Bispecific antigen binding protein with fviii mimetic activity

Abstract

The present invention relates to FVIII mimetic antigen binding proteins. The present invention also relates to polynucleotides comprising a nucleotide sequence encoding an FVIII mimetic antigen binding protein, viral particles comprising the polynucleotides and treatments utilising the antigen binding proteins and polynucleotides.

Description

[0001]ANTIGEN BINDING PROTEIN Field of the Invention The present invention relates to antigen binding proteins. The present invention also relates to polynucleotides comprising a nucleotide sequence encoding an antigen binding protein, viral particles comprising said polynucleotide and treatments utilising said antigen binding protein and polynucleotide. Background to the Invention Coagulation Factor VIII (FVIII) is a critical cofactor of the coagulation cascade, promoting the catalytic conversion of Factor X (FX) into activated FX (FXa) by forming a complex with activated Factor IX (FIXa) and FX. In Haemophilia A (an X-linked monogenic disorder with a prevalence of 1 in 5,000 male births) the quantitative of function deficiency in FVIII disrupts the coagulation cascade, therefore leading to life- threatening, spontaneous bleeding diathesis. FVIII replacement, the standard of care treatment, requires frequent intravenous infusions of FVIII. However approximately 30% of treated patients develop anti-FVIII neutralizing antibodies, rendering FVIII replacement inefficient and significantly reducing life expectancy. The development of FVIII mimetic antibodies with emicizumab, a bispecific antibody approved in late 2017, has provided with an alternative option for patient with inhibitors. Indeed, FVIII mimetic antibodies are a class of non-FVIII based therapies which work by simultaneously binding coagulation FIXa and FX to promote the catalytic conversion of FX into activated FXa via FIXa, therefore replacing one of the pivotal functions of FVIII to sustain thrombin generation and clot formation. The recent approval of gene therapy for haemophilia A (HA) using adeno- associated viruses (AAVs) marