1=VH and V2=VL; or V1=VL and V2=VH); and (ii) the second polypeptide comprises a configuration of, in N- to C-terminal direction, V3-Hinge-CH2-CH3(with optional hole that pairs with the knob; or optionally a second charged amino acid that pairs with the first charged amino acid)-TD, wherein V3 is an antibody single variable domain that is capable of binding to the second antigen. In an alternatiave, hinge is absent from the first and second polypeptides. Optionally, the first charge is a positive charge and the second charge is a negative charge. Optionally, the second charge is a positive charge and the first charge is a negative charge. This arrangement, wherein the second polypeptide is devoid of a CH1, avoids the need for a polypeptide (such as a fourth polypeptide) that pairs with the second polypeptide. Thus, the third polypeptide will pair with the first polypeptide and undesirable pairing of the third polypeptide with the second polypeptide is avoided. This is useful for providing favourable yields of the desired dimer (comprising the first, second and third polypeptides with the third polypeptide paired with the first, but not the second polypeptide) and reduce contamination by the undesired configuration (comprising the first, second and third polypeptides with the third polypeptide paired with the first and the second polypeptides). INHALABLE COMPOSITIONS: [00583] A inhalable pharmaceutical composition (or dose of said composition) is provided which comprises particles of any multimer disclosed herein in the size range from 0.5 to 5.0 μm. For example, at least 60% (eg, 60-80% or 60-90%) of particles are in said size range. Optionally, at least 20% (eg, 20-40% or 20-35% or 20-30%) of particles are in the size range >4.7 μm (coarse particles), and optionally in the size range >4.7 μm but no more than 5.0 μm. Optionally, at least 50% (eg, at least 60%, 50-80%, 50-75%, 50-70% 50-65%) of particles are in the size range <4.7 μm (fine particles). Optionally, at least 15% (eg, at least 10%, at least 5%, at least 4, 3, 2 or 1%) of particles are in the size range <1.0 μm (ultra-fine particles). Preferably, the particles are nebulised particles. For example, the composition or dose is comprised by a nebuliser. For example, the composition or dose is comprised by an inhaler. For example, the composition or dose is obtainable by nebulising the multimer, eg, using an Aeroneb Solo™ nebuliser. The composition or dose comprises the multimer and a pharmaceutically acceptable carrier; such carriers for inhalable formulations will be familiar to the skilled addressee. [00584] In a preferred example, a) at least 20% (eg, 20-40% or 20-35% or 20-30%) of multimer particles are in the size range >4.7 μm, and optionally in the size range >4.7 μm but no more than 5.0 μm; b) at least 50% (eg, at least 60%, 50-80%, 50-75%, 50-70% 50-65%) of multimer particles are in the size range <4.7 μm; and c) at least 15% (eg, at least 10%, at least 5%, at least 4, 3, 2 or 1%) of multimer particles are in the size range <1.0 μm (ultra fine particles). [00585] In a preferred example, a) at least 20% of multimer particles are in the size range >4.7 μm, and optionally no more than 5.0 μm; and b) at least 50% of multimer particles are in the size range <4.7 μm, and optionally at least 15% of multimer particles are in the size range <1.0 μm. [00586] In a preferred example, a) at least 20% of multimer particles are in the size range >4.7 μm, and optionally no more than 5.0 μm; b) at least 50% of multimer particles are in the size range <4.7 μm; and c) at least 15% of multimer particles are in the size range <1.0 μm. [00587] The composition may comprise particles of the multimer and the median mass aerodynamic particle diameter (MMAD) is 2 to 4.5, eg, 2.5 to 4 or 3 to 3.5 μm. [00588] In an example, the multimer comprises at least 4 copies of an antibody single variable domain, eg, a that specifically binds to a virus antigen, for example a RSV or SARS-CoV-2 antigen, eg, RBD or NTD. For example, the variable domain is CoVnb-112 (also called Nb-112 herein (SEQ ID: 1*288), and the virus antigen is a SARS-CoV-2 antigen), Nb11-59 (Novamab Biopharmaceuticals Co. Ltd, and the virus antigen is a SARS-CoV-2 antigen) or a variable domain of ALX-0171 (Ablynx BV, and the virus antigen is an RSV antigen). [00589] Preferably, the polypeptide herein comprises the amino acid sequence of any one of SEQ IDs: 1*289 to 1*292. Preferably, the multimer herein comprises 4 copies of a polypeptide that comprises the amino acid sequence of any one of SEQ IDs: 1*289 to 1*292, or an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to the amino acid sequence of any one of SEQ IDs: 1*289 to 1*292. The pharmaceutical composition herein may comprise such a multimer, eg, for administration to a human or animal subject for treating or preventing a lung condition. The lung condition may be a lung infection, such as a viral infection, or symptom thereof. MULTIMERS FOR RESISTING SARS-COV-2 MUTATION: [00590] The polypeptide described herein may, for example, comprise a SARS-CoV-2 antigen binding domain disclosed herein or a binding domain (eg, an antibody single variable domain) that competes with a SARS-CoV-2 antigen binding domain disclosed herein for binding to SARS-CoV-2 spike in an in vitro competition assay. In vitro competition may be determined by standard SPR or ELISA, for example. Any SPR herein is, for example, surface plasmon resonance (SPR) at 37°C and pH 7.6. [00591] The polypeptide described herein may, for example, comprise a SARS-CoV-2 antigen binding domain disclosed herein or a binding domain (eg, an antibody single variable domain) that binds to the same SARS-CoV-2 spike epitope (or an overlapping epitope) as a SARS-CoV-2 antigen binding domain disclosed herein. [00592] The polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike. [00593] The polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state. Similarly, the multimer herein may comprise copies of such a binding domain. The multimer described herein may, for example, bind to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike. The multimer described herein may, for example, bind to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state. [00594] The multimer described herein may, for example, comprise copies of a SARS-CoV-2 antigen binding domain, wherein the multimer competes with a SARS-CoV-2 antigen binding domain- containing multimer (eg, Q185B see right-hand-side schematic in Figure 14B, a tetramer of SEQ ID: 1*236) disclosed herein for binding to SARS-CoV-2 spike in an in vitro competition assay. In vitro competition may be determined by standard SPR or ELISA, for example. Any SPR herein is, for example, surface plasmon resonance (SPR) at 37°C and pH 7.6. [00595] The multimer described herein may, for example, comprise copies of a SARS-CoV-2 antigen binding domain, wherein the multimer binds to the same SARS-CoV-2 spike epitope (or an overlapping epitope) as a SARS-CoV-2 antigen binding domain-containing multimer (eg, Q185B see right-hand-side schematic in Figure 14B, a tetramer of SEQ ID: 1*236) disclosed herein. [00596] The polypeptide described herein may, for example, comprise binding domain QB-GB or a binding domain (eg, an antibody single variable domain) that competes with QB-GB for binding to SARS-CoV-2 spike in an in vitro competition assay. In vitro competition may be determined by standard SPR or ELISA, for example. Any SPR herein is, for example, surface plasmon resonance (SPR) at 37°C and pH 7.6. [00597] The polypeptide described herein may, for example, comprise binding domain QB-GB or a binding domain (eg, an antibody single variable domain) that binds to the same SARS-CoV-2 spike epitope (or an overlapping epitope) as QB-GB. [00598] The polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike. [00599] The polypeptide described herein may, for example, comprise a binding domain that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state. [00600] Similarly, the multimer herein may comprise copies of such a binding domain. [00601] As explained in Example 37 Quad multimers that have such features have been found to be highly advantageous and may be more resistant to receptor-driven selection pressure associated with SARS-Cov-2 mutation. [00602] Furthermore, there is provided a method of producing a polypeptide multimer, the method comprising multimerising first, second, third and fourth copies of a polypeptide (eg, any polypeptide disclosed herein) that comprises at least one copy of an SARS-CoV-2 antigen binding domain (eg, QB-GB or a binding domain (eg, an antibody single variable domain) that competes with QB-GB for binding to SARS-CoV-2 spike in an in vitro competition assay, and optionally formulating the multimer in a pharmaceutical composition for administration (eg, injected or pulmonary administration) to a human or animal subject to treat or prevent a coronavirus (preferably, SARS- CoV-2) infection. [00603] Furthermore, there is provided a method of producing a polypeptide multimer, the method comprising multimerising first, second, third and fourth copies of a polypeptide (eg, any polypeptide disclosed herein) that comprises at least one copy of an SARS-CoV-2 antigen binding domain (such as an antibody variable domain) that binds to the same SARS-CoV-2 spike epitope (or an overlapping epitope) as QB-GB, and optionally formulating the multimer in a pharmaceutical composition for administration (eg, injected or pulmonary administration) to a human or animal subject to treat or prevent a coronavirus (preferably, SARS-CoV-2) infection. [00604] Furthermore, there is provided a method of producing a polypeptide multimer, the method comprising multimerising first, second, third and fourth copies of a polypeptide (eg, any polypeptide disclosed herein) that comprises at least one copy of an SARS-CoV-2 antigen binding domain (such as an antibody variable domain) that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike, and optionally formulating the multimer in a pharmaceutical composition for administration (eg, injected or pulmonary administration) to a human or animal subject to treat or prevent a coronavirus (preferably, SARS-CoV-2) infection. [00605] Furthermore, there is provided a method of producing a polypeptide multimer, the method comprising multimerising first, second, third and fourth copies of a polypeptide (eg, any polypeptide disclosed herein) that comprises at least one copy of an SARS-CoV-2 antigen binding domain (such as an antibody variable domain) that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike that is in the up state, and optionally formulating the multimer in a pharmaceutical composition for administration (eg, injected or pulmonary administration) to a human or animal subject to treat or prevent a coronavirus (preferably, SARS-CoV-2) infection. The binding domain may be an immunoglobulin domain (eg, an antibody variable domain or single variable domain (dAb or nanboby), or any other type of binding site or domain disclosed herein. [00606] Compositions comprising a multimer of the invention (eg, QB-GB or a multimer that competes with QB-BB (or QB-GB) for binding to SARS-CoV-2 spike) and an anti-spike antibody (eg, wherein the antibody is regdanvimab, REGKINORA™, REGN10987, REGN10933 or CB6) may be useful for resisting mutation in the viral spike protein and/or for enhancing efficacy of treatment or prevention of SARS-CoV-2 (or SARS-CoV-1 or another coronavirus) infection or a symptom thereof in a human or animal subject. Novel Antibody Variable Domains & Multimers [00607] The invention provides novel antibody variable domains that are capable of binding to coronavirus spike protein. [00608] Thus, there is provided:- An antibody variable domain that binds to coronavirus virus spike (eg, SARS-CoV-2 spike, SARS- CoV-1 spike or beta-coronavirus spike) and comprises an amino acid sequence selected from SEQ IDs: A-L S and T, or an amino acid sequence that is identical to a said selected sequence except for 1- 25 amino acid differences. [00609] All sequences of the variable domains are written herein in the N- to C-terminal direction. [00610] The number of changes may be 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1. The number of differences is preferably 14 or less, eg, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1. The number of differences may be 1-3. The number of differences may be 1. The number of differences may be 2. The number of differences may be 3. The number may be 8. Usefully, at least one of said differences (or optionally each of the differences) is a substitution of an amino acid of said selected sequence for the amino acid found at the corresponding position of the amino acid sequence of human germline gene segment IGHV3-23 (optionally IGHV3-23*01 or IGHV3-23*04). This is advantageous when administering the variable domain or products comprising the variable domain (eg, a multimer herein) to a human subject, such as to treat or prevent a coronaviral infection or a symptom thereof. Proteins with human germline residues are likely to be more compatible (eg, less immunogenic) to human recipients than proteins with non-human residues at the equivalent positions, for example. Thus, one aspect is the discovery by design of positions in the novel anti-spike sequences (SEQ IDs: A-L, S and T) that are permissive for change (eg, change to a human germline amino acid) and those positions that are desirably left untouched for providing desirable antigen-binding affinity and/or expression in mammalian cells (see Examples 38-40 herein). In particular, the novel variable domains are based on human IGHV3-23 gene segment and, thus, we provide information to enable design of humanised versions where amino acids can be reverted to the amino acids found at equivalent positions in human IGHV3-23. [00611] Preferably, said selected sequence is SEQ ID: A. Preferably, said selected sequence is SEQ ID: I. [00612] By experimental design, we found that it may be advantageous for neutralization potency that there is no said difference at the amino acid corresponding to position 35 or 50 of the selected sequence (Example 39). For example, there may be no said difference at both of these positions. Additionally or alternatively, there may be a said difference at the amino acid position corresponding to position 61 of the selected sequence. We found this position was permissive for change and can even enhance neutralization potency when reverted to the corresponding human germline amino acid. [00613] An amino acid “position” of the variable domain of the invention is a position that corresponds to the position in the selected sequence (eg, in SEQ ID: A). The skilled person will readily understand that corresponding positions can be conventionally determined by sequence alignment. Thus, where there is amino acid addition or deletion as part of said differences from the selected sequence, the alignment is made routinely by taking into account such addition and deletion, in order to provide optimal alignment (with introduction of notional “gaps” in the alignment, for example, to account for additions of amino acids versus the selected sequence). [00614] For example, in an alignment:- Selected Sequence: A1-B2-C3----E4 V Domain Sequence: A1-B2-C3-X-E5 [00615] Here, the sequences (written in the N- to C-terminal direction) differ by the addition of amino acid X in the V domain of the invention. By introduction of a notional “gap” in the alignment between C3 and E4 in the selected sequence, it can be seen that E5 in the V domain sequence here corresponds to E4 in the selected sequence. Thus, in this example it can be said that for the V domain of the invention “the amino acid corresponding to position 4 of the selected sequence is an E” (even though E is actually at position 5 in the V domain sequence). The phrase “the amino acid corresponding to position […] of the selected sequence” herein is therefore to be interpreted similarly. [00616] When there are no substitutions or additions of amino acids in the V domain compared to the selected sequence, the actual position number of each amino acid in the V domain sequence is the same as the corresponding amino acid in the selected sequence. [00617] For example, in an alignment amino acid F is actually at position 4 in the V domain (and “corresponds to” E at position 4 of the selected sequence):- Selected Sequence: A1-B2-C3-E4 V Domain Sequence: A1-B2-C3-F4 [00618] Here, conventionally the F can be referred to as “4F” and the E as “4E” in their respective sequences; and in the previous example the V domain sequence comprised 5E (which corresponds to 4E in the selected sequence). Positions can, as the skilled addressee will appreciate, be similarly labelled and understood herein. [00619] Optionally, (a) the amino acid corresponding to position 61 of the selected sequence is an amino acid other than a threonine, optionally wherein the amino acid is an alanine; or (b) the amino acid corresponding to position 61 of the selected sequence is a threonine. [00620] Preferably, the amino acid corresponding to position 61 of the selected sequence is an amino acid other than a threonine, optionally wherein the amino acid is an alanine. [00621] Optionally, (a) the amino acid corresponding to position 35 of the selected sequence is a serine or the amino acid corresponding to position 50 of the selected sequence is an alanine; or (b) the amino acid corresponding to position 35 of the selected sequence is a glycine or the amino acid corresponding to position 50 of the selected sequence is a threonine. [00622] Preferably, the amino acid corresponding to position 35 of the selected sequence is a serine or the amino acid corresponding to position 50 of the selected sequence is an alanine. [00623] Optionally, the amino acid corresponding to position 37 of the selected sequence is a phenylalanine and/or the amino acid corresponding to position 47 of the selected sequence is a phenylalanine. [00624] Optionally, the amino acid sequence of the variable domain comprises (a) one or more amino acids selected from a glutamic acid at a position corresponding to position 1 of the selected sequence, a leucine at a position corresponding to position 5 of the selected sequence and a proline at a position corresponding to position 14 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids; (b) a serine or glycine at a position corresponding to position 35 of the selected sequence; (c) one or more amino acids selected from a glycine at a position corresponding to position 44 of the selected sequence, a leucine at a position corresponding to position 45 of the selected sequence and a serine at a position corresponding to position 49 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids; (d) one or more amino acids selected from a serine at a position corresponding to position 75 of the selected sequence, a leucine at a position corresponding to position 79 of the selected sequence, an arginine at a position corresponding to position 87 of the selected sequence, an alanine at a position corresponding to position 88 of the selected sequence and a glutamic acid at a position corresponding to position 89 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids; and/or (e) a leucine at a position corresponding to position 120 of the selected sequence. [00625] Preferably, the amino acid sequence of the variable domain comprises (a) a glutamic acid at a position corresponding to position 1 of the selected sequence, a leucine at a position corresponding to position 5 of the selected sequence and a proline at a position corresponding to position 14 of the selected sequence; (b) a serine or glycine (preferably a serine) at a position corresponding to position 35 of the selected sequence; (c) a glycine at a position corresponding to position 44 of the selected sequence, a leucine at a position corresponding to position 45 of the selected sequence and a serine at a position corresponding to position 49 of the selected sequence; (d) a serine at a position corresponding to position 75 of the selected sequence, a leucine at a position corresponding to position 79 of the selected sequence, an arginine at a position corresponding to position 87 of the selected sequence, an alanine at a position corresponding to position 88 of the selected sequence and a glutamic acid at a position corresponding to position 89 of the selected sequence; and (e) a leucine at a position corresponding to position 120 of the selected sequence. [00626] The amino acid of the variable domain may comprise residues as follows:- (a) all of the amino acids according to claim 8(a), (c), (d) and (e); and (b) an amino acid according to claim 8(b). [00627] The amino acid of the variable domain may comprise residues as follows:- (a) an arginine or phenylalanine at a position corresponding to position 27 of the selected sequence; (b) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and/or (c) an alanine or serine at a position corresponding to position 49 of the selected sequence. [00628] The amino acid of the variable domain may comprise residues as follows:- A: (a) an arginine at a position corresponding to position 27 of the selected sequence; (b) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and (c) a serine at a position corresponding to position 49 of the selected sequence; or B: (d) a phenylalanine at a position corresponding to position 27 of the selected sequence; (e) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and (f) a serine at a position corresponding to position 49 of the selected sequence. [00629] The amino acid of the variable domain may comprise residues as follows:- (a) a phenylalanine at a position corresponding to position 27 of the selected sequence; (b) a serine at a position corresponding to position 31 of the selected sequence; and/or (c) a glycine at a position corresponding to position 53 of the selected sequence. [00630] The framework 1 (FR1) of the variable domain may comprise SEQ ID: X or 309. [00631] Preferably, each of said differences may be in the FR1, complementarity determining region 1 (CDR1), FR2, CDR2, FR3 or FR4. [00632] Each said difference may be an amino acid substitution, ie, a replacement of an amino acid of the selected sequence with a different amino acid. In this case, there are no additions or deletions of amino acids, such that the lengths of said amino acid sequence of the variable domain and the selected sequence are the same. [00633] Each amino acid difference in the amino acid sequence of the variable domain compared to the selected sequence may be a substitution, addition or deletion. [00634] The amino acid sequence of the domain may comprise one or more sequence motifs selected from (a) EVQLLESGGGLVQP (SEQ ID: X) at the N-terminal end of FR1 or EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID: Y) in FR1; (b) GRTFSEYAMS (SEQ ID: Z) or GRTFSEYAMG (SEQ ID: AA) in CDR1; (c) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence and/or GLEFVS (SEQ ID: CC) in FR2 wherein the F in SEQ ID: CC is at a position that corresponds to position 47 in the selected sequence; or (ii) WFRQAPGKGLEFVS (SEQ ID: DD) in FR2; (d) (i) AISW (SEQ ID: DD) at the N-terminal end of CDR2 and/or TYYA (SEQ ID: EE) at the C-terminal end of CDR2; or (ii) AISWSGGSTY (SEQ ID: FF) in CDR2; (e) (i) YADSV (SEQ ID: LL) at the N-terminal end of FR3 and/or RAEDTAVYYCA (SEQ ID: GG) at the C-terminal end of FR3; or (ii) YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA (SEQ ID: HH) in FR3; (f) AAGLGTVVSEWDYDYDYW (SEQ ID: II) in CDR3; and/or (g) GQGTLVTVSS (SEQ ID: JJ) in FR4. [00635] For example, the amino acid sequence of the variable domain comprises a tryptophan at a position corresponding to position 53 of the selected sequence. For example, the amino acid sequence of the variable domain comprises a glycine at a position corresponding to position 53 of the selected sequence. [00636] Preferably, the amino acid sequence of the variable domain comprises (a) a glutamic acid at a position corresponding to position 1 of the selected sequence, a leucine at a position corresponding to position 5 of the selected sequence and a proline at a position corresponding to position 14 of the selected sequence; (b) a serine or glycine (preferably a serine) at a position corresponding to position 35 of the selected sequence; (c) a glycine at a position corresponding to position 44 of the selected sequence, a leucine at a position corresponding to position 45 of the selected sequence and a serine at a position corresponding to position 49 of the selected sequence; (d) a serine at a position corresponding to position 75 of the selected sequence, a leucine at a position corresponding to position 79 of the selected sequence, an arginine at a position corresponding to position 87 of the selected sequence, an alanine at a position corresponding to position 88 of the selected sequence and a glutamic acid at a position corresponding to position 89 of the selected sequence; (e) a leucine at a position corresponding to position 120 of the selected sequence; (f) an amino acid other than a threonine, optionally comprising an alanine, at a position corresponding to position 61 of the selected sequence; (g) a serine at a position corresponding to position 35 of the selected sequence; (h) an alanine at a position corresponding to position 50 of the selected sequence; (i) an arginine or phenylalanine at a position corresponding to position 27 of the selected sequence; (j) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and (k) a serine at a position corresponding to position 49 of the selected sequence. [00637] Preferably, the amino acid sequence of the domain comprises:- (a) EVQLLESGGGLVQP (SEQ ID: X) at the N-terminal end of FR1; (b) GRTFSEYAMS (SEQ ID: Z) or GRTFSEYAMG (SEQ ID: AA) in CDR1; (c) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence and GLEFVS (SEQ ID: CC) in FR2 wherein the F in SEQ ID: CC is at a position that corresponds to position 47 in the selected sequence; (d) (i) AISW (SEQ ID: DD) at the N-terminal end of CDR2 and TYYA (SEQ ID: EE) at the C-terminal end of CDR2; (e) (i) YADSV (SEQ ID: LL) at the N-terminal end of FR3 and RAEDTAVYYCA (SEQ ID: GG) at the C-terminal end of FR3; or (ii) YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA (SEQ ID: HH) in FR3; and (f) GQGTLVTVSS (SEQ ID: JJ) in FR4. [00638] Alternatively in (d) in the immediately preceding paragraph, the amino acid sequence of the variable domain comprises TISW (SEQ ID: KK). [00639] Alternatively in (e) in the immediately preceding paragraph, the amino acid sequence of the variable domain comprises YTDSV (SEQ ID: MM) or YTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA (SEQ ID: NN). [00640] The invention provides:- An isolated nucleic acid (eg, a DNA or RNA, such as mRNA or cDNA) encoding the antibody variable domain, optionally wherein the nucleic acid is comprised by an expression vector for expressing the variable domain or a polypeptide comprising the variable domain. [00641] The nucleic acid or vector may be comprised by a host cell, such as a mammalian cell (eg, a HEK, CHO or Cos cell) for expression of the domain or polypeptide. [00642] The invention provides:- A polypeptide comprising the amino acid sequence of an antibody variable domain of any preceding claim and one or more further amino acid sequences, optionally wherein the polypeptide comprises a self-assembly multimerization domain (SAM domain). [00643] The SAM may be any SAM, such as a tetramerisation domain (TD), disclosed herein, eg, a p53 tetramerisation domain (p53 TD). The polypeptide may be isolated or recombinant. [00644] Optionally, the polypeptide comprises at least 2 copies of the amino acid sequence of the variable domain (the polypeptide may comprise 2, 3, 4, 5, 6, 7, 8, 9 or 10 copies (but no more than said number) of the variable domain). Additionally or alternatively, the polypeptide may comprise an amino acid sequence encoding an ACE2 peptide (eg, an ACE2 extracellular domain or any other ACE2 amino acid sequence disclosed herein). [00645] For example, the polypeptide comprises (in N- to C-terminal direction):- (i) A said ACE2 peptide, TD (eg, p53 TD) and said variable domain; (ii) Said variable domain, TD (eg, p53 TD) and a said ACE2 peptide; (iii) A said ACE2 peptide, an antibody Fc region and said variable; or (iv) Said variable domain, an antibody Fc region and a said ACE2 peptide. [00646] The invention provides:- A multimer comprising a plurality (optionally comprising 4) copies of the variable domain or polypeptide. [00647] For example, the multimer may comprise 4, 18, 12, 16, 20, 24, 28 or 42 copies (but no more than said number) of the variable domain. For example, the multimer may comprise 4 (but no more than 4) copies of the polypeptide. Thus, there is also provided:- [00648] A tetramer of first, second, third and fourth copies of the polypeptide, wherein each copy comprises a self-assembly multimerization domain (SAM domain), eg, a p53 domain. [00649] There is provided:- A pharmaceutical composition comprising the variable domain, polypeptide, multimer or tetramer and a pharmaceutically acceptable excipient, diluent or carrier. [00650] Optionally, the composition comprises an anti-inflammatory agent (eg, an anti-IL6R antibody), anti-viral agent (eg, an anti-caronavirus antibody (such as an anti-SARS-CoV-2 antibody) or vaccine), immunosuppressant and/or an ACE2 peptide (eg, ACE2 extracellular domain) or ACE2 receptor mutimer. The composition may comprise an antibody medicament, eg, an anti-inflammatory antibody, such as an anti-IL-6R (eg, sarilumab or tocilizumab) or TNF alpha antibody (eg, adalimumab). The composition may comprise an ACE2 peptide multimer, eg, a dimer, trimer or tetramer of an ACE2 peptide-Fc polypeptide. The ACE2 peptide may comprise any ACE2 amino acid sequence disclosed herein, eg, ACE2(18-740) or ACE2(18-615). [00651] There is provided:- A medical device (eg, a syringe, inhaler or IV bag) comprising the composition. [00652] There is provided:- A method of treating or preventing a coronavirus virus (eg, SARS-CoV-2, SARS-CoV-1 or beta- coronavirus) infection in a human or animal subject or a symptom thereof (eg, an immune or inflammatory response), the method comprising administering the composition to the subject. Use of the composition of the variable domain, the polypeptide, the multimer or the tetramer in the manufacture of a pharmaceutical composition for administration to a human or animal subject for treating or preventing a coronavirus virus (eg, SARS-CoV-2, SARS-CoV-1 or beta-coronavirus) infection in a human or animal subject or a symptom thereof (eg, an immune or inflammatory response). [00653] The subject may be a male or female. The subject may have a Body Mass Index (BMI) greater than 25, 28, 30, 32, 33, 34, 35, 36, 37, 38, 39 or 40, preferably greater than 30. The subject may be a BAME (Black, Asian or Minority Ethnic) human. The subject may be at least 80, 75, 70, 65, 60, 55, 5045, 40, 35, 30, 25 or 28 years of age, preferably at least 70 years of age. The subject may have a cardiovascular disease, diabetes, chronic respiratory disease or cancer. The subject may have previously suffered from such a condition. Optionally, in this paragraph the virus is a SARS virus, eg, SARS-CoV-2. [00654] Administration to the subject may be into the bloodstream (eg, IV administration). Administration to the subject may be inhaled administration (eg, using a nebulizer or inhaler device). Administration may be intravenously, intraperitoneal or subcuteaneous. Any route of administration disclosed herein may be used. Any nebulised or inhalable formulation disclosed herein may be applied mutatis mutandis to the administration or forumulation of the variable domain, multimer, tetramer or pharmaceutical composition. [00655] The invention provides:- A method of detecting the presence of a virus in a sample (eg, a biological sample), the method comprising contacting the variable domain, polypeptide, multimer or tetramer with the sample and detecting virus or virus spike protein is bound to the variable domain, polypeptide, multimer or tetramer. [00656] The spike protein may be all or part of the spike. [00657] The sample is, eg, a blood sample, nasal swab sample, oral cavity sample or sputum sample. The sample may be a sample that has been obtained from a human or animal subject. [00658] ELISA detection or any other routine method can be used, as will be familiar to the skilled person. The sample may be immobilised on a solid support or comprised by a liquid. [00659] Preferably the virus or coronavirus virus herein is, eg, SARS-CoV-2, SARS-CoV-1 or a beta- coronavirus. Multimer Purification, Assay & Diagnostics Methods [00660] In experiments we observed that multimers of the invention comprising at least 4 copies of an antibody VH domain with or without an antibody Fc region could be usefully purified without the need for affinity tags (such as a His tag) by binding to Protein A. Binding was observed to be much greater than binding of VH monomer to Protein A. The protein A may be immobilised on a solid support, eg, a resin. Particularly, the purification of multimers in this way may be advantageous where the VH is a IGHV3 variable domain (ie, a recombinant of a human IGHV3 gene segment), as such VH bind particularly well to the protein A.Thus, the invention provides:- A method of binding a multimer to a solid support, the method comprising contacting a solid support (eg, a gel, resin or bead) with the multimer, wherein protein A is immobilised on the solid support prior to said contacting and the multimer is bound by protein A, optionally further comprising separating the bound multimer from the protein A. A method of isolating a multimer from a sample comprising the multimer, the method comprising contacting the sample with a solid support (eg, a gel, resin or bead), wherein protein A is immobilised on the solid support prior to said contacting and the multimer is bound by protein A, optionally further comprising separating the bound multimer from the protein A. [00661] The sample may be any sample disclosed herein. The sample may be a product of chemical or biological experiment (eg, that has been carried out in vivo). The method may be a forensics method or food or medical testing method. The method may be a method of diagnosis (eg, to detect the presence of the multimer in the sample). [00662] Preferably, the multimer comprises 4 (eg, no more than 4) copies of an antibody VH domain. For example, the multimer comprises 4, 8, 12, 16, 20, 24, 28 or 32 (eg, no more than said number) copies of an antibody VH domain. The VH may be a human IGHV3 variable domain (eg, a recombinant of human gene segment VH3-23, eg, VH3-23*01 or *04). [00663] The method may comprise detecting the binding of the multimer to the protein A. The skilled person will know of conventional assay techniques for this purpose. [00664] The VH may be any suitable variable domain disclosed herein. The multimer may comprise one or more antibody Fc regions. The multimer may be devoid of an antibody Fc region. Examples of Determining Competition Antigen binding affinity by SPR [00665] Antigen binding ability, specificity and affinity (Kd, Koff and/or Kon) can be determined by any routine method in the art, e.g. by surface plasmon resonance (SPR). The term “Kd” or “KD”, as used herein, is intended to refer to the equilibrium dissociation constant of a particular binding moieity (eg, multimer or binding domain)-antigen interaction. Such binding measurements can be made using a variety of binding assays known in the art, e.g. using surface plasmon resonance (SPR), such as by BiacoreTM or using the ProteOn XPR36TM (Bio-Rad®), using KinExA® (Sapidyne Instruments, Inc), or using ForteBio Octet (Pall ForteBio Corp.). [00666] In one non-limiting embodiment, the surface plasmon resonance (SPR) is carried out at 25 oC. In another non-limiting embodiment, the SPR is carried out at 37 oC. [00667] In one non-limiting embodiment, the SPR is carried out at physiological pH, such as about pH7 or at pH7.6 (e.g. using Hepes buffered saline at pH 7.6 (also referred to as HBS-EP)). [00668] In one non-limiting embodiment, the SPR is carried out at a physiological salt level, e.g.150 mM NaCl. [00669] In one non-limiting embodiment, the SPR is carried out at a detergent level of no greater than 0.05% by volume, e.g. in the presence of P20 (polysorbate 20; e.g. Tween 20TM) at 0.05% and EDTA at 3 mM. [00670] In one non-limiting example, the SPR is carried out at 25 oC or 37 oC in a buffer at pH 7.6, 150 mM NaCl, 0.05% detergent (e.g. P20) and 3mM EDTA. The buffer can contain 10 mM Hepes. In one example, the SPR is carried out at 25 oC or 37 oC in HBS-EP. HBS-EP is available from Teknova Inc. (California; catalogue number H8022). [00671] In a non-limiting example (described for a multimer, but applicable to any other antigen binding domain, site or polypeptide), the affinity of an antigen binding multimer is determined using SPR by: a) Coupling anti-antibody constant region (such as when the multimer comprises an Fc (or coupling any other polypeptide capture reagent) (e.g. BiacoreTM BR-1008-38) to a biosensor chip (e.g. GLM chip); b) Exposing the capture reagent to a test multimer to capture the test multimer on the chip; c) Passing the test antigen over the chip’s capture surface at 1024 nM, 256 nM, 64 nM, 16 nM, 4 nM with a 0 nM (i.e. buffer alone); and d) Determining the affinity of binding of test multimer to test antigen using surface plasmon resonance, e.g. under an SPR condition discussed above (e.g. at 25 oC in physiological buffer). SPR can be carried out using any standard SPR apparatus, such as by BiacoreTM or using the ProteOn XPR36TM (Bio-Rad®). [00672] Regeneration of the capture surface can be carried out with 10 mM glycine at pH 1.7. This removes the captured multimer and allows the surface to be used for another interaction. The binding data can be fitted to 1:1 model inherent using standard techniques, e.g. using a model inherent to the ProteOn XPR36TM analysis software. Antigen binding affinity by ELISA [00673] Another non-limiting method for determining antigen binding affinity or the functional affinity (i.e. The overall binding strength for the antigen) of a given molecule could be by using a standard ELISA binding assay as described below: [00674] High protein binding ELISA plates are coated overnight at 4oC either directly with antigen or with capture antibody such as anti-IgG at concentration between 1 - 5 ug/mL prepared in PBS [00675] Coated ELISA plate is washed 3x with wash buffer (PBS containing 0.1% Tween 20). [00676] Plate is blocked with blocking buffer (1% BSA in PBS) except where capture antibody is used in the first step. In this case, target antigen at 1 – 5 ug/ml is added to the plate and incubated at room temperature for 1 hour before performing the blocking step. [00677] Test-multimer (or binding domain, site or polypeptide) is serially diluted in sample dilution buffer (0.1% BSA in PBS) before adding to the coated ELISA plate and the plate is incubated at room temperature for 1 hour after 3 washes with wash buffer. [00678] Detection antibody such as anti-IgG or anti-His tag conjugated to HRP is added to the plate and incubated at room temperature for 1 hour after 3 washes with wash buffer. [00679] Antigen binding signal is developed through the addition of TMB after 3 washes with wash buffer. The plate is incubated in the dark for 5 – 30 mins before the reaction is stop with the addition of 1M sulfuric acid. [00680] Assay signal is determined by measuring absorbance at 450nm using a plate reader. [00681] Half-maximal binding concentration of the test-multimer can be determined as readout of antigen binding affinity. Competition Binding Assays [00682] Competition binding assays can be used to determine whether a given molecule competes for the sample binding epitope or binding region on an antigen of interest compared to a test-multimer (or binding domain, site or multimer). In addition, competition assays can be used as a screening method to discover similar antigen binding molecules or molecules that compete with the test-multimer. There are multiple routine methods for performing competition assays such as those based on SPR, flow cytometry or ELISA. Non-Limiting SPR-based competition assay [00683] Test-antigen is immobilized on CM5 sensor chip. [00684] In the first injection, test multimer (or binding domain, site or polypeptide) at 1 ug/ml is flowed over the captured antigen surface for 60 seconds at 30 μL/minute to achieve saturation [00685] A second injection containing a mixture of test-multimer (binding domain, site or polypeptide) and competitor antigen binding molecule at the same concentration is injected [00686] Competition for binding to the test-multimer antigen binding site can be determined by reduction in test-multimer Kd with the addition of the competitor molecule. Non-Limiting Flow Cytometry-based competition assay [00687] A dilution series of competitor molecule is generated in FACS buffer (PBS + 2% FCS) from 1 ug/ml and mixed with a fixed concentration of test-multimer (or binding domain, site or polypeptide) conjugated to Alexa647. [00688] Antigen expressing cells are prepared through series of washes with PBS and resuspended in FACS buffer at 106 cells/ml. [00689] The mixture containing competitor molecule and Alexa647-conjugated test-multimer is added to the prepared cells and incubated at 4oC for 30 minutes [00690] The cell mixture is washed twice with PBS and then resuspended in FACS buffer [00691] Competition for test-multimer antigen binding site by competitor molecule is assessed by florescence intensity of cell surface stained Alexa647 Non-Limiting ELISA-based competition assay [00692] Coat ELISA plate overnight at 4oC with 100 ul of target antigen at 1 ug/mL diluted in PBS. [00693] For each subsequent steps, plate is incubated at room temperature for 1 hour with 3x plate washes using wash buffer (0.1% Tween 20 in PBS). [00694] ELISA plate is blocked with 200 ul blocking buffer (1% BSA in PBS) and incubated at room temperature for 1 hour. [00695] During the incubation period at step 3, in a separate plate serial dilution of competitor molecule is generated in sample buffer (0.1% BSA in PBS) containing a fixed amount of biotinylated test- multimer (or binding domain, site or polypeptide). The mixture is incubated at room temperature for 30 mins before adding 100 ul of the mix to the plate after step 3. For 100% binding or zero competition, wells with no added competitor molecules is prepared. For zero binding, wells with only sample buffer are also prepared. [00696] Plate is incubated at room temperature for 1 hour and then washed 3x with wash buffer. [00697] Streptavidin conjugated-HRP protein diluted to working concentration in sample buffer is added to the plate and incubated at room temperature for 1 hour. [00698] Assay signal is generated through the addition of 100 ul TMB/well (pre-warmed at room temperature) and incubate in the dark between 5 – 30 mins. [00699] Reaction is stopped with the addition of 50 ul/well of 1M Sulfuric acid. [00700] Assay signal is determined by measuring absorbance at 450nm using a plate reader. [00701] Competition for test-multimer antigen binding site is measured by the reduction in assay signal intensity. [00702] Thus, in an example, competition is determined by a SPR competition assay. Alternatively, for example, competition is determined by an ELISA competition assay. Alternatively, for example, competition is determined by flow cytometry competition assay. The assay may be any competition assay disclosed herein. [00703] Compositions comprising a multimer of the invention (eg, QB-GB or a multimer that competes with QB-BB for binding to SARS-CoV-2 spike) and an anti-spike antibody (eg, wherein the antibody is regdanvimab, REGKINORA™, REGN10987, REGN10933 or CB6) may be useful for resisting mutation in the viral spike protein and/or for enhancing efficacy of treatment or prevention of SARS-CoV-2 (or SARS-CoV-1 or another coronavirus) infection or a symptom thereof in a human or animal subject. [00704] PARAGRAPHS- There are provided the following Paragraphs. 1. A method of detecting the presence of an antigen (eg, a viral antigen) in a sample (eg, a biological sample), the method comprising contacting the multimer, dimer, polypeptide, kit or composition of the invention with the sample and detecting antigen (eg, virus spike protein) is bound to the multimer, dimer or polypeptide. 2. A pharmaceutical composition comprising (i) a multimer of the invention and (ii) an anti-SARS- CoV-2 antibody (eg, an anti-spike antibody) or an ACE2 peptide multimer, optionally wherein the multimer is according to any multimer disclosed herein. 3. The composition of Paragraph 2, wherein the polypeptide comprises a tetramerization domain (TD) and one or more copies of an antigen binding site or domain (BD), the polypeptide comprising or consisting of, in N- to C- terminal direction (a) BD-TD; (b) TD-BD; (c) BD-BD-TD; (d) TD-BD-BD; (e) BD-TD-BD-BD; (f) BD-BD-TD-BD; or (g) BD-BD-TD-BD-BD; wherein (a) BD is a binding domain (eg, an antibody single variable domain) that binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike; or (b) the multimer binds to the inner face of the RBD of SARS-CoV-2 spike. 4. The composition of Paragraph 2 or 3, wherein the antibody is selected from any antibody recited herein, optionally wherein the antibody is regdanvimab, REGKINORA™, REGN10987, REGN10933 or CB6. 5. The composition of Paragraph 2 or 3, wherein the ACE2 peptide multimer comprises 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 copies of an ACE2 peptide (eg, ACE2 extracellular domain, ACE2(18-615) or ACE2(18-740)). 6. The composition of Paragraph 5, wherein the ACE2 multimer is a multimer disclosed herein. 7. The composition of any one Paragraphs 2 to 6, further comprising an anti-inflammatory medicament (eg, an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)) or an immunosuppressant. 8. A medical device (eg, an inhaler, IV bag or syringe) comprising the composition of any one of Paragraphs 2 to 7. 9. A polypeptide comprising a first SARS-CoV-2 spike antigen binding site and a second SARS- CoV-2 spike antigen binding site, wherein the first binding site binds to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike or competes with QB-GB for binding to spike (eg, in an ELISA or SPR competition assay). 10. The polypeptide of Paragraph 9, wherein the first binding site is QB-GB. 11. The polypeptide of Paragraph 9 or 10, wherein the second binding site is a spike binding site of an antibody recited herein, optionally wherein the antibody is regdanvimab, REGKINORA™, REGN10987, REGN10933 or CB6. 12. The polypeptide of any one of Paragraph 9 to 11, wherein the polypeptide comprises a SAM, eg, a tetramerization domain (TD) (eg, a p53 TD), optionally wherein (a) The TD is between the binding sites; (b) the polypeptide comprises, in N- to C-terminal direction, the first binding site, TD and the second binding site; (c) polypeptide comprises, in N- to C-terminal direction, the second binding site, TD and the first binding site; (d) polypeptide comprises, in N- to C-terminal direction, the first binding site, the second binding site and TD; (e) polypeptide comprises, in N- to C-terminal direction TD, the first binding site and the second binding site. 13. A multimer comprising 4 copies of the polypeptide of any one of Paragraphs 9 to 12. 14. A pharmaceutical composition comprising a polypeptide or multimer of any one of Paragraphs 9 to 13 and an excipient, diluent or carrier. 15. The composition of Paragraphs 14, further comprising an anti-inflammatory medicament (eg, an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)) or an immunosuppressant. 16. A medical device (eg, an inhaler, IV bag or syringe) comprising the composition of Paragraphs 14 or 15. [00705] CONCEPTS:- There are provided the following concepts. 1. A protein multimer comprising 4 copies of a binding site, wherein the binding site is capable of binding to a virus spike protein of a coronavirus. The binding site may be any binding site, eg, VH or VL (or VH/VL pair) disclosed herein. 2. The multimer of Concept 1, wherein said virus is a first virus and the multimer is capable of binding to a second coronavirus, wherein the first and second viruses are different virus strains; optionally wherein the viruses are different SARS-CoV-2 strains. 3. The multimer of Concept 2, wherein the viruses have different forms of virus spike proteins and the multimer is capable of binding to the spike proteins. 4. The multimer of any preceding Concept, wherein the binding site is an antibody single variable domain. 5. The multimer of any preceding Concept, wherein the binding site is a) an antigen binding site that is capable of binding to a SARS-CoV-2 spike glycoprotein; or b) an ACE2 or TMPRSS2 peptide. 6. The multimer of any preceding Concept, wherein the binding site is capable of binding to the inner face of the RBD (receptor-binding domain) of SARS-CoV-2 spike. 7. The multimer of any preceding Concept a) wherein the binding site comprises (i) an antibody VH domain comprising the SEQ ID: 1*307 or (ii) an antibody VH domain that comprises an amino acid sequence that is at least 70% identical to SEQ ID: 1*307 or that competes in an in vitro competition assay with the antibody VH domain of (i) for binding to SARS-CoV-2 spike; b) comprising 4 copies of an antigen binding site of an antibody, wherein the antibody is selected from a VH domain comprising the amino acid sequence of SEQ ID: 1*288 (or an antibody variable domain comprising an amino acid sequence that is at least 80% identical to SEQ ID: 1*288), REGN10987, REGN10933 and CB6; or c) comprising 4 copies of an antigen binding site of an antibody, wherein the multimer comprises a dimer of the antibody, wherein the antibody is selected from REGN10987, REGN10933 and CB6. 8. The multimer of any preceding Concept, wherein the multimer comprises at least 4 copies of a polypeptide, wherein the polypeptide comprises a self-assembly multimerization domain (SAM) (optionally a tetramerization domain, TD) and one or more copies of the antigen binding site. 9. The multimer of any one of Concepts 1-7, wherein the multimer is a protein dimer comprising 2 copies of a) the polypeptide defined in Concept 8, optionally wherein the polypeptide comprises (in N- to C-terminal direction) BD-BD-SAM, wherein BD is the binding site; or b) a polypeptide comprising one or more copies of the binding site and an antibody Fc region, wherein the multimer is a dimer and the Fc regions of the 2 polypeptide copies are associated together in the dimer. 10. The multimer of Concept 9, wherein the multimer comprises a) a first polypeptide comprising, in N- to C-terminal direction, BD-hinge-TD; BD-optional linker-BD-Hinge-TD; or BD-optional linker-CH1-Hinge-TD; or b) a TD and one or more copies of BD, the polypeptide comprising, in N- to C-terminal direction (i) BD-TD; (ii) TD-BD; (iii) BD-BD-TD; (iv) TD-BD-BD; (v) BD-TD-BD-BD; (vi) BD-BD-TD-BD; or (vii) BD-BD-TD-BD-BD. 11. The multimer of any preceding Concept, wherein the binding of the multimer (first multimer) to the first virus spike protein is stronger than the binding of a second multimer to the first virus spike protein, wherein the second multimer comprises 2 (but no more than 2) copies of said binding site and wherein a) the first multimer binds to the first virus spike protein with an OD450 from 1 to 3 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay (and optionally the second multimer binds to the first virus spike protein with an OD450 less than 0.5 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay); b) the first multimer (i) binds to a first virus spike protein trimer with an OD450 from 2 to 3 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay and (ii) binds to a first virus spike protein monomer with an OD450 from 1 to 2 in an ELISA assay in which the spike protein is at a concentration of 1 nM in the assay; and/or c) the first multimer binds to the first virus spike protein with an OD450 from 2 to 3 in an ELISA assay in which the spike protein is at a concentration of 10 nM in the assay (and optionally the second multimer binds to the first virus spike protein with an OD450 from 1 to 2 in an ELISA assay in which the spike protein is at a concentration of 10 nM in the assay). 12. The multimer of any preceding Concept, wherein the multimer comprises 6 copies of the binding site. 13. An inhalable pharmaceutical composition comprising a multimer of any preceding Concept, optionally wherein the composition is a nebulised composition. 14. The composition of Concept 13, wherein (i) the composition comprises particles of the multimer and (a) at least 20% of multimer particles are in the size range >4.7 μm, and optionally no more than 5.0 μm; and (b) at least 50% of multimer particles are in the size range <4.7 μm, and optionally at least 15% of multimer particles are in the size range <1.0 μm; or (ii) the composition comprises particles of the multimer and the median mass aerodynamic particle diameter (MMAD) is 3 to 3.5 μm. 15. The composition of Concept 13 or 14 further comprising an anti-inflammatory medicament (eg, an anti-IL6R antibody (such as sarilumab or tocilizumab) or an anti-TNF alpha antibody (such as adalimumab)) or an immunosuppressant.. 16. An inhalation device (optionally a nebuliser or inhaler) comprising the composition of any of Concepts 13 to 15. 17. A mixture of at least 2 different multimers as recited in any one of Concepts 1-12, wherein a first of said multimers comprises 4 copies of an antigen binding site that is capable of binding to a first spike antigen; and a second of said multimers comprises 4 copies of an antigen binding site that is capable of binding to a second spike antigen, and the antigens are different. 18. A method of expanding the antigen binding specificity of a binding site, wherein the binding site binds or neutralises a first antigen, but not a second antigen when the binding site is comprised in monovalent form by a protein that specifically binds to the first antigen, the method comprising providing a plurality of copies of a polypeptide, and multimerising at least 4 of the polypeptides to produce a multimer comprising at least 4 copies of the polypeptide, wherein the polypeptide comprises one, two or more copies of the binding site, whereby binding sites of the multimer are capable of binding the first and second antigens; optionally wherein the multimer is according to any one of Concepts 1-12. 19. A multimer obtainable by the method of Concept 18 wherein the multimer is for targeting a virus whose antigens evolve through mutation during viral infection of a human subject, optionally for treating a coronavirus infection. 20. A pharmaceutical composition comprising a multimer of any one of Concepts 1-12 and 19, optionally wherein the composition is comprised by a sterile medical container or device, such as a syringe, vial, inhaler or injection device. 21. The multimer or composition of any one of Concepts 1-12, 19 and 20 for use as a medicament, optionally for treating or preventing viral pneumonia in a human or animal subject, such as wherein the subject is suffering from or is at risk of suffering from a coronavirus infection. 22. A method of binding multiple copies of an antigen, the method comprising combining the copies with a multimer or composition of Concepts 1-12, 19 and 21, wherein the copies are bound by the multimer, and optionally the method comprising isolating the multimer bound to the antigen copies. 23. A method of detecting the presence of anti-first antigen antibodies in a bodily fluid sample of a human or animal, the method comprising carrying out an ELISA assay, wherein the assay comprises a) Optionally diluting the serum sample from 10 to 106-fold; b) contacting the first antigen with the sample (optionally which has been diluted in step (a)) whereby anti-first antigen antibodies present in the sample bind to the first antigen (eg, spike protein) to produce antigen/antibody complexes; and c) contacting and binding the first antigen or anti-first antigen antibodies with copies of the multimer defined in one of Concepts 1-12, 19 and 21; and d) detecting multimer bound to antigen/antibody complexes, such as by determining optical density; wherein the steps can be carried out in the order (a) (b) (c) and (d) or (a) (c) (b) and (d), or wherein steps (b) and (c) are carried out simultaneously and between steps (a) and (d). 24. A method for detecting the presence of an antigen in a sample, the method comprising combining the sample with a multimer as defined in one of Concepts 1-12, 19 and 21, allowing antigen in the sample to bind multimers to form antigen/multimer complexes and detecting antigen/multimer complexes. 25. A method of expanding a utility of an antigen binding site, the method comprising producing a multimer as defined in one of Concepts 1-12, 19 and 21, wherein the multimer comprises at least 4 copies of the binding site. 26. A method for the treatment or prevention of a disease or condition in a human or animal subject), the method comprising administering to the subject a plurality of multimers as defined in one of Concepts 1-12, 19 and 21. 27. A multimer according to any one of Concepts 1-12, 19 and 21 that is capable of binding to different forms of a virus spike protein for treating, preventing or reducing in a human or animal infection by a virus comprising a first form of spike protein, and for treating, preventing or reducing infection by a virus comprising a second form of the spike protein. 28. A multimer according to any one of Concepts 1-12, 19 and 21 that is capable of binding to different forms of a virus spike protein for treating or preventing or reducing a seasonal viral infection in a human or animal. 29. A medicament for administration to a human or animal subject for treating or preventing a seasonal virus, wherein the medicament comprises a plurality of multimers according to any one of Concepts 1-12, 19 and 21, wherein the medicament comprises a pharmaceutically acceptable diluent, carrier or excipient. 30. The medicament of Concept 29, wherein the medicament is a multi-seasonal anti-viral medicament comprising a plurality of said multimers, wherein the multimers are capable of binding to first and second strains of the virus, wherein the strains differ in a surface-exposed antigen (optionally spike) to which the multimers can bind. 31. A multimer according to any one of Concepts 1-12, 19 and 21 for use in a method for reducing the first virus in an animal to reduce a zoonotic population of viruses that are transmissible to humans, wherein the viruses are capable of causing a disease or condition (or death) in humans. 32. The multimer or medicament of any one of Concepts 27-31, wherein each virus is a SARS virus, optionally SARS-Cov, SARS-Cov-2 or MERS-Cov. [00706] Surprisingly, we discovered that multimers of variable domains comprising one or more of the following features are able to neutralize divergent strains of SARS-CoV-2, such as delta and omicron:- A variable domain that comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S- V, or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences. Preferably, the amino acid sequence of the variable domain comprises (a) a glutamic acid at a position corresponding to position 1 of the selected sequence and a proline at a position corresponding to position 14 of the selected sequence; (b) an arginine at a position corresponding to position 87 of the selected sequence and a glutamic acid at a position corresponding to position 89 of the selected sequence; and/or (c) a leucine at a position corresponding to position 120 of the selected sequence. Preferably, the amino acid corresponding to position 37 of the selected sequence is a phenylalanine and/or the amino acid corresponding to position 47 of the selected sequence is a phenylalanine. Preferably, the amino acid of the variable domain comprises (a) an arginine at a position corresponding to position 27 of the selected sequence; and/or (b) a glutamic acid at a position corresponding to position 31 of the selected sequence. Most preferably, the amino acid sequence of the domain comprises (d) a glutamic acid at position 1; (e) a proline at position 14; (f) an arginine at position 27; (g) a glutamic acid at position 31; (h) a phenylalanine at position 37; (i) a phenylalanine at position 47; (j) an arginine at position 87; (k) a glutamic acid at position 89; and (l) a leucine at position 120. Preferably, the amino acid sequence of the domain comprises one or more sequence motifs selected from (a) GRTFSEYAMG (SEQ ID: AA) in CDR1; (b) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence; and (c) AAGLGTVVSEWDYDYDYW (SEQ ID: II) in CDR3. In an example, the domain comprises all of these preferred features of paragraph [00706]. Variable domain Q225 is an example and this is surprisingly effective for neutralizing divergent SARS-Cov-2 strains such as delta and omicron. [00707] Multimers of such a variable domain (preferably multimers having 4 copies of the domain) are useful to treat humans against multiple coronavirus strains. Thus, in an example, there is provided the following Aspects 1. An antibody variable domain for use as a medicament for treating humans against multiple different strains of SARS-CoV-2, wherein the variable domain is capable of binding and neutralising a SARS-CoV-2 virus and the variable domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V, or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences. Alternatively, Aspect 1 provides: An antibody variable domain for use as a medicament effective for treating a human subject against a plurality of strains of SARS-CoV-2, wherein the variable domain is capable of binding and neutralising a SARS-CoV-2 virus and the variable domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V, or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences. 2. Preferably, the sequence is I. Preferably, the sequence is V. 3. The variable domain of Aspect 1, wherein the virus is SARS-CoV-2 omicron; or a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron. Optionally, the virus is delta, alpha, the L strain, a virus strain comprising a spike containing a D614G mutation or a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron. Optionally, the genome comprises up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron. 4. The variable domain of any preceding Aspect, wherein said strains comprise SARS-CoV-2 omicron; and optionally one or more virus strains selected from delta, alpha, the L strain, a virus strain comprising a spike containing a D614G mutation and a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron. Preferably, the strains comprise delta and optionally a virus strain comprising a spike containing a D614G mutation. Optionally, the genome comprises up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron. 5. The variable domain of any preceding Aspect, wherein said strains comprise SARS-CoV-2 delta, omicron and a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 delta or omicron. Optionally, the genome comprises up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron. 6. The variable domain of any preceding Aspect for treating a human subject against SARS-CoV-2 omicron or a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron. Optionally, the genome comprises up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron. 7. The variable domain of any preceding Aspect wherein the treating is therapeutically or prophylactically treating. 8. The variable domain of any preceding Aspect wherein said selected sequence is SEQ ID: V or I. 9. A multimer comprising a plurality of copies of a variable domain according to any preceding Aspects. Multimers comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of REGN10933, (iv) 4 copies of an antigen binding site of CB6, or (v) 4 copies of an antigen binding site of regdanvimab can neutralise SARS-CoV-2 (as explained above) and are useful for treating or preventing infection of humans (or a human) against multiple strains of SARS-CoV-2 wherein the strains comprise omicron. Thus, in an alternative, Aspect 9 provides:- A multimer comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of REGN10933, (iv) 4 copies of an antigen binding site of CB6, or (v) 4 copies of an antigen binding site of regdanvimab. 10. The multimer of Aspect 9, wherein the multimer comprises at least 4 copies of the variable domain or binding site, optionally the multimer comprises no more than 4, 8 or 16 copies of said domain or binding site. 11. The multimer of Aspect 9 or 10, wherein the multimer comprises a plurality of antibody Fc regions. 12. The multimer of Aspect 9, 10 or 11, wherein the multimer comprises a plurality of copies of a polypeptide, wherein the polypeptide comprises at least one (preferably 2) copy(ies) of the variable domain or binding site and an antibody Fc region. For example, the multimer comprises at least 2 (and optionally no more than 2, or optionally no more than 4) copies of the polypeptide. Optionally, the polypeptide comprises in N- to C- terminal direction: V-V-Fc, wherein V is a variable domain according to any of Aspects 1-7. Such a format has been demonstrated in Example 41 to provide multimers that can recognise and neutralise multiple strains of SARS-Cov-2. In an example, the polypeptide comprises in N- to C- terminal direction: V-V-Fc-V-V. The multimer may be comprised by a medical or sterile container, eg, a syringe, vial, IV bag, container connected to a needle or a subcutaneous injection administration device. 13. A pharmaceutical composition comprising the multimer of any one of Aspects 9 to 12 and a pharmaceutically acceptable diluent, carrier or excipient. 14. A method of treating a human for a SARS-CoV-2 virus infection, wherein the infection is an infection of SARS-CoV-2 delta or omicron; or a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron, wherein the method comprises administering (optionally by injection or inhalation) a medicament comprising (i) a multimer of a variable domain that is capable of binding and neutralising a SARS-CoV-2 virus and the variable domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V, or an amino acid sequence that is identical to a said selected sequence except for 1- 25 amino acid differences; or (ii) a multimer comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of REGN10933, (iv) 4 copies of an antigen binding site of CB6, or (v) 4 copies of an antigen binding site of regdanvimab. 15. The method of Aspect 14, wherein the multimer is according to any one of Aspects 9-12. CONCEPTS: There are provided the following Concepts. These are not to be interpreted as Claims. 1. A multimer of a first antibody variable domain for use as a medicament in a method for treating humans against multiple different strains of SARS-CoV-2, wherein the multimer is capable of inhibiting infection of human cells (eg, HEK293 cells) by SARS-CoV-2 omicron and the first variable domain is capable of inhibiting the binding of a second antibody variable domain to SARS-CoV-2 omicron spike, wherein the second domain comprises the amino acid sequence of SEQ ID: U; and wherein said strains comprise SARS-CoV-2 omicron. The first and second domains are different from each other, optionally wherein the first domain is a humanised version of the second domain, the second domain being a Camelid VHH domain. In an alternative, Concept 1 provides:- A multimer for use as a medicament in a method for treating humans against multiple different strains of SARS-CoV-2, wherein the multimer is capable of inhibiting infection of human cells (eg, HEK293 cells) by SARS-CoV-2 omicron, the multimer comprising (i) 4 copies of an antigen binding site of REGN10987, (ii) 4 copies of an antigen binding site of REGN10933, (iii) 4 copies of an antigen binding site of REGN10987 and 4 copies of an antigen binding site of REGN10933, (iv) 4 copies of an antigen binding site of CB6, or (v) 4 copies of an antigen binding site of regdanvimab. Inhibition of infection may be inhibition of infection by at least 60, 70, 80, 90 or 95% compared to a control in a virus or pseudovirus neutralisation assay. Inhibition of infection may be inhibition of infection by 100% compared to a control in a virus or pseudovirus neutralisation assay. The control comprises contacting human cells with SARS-CoV-2 omicron in the absence of the multimer. As will be clear to the skilled person, the test and control samples are otherwise tested under identical conditions. 2. The multimer of Concept 1, wherein the multimer comprises 4 copies of the first variable domain or binding site, and optionally the multimer comprises no more than 4, 8 or 16 copies of said first domain or binding site. Preferably, the multimer comprises 4 copies (but no more than 4 copies) of the first domain or binding site. Preferably, the multimer comprises 8 copies (but no more than 8 copies) of the first domain or binding site. Preferably, the multimer comprises 16 copies (but no more than 16 copies) of the first domain or binding site. 3. The multimer of Concept 1 or 2, wherein the multimer comprises a plurality of copies of a polypeptide, wherein the polypeptide comprises at least one (preferably 2) copy(ies) of the variable domain or binding site and an antibody Fc region. 4. The multimer of Concept 3, wherein the polypeptide comprises in N- to C-terminal direction: V- V-Fc, wherein V is the first variable domain. 5. The multimer of any preceding Concept, wherein the first variable domain is capable of inhibiting the binding of the second antibody variable domain with SARS-CoV-2 omicron spike as determined by a surface plasmon resonance (SPR) or ELISA competition assay. Inhibition of binding may be by at least 60, 70, 80, 90 or 95% as determined by a surface plasmon resonance (SPR) or ELISA assay. 6. The multimer of any preceding Concept, wherein the multimer is comprised by a medical or sterile container, optionally wherein the multimer is comprised by a syringe, vial, IV bag, container connected to a needle or a subcutaneous injection administration device. The container may comprise an immunosuppressant or anti-inflammatory agent, eg, an anti-IL6 antibody, anti-IL-6R antibody or a steroid. 7. The multimer of any preceding Concept, wherein the multimer is capable of inhibiting infection of human HEK293 cells by SARS-CoV-2 omicron virus or pseudovirus comprising omicron spike in a virus neutralisation assay with an IC50 <0.1 nM (preferably <0.02 nM) and/or the method comprises administering the multimer to a human subject or human subjects and inhibiting infection of human cells of the subject(s) by SARS-CoV-2 virus with an IC50 <0.1 nM (preferably <0.02 nM), optionally wherein the virus is SARS-CoV-2 omicron or a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron. The neutralisation assay may be a pseudovirus assay, as will be apparent to the skilled addressee. 8. The multimer of any preceding Concept, wherein said strains comprise one or more virus strains selected from delta, alpha, the L strain (Wuhan strain), a virus strain comprising a spike containing a D614G mutation and a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron. 9. The multimer of any preceding Concept, wherein said strains comprise SARS-CoV-2 delta and optionally a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron. Wherever changes “up to 65” are disclosed anywhere herein, the changes may be up to 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60. For example, the changes are no more than 7 or 8. 10. The multimer of any preceding Concept, wherein said first domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V (preferably I or V) or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences. For example wherever “1-25 amino acid differences” are disclosed anywhere herein, the differences may be up to 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or 20. 11. An antibody variable domain for use as the first domain of the multimer of any preceding Concept, wherein the domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L, S and T (preferably I), or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences, wherein the variable domain is capable of inhibiting the binding of a second antibody variable domain to SARS-CoV-2 omicron spike, wherein the second domain comprises the amino acid sequence of SEQ ID: U. 12. The variable domain of Concept 11, wherein the variable domain is capable of inhibiting the binding of the second antibody variable domain to a SARS-CoV-2 strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron. 13. The multimer or variable domain of any preceding Concept for treating a human subject against SARS-CoV-2 omicron or a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron. 14. The multimer or variable domain of any one of Concepts 1-10 and 13, wherein the treating is therapeutically or prophylactically treating. 15. The variable domain of any one of Concepts 11-14, wherein the amino acid sequence comprises (a) a glutamic acid at position 1; (b) a proline at position 14; (c) an arginine at position 27; (d) a glutamic acid at position 31; (e) a phenylalanine at position 37; (f) a phenylalanine at position 47; (g) an arginine at position 87; (h) a glutamic acid at position 89; and (i) a leucine at position 120. 16. The multimer of Concept 10 or the antibody variable domain of any one of Concepts 11-15, wherein said number of differences is from 1 to 14; optionally no more than 7 or 8. 17. The antibody variable domain of any one of Concepts 11-16, wherein there is no said difference at the amino acid corresponding to position 35 and/or 50 of the selected sequence; and/or wherein there is a said difference at the amino acid position corresponding to position 61 of the selected sequence. 18. The antibody variable domain of any one of Concepts 11-17, wherein (a) the amino acid corresponding to position 61 of the selected sequence is an amino acid other than a threonine, optionally wherein the amino acid is an alanine; or (b) the amino acid corresponding to position 61 of the selected sequence is a threonine. 19. The antibody variable domain of any one of Concepts 11-18, wherein (a) the amino acid corresponding to position 35 of the selected sequence is a serine or the amino acid corresponding to position 50 of the selected sequence is an alanine; or (b) the amino acid corresponding to position 35 of the selected sequence is a glycine or the amino acid corresponding to position 50 of the selected sequence is a threonine. 20. The antibody variable domain of any one of Concepts 11-19, wherein the amino acid corresponding to position 37 of the selected sequence is a phenylalanine and/or the amino acid corresponding to position 47 of the selected sequence is a phenylalanine. 21. The antibody variable domain of any one of Concepts 11-20, wherein the amino acid sequence of the variable domain comprises (a) one or more amino acids selected from a glutamic acid at a position corresponding to position 1 of the selected sequence, a leucine at a position corresponding to position 5 of the selected sequence and a proline at a position corresponding to position 14 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids; (b) a serine or glycine at a position corresponding to position 35 of the selected sequence; (c) one or more amino acids selected from a glycine at a position corresponding to position 44 of the selected sequence, a leucine at a position corresponding to position 45 of the selected sequence and a serine at a position corresponding to position 49 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids (d) one or more amino acids selected from a serine at a position corresponding to position 75 of the selected sequence, a leucine at a position corresponding to position 79 of the selected sequence, an arginine at a position corresponding to position 87 of the selected sequence, an alanine at a position corresponding to position 88 of the selected sequence and a glutamic acid at a position corresponding to position 89 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids; and/or (e) a leucine at a position corresponding to position 120 of the selected sequence. 22. The antibody variable domain of any one of Concepts 11-21, wherein the amino acid of the variable domain comprises residues (f) all of the amino acids according to Concept 21(a), (c), (d) and (e); and (g) an amino acid according to Concept 21(b). 23. The antibody variable domain of any one of Concepts 11-22, wherein the amino acid of the variable domain comprises (a) an arginine or phenylalanine at a position corresponding to position 27 of the selected sequence; (b) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and/or (c) an alanine or serine at a position corresponding to position 49 of the selected sequence. 24. The antibody variable domain of any one of Concepts 11-23, wherein the amino acid of the variable domain comprises A: (a) an arginine at a position corresponding to position 27 of the selected sequence; (b) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and (c) a serine at a position corresponding to position 49 of the selected sequence; or B: (d) a phenylalanine at a position corresponding to position 27 of the selected sequence; (e) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and (f) a serine at a position corresponding to position 49 of the selected sequence. 25. The antibody variable domain of any one of Concepts 11-24, wherein the amino acid of the variable domain comprises (a) a phenylalanine at a position corresponding to position 27 of the selected sequence; (b) a serine at a position corresponding to position 31 of the selected sequence; and/or (c) a glycine at a position corresponding to position 53 of the selected sequence. 26. The antibody variable domain of any one of Concepts 11-25, wherein framework 1 (FR1) of the variable domain comprises at the N-terminal end of FR1, the amino acid sequence EVQLLESGGGLVQP (SEQ ID: W) or EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID: X). 27. The multimer of Concept 10 or the antibody variable domain of any one of Concepts 11-26, wherein at least one of said differences (or optionally each of the differences) is a substitution of an amino acid of said selected sequence for the amino acid found at the corresponding position of the amino acid sequence of human germline gene segment IGHV3-23 (optionally IGHV3-23*01 or IGHV3-23*04). 28. The antibody variable domain of any one of Concepts 11-27, wherein each of said differences is in the FR1, complementarity determining region 1 (CDR1), FR2, CDR2, FR3 or FR4. 29. The multimer of Concept 10 or the antibody variable domain of any one of Concepts 11-28, wherein each said difference is an amino acid substitution. 30. The antibody variable domain of any one of Concepts 11-29, wherein said amino acid sequence of the domain comprises one or more sequence motifs selected from (a) EVQLLESGGGLVQP (SEQ ID: W) at the N-terminal end of FR1 or EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID: X) in FR1; (b) GRTFSEYAMS (SEQ ID: Z) or GRTFSEYAMG (SEQ ID: AA) in CDR1; (c) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence and/or GLEFVS (SEQ ID: CC) in FR2 wherein the F in SEQ ID: CC is at a position that corresponds to position 47 in the selected sequence; or (ii) WFRQAPGKGLEFVS (SEQ ID: DD) in FR2; (d) (i) AISW (SEQ ID: DD) at the N-terminal end of CDR2 and/or TYYA (SEQ ID: EE) at the C-terminal end of CDR2; or (ii) AISWSGGSTY (SEQ ID: FF) in CDR2; (e) (i) YADSV (SEQ ID: LL) at the N-terminal end of FR3 and/or RAEDTAVYYCA (SEQ ID: GG) at the C-terminal end of FR3; or (ii) YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA (SEQ ID: HH) in FR3; (f) AAGLGTVVSEWDYDYDYW (SEQ ID: II) in CDR3; and/or (g) GQGTLVTVSS (SEQ ID: JJ) in FR4. 31. The antibody variable domain of any one of Concepts 11-30, wherein said amino acid sequence of the domain comprises (h) a glutamic acid at position 1; (i) a proline at position 14; (j) an arginine at position 27; (k) a glutamic acid at position 31; (l) a phenylalanine at position 37; (m) a phenylalanine at position 47; (n) an arginine at position 87; (o) a glutamic acid at position 89; and (p) a leucine at position 120. 32. The antibody variable domain of any one of Concepts 11-31, wherein said amino acid sequence of the domain comprises (a) GRTFSEYAMG (SEQ ID: AA) in CDR1; (b) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence; and (c) AAGLGTVVSEWDYDYDYW (SEQ ID: II) in CDR3. 33. An isolated nucleic acid encoding an antibody variable domain of any one of Concepts 11-32, optionally wherein the nucleic acid is comprised by an expression vector for expressing the variable domain or a polypeptide comprising the variable domain. 34. A multimer according to any one of Concepts 1-10, wherein the first variable domain is according to any one of Concepts 11-32. 35. A pharmaceutical composition comprising the multimer of any one of Concepts 1-10 and 34, and a pharmaceutically acceptable diluent, carrier or excipient. 36. A method of treating a human for a SARS-CoV-2 virus infection, wherein the infection is an infection of SARS-CoV-2 delta or omicron; or a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron, wherein the method comprises administering (optionally by injection or inhalation) a medicament comprising a multimer of any one of Concepts 1-10 and 34. 37. A polypeptide comprising the amino acid sequence of an antibody variable domain of any one of Concepts 111-32 and one or more further amino acid sequences, optionally wherein the polypeptide comprises a self-assembly multimerization domain (SAM domain), eg, a p53 domain and/or an Fc region. 38. The polypeptide of Concept 37, comprising at least 2 copies of the amino acid sequence of the variable domain, and optionally an amino acid sequence encoding an ACE2 peptide (eg, an ACE2 extracellular domain). 39. A tetramer of polypeptides of Concept 37 or 38, wherein each polypeptide comprises a self- assembly multimerization domain (SAM domain), eg, a p53 domain. 40. A medical device (eg, a syringe, inhaler or IV bag) comprising the composition of Concept 35. 41. A method of treating or preventing a coronavirus virus (eg, SARS-CoV-2, SARS-CoV-1 or beta-coronavirus) infection in a human or animal subject or a symptom thereof (eg, an immune or inflammatory response), the method comprising administering the composition of Concept 35 or 40 to the subject. 42. Use of the composition of any one of Concepts 35 or 40 or multimer of any one of Concepts 1-10 and 34 in the manufacture of a medicament for administration to a human or animal subject for treating or preventing a coronavirus virus (eg, SARS-CoV-2, SARS-CoV-1 or beta-coronavirus) infection in a human or animal subject or a symptom thereof (eg, an immune or inflammatory response). 43. A method of detecting the presence of a virus in a sample (eg, a biological sample), the method comprising contacting the variable domain, polypeptide, multimer of any one of Concepts 1-10 and 34 with the sample and detecting virus or virus spike protein is bound to the variable domain, polypeptide, multimer or tetramer. 44. A method of isolating a multimer of any of Concepts 1-10 and 34 from a sample comprising the multimer, the method comprising contacting the sample with a solid support (eg, a gel, resin or bead), wherein protein A is immobilised on the solid support prior to said contacting and the multimer is bound by protein A, optionally further comprising separating the bound multimer from the protein A. 45. The method of Concept 45, wherein the multimer comprises 4 copies of a human IGHV3 variable domain. 46. A multimer of a first antibody variable domain for use as a medicament to treat or prevent the infection of a human by the omicron strain of SARS-CoV-2 or a SARS-CoV-2 strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron, wherein the multimer is capable of inhibiting infection of human cells by SARS-CoV-2 omicron and the first variable domain is capable of inhibiting the binding of a second antibody variable domain to SARS-CoV-2 omicron spike, wherein the second domain comprises the amino acid sequence of SEQ ID: U. 47. The multimer of Concept 46, wherein the multimer comprises 4 copies of the first variable domain, and optionally the multimer comprises no more than 4, 8 or 16 copies of said first domain. 48. A multimer according to Concept 46 or 47, wherein the first variable domain is according to any one of Concepts 11-32. [00708] It was surprisingly found (Example 42) that multimers with features (a)-(x) below are capable of neturalizing SARS-CoV-2 omicron in a virus neutralization assay. Moreover, neutralization was surprisingly found to be potent (neutralization in a virus neutralization assay with an IC50 of <50 ng/mL). Advantageously, neutralization of multiple strains SARS-Cov-2, including SARS-CoV-2 D614G, omicron, alpha, beta and delta was observed. Also surprisingly, neutralization of SARS-Cov- 1 and SHC01 was observed. [00709] The invention provides:- A multimer of comprising 4 copies of a first polypeptide for use as a medicament in a method for treating humans against multiple different strains of SARS-CoV-2, wherein the multimer is capable of inhibiting infection of human cells by SARS-CoV-2 omicron, wherein the first polypeptide is according to any one of (a)-(r), (a) V-TD (b) V-CH2-CH3-TD (c) V-CH1-CH2-CH3-TD (d) V-CH1-TD (e) V-V-TD (f) V-V-CH2-CH3-TD (g) V-V-TD (h) V1-V2-TD (i) V1-V2-CH2-CH3-TD (j) V1-V2-TD (k) V-V-CH1-TD (l) V-V-TD-V (m) V-V-TD-V-V (n) V-V-TD-V (o) V-V-TD-V-V (p) V-V-CH1-TD-V-V (q) V-V-CH1-CH2-CH3-TD (r) V1-V2-CH1-CH2-CH3-TD wherein (s) when the multimer comprises copies of first polypeptide (c), (d) or (p), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V-CL, wherein the CL is paired with CH1 of the respective first polypeptide; (t) when the multimer comprises copies of first polypeptide (k) or (q), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V-V-CL, wherein the CL is paired with CH1 of the respective first polypeptide; (u) when the multimer comprises copies of first polypeptide (r), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V1-V2-CL, wherein the CL is paired with CH1 of the respective first polypeptide; (v) each V is an antibody variable domain (eg, an antibody single variable domain) that is capable of specifically binding to an antigen; and V1 and V2 are different variable domains and capable of specifically binding to different antigens or epitopes; (w) each V or V1 specifically binds to SARS-CoV-2 omicron spike; and (x) TD is a self-associating tetramerisation domain. [00710] In an alternative, each V is a peptide or a non-immunoglobulin binding domain that specifically binds to an antigen or epitope. In an embodiment Vs comprised by paired first and second polypeptides together form an antigen binding site (eg, a VH/VL pair that is capable of specifically to an antigen). For example, the binding site is the binding site of an antibody selected from an antibody selected from REGN10987, REGN10933, regdanvimab, REGKINORA™ and CB6 (etesevimab). Preferably, the antibody is REGN10987 (imdevimab). Preferably, the antibody is REGN10933 (casirivimab). In an embodiment, the first polypeptide is according to (c) and the first polypeptide is a heavy chain polypeptide of imdevimab and the second polyeptide is a light chain of imdevimab. In an embodiment, the first polypeptide is according to (c) and the first polypeptide is a heavy chain polypeptide of casirivimab and the second polyeptide is a light chain of casirivimab. In an embodiment, the first polypeptide is according to (c) and the first polypeptide is a heavy chain polypeptide of etesevimab and the second polyeptide is a light chain of etesevimab. [00711] V1 may specifically bind to a SARS-CoV-2 spike epitope and V2 may specifically bind to a different coronavirus antigen or epitope (eg, a different SARS-Cov-2 spike epitope or a protein of a coronavirus (eg, SARS-CoV)). In an example, the multimer has any other features of a multimer disclosed herein. Instead of a single V or 2 Vs at the N-terminus of a format, the first polypeptide may instead have 3 Vs at its N-terminus. Instead of a single V or 2 Vs at the C-terminus of a format, the first polypeptide may instead have 3 Vs at its C-terminus. In these embodiments, where the first polypeptide is paired with a second polypeptide, each V of the first polypeptide is paired with a respective V of the second polypeptide (thus, the second polypeptide in these embodiments comprises 3 Vs at the N- and/or C-terminus). [00712] A hinge region (intact hinge or a hinge devoid of a core hinge region) may be present between CH1 (where the first polypeptide comprises a CH1) and the immediately adjacent V at the N-terminal side of the CH1. In these embodiments, the N-terminal-most cysteine of the hinge may be omitted. This is useful where the first polypeptide is not paired with a second polypeptide, and may be advantageous for production of the multimers. [00713] Preferably, the strains are selected from D614G, omicron, alpha, beta and delta. Preferably, the strains comprise omicron and one or more strains selected from D614G, alpha, beta and delta. [00714] Alternatively, the multimer is for treating or preventing a SARS-CoV-2 infection in a human or animal, eg, SARS-CoV-2 omicron infection. In an example, the infection is selected from a SARS- CoV-2 D614G, omicron, alpha, beta or delta infection. Alternatively, the multimer is for treating or preventing a SARS-CoV-1 infection in a human or animal. [00715] In an embodiment, V, V1 or V2 may be an anti-spike (eg, anti-SARS-CoV-2 omicron spike) variable domain as disclosed herein, eg, the variable domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V (preferably I or V) or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences. In an example, the variable domain (V, V1 or V2) is capable of inhibiting the binding of a second antibody variable domain to SARS-CoV-2 omicron spike, wherein the second domain comprises the amino acid sequence of SEQ ID: U; and wherein said strains comprise SARS-CoV-2 omicron. [00716] Preferably, the multimer is capable of neutralising SARS-CoV-2 omicron in a virus neutralization assay with an IC50 of <500 ng/mL. [00717] Thus, in an example the multimer is capable of neutralising SARS-CoV-2 omicron in a virus neutralization assay with an IC50 of <500, 400, 300, 200, 100, 50, 40, 30, 20, or 10 ng/mL in a SARS-CoV-2 omicron neutralization assay, wherein the assay comprises combining the multimer with SARS-CoV-2 omicron viruses that express green fluorescent protein (GFP) to form a mixture, incubating the mixture for 45 minutes, combining the mixture with human target HEK293T cells expressing ACE2 and TMPRSS2, incubating the mixture comprising the multimer, cells and viruses for 72 hours, determining the number of target cells that have been virally infected by determining the number of target cells expressing GFP, calculating from this number the percentage of virus neutralized by the multimer, normalizing the percentage by comparing with control wells containing virus and target cells in the absence of multimers, and determining from the normalized percentage the IC50 with which the multimer neutralizes viruses. [00718] Examples of the formats are as follows (all of which have advantageously been shown to neutralise SARS-CoV-2 omicron in a virus neutralisation assay):- (i) V-V-hinge-TD (ii) V-V-hinge-TD-V (iii) V-V-hinge-TD-V-V (iv) V-V-CH1-hinge-TD/V-V-CL (v) V-CH1-hinge-TD/V-CL (vi) V-V-CH1-hinge-CH2-CH-3-TD/V-V-CL (vii) V-CH1-hinge-CH2-CH-3-TD/V-CL (viii) V-V-hinge-CH2-CH-3-TD (ix) V1-V2-hinge-TD (x) V1-V2-CH1-Hinge-CH2-CH3-TD/ V1-V2-CL (xi) V-CH1-hinge*-CH2-CH3-TD/V-CL (xii) V-hinge-CH2-CH3-TD (xiii) V1-V2-hinge-CH2-CH3-TD (xiv) V-V-V-hinge-CH2-CH3-TD (xv) V-V-hinge-CH2-CH3-TD-V (xvi) V-V-hinge-CH2-CH3-TD-V-V (xvii) V-V-CH1-hinge*-CH2-CH3-TD/ V-CL (xviii) V-CH1-hinge*-CH2-CH3-TD-V/V-CL (xix) EK1-hinge-CH2-CH3-TD-V (xx) EK1-hinge-CH2-CH3-TD-V-V *hinge devoid of core hinge region [00719] Examples of multimers according to formats (a)-(r) above shown in Table F; thus the multimer of the present invention (eg, for use in treating or preventing omicron or multiple SARS- CoV-2 strains) is optionally as shown in any of the figures in Table F. Thus, the multimer optionally comprises the format shown in any one of Figures 57-A, 57-C, 57-E, 57-G, 57-F, 57-I, 59-A, 59-C, 59-E, 59-B, 59-D, 59-F, 60-A, 60K, 60-C, 60-D, 60-E, 60-F, 60-G; 60-H, 60-I and 60-J of WO2021190980 (which figures and their legends are explicitly incorporated herein for possible use in the present invention). [00720] Any example, configuration, Aspect, Concept, Clause or Paragraph or disclosure herein is combinable with any feature of any further example, configuration, Aspect, Concept, Clause or Paragraph or disclosure herein. [00721] It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognise, or be able to ascertain using no more than routine study, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims. All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications (including US equivalents of all mentioned patent applications and patents) are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or." Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects. [00722] As used in this specification and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps [00723] The term "or combinations thereof" as used herein refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context. [00724] Any part of this disclosure may be read in combination with any other part of the disclosure, unless otherwise apparent from the context. [00725] All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims. EXAMPLES   [00726] All of Figures 1-63 herein are indentical to Figures 1-63 respectively of WO2021/190980, which Figures of WO2021/190980 and the description of such Figures under” BRIEF DESCRIPTION OF THE DRAWINGS” in WO2021/190980 in their entirety are expressly incorporated herein. EXAMPLE 1: Generation of tetravalent and octavalent soluble heterodimeric NY-ESO-1 TCR molecules [00727] This example demonstrates a method for generating tetravalent and octavalent soluble heterodimeric TCR molecules referred to as ts-NY-ESO-1 TCR and os-NY-ESO-1 TCR respectively. These formats overcome the problems associated with solubility and avidity for cognate ligand at the target site. [00728] To exemplify ts-NY-ESO-1 TCR and os-NY-ESO-1 TCR as stable and soluble molecules, TCR αβ variable sequences with high affinity for NY-ESO-1 together with immunoglobulin constant domains and the NHR2 tetramerisation domain are used in this example. [00729] The high-affinity NY-ESO TCR αβ chains (composing of TCR Vα-Cα and Vβ-Cβ respectively) specific for SLLMWITQC-HLA-A*0201 used in this example is as reported in WO 2005/113595 A2 with the inclusion of a signal peptide sequence (MGWSCIILFLVATATGVHS). To aid protein purification, a histidine tag was incorporated to the C-terminus of NHR2 domain. [00730] DNA constructs encoding components of ts-NY-ESO-1 TCR and os-NY-ESO-1 TCR are synthetically constructed as a two-vector system to allow for their soluble expression and functional assembly in mammalian cells. A schematic representation of the two assembled TCR chains (α and β chains) whose DNA sequences are synthesized for cloning into the expression vector are shown in Figures 3 and 4 and their amino acid sequences are shown in Figures 5 and 6. [00731] The pTT5 vector system allows for high-level transient production of recombinant proteins in suspension-adapted HEK293 EBNA cells (Zhang et al., 2009). It contains origin of replication (oriP) that is recognized by the viral protein Epstein-Barr Nuclear Antigen 1 (EBNA-1), which together with the host cell replication factor mediates episomal replication of the DNA plasmid allowing enhanced expression of recombinant protein. Therefore the pTT5 expression vector is selected for cloning the components for the ts-NY-ESO-1 TCR and os-NY-ESO-1 TCR molecules. [00732] Synthesized DNA fragments containing the TCR αβ chains are digested with restriction enzymes at the restriction sites (RS) (FastDigest, Fermantas) and the DNA separated out on a 1% agarose gel. The correct size DNA fragments is excised and the DNA purified using Qiagen gel extraction kit. The pTT5 vector was also digested with the same restriction enzymes and the linearized plasmid DNA is purified from excised agarose gel. The digested TCR αβ chains is cloned into the digested pTT5 vector to give four expression vectors (pTT5-ts-NY-ESO-1-TCRα, pTT5-ts- ESO-1-TCRβ, pTT5-os-NY-ESO-1-TCRα and pTT5-os-ESO-1-TCRβ). [00733] Expression of tetravalent and octavalent soluble NY-ESO TCR [00734] Functional expression of ts-NY-ESO-1 TCR and os-NY-ESO-1 TCR is carried out in suspension-adapted HEK293 EBNA cells. HEK293-EBNA cells are cultured in serum-free Dulbecco’s Modified Eagle Medium (DMEM, high glucose (4.5 g/L) with 2 mM L-glutamine) at 37oC, 5% CO2 and 95% humidity. [00735] For each transfection, HEK293-EBNA cells (3 x 107 cells) are freshly seeded into 250 mL Erlenmeyer shaker Flask (Corning) from ~60% confluent cells. Transfections are carried out using FreeStyle MAX cationic lipid base reagent (Life Technologies) according to the supplier’s guidelines. For expression of ts-NY-ESO-1 TCR, 37.5 μg of total plasmid DNA (18.75 μg plasmid DNA each of pTT5-ts-NY-ESO-1-TCRα and pTT5-ts-ESO-1-TCRβ vectors are used or varying amounts of the two expression plasmids) are used per transfection. Similarly for expression of os-NY-ESO-1 TCR, 18.75 μg plasmid DNA each of pTT5-os-NY-ESO-1-TCRα and pTT5-os-ESO-1-TCRβ isare used for transfection. Following transfection, cells were recovered in fresh medium and cultivated at 37oC with 5% CO2 in an orbital shaker at 110 rpm for between 4 – 8 days. Smaller scale transfections are done similarly in 6 well or 24 well plates. Analysis of Expressed Soluble eTCR2-BiTE [00736] The ts-NY-ESO-1 TCR and os-NY-ESO-1 TCR protein molecules secreted into the supernatant are analyzed either directly by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) or after protein purification. Protein samples and standards are prepared under both reducing and non-reducing conditions. SDS-PAGE was performed using cast mini gels for protein electrophoresis in a Mini-PROTEAN Tetra cell electrophoresis system (Bio-Rad). Coomassie blue dye was used to stain proteins in SDS-PAGE gel. Purification of ts-NY-ESO-1 TCR and os-NY-ESO-1 TCR protein molecules [00737] Soluble ts-NY-ESO-1 TCR and os-NY-ESO-1 TCR from cell supernatant are purified in two steps. In the first step immobilized metal affinity chromatography (IMAC) are used with nitrilotriacetic acid (NTA) agarose resin loaded with nickel (HisPur Ni-NTA Superflow agarose – Thermo fisher). The binding and washing buffer consists of Tris-buffer saline (TBS) at pH7.2 containing low concentration of imidazole (10-25mM). Elution and recovery of the His-tagged ts-NY- ESO-1 TCR and os-NY-ESO-1 TCR from the IMAC column are achieved by washing with high concentration of imidazole (>200mM). The eluted protein fractions are analysed by SDS-PAGE and the fractions containing the protein of interest are pooled. The pooled protein fraction is used directly in binding assays or further purified in a second step involving size-exclusion chromatography (SEC). Superdex 200 increase prepacked column (Gelifesciences) are used to separate out monomer, oligomer and any aggregated forms of the target protein. Surface Plasmon Resonance [00738] The specific binding and affinity analysis of ts-NY-ESO-1 TCR and os-NY-ESO-1 TCR to its pMHC is performed using BIAcore. Briefly, the purified Histidine-tagged ts-NY-ESO-1 TCR and os- NY-ESO-1 TCR proteins are captured onto sensor surface via Ni2+ chelation of nitrilotriacetic acid (NTA). Varying concentration of the analyte solution containing NY-ESO pep(SLLMWITQV)-MHC (ProImmune)is injected and the binding signals were monitored  EXAMPLE 2: Generation of tetravalent and octavalent soluble NY-ESO TCR-IL2 fusion molecule [00739] The DNA encoding the domains required for expressing ts-NY-ESO-1 TCR-IL2 and os-NY- ESO-1 TCR-IL2 protein complexes are synthesized and cloned into the expression vector pTT5 as described above. A schematic representation of the domains within the TCR αβ chains for ts-NY- ESO-1 TCR-IL2 and os-NY-ESO-1 TCR-IL2 are shown in Figures 7 and 8 and the amino acids sequences are shown in Figures 9 and 10. Expression, purification and characterization of ts-NY-ESO-1 TCR-IL2 and os-NY-ESO-1 TCR-IL2 are carried out as described above. EXAMPLE 3: High yield tetramer secretion [00740] Briefly, using conventional genetic engineering techniques, a HEK293-T cell line was made that encodes Quad 16 (figures 14 and 15) and another HEK293-T cell line was made that encodes Quad 17 (figures 14 and 15). [00741] Protein expression took place and protein was secreted from the cell lines. Samples of the medium in which the cells were incubated were subjected to PAGE under denaturing conditions (SDS-PAGE) or under native conditions (no SDS). The former was further under reduced conditions (using mercaptoethanol), whereas the latter was not. [00742] The reduced gel showed a distinct banding (Figure 16) at the expected monomer size. Surprisingly, the unreduced, native gel showed no detectable banding at the monomer, dimer or trimer size, but instead heavy banding was seen at the tetramer size indicating that a very high yield of tetramer had been obtained, and this was confirmed by SEC to be of high purity. [00743] For Quad 16, the tetramer peak from SEC was run on SDS-PAGE and the obtained band was cut out for mass spectrometry. The data were obtained with trypsin digests and p53 was detected in 100% of the protein. This was conclusive evidence that the secreted Quad 16 was multimerised EXAMPLE 4: Intracellular protein expression of extracellular portion of TCR fused to NHR2 TD Expression vector [00744] All DNA fragments were synthesized and cloned into the expression vector, pEF/myc/cyto (Invitrogen) by Twist Bioscience (California). Schematics and sequences of the synthesized DNA fragments and Quad polypeptides are shown in Figure 21, and the sequence tables herein. DNA Preparation [00745] Lyophilised plasmid DNA synthesized by Twist Bioscience, were resuspended with MQ water to a concentration of 50 ng/μl.50 ng of DNA was transformed into 50μl of competent DH5α cells using a conventional heat shock method. The cells were plated on LB agar plates containing 100 μg/mL ampicillin and grown overnight at 37 °C. Individual colonies were picked and grown overnight at 37 °C, 220 rpm. The DNA was purified from the cells using the QIAprep Spin Miniprep Kit, according to the manufacturers instructions (Qiagen). Transfections in HEK293T cell [00746] Briefly, HEK293T cells were maintained in high glucose DMEM supplemented with 10% FBS and Pen/Strep. Cells were seeded at 6 x 105 cells per well of a 6-well plate in 2ml media and were allowed to adhere overnight at 37 °C, 5% CO2.7.5 μl of Lipofectamine 2000 was diluted in 150 μl of OptiMem and incubated at room temperature for 5 mins. Plasmid DNA (2.5 μg) was diluted in 150 μl of OptiMem. Diluted DNA was combined with the diluted Lipofectamine 2000, mixed gently and incubated at R.T. for 20 mins. The 300 μl of complexes were added to one well of the 6-well plates. When analysis required the media to be serum free, the media was aspirated and replaced with CD293 media 6 hours post-transfection. The cells were incubated for 48 hours at 37 °C, 5% CO2 prior to analysis. [00747] Accordingly, different formats of TCR-linked NHR2 tetramerisation domain (TD) constructs (Quads) were transfected into HEK293T cells. Quads 3 & 4 resembling a TCR tetravalent format (structure schematically represented in Figures 1 & 3) and Quads 12 & 13 resembling a TCR octavalent format (Structure schematically represented in Figures 2 & 4) were transfected for protein expression analysis. Protein samples were prepared from transfected HEK293T cells as follows to check for intracellularly expressed protein. Briefly cells were washed once with 2ml PBS, which was subsequently aspirated.150 μl of Trypsin-EDTA (0.05%) was added to each well and the cells were incubated at R.T. for ~1 min. The plate was tapped to lift any strongly adhering cells.850 μl of media was added to each well to inactivate the trypsin. The cells were transferred to a 1.5 ml eppendorf and spun at 1,000 rpm for 5 mins. The supernatant was aspirated and the pellets stored on ice. The cells were resuspended in 400 μl cell lysis buffer (10 mM Tris pH 7.5, 1% SDS) containing Protease Inhibitor Cocktail Set III (Calbiochem), diluted 1/200. The samples were vortexed vigorously and incubated on ice for 20 mins. The cells were sonicated using a Branson Ultrasonics Sonifier™ (Thermo Fisher Scientific). The amplitude was set to 30% and the cells were sonicated for a total of 24 seconds (6 secs on, 3 secs off x4). The total protein concentration was quantified using the Pierce BCA Protein Assay Kit™, according to the manufacturer’s instructions.100μg was diluted with MQ water to give a volume of 80μl.20μl of 5x SDS loading buffer was then added giving samples of 1 mg/ml. Samples were incubated at 95 °C for 5 min prior to SDS-PAGE and Western blot analysis. [00748] Protein samples were separated on SDS-PAGE under denaturing condition. Typically, 25 μg of whole cell lysate (25μl) were loaded on to the gel for Western blot analysis.5 μl of PageRule Prestained 10-180 kDa Protein Ladder was loaded into the gel alongside the protein samples. The gels were run in Tris-Glycine buffer containing 0.1% SDS. A constant voltage of 150 volts was used and the gels were run for ~70 mins until the dye front has migrated fμlly. [00749] SDS-PAGE (15% Bis-Tris) gels were prepared using the following resolving and stacking gels. [00750] Resolving Gel: . 5 ml 30% Bis-Acrylamide . 2.6 ml 1.5 M Tris (pH 8.8) . 50 μl 20% SDS . 100 μl 10% APS . 10 μl TEMED . 2.2 ml MQ Water [00751] Stacking Gel: . 0.75 ml 30% Bis-Acrylamide . 1.25 ml 1.5 M Tris (pH 8.8) . 25 μl 20% SDS . 50 μl 10% APS . 5 μl TEMED . 2.9 ml MQ Water [00752] Western blotting was performed for the specific and sensitive detection of protein expression of TCR-NHR2 TD fusion proteins from Quads 3, 4, 12 and 13. Proteins separated out on SDS-PAGE were transferred onto Amersham Hybond™ 0.45 μM PVDF membrane as follows. Briefly, Amersham Hybond 0.45 μM PVDF membrane was activated with MeOH for ~1 min and rinsed with transfer buffer (25 mM Tris, 190 mM Glycine, 20% MeOH) before use. The sponge, filter paper, gel, membrane, filter paper, sponge stack was prepared and placed in the cassette for transfer. Transfer was carried out on ice at 280 mA for 75 mins. The membrane was incubated for ~2 hours in blocking buffer (TBST, 5% milk powder). The membrane was washed briefly with TBST before being incubated at 4 °C overnight with anti-human IgG HRP (Thermo, 31410) diluted 1/2500 in TBST, 1% milk powder. The membrane was washed thoroughly (three washes of TBST, 15 mins each) before being developed using the Pierce ECL Western Blotting Substrate. [00753] Using anti-human IgG detection antibody to probe Western blots, specific protein band at the expected molecular weight can be detected from samples prepared from Quads 3 (46.1 kDa), 4 (46.4 kDa), 12 (47.8 kDa) and 13 (48.1 kDa) (Figures 17A and 17B). These data confirm intracellular protein expression of TCR-NHR2 TD fusion proteins in HEK293T cells. [00754] For all of the Quads analysed, a clear single band can be detected indicating TRV .-TRC .- IgG1-CH1 (+/- IgG hinge domain) fusions with the NHR2 TD are stable. These expression data also confirm the possibility of assembling tetravalent (Quads 3 & 4) and octavalent (Quads 12 & 13) molecules as exemplified in this example. [00755] The difference between Quads 3 and 4 is the presence of a small peptide linker (G4S) located between the IgG1 CH1 domain and NHR2 TD. This is also true for Quads 12 and 13 where Q13 contains a peptide linker between the IgG1 CH1 domain and NHR2 TD. From the expression data, it can be seen the peptide linker does not effect protein expression. However, it may be desirable to include a peptide linker to aid antigen binding and or stabilizing the multimerisation complex in these TCR-NHR2 TD formats. EXAMPLE 5: Soluble protein expression of extracellular portion of TCR fused to NHR2 TD [00756] TCR-NHR2 TD fusion proteins were shown in Example 4 to be expressed intracellularly in HEK293T cells. Here again Quads 3, 4, 12 and 13 were used to demonstrate soluble expression of these fusion proteins. As described above, Quads 3, 4, 12 and 13 were transfected into HEK293T cells and soluble proteins from the cell supernatant were concentrated. Briefly, the media was harvested 48 hours post-transfection and centrifuged at 2,000 rpm for 5 mins to remove any cells or debris. Typically, 500 μl of media was concentrated to 100 μl using Amicon™ Ultra 0.5 Centrifugal Units with a MWCO of 10 kDa.25 μl of 5x SDS loading buffer was added to the sample, which was then incubated at 95 °C for 5 mins prior to gel/Western blot analysis. Concentrated protein samples were separated out on SDS-PAGE gel and transferred onto Amersham Hybond 0.45 μM PVDF membrane. Western blotting and protein detection was done using anti-human IgG HRP using the methods described above. [00757] Protein samples concentrated and prepared from cell supernatants show specific protein band at the expected molecular weight on Western blots corresponding to Quads 3 (46.1 kDa), 4 (46.4 kDa), 12 (47.8 kDa) and 13 (48.1 kDa) (Figures 18A and 18B). The Western blot expression data unequivocally shows soluble expression of TCR-NHR2 TD fusion proteins in HEK293T. These data are the first report demonstrating soluble expression of TCR-NHR2 TD fusion proteins expressed in eukaryotic cells such as HEK293T cells. [00758] Detection of soluble protein expression from both tetrameric (Quads 3 & 4) and octameric (Quads 12 & 13) TCR-NHR2 TD formats highlights the potential applicability of NHR2 TD in a broad setting. Use of NHR2 TD fusion molecules could be used for the preparation of therapeutic molecules and protein molecules for use in diagnostics and imaging. EXAMPLE 6: Intracellular protein expression of antibody fragments fused to NHR2 TD [00759] To further exemplify the versatility of NHR2 TD, several different antibody fragment formats fused to NHR2 TD were constructed for testing their expression in HEK293T cells. [00760] Quads 14 and 15 contain an antibody VH domain fused to NHR2 TD either with or without a peptide linker located between the VH and NHR2 TD as schematically depicted in Figures 11 and 21. The VH domain in Quads 14 and 15 are specific for GFP (green fluorescent protein). Several other versions of this format were also constructed and tested with VH specific for therapeutically useful drug targets. Sequences of the binding domains are listed in Table 4. Some of these include Quad 34 (specific for TNF ^), Quad 38 (specific for VEGF), Quad 40 (specific for EGFR) and Quad 44 (specific for CD38). [00761] Quads 38 and 44 were further developed to include an additional binding arm with the inclusion of a second VH domain specific for EGFR and CD138 respectively yielding Quads 42 and 46. Quads 42 and 46 represent bispecific molecules with the capability to multimerise via the NHR2 TD domain to form bispecific tetramers. [00762] In another example, an effector molecule (human IL2) was linked to the C-terminus of Quads 14 & 15 resulting in Quads 18 and 19, whereby the VH-NHR2-IL2 molecule is tetravalent and bifunctional. [00763] In another example, antibody Fab fragment (VH-CH1) was linked to NHR2 TD (Quads 23 and 24) and as schematically depicted in Figure 12. Quads 23 and 24 represent tetravalent Fab molecules when co-expressed or mixed and assembled in-vitro with a second chain containing immunoglobulin light chain (e.g. Quad 25). [00764] In yet another example, a human IgG1 hinge domain was included to Quads 23 and 24, which is referred to as Quads 26 and 27 and as schematically depicted in Figure 13. Quads 26 and 27 represent octavalent Fab molecules when co-expressed or mixed and assembled in-vitro with a second chain containing immunoglobulin light chain domains (e.g. Quad 25). [00765] The following Quad vectors, Quads 14, 15, 18, 19, 23, 24, 26, 27, 34, 38, 40, 42, 44 and 46 all of which are His-tagged were transfected in HEK293T cells. Protein samples were prepared from whole-cell extracts as described above, separated out on SDS-PAGE and transferred onto Amersham Hybond 0.45 μM PVDF membrane. Specific protein expression were probed using anti-His HRP (Sigma, A7058) diluted 1/2500 in TBST, 1% milk powder. [00766] Specific protein expression in whole cell extracts could be detected for all the different antibody-NHR2 TD fusion proteins tested using Quads 14, 15, 18, 19, 23, 24, 26, 27, 34, 38, 40, 42, 44 and 46 (Figures 19A-D). Interestingly, Quads 18 and 19 containing an effector domain (IL2) fused to the C-terminus of NHR2 TD domain, in addition to the VH binding domain fused to the N- terminus of NHR2 TD showed good protein expression. [00767] Expression of Quads 23 and 24 polypeptides highlights the potential to use NHR2 TD to form tetravalent antibody Fab molecules when co-expressed or mixed in-vitro with a partner soluble Quad molecule (e.g. Quad 25). Similarly expression of Quads 26 and 27, which include human IgG1 hinge domain highlight the potential to use NHR2 TD to form octavalent antibody Fab molecules when co- expressed or mixed in-vitro with a partner soluble second partner chain (e.g. Quad 25). [00768] Quads 42 and 46 bispecific molecules containing an additional VH domain fused to the C- terminus of NHR2 TD domain also showed good protein expression. These data highlights the versatility of the NHR2 TD domain and its ability to be fused to different binding and effector molecules for developing a vast array of protein formats. The data also suggest it is possible to fuse protein molecules to both the N-terminus and C-terminus of NHR2 TD, which allows for the development of bispecific multivalent protein molecules. EXAMPLE 7: Multivalent assembly of antibody fragments fused to NHR2 TD [00769] NHR2 TD is responsible for the oligomerisation of ETO into a tetrameric complex. Using the NHR2 TD domain, it is possible to fuse binding domains and effector molecules to the N-terminus or C-terminus or both N- and C-terminus without effecting expression as shown in examples 4-6. Binding domains could be TCR variable and constant domains, antibody and antibody fragments or effector molecules such as IL2. It is also possible to express proteins in a soluble format when fused to NHR2 TD (Figure 18) despite NHR2 TD being a part of an intracellularly expressed protein where in nature it is only expressed inside the cell. [00770] To demonstrate whether NHR2 TD retains its potential to oligomerise once it is fused to a binding domain, Quads 14 and 15 were expressed in HEK293T cells and protein samples were prepared from whole cell extracts as described above. Protein samples were separated out on PAGE gel under denaturing and non-denaturing (native) conditions. Native gels were prepared using the protocol described above, but without SDS. Proteins from PAGE gels were transferred onto Amersham Hybond 0.45 μM PVDF membrane. Specific protein expression was probed with anti- human IgG HRP detection antibody. [00771] As expected under denaturing conditions, expression of VH-NHR2 TD from Quads 14 and 15 can be seen as a monomer where a specific protein band can be detected at the expected molecular weight (22 and 22.3 kDa) (Figure 20A). Under non-denaturing and thus native conditions, interestingly no monomer or dimer of VH-NHR2 TD from Quads 14 and 15 can be detected (Figure 20B). Only a high molecular weight protein band believed to be tetramers of VH-NHR2 TD from Quads 14 and 15 can be detected. The assembly of tetramers appears to be highly efficient and pure judging by the protein intensity and the absence of any detectable monomers and dimers of Quads 14 and 15. Together with the data in examples 4-7, there is conclusive evidence NHR2 TD is highly versatile allowing fusion of various protein binding domains and effector molecules. NHR2 TD allows soluble expression of proteins from eukaryotic cells such as HEK293T cells and they form highly stable and pure tetrameric molecules. FURTHER EXAMPLES METHODS [00772] Expression vectors [00773] All DNA fragments were synthesized by Twist Bioscience (California) and cloned into the expression vector, pEF/myc/cyto (Invitrogen). Schematics and sequences of the synthesized DNA fragments are shown in Figure 22 and Tables 8 –10, respectively. [00774] Plasmid DNA Preparation [00775] Lyophilised plasmid DNA synthesized by Twist Bioscience, were resuspended with MQ water to a concentration of 50 ng/μl. Competent E. coli DH5α cells were transformed with 50 ng of DNA using a conventional heat shock method. Transformed cells were plated on LB agar plates containing 100 μg/mL ampicillin and grown overnight at 37 °C. Individual colonies were picked and grown in LB broth overnight at 37 °C, 220 rpm. Plasmid DNA were purified from the cells using Qiagen plasmid extraction kits, according to the manufacturer’s instructions (Qiagen). [00776] Expression of Quad Proteins in Expi293F Cells [00777] Expi293F ^ cells (Thermo Fisher Scientific) were cultured in Expi293 ^ Expression Medium (Thermo Fisher Scientific) according to the manufacturer’s recommendations. The only exception was that 5% CO2 was added directly to the flasks when the cells were split and non-vented caps were used. [00778] Two methods involving different transfection reagents were utilised for protein expression. The methods for 30ml cultures are described below and the protocol was adapted to either scaled up or down according to the experimental requirements. [00779] For PEI transfections the cells were counted one day prior to transfection using a NC-3000 ^ (ChemoMetec) and were diluted to 1.5 x 106 cells/ml using Expi293 ^ Expression Medium. The cells were cultured in 5% CO2 at 37.C, 125 rpm overnight. The following day the cells were counted, spun down for 5 minutes at 1000 rpm and resuspended at 2 x 106 cells/ml in 30 ml of fresh media.33 ug of plasmid DNA was added to 900 ul media and 90 ul of PEI Max (Polysciences Inc.) was added to 900 ul media. The DNA and transfection reagent samples were mixed and incubated at room temperature for 15 minutes. The DNA/transfection reagent mixture was added to the cells, which were cultured as before and incubated for a further 72hrs. [00780] For transfections with Expifectamine ^ 293 Reagent (Thermo Fisher Scientific) the cells were also diluted to 1.5 x 106 cells/ml in Expi293 ^ Expression Medium one day prior to transfection. On the day of transfection the cells were centrifuged and resuspended at 2.5 x 106 cells/ml in 30 ml of fresh media. Two tubes containing 1.5 ml of Gibco ^ Opti-MEM ^ (Thermo Fisher Scientific) were prepared.30ug of plasmid DNA was added to one tube and 80 ul of Expifectamine was added to the other. The solutions were mixed and incubated at room temperature for 30 minutes. The DNA- transfection reagent complex was added to the cells, which were cultured in 5% CO2 at 37.C, 125 rpm. Following 16-18hrs incubation, transfection enhancers 1 and 2 were added to the cells according to the manufacturers protocol. The cells were incubated for a further 96 hours. [00781] Purification of His-Tagged Proteins [00782] The cells were harvested by centrifugation for 10 minutes at 4000 rpm. The ~30ml supernatant was filtered through a 0.22.m filter and diluted to 50ml with binding buffer (50mM HEPES, pH 7,4, 250mM NaCl, 20mM imidazole) containing Complete ^ EDTA-free protease inhibitors (Roche) to facilitate binding to the column. A 1ml HisTrap ^ HP column (GE Healthcare) was connected to an ÄKTA Start (GE Healthcare) and pre-equilibrated with binding buffer. The protein-containing media was loaded onto the column using a flow rate of 1 ml/min. The column was washed with >10 CV of binding buffer before the protein was eluted using a 20-300 mM imidazole gradient over 12ml.0.5ml fractions were collected and analysed by SDS-PAGE. Protein containing fractions were pooled and concentrated using Amicon ^ Ultra centrifugal filter units (Millipore). [00783] Following affinity chromatography the proteins were either snap frozen and stored at -80.C, dialysed into an alternative buffer for a specific application of gel filtrated to assess the molecular weight of the various Quad formats. For the latter analyses, protein samples were concentrated to 1.5- 2 ml and gel filtrated on a Superdex 7516/600 column (GE Healthcare) using 10 mM HEPES, pH 7.4, 250 mM NaCl. [00784] SDS-PAGE [00785] Purified proteins were analysed by separating out on SDS-PAGE under denaturing condition. Typically, 1-2 μg of purified protein were loaded per lane on SDS-PAGE gel. The gels were run in Tris-Glycine buffer containing 0.1% SDS. A constant voltage of 150 volts was used and the gels were run for ~70 mins until the dye front has migrated fully. [00786] SDS-PAGE (15% Bis-Tris) gels were prepared using the following resolving and stacking gels. [00787] Resolving Gel: . 5 ml 30% Bis-Acrylamide . 2.6 ml 1.5 M Tris (pH 8.8) . 50 μl 20% SDS . 100 μl 10% APS . 10 μl TEMED . 2.2 ml MQ Water [00788] Stacking Gel: . 0.75 ml 30% Bis-Acrylamide . 1.25 ml 1.5 M Tris (pH 8.8) . 25 μl 20% SDS . 50 μl 10% APS . 5 μl TEMED . 2.9 ml MQ Water [00789] General direct binding ELISA assay [00790] The potential of the purified Quad proteins to bind its target protein was confirmed by directing binding ELISA. Briefly, high binding 96 well plates (Corning) were used for coating recombinant target protein (1-5 ug/ml diluted in PBS or as indicated), which were typically stored at 4oC overnight. Plates are then washed 3 times with 200ul wash buffer (PBS + 0.1% Tween) and blocked using 200ul blocking buffer (PBS + 1% BSA) for 1 hour at room temperature. Purified protein samples are typically serially diluted in dilution buffer (PBS + 0.1% BSA) and 100ul/well is added. Samples are incubated at room temperature for 1 hour after which the plate is washed again 3 times using 200ul wash buffer. Anti-His HRP (Abcam) Detection antibody diluted according to the manufacturer recommendation is added and incubated at room temperature for 1 hour. The plate is washed for the final time using 3x 200ul wash buffer and 50 ul pre-warmed detection reagent (TMB – Sigma) is added per well and the plate incubated in the dark for 10-30 mins. The reaction is stopped by adding 25 ul/well of 1M sulfuric acid. The absorbance at 450 nm was read using a CLARIOstar microplate reader (BMG Labtech). EXAMPLE 8: Expression of monospecific tetravalent dAb Quad [00791] A multimer format (“Quad” format) where a single domain of an antibody variable fragment (dAb) (VH or VL either V . or V .) fused to p53 tetramerisation domain is exemplified in this example. The dAb VH sequence for anti-IL17A (sequence adapted from WO 2010/142551 A2) was engineered into a tetravalent dAb Quad format (Quad 57) (SEQ ID: 1*146). Expression vector for Quad 57 was synthesized by Twist Bioscience and expressed in HEK293 cells as described above. Secreted Quad 57 protein was collected from cell supernatant and purified using HisTrap HP column. To demonstrate soluble expression and purity of Quad 57, a small portion of the purified protein (1.5 ug) was separated out on SDS-PAGE gel (Figure 23). A pure protein could be detected at the expected size (18 kDa) corresponding to Quad 57 confirming soluble expression of a tetravalent dAb Quad protein. A schematic representation of a tetravalent monospecific dAb Quad is shown in Figure 22-A (ie, embodiment A of Figure 22A). EXAMPLE 9: Expression and binding analysis of bispecific tetravalent dAb Quad [00792] A bispecific tetravalent dAb Quad is exemplified in this example where two different dAb binding domains are linked to p53 tetramerisation domain via the N- and C-terminus and as schematically represented in Figure 22-C (ie, embodiment C of Figure 22A). [00793] In a specific example of a bispecific tetravalent dAb Quad, an anti-TNFa dAb VH binding domain from Ozoralizumab was linked to the N-terminus of p53 tetramerisation domain and an anti- IL17A dAb VH binding domain (sequence adapted from WO2010/142551 A2) was linked to the C- terminus of the p53 tetramerisation domain (Quad 54) (SEQ ID: 1*143). Although in this specific example both the dAb binding domains were VH’s, the dAb binding domains could be V κ or V λ or a combination of the different dAb formats. [00794] To demonstrate whether such a bispecific tetravalent dAb Quad format could be expressed as a soluble protein, expression construct containing dual anti-TNFa and anti-IL17A dAb binding domains were synthesized as a Quad format and expressed in HEK293 cells. Following protein purification from culture supernatant using HisTrap HP column, ~1.5 ug of the purified protein was separated out on SDS-PAGE gel (Figure 24A). From the SDS-PAGE gel, a pure product at the expected size (30.7 kDa) could be seen confirming expression of soluble bispecific tetravalent dAb Quad. [00795] To further exemplify the functionality of such bispecific tetravalent anti-TNFa x anti-IL17A dAb Quad, direct binding ELISA assay was performed. High protein binding 96 well plates (corning) were coated with 1 ug/ml recombinant human TNFa protein (Abcam) and direct binding ELISA assay was performed with serially diluted Quad 54 protein using the method described above. A typical sigmoidal dose response curve was yielded from Quad 54 direct binding ELISA with recombinant human TNFa protein with a half-maximal binding at the low pM range (~10 pM) (Figure 24B). This confirms that not only can bispecific tetravalent anti-TNFa x anti-IL17A dAb Quads could be expressed as soluble proteins, they are also functional in that they can bind their target protein with high binding strength. The high binding strength is likely a measure of the increased avidity gained through tetravalent binding and this highlights an important feature of Quad multivalent molecules. EXAMPLE 10: Expression, binding and functional analysis of monospecific tetravalent scFv Quads [00796] In this example, scFv binding domains for two different targets were selected and linked separately to the N-terminus of p53 tetramerisation domain to generate monospecific tetravalent scFv Quads as schematically represented in Figure 22-D (ie, embodiment D of Figure 22B). [00797] In one example the scFv binding domain was an anti-TNFa where the V ^ and V . sequence was adapted from Humira into a scFv Quad format. To analyse whether the presence of a peptide linker effected the expression and binding of the Quad molecule to its target protein, in this example the anti-TNFa scFv binding domain was linked to the N-terminus of p53 tetramerisation domain either via a (G4S)3 peptide linker (Quad 63) (SEQ ID: 1*147) or without a peptide linker (Quad 51) (SEQ ID: 1*139). [00798] In another example, the scFv binding domain was an anti-CD20 adapted from Wu et al., (Wu et al.2001). The anti-CD20 scFv binding domain was engineered into a tetravalent Quad format by linking the binding domain directly to the N-terminus of p53 tetramerisation domain without a peptide linker (Quad 53 Tet) (SEQ ID: 1*141). [00799] All tetravalent scFv Quads were transfected into HEK293 cells and soluble protein from the culture supernatant were purified using HisTrap ^ HP column as described above. A small amount of the purified protein (~1.5 ug) was separated out on SDS-PAGE gels to confirm expression and purity. [00800] Anti-TNFa scFv Quads (Quads 51 & 63) were found to express well as soluble protein and the presence or absence of the peptide linker joining the scFv to the N-terminus of p53 tetramerisation domain did not appear to effect expression (Figure 25A). Furthermore the purity of the secreted soluble Quad proteins appears to be highly pure (>99%). To characterize these Quads further, both Quad 51 and Quad 63 were analysed in a direct binding ELISA assay using recombinant human TNFa (Abcam). High binding 96 well plates (Costar) was coated with 1 ug/ml of human TNFa protein and ELISA binding assay was performed using serially diluted Quad 51 and Quad 63 proteins as described above. A dose-dependent increase in binding was observed for both Quad 51 and Quad 63 confirming these anti-TNFa scFv’s were assembled correctly and their native binding functionality were retained in this Quad format. Furthermore, the binding profile for Quad 51 and Quad 63 was found to be highly similar with both Quads having a half-maximal binding concentration in the low pM range (~30 pM) (Figure 25B). Combinedly, these data confirm the presence or absence of the peptide linker does not effect protein expression or Quad binding strength to their target protein. [00801] To further functionally characterize the activity of anti-TNFa Quad 51 molecule to neutralize TNFa, a cell-based assay was performed using WEHI-13VAR cells (ATCC), which is highly sensitive to TNFa. The bioassay using WEHI cells was set-up as described below. A monovalent anti-TNFa (W51ScFv) was included in the assay as a control (SEQ ID: 1*150) and Humira was used as a positive control. W51ScFv was generated by modifying Quad 51 where the p53 tetramerisation domain was removed. Expression of W51ScFV was confirmed by SDS-PAGE (Figure 25C). [00802] Briefly, WEHI-13VAR cells were seeded at 1 x 104 cells per well in a 96-well plate in RPMI- 1640, 10% FBS and incubated overnight at 37.C, 5% CO2. The media was aspirated from the cells and replaced with media containing 2 ug/ml actinomycin D, 0.1 ng/ml recombinant human TNF ^ (ab9649, Abcam) and 0-2400 pM Q51, Q35, W51ScFV and Humira. The samples were set up in quadruplicate with no TNF ^ and no antibody controls. The cells were incubated under standard culture conditions for a further 20-22 hours. [00803] To assess cell viability, ATP generated by metabolically active cells was quantified using the CellTiterGlo Luminescent Cell Viability Assay (Promega) according to the manufacturers’ instructions. Luminescent signals were measured using a CLARIOstar microplate reader (BMG Labtech) The luminescence signals obtained from the compound treated cells were normalised against the media on controls. The effective dose (ED) at which 50% of the WEHI cells retained viability was calculated and the ED50 for Quad 51, Humira and W51ScFV is summarised in Table 11. [00804] As expected, Quad 51 having four anti-TNFa binding domains was found to be most effective at neutralising the cytotoxic effect of recombinant human TNFa protein on WEHI cells compared to Humira, which has two binding domains for TNFa. The W51ScFv control having only a single binding domain for TNFa had the highest ED50. The increasing valency of the anti-TNFa molecules for TNFa correlated inversely with a decrease in ED50 values. These data highlights the enhanced functional potency of Quad molecules with increasing valency and this aligns with the general concept of avidity verses potency as reported by numerous studies (Alam et al.2018; Rudnick & Adams 2009; Adams et al.2006; Bru nker et al.2016). Furthermore, the increase in avidity of Quad molecules can be used to drive selectively of tumour associated antigens that are highly expressed on tumour cells and thus limit the on-target off-tumour effect on healthy cells as reported in an example outlined by Slaga et al (Slaga et al.2018). [00805] To further demonstrate the ability of anti-TNFa Quad 51 to block TNFa induced activation of Caspase 3, Western blot analysis were performed alongside Humira and W51ScFv as controls. Briefly, WEHI-13VAR cells were seeded at 2.5 x 106 cells per well in a 6-well plate in culture media (RPMI-1640, 10% FBS) and incubated overnight. The media was replaced with media containing 2 ug/ml actinomycin D, 1 ng/ml recombinant human TNF α and 500 pM of Quad 51, W51ScFV and Humira. Culture media only and culture media containing 2 ug/ml actinomycin D were included as controls. The cells were incubated with TNF α and +/- anti-TNFa molecules for 10 hours. [00806] The cells were lysed using RIPA buffer (50mM Tris, pH 8.0, 150 mM NaCl, 1% Triton X- 100, 0.5% sodium deoxycholate, 0.1% SDS) containing 1 mM DTT and Complete TMTA-freeAe protease inhibitor (Roche). Cell lysates were sonicated using a Bioruptor TM Pico Sonication System (Diagenode) and the protein concentration of each sample was quantified using the Pierce BCA Protein Assay Kit (Thermo Fisher Scientific).10ug of protein was electrophoresed on a 12% Bis-Tris gel and bands were subsequently transferred to Amersham TM Hybond ® P 0.45 μm PVDF membranes (GE Healthcare). The membranes were blocked with 10%-BSA-TBST or 5%-milk-TBST before being incubated overnight at 40C with appropriate antibodies (anti Caspase-3 (1/1000, CST, 9665) and anti-Cleaved Caspase-3 (1/100, CST, 9664). The membranes were washed with TBST and incubated with anti-rabbit IgG HRP-linked (1/2500, CST, 7074S) secondary antibody for 2 hours at room temperature. Following thorough washing, the membranes were developed using Pierce TM ECL Western Blotting Substrate (Thermo Fisher Scientific) and CL-XPosure TM films (Thermo Fisher Scientific). [00807] From the Western blots, it can be seen that Quad 51 can effectively neutralise TNFa mediated activation of Caspase-3 with no detectable cleaved Caspase-3, similar to Humira (Figure 25D). Whereas the monovalent W51ScFv anti-TNFa control molecule with high ED50 value, is not able to completely neutralize TNFa mediated activation of Caspase-3 and this is indicated by the presence of cleaved Caspase-3 in this sample. These data confirm that the mechanism of action of Quad 51 is through a signaling mechanism similar to Humira™. In a second example, the anti-CD20 scFv Quad (Quad 53 Tet) was expressed in HEK293 cells and following purification, protein expression analysis and protein binding assays were performed. SDS- PAGE analysis confirmed soluble expression of Quad 53 Tet as a highly pure protein (>99%) (Figure 25E). ELISA binding assay using recombinant human CD20 protein (Abcam) using serially diluted Quad 53 Tet protein confirmed a dose-dependent increase in binding. The ability of the anti-CD20 scFv Quad to retain binding to CD20 once again confirms correct assembly of this Quad format into a functional molecule (Figure 25F). EXAMPLE 11: Expression and binding analysis of monospecific octavalent scFv Quad [00808] In this example, the valency of the scFv binding domain was increased from four (tetravalent) to eight (octavalent). This was achieved by linking an scFv to both N- and C-terminus of the p53 tetramerisation domain as schematically represented in Figure 22-E. [00809] As described in example 10, the anti-CD20 scFv binding domain was used in this example to construct a monospecific octavalent anti-CD20 scFv Quad (Quad 53 Oct) (SEQ ID: 1*142). In this specific example, scFv’s were linked to the N- and C-terminus of the p53 tetramerisation domain without peptide linkers, however, in other examples of this format, peptide linkers could be introduced at either or both ends to aid flexibility of the binding domain. [00810] Following expression and purification of Quad 53 Oct protein from culture supernatant, protein expression analysis and ELISA binding assays were performed. Protein separated out on SDS- PAGE gel confirmed soluble expression of Quad 53 Oct with high purity (>99%) (Figure 26A). ELISA binding assay was also performed using recombinant CD20 and serially diluted Quad 53 Oct protein (Figure 26B). A dose-depended increase in binding could be seen confirming correct assembly of anti-CD20 scFv in an octavalent format. [00811] To analyse the effect of increasing valency on target protein binding, scFv anti-CD20 without the tetramerisation domain was constructed to act as a monovalent control (Quad 53 Mon) (SEQ ID: 1*140). Following protein expression and purification, all three Quad 53 anti-CD20 scFv molecules (monovalent, tetravalent and octavalent) were separated out side-by-side on a SDS-PAGE gel (Figure 26C) and ELISA binding assay was performed (Figure 26D). With all three Quad 53 molecules, a dose-dependent increase in binding could be seen and the overall increase in binding strength was reflected by the increase in the valency. The octavalent anti-CD20 scFv version was found to have the highest overall binding strength, followed by the tetravalent and then the monovalent version. It is noteworthy, due to the nature of direct binding ELISA where the target protein is densely coated onto 96 well plates resulting in rapid Quad 53 binding saturation to CD20, the true avidity (total binding strength) can not be accurately determined using this method. Despite these limitations of direct binding ELISA, a representative increase in binding could still be observed with increasing valency as seen in Figure 26D. EXAMPLE 12: Expression and binding analysis of bispecific tetravalent scFv Quad [00812] In this example, two different scFv binding domains with specificity for two different target proteins were linked to the p53 tetramerisation domain via the N- and C-terminus to give a bispecific tetravalent scFv Quad as exemplified schematically in Figure 22-F. [00813] The specific scFv binding domains used in this example has specificity for anti-TNFa and anti-IL17A. The anti-TNFa scFv sequence was adapted from Humira and the anti-IL17A scFv sequence was adapted from Ixekizumab (Eli Lilly) into a bispecific Quad format (Quad 55) (SEQ ID: 1*144). To confirm soluble expression, Quad 55 was expressed in HEK293 cells and the secreted protein was purified from culture supernatant followed by protein analysis. (Figure 27A). Protein analysed by SDS-PAGE confirmed soluble expression of this bispecific scFv Quad format with high purity (>99%). To further anaylse whether this format was functional, ELISA binding assay was performed for the anti-TNFa scFv arm (Figure 6B). A dose-dependent increase in binding of Quad 55 to recombinant human TNFa could be seen confirming Quad 55 was assembled correctly. Furthermore, Q55 appears to have a similar half-maximal binding in the low pM range to that of Quad 51 detailed in Example 10. EXAMPLE 13: Expression and binding analysis of bispecific Tetravalent scFv x dAb Quad [00814] In this example, two different binding domain formats with specificity for two different target proteins were linked to the N- and C-terminus of p53 tetramerisation domain respectively, as exemplified schematically in Figure 22-G. [00815] The first binding domain was an anti-TNFa scFv as detailed in Example 12, which was linked to the p53 tetramerisation domain via the N-terminus. The second binding domain was an anti-IL17A dAb sequenced, which was linked to the p53 tetramerisation domain via the C-terminus as detailed in Example 9 (Quad 56) (SEQ ID: 1*145). [00816] Soluble expression of this bispecific tetravalent scFv x dAb Quad format was confirmed by analysing the purified protein on SDS-PAGE gel (Figure 28A). In additional ELISA binding assay was performed for the anti-TNFa binding arm (Figure 28B), where a dose-depended increase in binding was observed. This confirmed correct expression and assembly of this bispecific scFv x dAb Quad format. [00817] In the examples above (Examples 10, 12 & 13) different bispecific Quad formats (Quads 54- 56) with specificity for anti-TNFa x anti-IL17A were produced and analysed for expression and functionality by ELISA binding assay for the anti-TNFa binding arm. From the data presented thus far, it is clear that the p53 tetramerisation domain is highly versatile and amenable to fusion with different binding domains at either or both N- and C-terminus. To compare the functional binding strengths of Quads 54–56, the ELISA binding assay data for the anti-TNFa binding arm of the different bispecific Quads were plotted side-by-side (Figure 28C). The dose-response curves for all three bispecific Quad formats appear to be highly similar indicating that the binding domain format (scFv or dAb) does not affect binding. This further highlights the versatility and utility of the p53 tetramerisation domain to generate highly pure multivalent soluble proteins with high binding strength. EXAMPLE 14: Expression and binding analysis of tetravalent monospecific Ig scFv Quad v1 [00818] In this example, an scFv binding domain was linked to the lower hinge/CH2 domain of IgG1 Fc without the core and upper hinge region to generate a scFv monomeric Ig Fc (scFv-mFc), ie wherein the Fc does not pair with another Fc when a multimer is formed using the polypeptide monomer. Typically a CXXC motif comprising cysteine residues present in the core hinge region is responsible for forming inter-chain disulfide bonds. Thus, by excluding the core hinge region, the Fc region is restrained from forming a tightly packed homodimer structure typically found in native IgG antibodies. The lower hinge/CH2 domain was kept intact to allow proper interaction with Fcγ- receptors required for effector function. [00819] The scFv-mFc was engineered into a Quad format by linking it to the p53 tetramerisation domain via the N-terminus to generate a tetravalent monospecific Ig scFv Quad termed version 1 as schematically represented in Figure 22-I (ie, embodiment I shown in Figure 22D). [00820] In this example the upper hinge was also removed, but in other examples the upper hinge region can be optionally retained completely or only partially kept intact to generate dAb monomeric Ig Quads (exemplified schematically in Figure 22-H, L, W, X, Y, Z, AA, AB & AC), scFv monomeric Ig Quads (exemplified schematically in Figure 22-I, M, X, & AA) and Fab monomeric Ig Quads (exemplified schematically in Figure 22-J, K, N & O) with monospecific, bispecific, trispecific or tetraspecific specificity. Although in this specific example, human IgG1 was used as an example, the Fc region could be any of the other IgG isotypes including IgG2, IgG3, gG4 or derivative thereof. The amino acid sequences encoding human IgG hinge regions are shown in Table 12. [00821] The scFv binding domain used in this specific example was that of an anti-CD20 described in Example 10. The anti-CD20 scFv was linked to the lower hinge/CH2 domainof the Fc via a peptide (G4S)3 linker. The p53 tetramerisation domain was linked directly to the C-terminus of the CH3 domain without any peptide linkers (Quad 64) (SEQ ID: 1*148). An optional linker could be included at this junction between the CH3 domain and the multimerisation domain to provide flexibility. [00822] Following Quad 64 expression and purification, protein was quantified and analysed by SDS- PAGE (Figure 29A). Protein quantification using Nanospec confirmed high protein yield after HisTrap HP column purification with protein yield equivalent to 130 mg/L. In addition, a single protein band at the expected size (58.2 kDa) as seen on the SDS-PAGE gel confirmed expression of a highly pure (>99%) tetravalent monomeric Ig scFv Quad protein. To analyse whether the expressed Ig Quad protein was assembled correctly, ELISA binding assay was performed (Figure 29B). Quad 64 was found to retain binding to recombinant human CD20 in a dose-dependent manner confirming that it was assembled correctly and functionally active. EXAMPLE 15: Expression and binding analysis of tetravalent monospecific Ig scFv Quad v2 [00823] In this example, a different version of the tetravalent monomeric Ig scFv Quad described in Example 14 was constructed where the anti-CD20 scFv binding domain was linked directly to the N- terminus of the p53 tetramerisation domain. The mFc containing the lower hinge, CH2 and CH3 domains was directly linked to the C-terminus of the p53 tetramerisation domain. This version of tetravalent monomeric Ig scFv Quad is termed version 2 and is schematically represented in Figure 22-M (ie, embodiment M shown in Figure 22F). [00824] Although in the specific example described below, the upper hinge was not included, in other examples the upper hinge region can be optionally retained completely or only partially kept intact. [00825] In other examples, the version 2 configuration could contain dAb binding domains as exemplified schematically in Figure 1-L, X, Z & AA, producing Quad molecules with monospecific, bispecific or trispecific specificity. In another example, the binding domain could be a Fab as exemplified schematically in Figure 22-N & O. In yet another example, version 2 could be made without mFc to give tetravalent Fabs either as monospecific (exemplified schematically in Figure 22- Q & R) or bispecific (exemplified schematically in Figure 22-S). [00826] The expression construct for the tetravalent monomeric Ig scFv Quad version 2 specific for CD20 (Quad 65) (SEQ ID: 1*149) was expressed in HEK293 cells and the soluble secreted protein was analysed by SDS-PAGE. Protein quantification using Nanospec confirmed high protein yield after HisTrap HP column purification with protein yield equivalent to 160 mg/L. In addition, a single protein band at the expected size (57.2 kDa) as seen on the SDS-PAGE gel confirmed expression with high purity (>99%) (Figure 30A). The integrity of the expressed protein was analysed by ELISA binding assay. Recombinant human CD20 protein was used in a direct binding ELISA using serially diluted Quad 65 protein. Quad 65 was found to bind CD20 in a dose-dependent manner (Figure 30B) confirming it assembled correctly and functionally active. [00827] The data outlined above and in Example 14, represents the first examples of soluble and functional expression of tetravalent monomeric Ig molecules. Such multivalent monomeric Fc formats would have several advantages over scaffold and antibody fragment based molecules lacking Fc. Firstly, the presence of an Fc region in a monomeric Quad format would allow neonatal Fc receptor (FcRn) binding providing an extended half-life of these molecules in-vivo. Secondly, the presence of an Fc region would have the ability to bind multiple Fc receptors to induce effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) as reported for monovalent monomeric Ig Fc molecules (Ying et al.2017; Ying et al.2012). Thirdly, the proof-of-concept data outlined in this example suggest that any given monoclonal IgG antibody could be rapidly formatted into a multivalent monomeric Ig Quad format as schematically represented in Figure 22- J, K, N & O). With these formats retaining the native binding domain architecture of an IgG antibody, multivalent monomeric Ig Quad formats would have substantially increased binding strength for its target protein due to the increased avidity gained through multivalency. Such monomeric Ig Quad format will provide novel class of therapeutic molecules with enhanced target protein neutralization potential (Boruah et al.2013; Shen et al.2019) as well as having enhanced efficiency to cross-link cell surface receptor to mediate apoptosis (Li et al.2018) and induce signaling through receptor super-clustering with enhanced agonistic potentials (Mayes et al. 2018). EXAMPLE 16 Expression of octavalent bispecific Quads [00828] In a specific example of an octavalent bispecific Quad, dAb binding domains for PD-L1 and 4-1BB were used for the dual targeting of an immune checkpoint inhibitor and an immune co- stimulatory molecule for the treatment of cancers. In other examples, dAb binding domains could have specificity for any immune checkpoint inhibitor and any co-stimulatory molecule or a mixture thereof to provide either a dual checkpoint inhibitor bispecific multimer (e.g. PD-L1 x CTLA-4) or a dual checkpoint inhibitor and immune co-stimulatory bispecific multimer (e.g. PD-L1 x 4-1BB) or a dual immune co-stimulatory bispecific multimer (e.g.4-1BB x OX40). [00829] To exemplify octavalent bispecific Quads, two different versions were constructed to demonstrate soluble Quad protein expression. In one format, the PD-L1 and 4-1BB dAb binding domains were linked to a p53 multimerisation domain as a tandem dAb at either the N- or C-terminus as schematically represented in Figure 31-A. [00830] In a second example of an octavalent bispecific multimer, the dAb binding domains for PD- L1 and 4-1BB were linked to the p53 tetramerisation domain at opposite ends respectively as schematically represented in Figure 31-B. [00831] The dAb binding domain sequence for PD-L1 and 4-1BB were adapted from WO2017/123650A2. In the first version of an octavalent bispecific Quad, a tandem dAb containing anti-PD-L1 and anti-4-1BB in a N-C terminus orientation was linked to the N-terminus of p53 tetramerisation domain without any peptide linkers. This version is referred to as Quad 68 (SEQ ID: 1*190). However, in other examples, the tandem dAb can be linked to the tetramerisation domain via an optional peptide linker and as further described in Table 8-P. [00832] In a second version of octavalent bispecific Quad multimer, the anti-PD-L1 dAb was linked to the N-terminus of p53 tetramerisation domain and the anti-4-1BB dAb was linked to the C-terminus. This version is refered to as Quad 69 (SEQ ID: 1*191). In this specific example the dAbs were linked to the tetramerisation domain without any peptide linkers. However, in other examples, dAbs can be linked to the tetramerisation domain via an optional linkers and as further described in Table 8-C. [00833] The expression construct for Quads 68 and 69 were expressed in HEK293 and the secreted soluble proteins were purified from cultured supernatant. The purified Quad proteins were analysed by SDS-PAGE (Figure 31-C & D). Protein quantification of Quad 68 and Quad 69 using Nanospec confirmed high protein yield after HisTrap HP column purification with protein yield equivalent to 297 mg/L and 360 mg/L respectively. The presence of a single protein band for both Quad 68 and Quad 69 at the expected size (32 kDa) as seen on the SDS-PAGE gel confirmed expression with high purity (>99%) (Figure 31-C and D). [00834] The configuration of the dAbs either in tandem (as in Quad 68) or in opposite orientation (as in Quad 69) are anticipated to engage with cancer cells via PD-L1 with higher potency and selectively than to T cells expressing 4-1BB. Therefore, T cells will preferentially be recruited to cancer cells only once the cancer cells are engaged with the Quad molecule allowing selective T cell activation with improved safety profile. EXAMPLE 17: Expression of tetravalent monomeric Ig dAb Quad and octavalent Fab-like dAb monomeric Ig Quad [00835] A dAb VH with specificity for TNF ^ as detailed in Example 9 was also used in this example to generate two new versions of monomeric Ig dAb Quads. In the first version, anti-TNF ^ dAb VH was linked directly to IgG CH1. The CH1 region was linked to the IgG1 Fc where the hinge region was modified so that the core hinge was removed (SEQ ID: 1*168 hinge sequence was used). The Fc region was linked to the N-terminus of the p53 TD domain yielding Quad 92. The presence of CH1 region in Q92 allowed for the generation of a second version of monomeric Ig Quad where Q92 when co-expressed with anti-TNF ^ dAb linked to Kappa light chain constant domain yielded an octavalent anti-TNF ^ Fab-like dAb monomeric Ig Quad (Q93) as schematically represented in Figure 33A. The molecular design of Q92 and Q93 is schematically represented in Figure 33B&C. [00836] Q92 alone or Q92 plus Q93 were expressed in HEK293 cells and the Quad proteins were purified directly from the culture supernatant. The purified proteins were analyzed by SDS-PAGE where pure products at the expected molecular weight (Q92 (tetravalent) – 55 kDa and Q92+Q93 (octavalent) – 79 kDa) could be seen confirming soluble expression of these Quad formats (Figure 33D). Although in this specific example, the dAb tetravalent version retained the CH1 region, in another example the CH1 domain could be removed to generate a slightly modified version of tetravalent dAb Quad as schematically represented in Figure 22F (embedded in Figure as L). EXAMPLE 18: Expression of monospecific and bispecific octavalent tandem dAb monomeric Ig Quads [00837] In this example, two different versions of monomeric Ig Quads were generated similar to that exemplified in Example 14. However, instead of using scFv as binding domains, in this specific example antibody single domains (VH) were linked in tandem with specificity for either PDL1 alone or PDL1 plus 4-1BB. In the first of these examples, a bispecific octavalent anti-PDL1/4-1BB monomeric Ig dAb Quad (Q113) was generated by linking in tandem an anti-PDL1 dAb with an anti- 4-1BB dAb separated by a flexible linker. This tandem bispecific binding module was linked to the lower hinge/CH2 region of IgG1 Fc without the core hinge region to generate a tandem dAb monomeric Ig Fc (ie, the resulting polypeptide comprised (in N- to C-terminal direction) an anti- PDL1 dAb, an anti-4-1BB dAb, lower hinge/CH2 region of IgG1 Fc without the core hinge region and IgG1 CH3) . The Fc region was linked to the N-terminus of p53-TD domain to generate a bispecific tandem dAb monomeric Ig Fc Quad as schematically represented in Figure 22O. In this example, the binding valency of both the anti-PDL1 and anti-4-1BB dAb domains were tetravalent for their target protein. This is an example of a multivalent 4 + 4 (octavalent) bispecific antibody containing Ig Fc region. The second example was exactly the same as Q113, except the tandem dAb consisted only of anti-PDL1 dAb domains generating an octavalent anti-PDL1 monomeric Ig Quad (Q114). [00838] Following Quad 113 and Q114 expression in HEK293 cells and purification of proteins from culture supernatant, the recovered proteins were analysed by SDS- PAGE (Figure 34A & B). For both Q113 and Q114, a single pure protein band at the expected molecular weight was observed confirming expression of these monomeric Ig Quads as highly pure (>99%) soluble Quads proteins. EXAMPLE 19: Expression of Fab monomeric Ig Quad [00839] In this specific example, monomeric Ig Quads were produced from IgG monoclonal antibodies where the native pairing of the variable heavy chain (VH) and variable light chain (VL) was kept intact. This was achieved by taking the Fab fragment of IgG monoclonal antibody and converting it into a monomeric Ig Quad as schematically represented in Figure 22E (embedded in Figure as J). To exemplify such Quad format, Fab fragments from two clinically approved monoclonal antibodies were used (adalimumab (Humira™) and avelumab (Bavencio™)). The VH- CH1 domain of either Humira or Avelumab was linked to the lower hinge/CH2 region of IgG1 Fc without the core hinge region. The Fc region was linked to the N-terminus of p53-TD domain to generate the monomeric Ig Quad chain. To generate Humira and avelumab Fab monomeric Ig Quad, the native light chain VL-CL was co-expressed with the respective monomeric Ig Quad chain in HEK293 cells. [00840] Fab monomeric Ig Quad proteins were purified from the culture supernatant and analysed initially by SDS-PAGE (Figure 35A & B). Detection of a single protein band at the expected molecular weight on a non-reduced denaturing SDS-PAGE gel corresponding to either Humira or avelumab Fab monomeric Ig Quad, confirmed both soluble expression and high purity of these monomeric Ig formats. The absence of any detectable free HC or free LC in these Fab monomeric Ig Quad protein preps further confirmed the high stability of these formats. To confirm the native molecular mass and oligomeric state of these Fab monomeric Ig Quad proteins, Humira Fab monomeric Ig Quad protein was analysed by size-exclusion chromatography (Figure 35C). The size exclusion chromatography profile for Humira Fab monomeric Ig Quad protein had a clear dominant peak eluted at the expected volume consistent with the tetrameric molecular weight of 315.8 kDa. These data further confirm the high purity of these Quad proteins, which are stable and present in a homogeneous tetrameric form without the presence of any aggregates. Further examples of Fab monomeric Ig Quad could be generated from any given monoclonal antibody where the intact Fab is used to generate Quads without altering the native VH and VL pairing or it’s native antigen binding potential. EXAMPLE 20: Expression of extracellular protein domain as monomeric Ig Quads (Q96) [00841] In the above examples, antibody fragments were used to generate Quads. In this specific example the versatility of p53 TD domain was demonstrated further whereby extracellular domains of cell surface receptors were multimerised into a Quad format without affecting its ability to bind its natural ligand. To exemplify this, the soluble extracellular domains used in the VEGF trap aflibercept (Eylea™) was used as an example. The Ig domain 2 from VEGFR1 and Ig domain 3 from VEGFR2 similar to Eylea was linked to monomeric Ig Quad similarly to that exemplified in Examples 17-19 and as schematically represented in Figure 36A (Q96). [00842] Q96 was expressed in HEK293 cells and soluble protein was purified directly from the culture supernatant. SDS-PAGE analysis confirmed expression of Q96 as a highly pure Quad with a single protein band at the expected molecular weight (Figure 36B). The integrity of Q96 was analysed further by ELISA binding assay as described above to confirm binding to VEGF-A ligand. ELISA plates were coated with VEGF-A at 0.5 ug/ml and serially diluted (1 in 3 folds diluted starting from 5 nM) Q96 protein was added to the coated VEGF-A plate. Anti-His HRP detection antibody was used for detection of Q96 binding to VEGF-A. Q96 bound VEGF-A in a dose dependent manner confirming this format containing extracellular domains of VEGFR1 and VEGFR2 assembled correctly and it retained it’s native ligand binding potential (Figure 36C). EXAMPLE 21: Expression, binding and functional potency of non-Ig tetravalent and non-Ig octavalent anti-TNF ^ dAb Quads [00843] Similar to Example 8, antibody single domains were used to generate monospecific tetravalent and octavalent Quads without IgG Fc (referred to herein by shorhand “non-Ig”). Anti- TNF ^ dAb VH was linked directly to p53 TD at either the N-terminus to generate tetravalent Quad (Q88 tetravalent) or at both N- and C-terminus to generate octavalent anti-TNF ^ dAb Quad (Q88 octavalent) as schematically represented in Figure 22A (embedded in figure as A and B respectively). The original anti-TNF ^ dAb without the TD domain was also produced for use as a monovalent control (Q88 monovalent). The molecular designs are schematically shown in Figure 37A, which also highlights the modular design of these Quads. [00844] Following expression in HEK293 cells and Quad protein purification directly from culture supernatant, initial protein analysis was carried out by SDS-PAGE. The multivalent anti-TNF ^ dAb Quads expressed as highly pure proteins as judged by a single band on the SDS-PAGE gels corresponding to the expected molecular weight (Figure 37B). To further analyse these multivalent Quads and the effect avidity has on TNF ^ binding and TNF ^ neutralization, ELISA binding assay and WEHI cell-based bioassay were performed as described in Examples 9 and 10. Increase in TNF ^ binding strength can be seen for both tetravalent and octavalent anti-TNF ^ dAb Quads compared to the anti-TNF ^ monovalent control in ELISA binding assay (Figure 37C). Surprisingly, the TNFα binding potential between the octavalent and the tetravalent versions could not be resolved in the ELISA binding assays. Similarly, surprisingly the binding strength for the tetravalent and octavalent anti-TNF ^ dAb monomeric Ig Quad versions detailed in Example 17 could not be resolved and only a small increase in TNFα binding strength was observed in ELISA binding assay (Figure 37D). This may be because the binding strength is greatly enhanced and the tetramethylbenzidine-based colorimetric signal is rapidly saturated by these multivalent Quads, and thus the dynamic detection range for this ELISA binding assay is not adequate to differentiate the enhanced binding strength beyond a certain point. [00845] Increase in TNF ^ binding domain valency was further investigated in WEHI bioassay where the potency of the anti-TNF ^ Quad molecules to neutralize TNF ^-mediated cytotoxicity of EHI cells were compared. WEHI bioassay was performed as described in Example 10 using both non-Ig and Ig-like anti-TNF α dAb Quads (Figures 37E & F). Unlike the ELISA binding assay, in this cell-based bioassay, surprisingly a substantial increase in potency can be seen with increasing anti-TNF α binding domains including major difference in potencies between the tetravalent and octavalent versions. The EC50 values and the fold enhancement of potency of these molecules are summarized in Table 15. EXAMPLE 22: Expression and functional potency of non-Ig dodeca and hexadeca valent anti-TNF α dAb Quads [00846] To extend the concept of multivalency further and beyond tetra- and octa-valency, two further formats of anti-TNF α dAb Quads were generated with either 12 (AKA dodeca, 12-valent or 12-mer herein) or 16 (hexadeca, 16-valent or 16-mer herein) anti-TNF α dAb binding domains in a non-Ig format. The modular design and structural arrangements of these Quads can be seen in the schematic illustration in Figure 38A&B. [00847] In the dodeca version, the first chain contained tandem anti-TNF α dAbs linked to IgG CH1, which in turn is linked to the TD domain (Q142). The second chain contained a single anti- TNF α dAb linked to either kappa (Q135) or lambda (Q136) light chain constant region. Dodeca- valent Quads were generated by co-expressing the two chains in HEK293 cells where heterodimerisation of the two chains occurred through interaction between CH1 and C-kappa or C- Lambda constant region. The TD domain allowed tetramerisation of these two assembled chains into a tetramer. [00848] For the hexadeca-valent anti-TNF α dAb Quad, the first chain was exactly the same as the dodeca valent format, however, the second chain contained a tandem anti-TNF α dAb linked to either kappa (Q145) or lambda (Q144) light chain constant region. Co-expression of these two chains allowed generation of hexadeca-valent anti-TNF α Quads. [00849] The dodeca- and hexadeca anti-TNF α dAb Quads were expressed in HEK293 cells and the Quad proteins were purified directly from culture supernatant. The purified proteins were analysed by SDS-PAGE (Figure 38C). The presence of a predominant protein band at the expected molecular weight confirmed these multivalent anti-TNF α dAb Quads can be expressed as highly pure soluble Quad proteins. Furthermore, it confirmed that these multivalent Quads can be generated using either kappa or lambda light chain constant region. [00850] WEHI bioassay was performed using the purified dodeca- and hexadeca anti-TNF α dAb Quads and the TNF α neutralization potency was compared to the monovalent anti-TNF α dAb control (Figures 38D&E). The increase anti-TNF α dAb binding domain valency in the dodeca- and hexadeca-valent Quad formats substantially increased the TNF α neutralization potency. The EC50 of these Quads are summarized in Table 16. [00851] Thus, it has been demonstrated that constructs of the invention can surprisingly achieve highly significant increases in antigen binding potency (762-fold in Table 16, for example) and advantageously this can be achieved using different types of binding site (eg, dAb or Fab-like), with or without antibody Fc presence, with possibility of repurposing clinically approved antibodies to retain their tested binding sites and at very high purity levels (almost 100% purity). EXAMPLE 23: Expression non-Ig Tetravalent Fab Quad [00852] In example 19 production of tetravalent Humira Fab monomeric Ig Quad was exemplified. In this specific example, Humira Fab with intact light chain (LC) and heavy chain (HC) but without Fc region (non-Ig version) was generated. The p53 TD domain was linked at the C- terminus of Humira HC CH1 domain where the hinge region was modified to be devoid of core hinge (ie, upper hinge sequence without core or lower hinge sequence; SEQ ID: 1*183 was used). Co-expression of this modified HC with the native Humira LC, allowed generation of tetravalent Humira Fab-TD with significantly reduced molecular size compared to the Humira Fab monomeric Ig-TD version. A schematic structural representation of Humira Fab-TD is shown in Figure 40A. “Non-Ig” multimer refers to Quad multimers where the starting monomeric building block does not contain an Fc, as suppose to an “Ig-like” multimer where the starting monomeric building block contain Fc. [00853] The Humira Fab-TD Quad was expressed in HEK293 cells and the Quad protein was purified directly from culture supernatant. The purified protein was analysed by SDS-PAGE (Figure 40B). The presence of a single protein band at the expected molecular weight confirmed that Humira Fab-TD could be expressed as a soluble protein with high purity (>99% pure). [00854] To further characterize this Quad protein, TNF α binding assay using ELISA andTNF α neutralization potential using WEHI bioassay was performed. As a control Humira Fab was used as a monovalent control. From the ELISA binding assay, it can be seen Humira Fab-TD could bind TNFa with higher binding strength than the Humira Fab monovalent control (Figure 40C). Similar in the TNF α neutralization bioassay, Humira Fab-TD was able to neutralize TNF α mediated toxicity at higher potency than Humira Fab monovalent control (Figure 40D). These data confirm that by increasing the valency, the functional affinity is increased resulting in stronger binding and this also enhances the functional potency of Quads compared to the monovalent control. EXAMPLE 24: Octavalent Fab as non-Ig and Ig-like Quads [00855] In the examples above, Fabs from antibodies were used to generate tetravalent Quads either as Ig-like (Example 19) or non Ig-like (Example 23). Further iterations of Fab Quads can be made to generate Fabs with octavalent valences either as Ig-like or non Ig-like. [00856] To generate octavalent non Ig-like Fab Quads, a Fab with an intact hinge region will be used where p53 TD domain is linked directly to the hinge region optionally via a flexible peptide linker. The intact core hinge region will allow homodimerization of the Fab-TD when co- expressed with its native LC to generate F(ab’)2 and as such the monomeric building block will be bivalent. In turn, the TD domain will allow tetramerization of the F(ab’)2 to generate an octavalent Fab Quad as schematically shown in Figure 41A. [00857] Similarly, to generate octavalent Ig-like Fab Quads, a TD, eg, a p53 TD domain, will be linked directly to the C-terminus of CH3 domain of an unmodified HC of a predetermined antibody via an optional peptide linker. When this is co-expressed with its native LC from the antibody, the monomeric building block will effectively resemble a fully assembled Ig antibody with p53 TD domains linked to it at the C-terminus of the HC of the assembled antibody. The TD domain in turn will allow tetramerization of the monomeric building blocks to generate an octavalent Fab Ig-like Quad as schematically shown in Figure 41B. This embodiment is useful to tetramerize any predetermined antibody, such as any predetermined antibody disclosed herein. Thus, for example, a clinically approved antibody can be formatted according to the invention using SAM (eg, TD) mulimerisation to produce a multimer with many more than 2 binding sites for the cognate antigen. For example, the antibody can be bococizumab, alirocumab or evolocumab. In an alternative, instead of using an antibody with SAM (eg, TD), one can use an antigen-binding trap that comprises one or more antigen binding sites and an Fc. For example, one can use aflibercept-SAM as a monomer or aflibercept-TD (such as a p53 or homologue TD as disclosed herein). Thus, a tetramer of aflibercept will be formed by multimerization of the TDs. [00858] Thus, an embodiment provides an antibody comprising a heavy chain, wherein the heavy chain comprises a SAM, eg, a TD (such as a p53 or homologue TD as disclosed herein). The TD may be at the C-terminus of the heavy chain. For example, the heavy chain comprises (in N-to C- terminal direction) a VH, an antibody CH1, a hinge, a CH2, a CH3 and a SAM (eg, a TD). In an example, the heavy chain is paired with a light chain (eg, wherein the light chain comprises (in N- to C-terminal direction) a VL and an antibody CL), wherein a VH and VL comprised by the heavy and light chain pair form an antigen binding site. In an example, the antibody is a 4-chain antibody, such as comprising first and second copies of the heavy and light chain pairs (ie, a first heavy chain paired with a first light chain, a second heavy chain paired with a second light chain, wherein each pair comprises a VH/VL antigen binding site, and wherein the heavy chains are paired together (such as via disulphide bonding in the constant region)). In an example, there is provided a tetramer of such an antibody, wherein the heavy chain of each antibody comprises a TD at its C-terminus and 4 copies of the antibody are tetramerised by the TDs. See, eg, Fig 41B. [00859] In an example, there is provided an antibody light chain comprising in N-to C-terminal direction) an antibody V domain (eg, a VL, such as a Vκ or a Vλ; or a VH), an antibody CL and a SAM, eg, a TD (such as a p53 or homologue TD as disclosed herein). For example, there is provided a multimer (eg, a tetramer) of such a light chain, optionally wherein the light chain (or each light chain in the multimer) is paired with a second antibody chain comprising (in N- to C- terminal direction) another V domain and a CH1, wherein the V domain and CL of the light chain are paired respectively with the other V domain and CH1. EXAMPLE 25: Expanding Antigen Specificity Through Multimerisation [00860] Reference is made to Figures 42 to 44 which demonstrate the surprising effect of multimersation to increase valency of binding sites for a cell-surface human receptor (target X). Antibodies (benchmark dAb or 4-chain antibody) having one or two binding sites for X do not bind target Y (X and Y each being cognate receptors for ligand Z). Multimers of the invention were produced each comprising 4 or 8 anti-X binding sites based on such sites of the dAb or 4- chain antibody; p53 was used as a TD. It was surprisingly found that the multimers of the invention could bind to target X and Y. X=BCMA, Y-TACI and Z=APRIL. BCMA is also known as B-cell maturation antigen (BCMA or BCM), also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17). TACI is lso known as transmembrane activator and CAML interactor (TACI), also known as tumor necrosis factor receptor superfamily member 13B (TNFRSF13B). APRIL is also know as A proliferation-inducing ligand (APRIL), also known as tumor necrosis factor ligand superfamily member 13 (TNFSF13). [00861] Summary: . Different anti-X antibodies currently under clinical investigation were converted into Quads (ie, multimers of the invention) . All anti-X Quads expressed well and bound target X as expected . Unexpectedly when benchmark and Quad versions of the anti-X were tested for target Y binding, both Type 1 & 3 versions bound Y when multimerised according to the invention (no such Y binding seen with benchmarks) . Multimerised Anti-X Quads are very interesting as they can bind and neutralize a second receptor (which mimics the natural ligand) . Given an antibody can bind a specific epitope, multimers of the invention could potentially be used to mimic ligands that bind multiple receptors or ligands due to enhanced binding strength A further application for multimers of the invention therefore could be in virus neutralization such as HIV or COVID 19 where virus evolves through mutations – normal bivalent antibody will have reduced binding towards the virus as it evolves and may not be picked up in screens using different virus isolates; see Example 37: Anti-SARS-CoV-2 Quads to Combat Viral Mutation where multimerization enables an anti-spike multimer to surprisingly bind to different mutated forms of SARS-CoV-2 spike. This will be useful for binding to first and second different versions of the SARS-CoV-2 virus, useful for providing resistance to evolving mutation of the virus. . Multimerisation technology of the invention could be used to identify and isolate virus neutralizing antibodies from surviving patients (ie, patients partially or completely resistance to a virus or who show reduced or no symptoms thereof). . Multimers of the invention could be used to develop antibodies with broader/stronger neutralization potential for viruses than a normal IgG antibody EXAMPLE 26: Expanding Medical Utility of Binding Sites Through Multimerization [00862] This example demonstrates how advantageously multimerization of the invention can repurpose a binding site which otherwise would not be useful or much less useful for medical use (eg, for treatment or prophylaxis of a disease or condition mediated by or associated with an antigen to which the binding site binds). [00863] A multimer was produced by multimerising copies of a polypeptide. The polypeptide had the sequence of CR3022 VH Fab-TD shown in Table 23, and comprised (in N- to C-terminal direction) a single copy of the VH domain of CR3022, and a human p53TD. Each polypeptide was paired with a light chain, wherein the light chain comprised (in N- to C-terminal direction) a single copy of the VL domain of CR3022 and a human Ck domain. [00864] ELISA was carried out using the example assay method given above. Briefly, for Figure 46, High binding ELISA plates were coated with either 100ng/well of SARS CoV-1 RDB or SARS-CoV-2 RBD protein and incubated at 4 degrees centigrade overnight. After blocking with 1% BSA for 1 hour at room temperature, plates were washed 3 times with PBS Tween and 100 ul/well serially diluted CR3022 IgG1 or CR3022-TD Quad was added and incubated at room temperature for a further 1 hour. The plates were washed again 3 times. HRP Protein L was added to detect CR3022 antibodies bound to RBD protein. [00865] CR3022 is a derivative of a human antibody isolated from a patient who recovered from SARS-CoV-1 infection. This antibody is known to bind the receptor binding domain (RBD) of CoV-1 strongly. It also cross-reacts with the RBD of CoV-2 strain but with significantly lower binding affinity as reflected in the above data. However the multimer version of CR3022 according to the invention massively improves the cross-reactive binding to RBD of CoV-2 and well as improving binding to the RBD domain CoV-1 strain (Fig 46) This makes the mulimter version of the CR3022 binding site a favorable candidate for developing as a novel SARS-CoV-2 neutralizing biologic compared to Ig antibodies. The mulimter version of the CR3022 binding site comprised 4 copies of the VH/VL antigen binding site of CR3022, as opposed to the 2 binding sites on the CR3022 Ig. EXAMPLE 27: Expanding Assay Utility of Binding Sites Through Multimerization [00866] This example demonstrates how advantageously multimerization of the invention can repurpose a binding site which otherwise would not be useful or much less useful for assay use (eg, detecting a pathogen or antigen that mediates, causes or is adversely associated with a disease or condition in a subject). Through multimerization of the invention, very high-order multimers (eg, containing 8-24 copies of a binding site) can easily be achieved in a stable multimer that can be readily expressed, such as in eukaryotic expression systems and host cells (as demonstrated in the exemplification above). The high-order multimers usefully can repurpose binding sites that individually have relatively low binding strength for an antigen, wherein in the multimers an avidity effect is produced rendering the combined binding strength of copies of the binding site well suited to very sensitive assay detection of low levels of antigens in samples. Usefully, for example, we demonstrate this even for very diluted samples where the antigen is at very low concentration. This is advantageous, for example where the antigen is an antigen of a pathogen (eg, a virus, bacterium or fungus that causes disease, such as in humans, animals or plants); or where the antigen is comprised by antibodies produced by a human or animal subject in response to immunisation, such as in response to a pathogen or a human protein in the subject. [00867] A multimer was produced by multimerising copies of a polypeptide. The polypeptide had the sequence of ACE2(18-615) Ig-TD shown in Table 24, and comprised (in N- to C-terminal direction) a single copy of the ACE2 amino acids 18-615, a human hinge region, a human CH2, a human CH3 and a human p53TD. [00868] ELISA was carried out using the example assay method given above. Briefly, for Figure 47, High binding ELISA plate was coated with 100ng/well of ACE2 Ig-TD Quad protein and incubated at 4 decrees centigrade overnight. After blocking with 1% BSA for 1 hour at room temperature, plates were washed 3 times with PBS + 0.1% Tween and 100 ul/well serially diluted SARS-CoV-2 Spike Trimer or SARS-CoV-2 RBD was added and incubated at room temperature for a further 1 hour. The plates were washed again 3 times and anti-His HRP conjugated antibody was used to detect either spike trimer or CoV-2 RBD bound to ACE2 Ig-TD. [00869] ELISA was carried out using the example assay method given above. Briefly, for Figure 48, High binding ELISA plate was coated with 100ng/well with ACE2 Ig-TD Quad protein and incubated at 4 oC overnight. After blocking with 1% BSA for 1 hour at room temperature, plate was washed 3 times with PBS + 0.1% Tween and 65 ul/well SARS-CoV-2 spike trimer or SARS- CoV-2 RBD at 5 nM fixed concentration was added to each well and incubated at room temperature for 1 hour. After another 3 washes using PBS + 0.1 % Tween, 65 ul of serially diluted serum starting from 1 in 100-fold dilution was added and plate incubated at room temperature for 1 hour. The plate was washed again 3 times. HRP Protein L was added to detect SARS-CoV-2 specific seroconverted human antibodies in serum. [00870] Spike glycoprotein is naturally assembled into a trimer. It can be produced recombinantly as a trimer or only the RBD domain can be produced as a monomer for use in in vitro assays. The spike protein binds ACE2 receptor as the initial step in the infection process. Thus, ACE2 can be potentially used as a decoy receptor to neutralize coronavirus. In this experiment, a tetravalent ACE2 Ig-TD multimer Quad (ie, an example of a multimer comprising more than 2 binding sites; this example had 4 ACE2 extracellular proteins) was generated and used to capture the two recombinant forms of the spike protein for comparison. Strikingly, ACE2 Ig-TD Quad binds the trimeric form, which is more analogous to the native form with significantly enhanced binding strength than the RBD domain alone suggesting ACE2 Ig-TD is a good candidate for developing as a super neutralizer of SARS-CoV-2. See Fig 47. [00871] As shown in the previous Fig 47, ACE2 Ig-TD can bind spike trimer with higher binding affinity than the RBD monomer. The captured recombinant spike proteins were used here to capture seroconverted human antibodies in serum (i.e. The fluid and solute component of blood, which does not play a role in clotting, as the skilled addressee knows). The ACE2 Ig-TD captured trimer can detect seroconverted SARS-CoV-2 antibodies in serum with higher sensitivity than ACE2 Ig-TD captured RBD domain monomer (Fig 48). It is therefore anticipated that ACE2 Ig- TD can not only be used as a decoy to potently neutralize SARS-CoV-2 for therapeutic or prophylactic medical use, but it can alternatively be used in sensitive serological assays for detecting SARS-CoV-2 specific seroconverted antibodies. Positive detection could be made in the range from 1000 to 10000-fold dilution, thereby showing the very high sensitivity of an ELISA assay using a multimer of the invention. EXAMPLE 28: Analysis of CR3022 and ACE2 based Quads for enhanced binding and neutralization potency Methods Expression vectors and plasmid DNA preparation [00872] All DNA fragments were synthesized by Twist Bioscience (California) and cloned into the expression vector. Lyophilised plasmid DNA synthesized by Twist Bioscience, were resuspended with MQ water to a concentration of 50 ng/μl. Competent E. coli DH5α cells were transformed TMth 50 ng of DNA using a conventional heat shock method. Transformed cells were plated on LB agar plates containing 100 μg/mL ampicillin and grown overnight at 37 °C. Individual colonies were picked and grown in LB broth overnight at 37 °C, 220 rpm. Plasmid DNA were purified from the cells using Qiagen plasmid extraction kits, according to the manufacturers instructions (Qiagen). Expression of Quad Proteins in Expi293F Cells [00873] Expi293F ^ cells (Thermo Fisher Scientific) were cultured in Expi293TM Expression Medium (Thermo Fisher Scientific) according to the manufacturer’s recommendations. The only exception was that 5% CO2 was added directly to the flasks when the cells were split and non- vented caps were used. [00874] Two methods involving different transfection reagents were utilised for protein expression. The methods for 30ml cultures are described below and the protocol was adapted to either scale up or down according to the experimental requirements. [00875] For PEI transfections the cells were counted one day prior to transfection using a NC- 3000TM (ChemoMetec) and were diluted to 1.5 x 106 cells/ml using Expi293TM Expression Medium. The cells were cultured in 5% CO2 at 37.C, 125 rpm overnight. The following day the cells were counted, spun down for 5 minutes at 1000 rpm and resuspended at 2 x 106 cells/ml in 30 ml of fresh media.33 ug of plasmid DNA was added to 900 ul media and 90 ul of PEI Max (Polysciences Inc.) was added to 900 ul media. The DNA and transfection reagent samples were mixed and incubated at room temperature for 15 minutes. The DNA/transfection reagent mixture was added to the cells, which were cultured as before and incubated for a further 72hrs. [00876] For transfections with Expifectamine ^ 293 Reagent (Thermo Fisher Scientific) the cells were also diluted to 1.5 x 106 cells/ml in Expi293 ^ Expression Medium one day prior to transfection. On the day of transfection the cells were centrifuged and resuspended at 2.5 x 106 cells/ml in 30 ml of fresh media. Two tubes containing 1.5 ml of GibcoTM Opti-MEMTM (Thermo Fisher Scientific) were prepared.30ug of plasmid DNA was added to one tube and 80 ul of Expifectamine was added to the other. The solutions were mixed and incubated at room temperature for 30 minutes. The DNA-transfection reagent complex was added to the cells, which were cultured in 5% CO2 at 37.C, 125 rpm. Following 16-18hrs incubation, transfection enhancers 1 and 2 were added to the cells according to the manufacturers protocol. The cells were incubated for a further 96 hours. Purification of His-Tagged Proteins [00877] The cells were harvested by centrifugation for 10 minutes at 4000 rpm. The ~30ml supernatant was filtered through a 0.22.m filter and diluted to 50ml with binding buffer (50mM HEPES, pH 7,4, 250mM NaCl, 20mM imidazole) containing CompleteTM EDTA-free protease inhibitors (Roche) to facilitate binding to the column. A 1ml HisTrapTM HP column (GE Healthcare) was connected to an ÄKTA Start (GE Healthcare) and pre-equilibrated with binding buffer. The protein-containing media was loaded onto the column using a flow rate of 1 ml/min. The column was washed with >10 CV of binding buffer before the protein was eluted using a 20- 300 mM imidazole gradient over 12ml.0.5ml fractions were collected and analysed by SDS- PAGE. Protein containing fractions were pooled and concentrated using AmiconTM Ultra centrifugal filter units (Millipore). SDS-PAGE [00878] Purified proteins were analysed by separating out on SDS-PAGE under denaturing condition. Typically, 1-2 μg of purified protein were loaded per lane on SDS-PAGE gel. The gels were run in Tris-Glycine buffer containing 0.1% SDS. A constant voltage of 150 volts was used and the gels were run for ~70 mins until the dye front has migrated fully. [00879] SDS-PAGE (15% Bis-Tris) gels were prepared using the following resolving and stacking gels. [00880] Resolving Gel: . 5 ml 30% Bis-Acrylamide . 2.6 ml 1.5 M Tris (pH 8.8) . 50 μl 20% SDS . 100 μl 10% APS . 10 μl TEMED . 2.2 ml MQ Water [00881] Stacking Gel: . 0.75 ml 30% Bis-Acrylamide . 1.25 ml 1.5 M Tris (pH 8.8) . 25 μl 20% SDS . 50 μl 10% APS . 5 μl TEMED . 2.9 ml MQ Water General binding ELISA assay [00882] The potential of the purified Quad proteins to bind its target protein was confirmed by indirect binding ELISA. Briefly, high binding 96 well plates (Corning) were used for coating recombinant target protein (1 - 2.5 ug/ml diluted in PBS or as indicated), which were typically stored at 4oC overnight. Plates are then washed 3 times with 200ul wash buffer (PBS + 0.1% Tween) and blocked using 200ul blocking buffer (PBS + 1% BSA) for 1 hour at room temperature. Purified protein samples are typically serially diluted in dilution buffer (PBS + 0.1% BSA) and 100ul/well is added. Samples are incubated at room temperature for 1 hour after which the plate is washed again 3 times using 200ul wash buffer. Detection antibodies as indicated in the text was diluted according to the manufacturer recommendation is added and incubated at room temperature for 1 hour. The plate is washed for the final time using 3x 200ul wash buffer and 50 ul pre-warmed detection reagent (TMB – Sigma) is added per well and the plate incubated in the dark for 10-30 mins. The reaction is stopped by adding 25 ul/well of 1M sulfuric acid. The absorbance at 450 nm was read using a CLARIOstar microplate reader (BMG Labtech). For competitive ELISA, a fixed amount of biotinylated spike protein or CoV-2 RBD protein (0.5 nM – 7.5 nM or as indicated) is mixed with the purified protein samples and pre-incubated at room temperature for 30 minutes prior to adding to protein coated ELISA plates. Europium labeled streptavidin is used as a detection reagent (Perkin Elmer). Analysis of enhanced binding and neutralization potency [00883] CR3022 is an antibody to SARS-CoV-1. It binds the receptor-binding domain (RBD) of CoV-1 more strongly than SARS-CoV-2 receptor binding domain (RBD). To enhance the CR3022 cross-reactive binding strength to CoV-2 RBD, the variable regions of CR3022 were used to generate different Fab Quad formats either with or without Fc region in order to increase the Fab binding domain valency from bivalent to tetravalent schematically shown in Figures 56A-C. [00884] Human ACE2 is a key receptor that SARS-CoV-2 virus uses to gain entry into cells to cause infection. The receptor-binding motif of SARS-CoV-2 is the main attachment point for ACE2. Thus, to generate a decoy ACE2 Quad to neutralize virus binding ACE2 expressed on host cell surface, an ACE2 Fc fusion Quad protein was generated. The extracellular domain of ACE2 was fused to IgG Fc directly at the hinge region, which was then linked to the p53 tetramerization domain as schematically shown in Figure 56D. [00885] CR3022, CR3022-based Quads and ACE2 Ig-TD proteins were produced in Expi293 cells as soluble secreted proteins and their binding to CoV-1 and CoV-2 RBD was analysed by indirect ELISA. For CR3022 based Quads, high-binding ELISA plates were coated with either 100 ng of CoV-1 or 100 ng CoV-2 RBD and serially diluted antibody was added from 50 nM. Bound antibody was detected using Pro L HRP. As expected, CR3022 showed stronger binding to CoV-1 RBD than CoV-2 RDB (Figures 56E-F). The Quad versions of CR3022 all showed significant increase in binding to CoV-1 RBD and in particular to CoV-2 RBD binding compared to CR3022. Thus, the increased Fab binding domain valency in the Quad formats allowed enhancement in cross-reactive binding to CoV-2 RBD. [00886] The different CR3022 Quad formats were also tested for their ability to neutralize ACE2:Spike interaction in a competitive ELISA. Recombinant ACE2-IgG (200 ng) was used to coat ELISA plates and then serially diluted antibody starting from 60 nM with a fixed amount of full-length spike trimer (7 nM) was preincubated at room temperature for 30 minutes before adding to each well. Wells with only spike protein added without any inhibiting antibody was used as 100% binding. Europium labelled streptavidin was used to detect the amount of spike protein that was bound to ACE2. CR3022 was unable to neutralize ACE2:spike interaction even at the maximum concentration used in this assay (Figure 56G). The three different Quad versions of CR3022 were all able to inhibit the interaction between ACE2 and spike protein. The increase in the functional affinity of these Quad formats helped promote not only the cross reactive binding to CoV-2 but it also helped in promoting cross-reactive neutralization. [00887] Similarly for the ACE2 Ig-TD tetravalent Quad, it was tested for it’s ability to bind both full-length spike protein trimer or CoV-2 RBD by indirect ELISA. ACE2 Ig-TD Quad (100 ng) was used to coat ELISA plates and serially diluted full-length spike protein or CoV-2 RBD from 100 nM was added to the coated ELISA plate. Bound spike protein or CoV-2 RBD to ACE2 was detected using anti-His HRP. ACE2 Ig-TD Quad bound both spike protein and CoV-2 RBD in a dose-dependent manner (Figure 56H). Stronger binding of ACE2 Ig-TD to the spike trimer can be seen than the CoV-2 RBD domain. This could be due to the spike protein being a trimer whereas the RBD domain is a monomer. Nevertheless, binding of ACE Ig-TD to the spike protein and RBD confirmed ACE2 in this Quad format was fully assembled. [00888] To examine whether ACE2 Ig-TD Quad was able to neutralize the interaction of either ACE2:CoV-1 RBD or ACE2:CoV-2 RBD, ELISA plates were coated with 200 ng of recombinant ACE2-Ig protein. Serially diluted ACE2 Ig-TD Quad from 100 nM with a fixed amount of CoV-1 or CoV-2 RBD (7 nM) was added to each well. Wells with only CoV-1 or CoV-2 RBD protein added without ACE2 Ig-TD was used as 100% binding. Bound CoV-1 RBD or CoV-2 RBD to ACE2 was detected using anti-His HRP (Figure 56-I). ACE2 Ig-TD Quad was able to neutralize the interaction of ACE2:CoV-1 RBD and ACE2:CoV-2 RBD interaction in a dose dependent manner confirming ACE2 Ig-TD is fully functional and it has the potential to be used as a decoy molecule to prevent SARS CoV-2 infection. [00889] To compare the neutralization potency of the CR3022 based Quads and ACE2 Ig-TD, the competition ELISA as described above was set up using 250 ng of recombinant ACE2-Ig protein to coat the ELISA plate and 7.5 nM fixed amount of CoV-2 RBD together with serially diluted CoV-2 inhibitor protein from 30 nM was added to each well. Wells with only CoV-2 RBD protein added without any inhibitor antibody was used as 100% binding. Europium labelled streptavidin was used to detect the amount of CoV-2 RBD protein that was bound to ACE2 (Figure 56-J). The data confirmed the CR3022 based Quads and the ACE2 Ig-TD were all able to inhibit ACE2:CoV2 RBD interaction in a dose dependent manner. The ACE2 Ig-TD was able to completely block ACE2:CoV2 RBD interaction at the higher doses (>3 nM) whereas both the CR3022 Quads tested in this assay were only able to inhibit approximately 70% of the ACE2:CoV2 RBD interaction. The IC50 values are summarized in Table 7. Example 29: Engineering SARS CoV-2 neutralizing VHH nanobody into Quad formats with increasing valency and potency [00890] To extend the utility, SARS CoV-2 cross-reactive nanobody termed ‘GB’ (or ‘QB-GB’) was used to format different versions of Quads with varying valency, size and structure and either with or without an Fc region. The valency of the different formats varied from monovalent to octavalent as shown schematically in Figures 57A-I. Expression of GB based Quads were carried out in Expi293 cells and the resulting proteins were analysed on reduced SDS-PAGE gel after affinity purification (Figure 57J). Protein polypeptides from all the expressed proteins migrated according to their expected molecular weight confirming correct expression and high purity. [00891] Next the GB Quad proteins were analysed for their ability to bind CoV-2 RBD in an indirect ELISA binding assay. ELISA plates were coated with 200 ng CoV-2 RBD protein and serially diluted GB Quad proteins from 100 nM was added to the wells. Binding of GB Quad proteins to CoV-2 RBD was detected using anti-FLAG HRP. With the exception of GB VHH (monovalent), which only showed very weak binding at the highest concentration (100 nM), all other GB-based Quad proteins showed a dose dependent binding to CoV-2 RBD (Figure 57K). It is noteworthy, in this binding assay, due to high avidity of these molecules and the limitations in the assay window; the difference in binding strengths between the molecules could not be differentiated. [00892] To tease out the difference in binding strength and to demonstrate the difference in the neutralization potencies between the different GB Quad molecules, a competitive ELISA was performed. ELISA plates were coated with 250 ng of recombinant ACE2 Ig fusion protein and serially diluted GB proteins from 15 nM with a fixed amount of CoV-2 RBD (2 nM) was added to the coated ELISA plate. Wells with only CoV-2 RBD protein added without GB protein was used as 100% binding. Europium labelled streptavidin was used to detect the amount of CoV-2 RBD protein that was bound to ACE2. The data were plotted as percentage inhibition of ACE2:CoV- RBD interaction in three groups (Figures 57L-N). GB VHH (Q176) and the non-Quad based GB formats (Q178 and Q180) were used in each plot as reference for comparison. In general, it can be seen the neutralization potential of GB proteins were significantly increased with increasing GB binding domain valency of Quad formats with the most potent being Q186, which is a -octavalent GB Quad with an IC50 value of 14.8 pM. [00893] As part of this experiment, two additional nanobodies termed ‘BG’ and ‘FE’ (also known as ‘QB-BD’ and ‘QB-FE’ respectively) were selected for testing as Quad formats to bind and neutralize SARS-CoV-2. Nanobody BG and FE were produced as monovalent VHH and also reformatted into octavalent monomeric Ig-TD format as schematically represented in Figures 57-O and Q. Combinatorially, they were tested for their ability to bind SARS CoV-2 RBD in an indirect binding ELISA and also for their ability to neutralize the interaction of ACE2:CoV-2 RBD in a competitive ELISA (Figures 57R-S). BG and FE VHH nanobodies were unable to bind RBD even at the highest concentration (100 nM) as a monovalent nonobody. The octavalent Quad formats of these two nanobodies bound CoV-2 RBD very well in a dose dependent manner and BG and FE appear to bind CoV-2 RBD in a similar manner. [00894] A competitive ELISA was performed only with the monomeric Ig-TD formats for BG and FE as described above and the non-Quad formats of GB VHH were included for comparison (Figure 57S). Both Quad version of the nanobodies were able to inhibit ACE2:CoV-2 interaction but only BG mIg-TD Quad was able to inhibit the interaction completely. FE mIg-TD appeared to inhibit a maximum of 70% of the ACE2:CoV-2 interaction similar to that observed with CR3022 based Quads outlined in Example 28. [00895] All the IC50 values from the competitive ELISA are summarized in Table 8. [00896] The exemplification of nanobody based Quad reformatting into multiple different formats highlighted the power of increasing binding domain valency has on the neutralization potency. In the competitive ELISA described above, the limited assay window together with the detection limitations prevented accurate measurements of some the most potent Quads such as the octavalent Quads causing rapid signal saturation. As a means to improve the assay signal and tease out the enhanced potency of two of the most potent GB-based Quads further, a competitive sandwich ELISA was performed with substantially reduced amounts of CoV-2 RBD similar to that reported by Hansen et al. In their sandwich ELISA a capture antibody was used to capture his-tagged ACE2 protein followed by the addition of a reduced amount of CoV-2 RBD (10-15 pM) plus serially diluted CoV-2 inhibitor antibody. To replicate a similar assay, ELISA plates were coated with 100 ng anti-human IgG to capture 200 ng of recombinant ACE2 IgG. Then to each well a fixed amount of CoV-2 RBD (0.5 nM) together with serially diluted CoV-2 inhibitor antibody (Q185 or Q186/Q182) was added. Europium labelled streptavidin was used to detect the amount of CoV-2 RBD protein that was bound to ACE2. In this assay set-up, the assay window was improved and the IC50 value for Q185 and Q186/Q182 (Figure 58) when compared to the lead SARS-CoV-2 antibody molecules reported by Hansen et al., indirectly confirm that both Q185 and Q186/Q182 Quads are significantly more potent than these SARS-CoV-2 neutralizing antibodies currently under clinical investigation. Example 30: Engineering of multivalent SARS CoV-2 neutralizing VHH nanobody linked in tandem into different Quad formats with increasing valency and potency [00897] In example 29, SARS CoV-2 cross-reactive nanobody ‘GB’ was formatted into different multivalent formats with varying size, shape and valency. In this example, the same SARS CoV-2 cross-reactive ‘GB’ nanobody was used to generate multivalent Quads where the VHH was linked in tandem via a flexible peptide linker as shown schematically in Figure 59-A (Q177B). In a similar strategy, a bispecific VHH Quad version was also generated by linking in tandem SARS-CoV-2 VHH ‘GB’ with a VHH with cross-reactivity to MERS-CoV RBD termed ‘EE’. The bispecific VHH tandem Quad is shown schematically in Figure 59-B (Q177C). In both of these examples, the tandem VHH is linked directly to the TD via a linker, which is rapidly assembled to form tetramers with valences of 8 for the monospecific Quad and 4 + 4 for the bispecific Quad format. [00898] Additional tandem VHH Quad formats were generated either as monospecific containing only ‘GB’ linked in tandem (Figures 59-C (Q179B) and 59-E (Q185B)) or as bispecific VHH formats containing ‘GB’ and ‘EE’ VHHs linked in tandem (Figures 59-D (Q179C) and 59-F (Q185C)). In both of these examples, the Ig core hinge region was kept intact allowing the formation of a homodimer intermediate. This homodimer intermediate is then rapidly dimerized to form a dimer of a dimer (tetramer) facilitated through tetramerization of the TD. [00899] The tandem VHH Quad formats generated in this example were expressed in Expi293F cells and the resulting proteins were affinity purified directly from the culture supernatant as described in example 29. The purified proteins were analysed by SAS-PAGE as denatured non-reduced protein and reduced protein (Figure 59-G). The proteins separated out on SAS-PAGE as non-reduced protein confirmed these Quads were highly pure with purity >95%. Further, the molecular weights of the different tandem Quad formats were also confirmed as the protein all separated out in SDS-PAGE according to their expected molecular weight. The reduction of the cysteine bonds present in the core hinge region of Quad formats Q179B, Q179C, Q185B and Q185C can be seen in the reduced SDS- PAGE where the molecule weigh of these Quads are reduced down from the dimeric intermediate state to the monomeric state. [00900] To further analyse these tandem VHH Quad formats, their enhanced potential to neutralize the interaction of SARS-CoV-2 spike protein with the ACE2 receptor, a competitive ELISA assay was performed as detailed in example 29 with the following conditions. High binding ELISA plates were coated with 100 ng of anti-human Ig, which was used to capture 100 ng of ACE2-Fc. A fixed amount of SARS-CoV-2 RBD biotinylated protein at 15 pM was pre-mixed for 30 mins with serially diluted 1 in 3 folds of anti-SARS-CoV-2 tandem VHH Quads from 30 nM before adding to the ELISA plate with the captured ACE2-Fc. Any SARS-CoV-2 RBD not competed by the Quad molecules were detected using anti-Strep-HRP detection antibody. The signal obtained from the wells with only RBD added without any competitor was used to determined 100% binding and wells with no added RBD or competitor molecule was used to determine zero binding. From this, the percentage inhibition of SARS-CoV-2 RBD interaction with ACE2 at different competitor concentration was plotted (Figure 59-H) and their potency was determined as summarized in Figure 59-I. As a reference comparator, three clinical stage SARS-CoV-2 antibodies with potential to compete the interaction of SARS-CoV-2 spike with ACE2 receptor (Hansen et al., 2020; Shi et al., 2020) were also included in this assay to determine the relative potency enhancement of the VHH tandem Quads. [00901] All of the tandem VHH Quads were found to be significantly more potent at neutralizing SARS-CoV-2 RBD interaction with ACE2 than the three clinical stage anti-SARS-CoV-2 antibodies. The most potent of the tandem VHH Quad (Q185B) with IC50 value of 0.03 pM was found to be between 23,000 – 63,000 times more potent than the three clinical stage antibodies in this competitive ELISA assay setting. The massive improvement in neutralization potency using tandem VHH to generate Quads clearly confirms the multivalent strategy is a good approach for improving antibody functionality. This opens up the scope to further developing Quad formats with even higher neutralization potencies. Example 31: Further engineering of multivalent SARS CoV-2 neutralizing VHH nanobody linked in tandem into different Quad formats with increasing valency and potency [00902] To extend the multivalent Quad formats beyond octavalency using tandem VHH, in this example twelve additional Quad formats were generated utilizing either the tandem ‘GB’ VHH or ‘GB’ and ‘EE’ VHH linked in tandem to generate monospecific and bispecific Quad formats respectively. The different Quad formats varied in shape, size and valency as schematically represented in Figures 60-A – 60-L. The valency of these multivalent Quad formats ranged from 12 – 24 for the monospecific Quads (Q203/Q205, Q177D, Q177E, Q185D, Q185E, Q209/Q182, Q209/Q205, Q210/Q205 & Q212/Q205) and 16 in an 8 + 8 configuration for the bispecific Quad formats (Q204/Q206, Q211/Q206 and Q213/Q206). [00903] The multivalent tandem VHH Quads were expressed in Expi293T cells as described in example 29. Surprisingly and like all of the previously described Quads formats, these tandem VHH formats all expressed well with high purity as soluble secreted protein with average protein titres >150 mg/L. Following affinity purification with Ni-NTA, the proteins were analyzed by SDS-PAGE with either non-reduced or reduced protein. All of the Quad proteins separated out on the non-reduced SDS-PAGE (Figure 60-M) according to their expected molecular weight corresponding to the monomeric form or according to their dimeric form where Quad formats are dimerized through the hinge region such as Q177E. The SDS-PAGE separating the reduced protein samples (Figure 60-N) nicely highlights the reduction in disulphide bonds in Quad formats containing two chains such as Q211/Q205 where the two chains are held together via disulphide bonds. Protein reduction can also be seen as expected in Quad formats with an intact hinge region containing disulphide bonds such as Q185E. By demonstrating protein reduction either by separating the two chains or by reducing a dimer into a monomer in Quad formats containing core hinge region confirms these Quad formats are assembled correctly. [00904] Given the further increase in binding domain valency in the Quad formats in this example compared to those in example 30, the expectation is that the neutralization potency would also be further improve. To demonstrate the potency enhancement, competitive ELISA was performed using a selection of Quad proteins with increased stringent condition. The competitive ELISA was performed similarly to that described in example 30 with the exception that 2 nM fixed amount of biotinylated SARS-CoV-2 RBD was used instead of 15 pM. The most potent Quad molecule described in example 30 (Q185B) along with the clinical stage mAb ‘REGN10987’ was also run alongside these Quads for comparison (Figure 60-O). From the initial observation, it is noteworthy the clinical stage mAb ‘REGN10987’ at these stringent assay conditions does not appear to be very potent compared to the multivalent Quad formats. For example at 1 nM concentration of anti-SARS-CoV-2, REGN10987 has almost zero neutralization potential whereas all of the Quad formats at 1 nM concentration can almost completely neutralize SARS-CoV-2 RBD interaction with ACE2. [00905] Furthermore and as expected, all of the new Quads tested in this example (Q203/Q205, Q177D, Q185D, Q185E, Q209/Q182 and Q209/Q205) showed improved neutralization potency compared to Q185B, which was found to be the most potent Quad in example 30. However, the extent of the improvement in potency between the new Quad formats highlighted in this example and Q185B was not observed as substantial given the binding domain valency difference between for example Q209/Q208 and Q185B being 24 and 8, respectively. The most likely explanation for this is probably due to the limited assay sensitivity and therefore any significantly gain in potency could not be differentiated due to the rapid saturation of the assay signal. To determine the true potency of these multivalent Quad formats, which are expected to be ultra-potent would warrant further investigation of these Quads in an in vivo setting where a measure of a biological effect rather than a assay signal would be measured and thus making it possible to differentiate and observe their true potency enhancement. Example 32: Improving SARS-CoV-2 neutralization potency of clinical stage mAbs by reformatting them into multivalent Quad formats [00906] The first-in-class clinical stage anti-SARS-CoV-2 mAbs REGN10987, REGN10933 (Hansen et al., 2020) and CB6 (Shi et al., 2020) are currently being trialed for their efficacy in reducing viral load and viral infections in COVID-19 patients. Given the results highlighted in the above examples whereby increasing the binding domain valency, a consistent improvement in neutralization potency could be observed in the in vitro neutralization assays. Further as shown in example 31, REGN10987 could not neutralize SARS-CoV-2 RBD binding to ACE2 using the stringent assay conditions compared to the multivalent Quads. In this example, the binding domains of REGN10987, REGN10933 and CB6 were used to reformat them into three different multivalent Quad formats to show 1) How the different formats can neutralize the SARS-CoV-2 binding to ACE2 and 2) Whether the different formats effect the neutralization potential due to their size and structural configuration. [00907] In the first format termed Ig-TD, the p53 tetramerization domain was directly linked to the C- terminus of the mAb with the CH3 domain as schematically shown in Figure 61-A. In the second format termed Fab-TD, the TD was directly linked to the upper hinge region but lacked the core hinge. In this example, the upper hinge region was directly linked to TD as shown schematically in Figure 61-B. The third format is similar to the Ig-TD format except the core hinge region only was removed where the upper and lower hinge region was kept intact to give a monomeric Ig-TD format as shown schematically in Figure 61-C. In all three examples, the TD facilitated the assembly of a tetramer and thus transforming the bivalent mAbs into tetravalent mAbs. [00908] The three different Quad formats of REGN10987, REGN10933 and CB6 were expressed in Expi293T cells. Like normal IgG antibodies, the Quad formats of these mAbs also expressed as soluble secreted proteins where the assembled tetrameric Quad proteins were harvested from the culture supernatant and affinity purified. The purified proteins were separated out on SDS-PAGE gels using either non-reduced or reduced proteins (Figures 61-D – 61-F). From the non-reduced SDS- PAGE, the Quad proteins appear to be highly pure (>95%) and in the reduced SDS-PAGE, reduction of the two chains can be seen, which confirms these Quad proteins were correctly assembled. To check for improved neutralization potency of the Quad formats over the parental IgG format, competitive ELISA was performed as described in example 29 with some changes in the assay conditions. Instead of SARS-CoV-2 RBD, biotinylated SARS-CoV-2 Spike trimer was used at a fixed concentration of 75 pM. For each of the clinical stage mAb, the three different Quad formats were compared for their neutralization potential compared to the parental IgG mAb and against Q185B as highlighted in Figures 61-G – 61-I. From the initial observation, it can be seen that all of the Quad formats had improved neutralization potency of SARS-CoV-2 spike interaction with ACE2 compared to the parental mAb but not as potent as the tandem VHH Quad, Q185B. Secondly, it can be seen the Ig-TD and mIg-TD Quad formats only had moderate enhancement in neutralization potency whereas the Fab-TD format consistently showed superiority for all three clinical stage mAbs in terms of improving the neutralization potency compared to the parental mAb as summarized in Figure 61-J. For example, REGN10987 Fab-TD format had a 600-fold improvement in neutralization potency over the parental mAb. From these data in this artificial in vitro neutralization assay setting, it can be seen that the size, shape and even the flexibility of the molecule could enhance the neutralization potential of inhibiting SARS-CoV-2 Spike protein binding to ACE2. The superior neutralization potency enhancement of Fab-TD format is something worth analyzing generally for antibodies, such as further to improve other SARS-CoV- 2 antibodies binding alternative epitopes within the spike protein with improved binding such as antibodies targeting the S2 ectodomain. Example 33: Design, expression and analysis of multivalent VHH nanobody formats based on Sequence Nb-112 [00909] As described in previous examples, VHH nanobodies can be rapidly designed into different multivalent formats starting from simple monomeric building blocks. The VHH sequence Nb-112 against SARS-CoV-2 spike protein described previously (Esparza et al., 2020) was used to design different multivalent formats with varying size, shape, flexibility and valency. Figures 62A & 62B depicts two such examples that were produced in this example where VHH Nb-112 was reformatted to yield tetravalent and octavalent Quad molecules. Nb-112 sequence could also be easily reformatted into any of the Quad formats described in the previous examples and as schematically shown in Figures 55-60. Optional Linkers 1 and 2 (GGGGSGGGGS and GGSGGS respectively) shown in Figure 62B were included in the octamer we constructed. We included GGGGSGGGGS Linker 1 in the tetramer we constructed (Figure 62A). It is possible in alternatives to omit linkers, or to use one linker (linker 1 or 2) in the octamer polypeptide. [00910] One of the advantages of these multivalent Quads, apart from them being highly soluble, stable and amenable to large-scale production, is that they are relatively small in size, particularly the tetravalent versions without Fc compared to standard mAbs. The relative small size would be particularly advantageous when formulating these molecules for delivery through inhalation. Owing to their high stability properties, Quad based nanobodies is likely to maintain the structural integrity and thus the functional properties to neutralize SARS-CoV-2 after nebulization. Further, given the size of these Quads being above the renal clearance threshold, Quads delivered through inhalation is likely to persist for a longer period and provide a molecule with significantly enhancement efficacy than the native VHH Nb-112 nanobody. [00911] The tetravalent (also called Q232) and octavalent (also called Q233) versions of Nb-112 were produced as schematically represented in Figures 62A and B for which the polypeptide sequences are shown in Table 24. The monovalent Nb-112 nanobody (also called Q231 was also produced for comparison. Expression vectors for producing Q231-Q233 where transfected into Expi293F cells and the proteins were produced as described in Example 28. Since the VH of Nb-112 nanobody is a VH3 subfamily member known to have intrinsic affinity for Protein A (Seldon et al., 2011), the harvested protein from culture supernatant were purified using MabSelect Sure (Sigma). The purified Q231- Q233 proteins were analysed on denaturing SDS-PAGE (Figure 62C-1). Protein polypeptides from all three proteins (Q231-Q233) migrated according to their expected molecular weight confirming correct expression and high purity. The protein yields after Protein A affinity purification was measured using Nanospec and it could be seen the tetravalent (Q232) and octavalent (Q233) versions of Nb-112 yielded excellent protein yields equivalent to 338 mg/L and 288 mg/L respectively (Figure 62C-2). The monovalent version (Q231) on the other hand being the smallest of the molecule surprisingly yielded very poor protein yield equivalent to only19 mg/L. To investigate whether this poor protein yield was due to poor expression or inadequate purification method and since a 6xhistidine tag was included onto the C-terminus, Q231 was purified using Ni-NTA column as described in Example 28. After measuring the protein yield using nanospec, the protein yields was found to be good and equivalent to 187 mg/L. This confirmed the expression of the monovalent Nb-112 (Q231) was fine and purification using Protein A resin through the monovalent interaction was not sufficient to efficiently purify this protein whereas surprisingly and advantageously the tetravalent and ocatvalent versions with enhanced binding to Protein A resin through multiple VH domain interaction with the resin allowed these multivalent proteins to be purified efficiently similar to a mAb containing an Fc region. [00912] To investigate the functionality of the multivalent Nb-112 Quad proteins, competitive ELISA was performed for their ability to neutralize the interaction of SARS-CoV-2 spike RBD with the ACE2 receptor. The monovalent Nb-112 was reported to be a potent neutralizer of spike RBD interaction with ACE2 (Esparza et al., 2020). Therefore, two different amounts of spike RBD were used in competition ELISA. Briefly, high binding ELISA plates were coated with 100 ng/well of anti- human IgG and incubated at 4oC overnight. After blocking with 1% BSA for 1 hour at room temperature, 100 ng/well ACE2-Fc was added and the plate incubated for a further 1 hour. The plates were washed 3 times with sample buffer (PBS containing 0.1% Tween) and 100 ul/well serially diluted anti-SARS-CoV-2 molecules (Q231-Q233 and REGN10933 as positive control) starting from 30 nM premixed at room temperature for 30 minutes with a fixed about of biotinylated SARS-CoV-2 RBD either at 2 nM (Figure 62D) or 150 pM (Figure 62E) was added to the coated plate. Wells with only sample buffer or only spike RBD protein added without any antibody was used to determine percentage neutralization. After incubating the plate for one 1 hour, the plates were washed again 3 times and a detection protein (Strep-HRP) was added to detect non-competed spike RBD that bound the captured ACE2 protein. After the final wash as above, the signal was generated with the addition of 100 ul TMB and the reaction was stopped with the addition of 50 ul 1M sulfuric acid. The absorbance at 450 nm was read using a microplate reader. The data was plotted as percentage neutralization over a range of anti-SARS-CoV-2 inhibitor concentration. [00913] From the data, a nice dose-dependent inhibition of SARS-CoV-2 interaction with ACE2 can be seen in the competitive ELISA at both the high (2nM –Figure 62D) and low (150 pM –Figure 62E) amounts of SARS-CoV-2 RBD used, confirming the produced multivalent Nb-112 molecules are functional. Furthermore, an increase in potency with increase binding domain valency of the Nb-112 molecules can be seen from the IC50 values. It is noteworthy, given Nb-112 is already highly potent and even more so than the clinical stage mAb (REGN10933) and given the ELISA has a limited assay window, it would not be possible to determine the true levels of potency enhancement of the multivalent Quads over the monovalent Nb-112 nanobody using this in vitro ELISA assay (it likely is even greater than measured). Nevertheless, a good correlation with increase binding domain valency with increase neutralization potency can be seen when comparing the potency between the tetravalent and octavalent versions of Nb-112 with the monovalent version. To determine the true potency enhancement of these multivalent Quads would require further characterizing in in vivo animal infection models. We expect them to be highly potent in aminals and man. Example 34: Design, expression and analysis of multivalent VHH nanobody formats based on Sequence Nb-112 with intact hinge region [00914] Following on from Example 33 where tetravalent and octavalent versions of Nb-112 were generated, in this example a modified tetravalent and octavalent version of Nb-112 were designed and produced where an intact hinge region was included in the construct. The hinge region allows for the dimerization of the monomeric building blocks to form dimers upon which these dimers are further dimerized in an anti-parallel manner through the p53 tetramerization domain to form tetramers. A schematic structural arrangement of these new tetravalent (also called Q246 or Nb-112-S-S-TD) and octavalent (also called Q247 or [Nb-112]2-S-S-TD) Quads can be seen in Figure 63A and B respectively and their polypeptide sequences are shown in Table 34. The presence of the disulfide bonds could provide enhanced stability and functional neutralization potency to these multivalent Quads formats and this would be advantageous particularly when formulating these nanobody Quads through nebulisation. [00915] Expression vectors for producing Q246 and Q247 were transfected into Expi293F cells and the proteins were produced as described in Example 28. As with Q232 and Q233 described in Example 33, the intrinsic binding properties of the VH3 subfamily for Protein A resin was exploited to purify both Q246 and Q247. The protein yields after Protein A affinity purification was measured using Nanospec and it can be seen the tetravalent (Q246) and octavalent (Q247) versions of Nb-112 yielded excellent protein titers equivalent to 350 mg/L and 265 mg/L respectively. The protein yields were similar to the tetravalent and octavalent versions described in Example 33 indicating that the present of the hinge region did not hamper protein production. To analyse the produced protein, a small aliquot (2 ug/well) were separated out on denaturing SDS-PAGE under non-reduced conditions alongside Nb-112 proteins produced in Example 33. For Q246 and Q247, the protein was also separated out under reduced conditions to visualize the monomeric building block polypeptide (Figure 63C). Protein polypeptides for Q246 and Q247 migrated according to their expected molecular weight under both non-reduced and reduced conditions. [00916] To investigate the functionality of the two new tetravalent and octavalent Nb-112 Quads (Q246 and Q247), a competitive ELISA was performed for their ability to neutralize the interaction of SARS-CoV-2 spike RBD with the ACE2 receptor as described in Example 33 using the same conditions. As a comparison, Q231-Q233 was also tested alongside Q246 and Q247 including the benchmark anti-SARS-CoV-2 antibody REGN10933. The data was plotted as percentage neutralization over a range of anti-SARS-CoV-2 inhibitor concentration (Figure 63D-1). [00917] From the in vitro neutralization assay data, a nice dose-dependent inhibition of SARS-CoV-2 interaction with ACE2 can be seen where the new tetravalent and octavalent versions (Q246 and Q247 respectively) were found to be significantly more potent than the monovalent Nb-112 VHH as seen from the IC50 values (Figure 63D-2). Interesting in this assay setting, the tetravalent versions (Q232 and Q246) had similar neutralization potencies to each other despite their differences in their structure. This was also true for the octavalent versions (Q233 and Q247). [00918] For the reasons discussed in Example 33 in terms of the high affinity of Nb-112 VHH and the limited assay window, the real differences in neutralization potences might not be possible to be differentiated in this in vitro artificial assay setting. A cell-based assay such as a pseudovirus neutralization assay or even better an in vivo animal model would be required to fully characterize and tease out potency differences between these multivalent Quad formats. However, on the whole a good correlation with increase binding domain valency with increase neutralization potency can be seen when comparing the neutralization potences between the tetravalent and octavalent versions of Nb- 112 to the monovalent version confirming that these new multivalent formats are functionally active and are capable of neutralizing SARS-CoV-2 through blocking its interaction with ACE2 receptor. Example 35: Production & Characterisation of Nebulised Quads [00919] Importantly, these Quad therapeutics may be delivered via inhalation to a human or animal subject. Inhalation has major advantages over other routes of administration and could be one of the most important potential uses for a therapeutic for SARS-CoV-2. For example, nebulisation may be performed using a commercially available human-use Aeroneb Solo™ system (https://www.aerogen.com/aerogen-solo-3/), interfaced with a nose mask. The Aeroneb Solo nebuliser can, thus, be used to produce ~ 3 micron particles of Quads for lung delivery. This is suitable for deep lung delivery. [00920] In an experiment, we will test once daily administration to lambs of a nebulised Quad. We expect that this will result in concentrations of the Quad in lung epithelial lining fluid that are at least 10 times higher than the in vitro EC50 of the Quad for the cognate virus (eg, SARS-CoV-2). We will assess whether there is any detectable infectious virus in lung epithelial lining fluid, with no or low detectable virus supporting that the proposed route of administration could reduce infectivity. After administration of nebulised Quad, we expect blood concentrations will be lower (eg, 1000 fold lower or less) than lung epithelial lining fluid concentrations, which is important because low blood concentrations likely reduce systemic toxicity and risk of host antibody formation. Alternative routes of administration of Quads include intravenous, intramuscular or subcutaneous administration [00921] Using the commercially available Aerogen Solo™ vibrating mesh nebuliser, we will nebulise Pichia pastoris-expressed Quad into an in line custom bead condenser. Analysis by size-exclusion chromatography on a Superdex™ 75 column will be carried out to establish no evidence of degradation or aggregation relative to the pre-nebulisation sample. From this, one can conclude that the Quad is resilient to degradation or aggregation during nebulisation. [00922] Fourt different Quads (Figs 62 & 63) as follows will be tested Quad 1- a multimer that comprises 4 copies of a polypeptide that comprises the amino acid sequence of SEQ ID: 1*289; Quad 2- a multimer that comprises 4 copies of a polypeptide that comprises the amino acid sequence of SEQ ID: 1*290; Quad 3- a multimer that comprises 4 copies of a polypeptide that comprises the amino acid sequence of SEQ ID: 1*291; and Quad 4- a multimer that comprises 4 copies of a polypeptide that comprises the amino acid sequence of SEQ ID: 1*292. Nebulisation stability assessment of Quads: [00923] Stability following nebulisation of Pichia pastoris expressed Quad (eg, a Quad comprising copies of NIH-CoVnb-112) will be performed using an Aerogen Solo High-Performance Vibrating Mesh™ nebuliser placed in line with a custom glass bead condenser. A plastic culture tube will be fitted with a glass-pore frit and filled with sterilized 5 mm borosilicate glass beads. A three-way stopcock will be positioned distal to the frit to prevent pressurization during nebulisation. A 2 mg/mL SEC polished Quad solution will be prepared in 0.9% normal saline to model potential patient delivery. The Quad will be nebulised and the resulting condensate incubated at 37 °C for 24 hr to mimic exposure to body temperature. The nebulised, 37 °C treated Quad will be then collected for stability assessments and protein concentration measurements by BCA assay. Equal masses of pre and post-nebulisation samples will be denatured in LDS sample buffer (Invitrogen) and run on a NuPAGE 12% Bis–Tris precast polyacrylamide gel with SeeBlue Plue 2™ protein standards. Additional pre- and post-nebulisation samples will be injected onto a Superdex 75 Increase 10/300 GL size exclusion column operating on an AKTA Pure 25 M™ system.# Stability of Quads in human plasma: [00924] To further assess the stability of the Quad (eg, a Quad comprising copies of NIH-CoVnb- 112), we will perform incubation of the Quad in pooled normal human plasma and recombinant human albumin followed by affinity measurement to assess preservation of antigen (eg, SARS-CoV-2 RBD) binding potential. [00925] A Quad (eg, a Quad comprising copies of NIH-CoVnb-112) expressed in Pichia pastoris will be diluted from a concentrated stock solution into apheresis derived pooled human plasma (#IPLA-N, Innovative Research) to a final concentration of 5 µM and incubated at 37 °C for either 24 hr or 48 hr with gentle rotation. An identical sample set will be prepared at 5 µM in a solution containing 35 mg/mL recombinant human albumin (#A9731, Sigma-Aldrich) and incubated at 37 °C for either 24 hr or 48 hr with gentle rotation. A no-incubation control for each the plasma and recombinant human albumin conditions will be prepared at 5 µM. The samples will be prepared in a manner providing all conditions complete at the same time. Quad binding to antigen (eg, SARS-CoV-2 RBD) following treatment in pooled human plasma at time zero, 24 hr, and 48 hr will, we expect, have negligible impact on binding. Similarly, Quad binding to antigen following treatment in recombinant human albumin at all time points will, we expect, have no apparent effect on binding. Such data will support the interpretation that the Quad is satisfactorily stable in the presence of plasma. [00926] The samples will be diluted 1:10 with 1xPBS to yield a final Quad concentration of 500 nM and Bio-layer Interferometry will be performed using immobilized biotinylated antigen (eg, SARS- CoV-2 S protein RBD) to determine retention of binding potential. Determining melting temperature and refolding by circular dichroism: [00927] Circular Dichroism (CD) will be performed using a Jasco J-815 Spectropolarimeter™. For thermal stability measurements the Quad will be diluted to 10 μg/mL in deionized water and placed in a quartz cuvette with 1 cm path length and CD measured at an ultraviolet wavelength of 205 nm. Quad will be heated from 25 °C to 85 °C at a rate of 2.5 °C/min while stirring and then cooled back to 25 °C at the same rate. We expect that measurements using circular dichroism (CD) during heating will reveal that the Quad structure resists unfolding at elevated temperature (eg, until 74 °C) and upon cooling most (eg, at least 50, 60, 70 or 80%) of the structure will return to the baseline CD value. These data will support an extremely stable, robust, high affinity format. Exemplary Nebulised Quad Compositions: Using Aerogen Solo™ with an 8 stage cascade impactor running at a continuous flow rate of 28.3 LPM – see Table 37. Example 36: Quad PK and Efficacy Model [00928] Quads (separately, Quads 1-4) will be produced using a HEK203, CHO or Pichia pastoris X- 33 expression system. Formulation buffer will contain NaCl as osmolality agent and phosphate as buffer component. Drug administration: [00929] An Aeroneb Solo™ System (Aerogen Ltd, Galway, Ireland), containing the Aeroneb Solo mesh nebulizer and the Aeroneb Pro-X™ controller will be used in accordance with the instruction manual as provided by the manufacturer. The estimated particle sizes obtained with these meshes will be around 3 to 3.5 μm (MMAD, Median mass aerodynamic diameter). The assembly and operation of the Aeroneb Solo System will be performed according to the nebulizer instruction manual. The nebulizer and the T-piece will be inserted into the breathing circuit. Air will be supplied to the system at an airflow speed of 2 L/min using a compressed air canister that is attached directly to the nebulizer T-piece. [00930] Testing will be performed in lambs. Prior to dosing, the nebulizer reservoir will be filled with following volumes of different concentrations of the Quad formulation: either 4 mL (3 mg/kg target inhaled dose), 1.3 mL (1 mg/kg target inhaled dose) 0.4 mL (0.3 mg/kg target inhaled dose), 0.2 mL (0.08 mg/kg target inhaled dose) or 0.1 mL (0.04 mg/kg target inhaled dose). A cone mask (Cat # 05305, A.M. Bickford, Inc, US) will be attached to the nebulizer T-piece and placed over each lamb’s nose, mandible and maxilla. The nebulizer will be turned on at a constant nebulization mode and the cone mask firmly held in place during the duration of the nebulization. Once the dose has been nebulized (i.e., when the nebulizer reservoir is empty), the face mask will be removed and the nebulizer switched off. The lamb will then be returned to its cage and general health (alertness, responsiveness, ability to stand and move) will be monitored for 10 minutes. Pharmacokinetics of Quads in neonatal lambs: [00931] Four independent studies will be performed in SARS-CoV-2-infected neonatal lambs. In all of these studies, blood samples will be taken at selected time points followingthe first dose and all the subsequent doses for pharmacokinetic (PK) purposes. On Day 6, bronchoalveolar lavage fluid (BALF) sampling will be performed post-mortem for PK analysis in the lung compartment. Once daily administration of Quad via inhalation for 5 or 3 consecutive days is expected to result in high concentrations of Quad in lung epithelial lining fluid (ELF). A dose-dependent increase in ELF concentrations is expected to be seen on day 6. Effect of daily Quad administration to neonatal lambs when started on day 1 post-infection: [00932] To assess the therapeutic efficacy of Quad when administered by inhalation, thirteen lambs (twelve lambs for analysis) will be inoculated with SARS-CoV-2 virus on day 0. The day after infection (day 1), the lambs will be randomized to either the placebo group or to Quad dose groups (0.3, 3 or 1mg/kg) and treated daily by inhalation for 5 consecutive days. Lambs will undergo daily physical examinations and body weights, heart rates, rectal temperatures, respiratory distress and viral infection-related symptoms will be recorded. On day 6, the animals will be euthanized and lung lavage samples and lung tissues will be obtained for analysis of viral load in lung, histopathology and immunohistochemical analysis. Viral inoculation by inhalation will be confirmed for robust infection of all the analyzed lambs by reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed on BALF and lung tissue. In the placebo-treated lambs, we expect gross and microscopic lung lesions induced by viral infection. We expect that treatment of lambs with Quad at all three doses will result in significant reductions in viral RNA copy numbers (eg, that range from 1.4 to 1.8 Log10 viral RNA copies/mL in BALF and between 0.8 to 1.9 Log10 viral RNA copies/mg in lung tissue). We expect that treated lambs will have much lower or undetectable infectious virus. Example 37: Anti-SARS-CoV-2 Quads to Combat Viral Mutation & Evolution [00933] Since SARS-CoV-2 first emerged, recurrent mutations in spike have occurred during both human-to-human transmission (and spillover/spillback events between humans and animals. Among mutations associated with enhancement of human-to-human transmission, N501Y occurred in three distinct emerging human variants: B.1.1.7 lineage (or 20IB/501Y.V1), B.1.351 lineage (or 20H/501Y.V2), and P.1 lineage (or 20J/501Y.V3) that were originally identified in the United Kingdom, South Africa and Japan/Brazil, respectively. The key involvement of residue 501 in ACE2 binding may contribute to increased prevalence of mutations at this site in multiple distinct SARS- CoV-2 strains. The B.1.351 and P.1 lineages also carry the RBM mutations E484K and K417N/T. Meanwhile, the N-terminal domain (NTD) deletion ∆HV69-70 arose in the mink-associated Cluster V strain and in B.1.1.7. The B.1.1.7 also has ∆Y144, and B.1.351 has a ∆LLA242-244 deletion. Other mutations that may facilitate immune escape (e.g., A222V, N439K and S477N) are frequently observed in patient samples. Three mutations in the receptor-binding motif (RBM) (Y453F, F486L and N501T), associated with cross-species transmission between minks and humans, emerged independently in distinct clusters, suggesting they could be vital points for new host adaptation. Additional selection pressures, not directly related to receptor adaptation may also exist, as evidenced by mutations outside the RBM in human-animal transmission (e.g., the N-terminal domain deletion ∆HV69-70, G261D and RBD point mutations V367F). [00934] Mutations in the spike protein can have various impacts on antibody binding footprints and affinity, ranging from no effect to substantial impairment of recognition and binding. Amino acid substitutions or deletions that appeared once in spike might appear elsewhere, new variants having a different assortment of mutations may emerge, and current variants may acquire new single mutations. Thus, work was carried out to dissect the effects of key mutations individually to understand they affect binding molecule (antibody or Quad) activities. First, the binding affinity for full-length G614 HexaPro spike ectodomain and to the monomeric receptor-binding domain (RBD) was determined. Using high-throughput surface plasmon resonance analysis, those binding molecules that react with the RBD were sorted into different “communities”. Communities were defined by shared competition profiles in a matrix, in which each antibody was evaluated for its ability to either pair with or compete with other antibodies for binding to spike. Some additional communities of binding moleucles were identified against the NTD (N-terminal domain) by mapping of antigenic sites using electron microscopy. In total, 14 different communities that react with the spike S1 domain were identified. The antigenic landscape of spike determined by these 14 communities can be divided into binding footprints that: (a) overlap with the RBM (receptor-binding motif), (b) approach the RBD from the outer edge, (c) involve the inner face of the RBD and are accessible only in the “up” state, or (d) include the NTD. [00935] To understand if certain binding molecule communities are more susceptible to particular emerging spike mutations than others, single-cycle VSV-based pseudoparticles bearing point mutations found in human and mink variants were generated and the susceptibility of each mutation to neutralization by the molecules was assessed. Notably, a Quad multimer comprising copies of variable domain QB-GB, which binds outside of the core RBM, was found to be resistant to all S1 mutations analyzed and retained neutralization comparable to the parent virus. This Quad was found to bind to the inner face of the RBD. Strong binding was observed (IC50 of 0.0017 μg/mL). Near 100% ACE2 blocking was surprisingly observed (99.84%), and yet the multimer does not contact core RBM residues. This Quad multimer and other multimers binding spike protein in the same region, therefore, may advantageously be more resistant to receptor-driven selection pressure. Example 38: New VH Single Variable Domains & Quad Formats [00936] Five new human VH domains (Table A; SEQ IDs: A-E) based on human germline gene segment IGHV3-23 were designed, formatted and produced as a tetravalent Quad format where the VH was linked to the p53-TD domain (Figures 64A & B). These Quad proteins were produced in Expi293F cells and purified using Protein A affinity purification as described in previous examples. A small aliquot of each purified protein was analysed on SDS-PAGE to check purity (Figure 64C). Apart from one VH format (Quad version 2), which did not yield any protein, most likely due to error in the DNA constructs acquired through DNA synthesis, all other VH formats expressed well and migrated according to their expected size as seen by a single prominent protein band on the SDS- PAGE. [00937] In the next step the functionality of these tetrameric Quad tetramers were analysed for their ability to block the interaction of Spike RBD binding to ACE2. This was carried out in an in vitro neutralization ELISA assay as described in previous examples. A fixed amount of SARS-CoV-2 RBD biotinylated at 150 pM was pre-mixed and incubated together with serially diluted Quad tetramers before adding to ELISA plates coated with ACE2-Fc protein. Wells with biotinylated RBD was used to determine zero percentage inhibition or 100% binding and this was used to determine the percentage inhibition of RBD binding to ACE2 for the different tetrameric Quads (Figure 64D). Quad with version 1 VH (Q195; SEQ ID: A) retained the ability to neutralize RBD binding to ACE2 but at ~12 fold reduced potency. However, for Quads with VH versions 3-5 the ability to neutralize RBD binding to ACE2 was completely lost. Example 39: Optimizing VH Q195 [00938] The VH version 1 (Q195) described in Example 38 displayed the ability to neutralize the interaction between Spike RBD and ACE2. To optimize the VH further and enhance the neutralization potency, VH Q195 sequence was used to identify key amino acid residues that are crucial for the neutralization activity. Three amino acids were identified within CDR-1, CDR-2 and in the framework region 3 (FR3) in sequence Q195 (at positions 35, 50 and 61 of SEQ ID: 1*195), as indicated in Figure 65A that were subjected to further analysis in this example for their contribution to the neutralization potency. [00939] A further four VH versions (versions 6 – 9; Q222-225; SEQ IDs: F-I) based on sequence Q195 were designed for analysis. In version 6 (Q222) all three identified amino acid residues were changed (Figure 65A). In versions 7-9 (Q223-Q225), each of these three amino acids were individually changed to identify which of these amino acids are crucial for SARS-CoV-2 spike binding and thus important for neutralization of SARS-CoV-2 spike binding to ACE2. Versions 6-9 were once again expressed as tetravalent Quad form in Expi293F cells and purified using Protein A affinity purification. The purified proteins were analysed on SDS-PAGE to check their purity (Figure 65B). All versions 6-9 expressed well and migrated on the SDS-PAGE according to their molecular weight. Next, functional activity was analysed as above in an in vitro neutralization ELISA assay using the same conditions described in Example 38. The neutralization profiles are shown in Figure 65C. Change of all three selected amino acid positions in sequence Q195 to non-human germline residues give version 6, surprisingly enhanced functional neutralization activity. However, providing the human germline serine residue (instead of a non-human germline glycine) in CDR-1 (position 35 of SEQ ID: A) or providing a human germline alanine residue (instead of a non-human germline threonine) in CDR-2 (position 50 of SEQ ID: A) reduced the neutralization potency versus version 6 (Q222), with the CDR-2 amino acid change having a greater reductive effect than the CDR-1 amino acid change. Interestingly and surprisingly, providing a human germline alanine residue (instead of a non-human germline threonine) in FR3 (position 61 of SEQ ID: A), whilst providing the first two selected amino acids (positions 35 and 50 of SEQ ID: A) as non-human germline glycine and threonine respectively (VH version 9, Q225, SEQ ID: I) enhanced the neutralization potency, indicating this second threonine residue in FR3 is not crucial for binding to spike and can be usefully humanized (ie, germlined). The Q225 sequence is an optimized version that expresses well and has desirable neutralization potency to the spike. The sequence identity between Q225 and human IGHV3-23 is 92.8% with the majority of the variation arising from within the CDR-1 and -2. Two additional amino acids (both phenylalanine marked with asterisk in Figure 65A, corresponding to positions 37 and 47 in Q195, SEQ ID: A) located within FR2 were kept unchanged versus Q195 in the Q225 sequence to avoid loss of antigen affinity and/or stability (and we observed, thus, the total loss of neutralization ability in VH versions 3-5 where these two phenylalanine residues were changed). Example 40: Further optimizing VH Sequence Q225 [00940] By sequence alignment of sequences with human IGHV3-23 (Figure 64A) we identified three amino acid residues within CDR-1 and -2 that could be changed to further optimize VH Q225. These three amino acid residues are highlighted in Figure 66 with arrows (at positions corresponding to positions 27, 31 and 53 of Q225, SEQ ID: I). We will explore providing human germline residues (ie, the residues found at corresponding positions of human germline gene segment IGHV3-23). These three amino acid residues will be individually changed to human IGHV3-23 residues (27F, 31S or 53G respectively in Q279-281) as shown in Figure 66 and then analysed for their contribution to neutralization potency in the in vitro neutralization ELISA assay. Amino acid residues that are found not to disrupt the neutralization potency after humanizing can be combined and used to generate a further optimal humanized version of Q225. Example 41: Demonstrating highly potent broadly neutralizing potential of GB VHH-based Quads in pseudotype neutralization assay [00941] In previous examples, GB-based Quads have been shown to strongly bind and potently neutralize SARS-CoV-2 through interaction via the spike protein. Further in a recent publication, another GB-based Quad molecule referred to as CoVIC-063 was shown to broadly neutralize spike variants including the Delta variant (Hastie et al., 2021). Amongst a panel of more than 380 anti- SARS-CoV-2 molecules submitted into a global consortium, CoVIC-063 was found to be one of the most potent broadly neutralizing molecules, which was resistant to all variants of SARS-CoV-2 virus tested in the study. [00942] To further exemplify the potency and breadth of the neutralization potency, two additional GB-based Quads were analysed in pseudovirus (PV) neutralization assay with different spike variants, including spike from the L strain (the original Wuhan strain), spike containing D614G mutation, and spike from the alpha, delta and the recent omicron variants of SARS-CoV-2 virus. In this example, two hexadecavalent GB-based VHH containing Quads were used where one molecule (Hu-Q179F) contains a human IgG Fc region linked to the binding domain whereas the second molecule (Hu- Q185E) did not contain an Fc. These molecules were used in the assay to neutralize the pseudovirus from infecting target HEK293T cells stably expressing human ACE2 and TMPRSS2. The pseudovirus, in addition to expressing the spike protein, also expressed GFP. The assay readout was a measure of the number of target cells expressing GFP after the addition of pseudovirus to the target cells as a means to calculate maximum infection (100%) in the absence of any inhibitor molecules such as Hu-Q179F and Hu-Q185E. Titrating amounts of Hu-Q179F and Hu-Q185E were used to measure the decreasing numbering of target cells expressing GFP as a means to calculate percentage neutralization as shown in Drawing 4. [00943] Both Hu-Q179F and Hu-Q185E showed potent and broadly neutralizing activity in the pseudovirus neutralization assay. For examples, advantageously the IC50 values for neutralizing the Wuhan spike for both Hu-Q179F and Hu-Q185E Quad molecules were <0.0001 nM making them the most potent neutralising molecules reported. The potent neutralization activity was surprisingly maintained with the different spike variants, including against the delta and omicron SARS-CoV-2 variants. The IC50 values for omicron was advantageously found to be extremely potent for both Hu- Q179F and Hu-Q185E Quad molecules with IC50 of 0.01125 nM and 0.0023 nM respectively. [00944] The Omicron variant has significantly more mutations than other variants in its S gene — the gene that encodes the virus’s spike protein, which is the key that provides the virus with access to our cells. Omicron has accumulated 50 mutations, including 32 mutations in the S gene. By contrast, the Alpha variant has nine mutations in its S gene, and Delta has between nine and 13 mutations. Thus, we have shown that multimers based on GB binding domain are capable of binding to spike of clinically-relevant and divergent SARS-CoV-2 viruses, such as delta and omicron. Thus, we propose that such multimers will be useful as a medicament against several SARS-CoV-2 variants, including delta and omicron and variants with S gene changes when compared with the S genes of Wuhan, delta and omicron strains. [00945] The anti-spike variable domains used in Hu-Q179F and Hu-Q185E were humanised versions of the VHH antibody variable domain “GB” (GB comprises SEQ ID: U corresponding to SEQ ID: 307 in WO2021/190980). The humanised VHH variable domains used in the present example and found to be surprisingly useful to address divergent variants each had the following sequence features:- The amino acid sequence of the variable domain comprises a) a glutamic acid at position 1; b) a proline at position 14; c) an arginine at position 27; d) a glutamic acid at position 31; e) a phenylalanine at position 37; f) a phenylalanine at position 47; g) an arginine at position 87; h) a glutamic acid at position 89; and i) a leucine at position 120. The multimers used comprised at least 4 copies of antibody variable domains (that are capable of inhibiting the binding of the VHH GB to omicron spike). Methods Pseudovirus neutralization assay [00946] Genes for expressing the original Wuhan spike and the D614G, Alpha, Delta and Omicron variants were generated by gene synthesis. Pseudotype viruses were prepared by transfecting HEK293T cells with a vector containing the spike gene and the viral vector containing HIV-1 gag-pol and GFP reporter gene using Fugene HD transfection reagent (Promega). Viral supernatants were collected 72 hours after transfection. After filtrating through 0.45um filter, the pseudotype viruses were used either directly in infection assay with HEK293T target cells stably expressing ACE2 and TMPRSS2 or stored at -80C. Infectivity of target cells was performed using 1/10 fold diluted psuedotype virus, which were added to 96-well plate containing 30,000 cells/well to determine 100% infection. For the neutralizing activity of GB-based Quads, the pseudotyped virus were incubated with titrating amounts of GB-Quad protein for 30-60 minutes prior to adding to target cells. The number of target cells expressing GFP was measured using CytoFLEX flow cytometer and the percentage of neutralization of the GB-based quads were calculated by normalising GFP expression to wells containing psedotype virus and cell only controls. Non-linear regression analysis was performed within GraphPad Prism to determine IC50 values. Example 42: Multimer Formats Displaying Neutralization of SARS-CoV-2 [00947] Several Quad multimers were made based on antibody variable domains that specifically bind to anti-SARS-CoV-2 spike. These were formatted into polypeptides with tetramerization domains (TD) to produce the following polypeptides:- (a) V-TD (b) V-CH2-CH3-TD (c) V-CH1-CH2-CH3-TD (d) V-CH1-TD (e) V-V-TD (f) V-V-CH2-CH3-TD (g) V-V-TD (h) V1-V2-TD (i) V1-V2-CH2-CH3-TD (j) V1-V2-TD (k) V-V-CH1-TD (l) V-V-TD-V (m) V-V-TD-V-V (n) V-V-TD-V (o) V-V-TD-V-V (p) V-V-CH1-TD-V-V (q) V-V-CH1-CH2-CH3-TD (r) V1-V2-CH1-CH2-CH3-TD [00948] When the multimer comprised copies of polypeptide (c), (d) or (p), each said polypeptide was paired with a respective copy of a second polypeptide, wherein each second polypeptide comprised (in N- to C-terminal direction) V-CL, wherein the CL is paired with CH1 of the respective first polypeptide. [00949] When the multimer comprised copies of polypeptide (k) or (q), each said polypeptide was paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V-V-CL, wherein the CL is paired with CH1 of the respective first polypeptide; [00950] When the multimer comprised copies of polypeptide (r), each said polypeptide was paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V1-V2-CL, wherein the CL is paired with CH1 of the respective first polypeptide; [00951] V1 and V2 were different variable domains and capable of specifically binding to SARS-CoV-2 omicron spike. Results: [00952] Neutralization capacity of the each multimer was tested against several different SARS-CoV-2 strains: SARS-CoV-2 D614G, omicron, alpha, beta and delta. It was surprisingly found that these multimers were capable of neturalizing SARS-CoV-2 omicron in a virus neutralization assay. Moreover, neutralization was surprisingly found to be potent (neutralization in a virus neutralization assay with an IC50 of <50 ng/mL). Advantageously, neutralization of multiple strains SARS-Cov-2, including SARS-CoV-2 D614G, omicron, alpha, beta and delta was observed. Also surprisingly, neutralization of SARS-Cov-1 and SHC01 was observed. Example 43: Exemplary Virus Neutralisation Assay [00953] An example of a suitable neutralization assay for use herein is as follows: viruses (eg, SARS-CoV-2 omicron viruses expressing green fluorescent protein (GFP)) are pre-incubated with titrating amounts of the multimer (serially diluted 1 in 4 fold from 50 nM to 0.01 nM) for 30-60 minutes (eg, 45 minutes) at 37 degrees centigrade prior to adding to human target cells (50,000 cells/well). 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TABLES ll of Tables 1-37 herein are indentical to Tables 1-37 respectively of WO2021/190980, which Tables of WO2021/190980 in their entirety are expressly incorporated herein. Sequences A-NN are described in Tables A & E herein. All other sequences herein are indentical to the respective sequences of WO2021/190980, which sequences of WO2021/190980 in their entirety are expressly incorporated herein. Table A: Amino acid sequences of Novel VH Single Variable Domains SEQ ID: Name AMINO ACID SEQUENCE
Figure imgf000311_0001
(Version LQMNSLRAEDTAVYYCAAAGLGTVVSEWDYDYDYWGQGTL 7 VH) VTVSS
Figure imgf000312_0001
Table B: Regdavimab (REGKIRONA™) Amino Acid Sequences In an example, a variable domain herein is a variable domain (eg, VH or VL) of regdanvimab or REGKINORA™. In an example, a binding site or binding domain herein is a binding site or binding domain (eg, VH/VL pair) of regdanvimab or REGKINORA™. In an example, an antibody herein (that can be used to make multimers of the invention) is regdanvimab or REGKINORA™. Heavy Chain (SEQ ID: M) QITLKESGPTLVKPTQTLTLTCSFSGFSLSTSGVGVGWIRQPPGKALEWLALIDWDDNKYHTT SLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIPGFLRYRNRYYYYGMDVWGQGTT VTVSS Light Chain (SEQ ID: N) ELVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFS GSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAGVFGGGTELTVL VH Domain (SEQ ID: O) QITLKESGPTLVKPTQTLTLTCSFSGFSLSTSGVGVGWIRQPPGKALEWLALIDWDDNKYHTT SLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIPGFLRYRNRYYYYGMDVWGQGTT VTVSS VL Domain (SEQ ID: P) ELVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFS GSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAGVFGGGTELTVL In an alternative herein, instead of using SEQ ID: O, there is used an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: O. In an alternative herein, instead of using SEQ ID: P, there is used an amino acid sequence that is at least 80, 85, 90, 95, 96, 97, 98 or 99% identical to SEQ ID: P. In an alternative herein, instead of using SEQ ID: O, there is used an amino acid sequence that is identical to SEQ ID: O except for 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 change (eg, change(s) outside CDR3). In an alternative herein, instead of using SEQ ID: P, there is used an amino acid sequence that is identical to SEQ ID: P except for 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 change (eg, change(s) outside CDR3). Table C. Amino Acid sequence of Hu-Q179F and Hu-Q185E Monomers The monomers self-tetramerise to produce Hu-Q179F and Hu-Q185E multimers respectively. SEQ ID: H 179F EV LLESGGGLV PGGSLRLSCAASGRTFSEYAMGWFR APGKGLEF
Figure imgf000314_0001
Table D Sequence ID: U (GB domain) QVQLQESGGGLVQAGGSLRLSCAASGRTFSEYAMGWFRQAPGKEREFVATISWSGGSTYYT DSVKGRFTISRDNAKNTVYLQMNSLKPDDTAVYYCAAAGLGTVVSEWDYDYDYWGQGTQ VTVSS Sequence ID: V EVQLVESGGGLVQPGGSLRLSCAASGRTFSEYAMGWFRQAPGKEREFVATISWSGGSTYYT DSVKGRFTISRDNAKNTVYLQMNSLRPADTAVYYCAAAGLGTVVSEWDYDYDYWGQGTL VTVSS Table E: Sequence Correlation Table SEQ ID: SEQ ID NO: SEQUENCE A 1 SEE TABLE A B 2 SEE TABLE A C 3 SEE TABLE A D 4 SEE TABLE A E 5 SEE TABLE A F 6 SEE TABLE A G 7 SEE TABLE A H 8 SEE TABLE A I 9 SEE TABLE A J 10 SEE TABLE A K 11 SEE TABLE A L 12 SEE TABLE A M 13 SEE TABLE B N 14 SEE TABLE B O 15 SEE TABLE B P 16 SEE TABLE B Q 17 SEE TABLE C R 18 SEE TABLE C S 19 SEE TABLE A T 20 SEE TABLE A U 21 SEE TABLE D V 22 SEE TABLE D W 23 EVQLLESGGGLVQP X 24 EVQLLESGGGLVQPGGSLRLSCAAS Z 25 GRTFSEYAMS AA 26 GRTFSEYAMG BB 27 WFRQAP CC 28 GLEFVS DD 29 AISW EE 30 TYYA FF 31 AISWSGGSTY GG 32 RAEDTAVYYCA HH 33 YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA II 34 AAGLGTVVSEWDYDYDYW JJ 35 GQGTLVTVSS KK 36 TISW LL 37 YADSV MM 38 YTDSV NN 39 YTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA SEQ IDs: 1*1 to 1*307 are identical to SEQ IDs: 1 to 307 respectively as written in WO2021/190980, which sequences of WO2021/190980 in their entirety are expressly incorporated herein.      Table F: Polypeptide Formats of Multimers that Neutralize Multiple SARS-CoV-2 Strains, including Omicron First Figure No in
Figure imgf000316_0001
Figure imgf000317_0001

Claims

CLAIMS:
1. A multimer of a first antibody variable domain for use as a medicament in a method for treating humans against multiple different strains of SARS-CoV-2, wherein the multimer is capable of inhibiting infection of human cells by SARS-CoV-2 omicron and the first variable domain is capable of inhibiting the binding of a second antibody variable domain to SARS-CoV-2 omicron spike, wherein the second domain comprises the amino acid sequence of SEQ ID: U; and wherein said strains comprise SARS-CoV-2 omicron.
2. The multimer of Claim 1, wherein the multimer comprises 4 copies of the first variable domain, and optionally the multimer comprises no more than 4, 8 or 16 copies of said first domain.
3. The multimer of Claim 1 or 2, wherein the multimer comprises a plurality of copies of a polypeptide, wherein the polypeptide comprises at least one (preferably 2) copy(ies) of the variable domain and an antibody Fc region.
4. The multimer of Claim 3, wherein the polypeptide comprises in N- to C-terminal direction: V-V-Fc, wherein V is the first variable domain.
5. The multimer of any preceding Claim, wherein the first variable domain is capable of inhibiting the binding of the second antibody variable domain with SARS-CoV-2 omicron spike as determined by a surface plasmon resonance (SPR) or ELISA competition assay.
6. A multimer of comprising 4 copies of a first polypeptide for use as a medicament in a method for treating humans against multiple different strains of SARS-CoV-2, wherein said strains comprise SARS-CoV-2 omicron, the multimer being capable of inhibiting infection of human cells by SARS-CoV-2 omicron, wherein the first polypeptide is according to any one of (a)-(r),
(a) V-TD
(b) V-CH2-CH3-TD
(c) V-CH 1 -CH2-CH3 -TD
(d) V-CH1-TD
(e) V-V-TD
(f) V V CH2 CH3 TD (h) V1-V2-TD
V 1 -V2-CH2-CH3-TD
CD V1-V2-TD
(k) V-V-CH1-TD
(D V-V-TD-V
(m) V-V-TD-V-V
(n) V-V-TD-V
(o) V-V-TD-V-V
(P) V-V-CH1-TD-V-V
(q) V-V-CH 1 -CH2-CH3 -TD
(r) V 1 -V2-CH 1 -CH2-CH3-TD wherein
(s) when the multimer comprises copies of first polypeptide (c), (d) or (p), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V-CL, wherein the CL is paired with CHI of the respective first polypeptide;
(t) when the multimer comprises copies of first polypeptide (k) or (q), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V-V-CL, wherein the CL is paired with CHI of the respective first polypeptide;
(u) when the multimer comprises copies of first polypeptide (r), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V1-V2-CL, wherein the CL is paired with CHI of the respective first polypeptide;
(v) each V is an antibody variable domain that is capable of specifically binding to an antigen; and VI and V2 are different variable domains and capable of specifically binding to different antigens or epitopes;
(w) each V or VI is a variable domain as recited in claim 1; and
(x) TD is a self-associating tetramerisation domain.
7. A multimer of comprising 4 copies of a first polypeptide for treating or preventing a SARS- CoV-2 omicron infection in a human or animal, wherein the first polypeptide is according to any one of (a)-(r),
(a) V-TD
(b) V-CH2-CH3-TD
(c) V-CH 1 -CH2-CH3 -TD
(d) V-CH1-TD
(e) V-V-TD
(f) V-V-CH2-CH3-TD
(g) V-V-TD
(h) VI-V2-TD
V I -V2-CH2-CH3-TD
CD V1-V2-TD
(k) V-V-CH1-TD
(l) V-V-TD-V
(m) V-V-TD-V-V
(n) V-V-TD-V
(o) V-V-TD-V-V (P) V-V-CH1-TD-V-V
(q) V-V-CH 1 -CH2-CH3 -TD
(r) V 1 -V2-CH 1 -CH2-CH3-TD wherein
(s) when the multimer comprises copies of first polypeptide (c), (d) or (p), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V-CL, wherein the CL is paired with CHI of the respective first polypeptide;
(t) when the multimer comprises copies of first polypeptide (k) or (q), each said first polypeptide is paired with a respective copy of a second polypeptide, wherein each second polypeptide comprises (in N- to C-terminal direction) V-V-CL, wherein the CL is paired with CHI of the respective first polypeptide;
(u) when the multimer comprises copies of first polypeptide (r), each said first polypeptide is comprises (in N- to C-terminal direction) V1-V2-CL, wherein the CL is paired with CHI of the respective first polypeptide;
(v) each V is an antibody variable domain (eg, an antibody single variable domain) that is capable of specifically binding to an antigen; and VI and V2 are different variable domains and capable of specifically binding to different antigens or epitopes;
(w) each V or VI is a variable domain as recited in claim 1; and
(x) TD is a self-associating tetramerisation domain.
8. The multimer of any preceding Claim, wherein said first domain, V, VI or V2 is an anti- SARS-CoV-2 omicron spike variable domain comprising an amino acid sequence selected from SEQ IDs: I, A-H, J-L and S-V (preferably I or V) or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences.
9. The multimer of any preceding Claim, wherein a) the multimer is capable of inhibiting infection of human HEK293 cells by SARS-CoV-2 omicron virus or pseudovirus comprising omicron spike in a virus neutralisation assay with an IC50 <0.1 nM (preferably <0.02 nM) and/or the method comprises administering the multimer to a human subject or human subjects and inhibiting infection of human cells of the subject(s) by SARS-CoV-2 virus with an IC50 <0.1 nM (preferably <0.02 nM), optionally wherein the virus is SARS-CoV-2 omicron or a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron; or b) the multimer is capable of inhibiting infection of human HEK293 cells by SARS-CoV-2 omicron virus or pseudovirus comprising omicron spike in a virus neutralisation assay with an IC50 <500ng/mL (preferably <50 ng/mL) and/or the method comprises administering the multimer to a human subject or human subjects and inhibiting infection of human cells of the subject(s) by SARS-CoV-2 virus with an IC50 <500ng/mL (preferably <50 ng/mL), optionally wherein the virus is SARS-CoV-2 omicron or a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron.
10. The multimer of any one of Claims 1-7 or 8-9 when dependent from any one of Claims 1-7, wherein said strains comprise one or more virus strains selected from delta, alpha, the L strain strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron.
11. The multimer of any one of Claims 1-7 or 8-9 when dependent from any one of Claims 1-7, wherein said strains comprise SARS-CoV-2 delta and optionally a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron.
12. An antibody variable domain for use as the first domain, V, VI or V2 of the multimer of any preceding Claim, wherein the domain comprises an amino acid sequence selected from SEQ IDs: I, A-H, J-L, S, T and V (preferably I), or an amino acid sequence that is identical to a said selected sequence except for 1-25 amino acid differences, wherein the variable domain is capable of inhibiting the binding of a second antibody variable domain to SARS-CoV-2 omicron spike, wherein the second domain comprises the amino acid sequence of SEQ ID: U.
13. The variable domain of Claim 12, wherein the variable domain is capable of inhibiting the binding of the second antibody variable domain to a SARS-CoV-2 strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron.
14. The variable domain of Claim 12 or 13, wherein the amino acid sequence comprises
(a) a glutamic acid at position 1 ;
(b) a proline at position 14;
(c) an arginine at position 27;
(d) a glutamic acid at position 31;
(e) a phenylalanine at position 37;
(f) a phenylalanine at position 47;
(g) an arginine at position 87;
(h) a glutamic acid at position 89; and
(i) a leucine at position 120.
15. The multimer or variable domain of any preceding Claim for treating a human subject against SARS-CoV-2 omicron or a virus strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS CoV 2 omicron.
16. The multimer or variable domain of any preceding Claim, wherein the treating is therapeutically or prophylactically treating.
17. The multimer of Claim 8 or any one of Claims 15-16 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 13-16 when dependent from Claim 13, wherein said number of differences is from 1 to 14; optionally no more than 7 or 8.
18. The multimer of Claim 8 or any one of Claims 15-17 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 13-17 when dependent from Claim 12, wherein there is no said difference at the amino acid corresponding to position 35 and/or 50 of the selected sequence; and/or wherein there is a said difference at the amino acid position corresponding to position 61 of the selected sequence.
19. The multimer of Claim 8 or any one of Claims 15-18 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 13-18 when dependent from Claim 12, wherein
(a) the amino acid corresponding to position 61 of the selected sequence is an amino acid other than a threonine, optionally wherein the amino acid is an alanine; or
(b) the amino acid corresponding to position 61 of the selected sequence is a threonine.
20. The multimer of Claim 8 or any one of Claims 15-19 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 12-19 when dependent from Claim 12, wherein
(a) the amino acid corresponding to position 35 of the selected sequence is a serine or the amino acid corresponding to position 50 of the selected sequence is an alanine; or
(b) the amino acid corresponding to position 35 of the selected sequence is a glycine or the amino acid corresponding to position 50 of the selected sequence is a threonine.
21. The multimer of Claim 8 or any one of Claims 15-20 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 13-20 when dependent from Claim 12, wherein the amino acid corresponding to position 37 of the selected sequence is a phenylalanine and/or the amino acid corresponding to position 47 of the selected sequence is a phlenylalanine
22. The multimer of Claim 8 or any one of Claims 15-21 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 13-21 when dependent from Claim 12, wherein the amino acid sequence of the variable domain comprises
(a) one or more amino acids selected from a glutamic acid at a position corresponding to position 1 of the selected sequence, a leucine at a position corresponding to position 5 of the selected sequence and a proline at a position corresponding to position 14 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids;
(b) a serine or glycine at a position corresponding to position 35 of the selected sequence;
(c) one or more amino acids selected from a glycine at a position corresponding to position 44 of the selected sequence, a leucine at a position corresponding to position 45 of the selected sequence and a serine at a position corresponding to position 49 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids
(d) one or more amino acids selected from a serine at a position corresponding to position 75 of the selected sequence, a leucine at a position corresponding to position 79 of the selected sequence, an arginine at a position corresponding to position 87 of the selected sequence, an alanine at a position corresponding to position 88 of the selected sequence and a glutamic acid at a position corresponding to position 89 of the selected sequence, optionally wherein the amino acid sequence comprises all of said amino acids; and/or
(e) a leucine at a position corresponding to position 120 of the selected sequence.
23. The multimer or antibody variable domain of Claim 22, wherein the amino acid of the variable domain comprises residues
(f) all of the amino acids according to claim 22(a), (c), (d) and (e); and
(g) an amino acid according to claim 22(b).
24. The multimer of Claim 8 or any one of Claims 15-23 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 13-23 when dependent from Claim 12, wherein the amino acid of the variable domain comprises
(a) an arginine or phenylalanine at a position corresponding to position 27 of the selected sequence;
(b) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and/or
(c) an alanine or serine at a position corresponding to position 49 of the selected sequence.
25. The multimer of Claim 8 or any one of Claims 15-24 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 13-24 when dependent from Claim 12, wherein the amino acid of the variable domain comprises
A:
(a) an arginine at a position corresponding to position 27 of the selected sequence;
(b) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and
(c) a serine at a position corresponding to position 49 of the selected sequence; or
B:
(d) a phenylalanine at a position corresponding to position 27 of the selected sequence;
(e) a glutamic acid or serine at a position corresponding to position 31 of the selected sequence; and
(f) a serine at a position corresponding to position 49 of the selected sequence.
26. The multimer of Claim 8 or any one of Claims 15-24 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 12-25 when dependent from Claim 12, wherein the amino acid of the variable domain comprises
(a) a phenylalanine at a position corresponding to position 27 of the selected sequence;
(b) a serine at a position corresponding to position 31 of the selected sequence; and/or
(c) a glycine at a position corresponding to position 53 of the selected sequence.
27. The multimer of Claim 8 or any one of Claims 15-26 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 13-26 when dependent from Claim 12, wherein framework 1 (FR1) of the variable domain comprises at the N-terminal end of FR1, the amino acid sequence EVQLLESGGGLVQP (SEQ ID: W) or EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID: X).
28. The multimer of Claim 8 or any one of Claims 15-27 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 13-27 when dependent from Claim 12, wherein at least one of said differences (or optionally each of the differences) is a substitution of an amino acid of said selected sequence for the amino acid found at the corresponding position of the amino acid sequence of human germline gene segment IGHV3- 23 (optionally IGHV3-23*01 or IGHV3-23*04).
29. The multimer of Claim 8 or any one of Claims 15-28 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 13-28 when dependent from Claim 12, wherein each of said differences is in the FR1, complementarity determining region 1 (CDR1), FR2, CDR2, FR3 or FR4.
30. The multimer of Claim 8 or any one of Claims 15-29 when dependent from Claim 8, or the antibody variable domain of Claim 12 or of any one of Claims 13-29 when dependent from Claim 12, wherein each said difference is an amino acid substitution.
31. The multimer or antibody variable domain of any preceding Claim, wherein the first variable domain, V, VI or V2 comprises an amino acid sequence that comprises one or more sequence motifs selected from
(a) EVQLLESGGGLVQP (SEQ ID: W) at the N-terminal end of FR1 or EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID: X) in FR1;
(b) GRTFSEYAMS (SEQ ID: Z) or GRTFSEYAMG (SEQ ID: AA) in CDR1;
(c) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence and/or GLEFVS (SEQ ID: CC) in FR2 wherein the F in SEQ ID: CC is at a position that corresponds to position 47 in the selected sequence; or (ii) WFRQAPGKGLEFVS (SEQ ID: DD) in FR2;
(d) (i) AISW (SEQ ID: DD) at the N-terminal end of CDR2 and/or TYYA (SEQ ID: EE) at the C-terminal end of CDR2; or (ii) AISWSGGSTY (SEQ ID: FF) in CDR2;
(e) (i) YADSV (SEQ ID: LL) at the N-terminal end of FR3 and/or RAEDTAVYYCA (SEQ ID: GG) at the C-terminal end of FR3; or (ii) YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA (SEQ ID: HH) in FR3;
(f) AAGLGTVVSEWDYDYDYW (SEQ ID: II) in CDR3; and/or
(g) GQGTLVTVSS (SEQ ID: JJ) in FR4.
32. The multimer or antibody variable domain of any preceding Claim, wherein the first variable domain, V, VI or V2 comprises an amino acid sequence that comprises
(a) GRTFSEYAMG (SEQ ID: AA) in CDR1;
(b) (i) WFRQAP (SEQ ID: BB) in FR2 wherein the F in SEQ ID: BB is at a position that corresponds to position 37 in the selected sequence; and (c) AAGLGTVVSEWDYDYDYW (SEQ ID: II) in CDR3.
33. An isolated nucleic acid encoding a first variable domain of the multimer; V, VI or V2 of the multimer; the polypeptide of the multimer; or the antibody variable domain of any preceding Claim, optionally wherein the nucleic acid is comprised by an expression vector for expressing the variable domain or a polypeptide comprising the variable domain.
34. A pharmaceutical composition comprising the multimer or variable domain of any one of Claims 1-32, and a pharmaceutically acceptable diluent, carrier or excipient.
35. A method of treating a human for a SARS-CoV-2 virus infection, wherein the infection is an infection of SARS-CoV-2 delta or omicron; or a virus whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome omicron, wherein the method comprises administering (optionally by injection or inhalation) the pharmaceutical composition of claim 34.
36. A polypeptide comprising the amino acid sequence of an antibody variable domain of any one of Claims 12-32 and one or more further amino acid sequences, optionally wherein the polypeptide comprises a self-assembly multimerization domain (SAM domain), eg, a p53 domain and/or an Fc region.
37. The polypeptide of Claim 36, comprising at least 2 copies of the amino acid sequence of the variable domain, and optionally an amino acid sequence encoding an ACE2 peptide (eg, an ACE2 extracellular domain).
38. A tetramer of polypeptides of Claim 36 or 37, wherein each polypeptide comprises a selfassembly multimerization domain (SAM domain), eg, a p53 domain.
39. A medical device (eg, a syringe, inhaler or IV bag) comprising the composition of Claim 34 or the tetramer of claim 38.
40. A method of treating or preventing a coronavirus virus (eg, SARS-CoV-2, SARS-CoV-1 or beta-coronavirus) infection in a human or animal subject or a symptom thereof (eg, an immune or inflammatory response), the method comprising administering the composition of Claim 34 or the tetramer of claim 38 to the subject.
41. Use of the multimer, variable domain, composition or tetramer of any one of Claims 1-32, 34 and 38 in the manufacture of a medicament for administration to a human or animal subject for treating or preventing a coronavirus virus (eg, SARS-CoV-2, SARS-CoV-1 or beta- coronavirus) infection in a human or animal subject or a symptom thereof (eg, an immune or inflammatory response).
42. A method of detecting the presence of a virus in a sample (eg, a biological sample), the method comprising contacting the multimer, variable domain, composition or tetramer of any one of Claims 1-32, 34 and 38 with the sample and detecting virus or virus spike protein is bound to the variable domain, multimer or tetramer.
43. A method of isolating a multimer of any of Claims 1-11 and 15-32 from a sample comprising the multimer, the method comprising contacting the sample with a solid support (eg, a gel, resin or bead), wherein protein A is immobilised on the solid support prior to said contacting and the multimer is bound by protein A, optionally further comprising separating the bound multimer from the protein A.
44. The method of claim 43, wherein the multimer comprises 4 copies of a human IGHV3 variable domain.
45. A multimer of a first antibody variable domain for use as a medicament to beat or prevent the infection of a human by the omicron strain of SARS-CoV-2 or a SARS-CoV-2 strain whose genome comprises up to 65 changes in the nucleotide sequence (S) that encodes spike compared to the genome of SARS-CoV-2 omicron, wherein the multimer is capable of inhibiting infection of human cells by SARS-CoV-2 omicron and the first variable domain is capable of inhibiting the binding of a second antibody variable domain to SARS-CoV-2 omicron spike, wherein the second domain comprises the amino acid sequence of SEQ ID: U.
46. The multimer of Claim 45, wherein the multimer comprises 4 copies of the first variable domain, and optionally the multimer comprises no more than 4, 8 or 16 copies of said first domain.
47. A multimer according to Claim 45 or 46, wherein the first variable domain is according to any one of Claims 12-32.
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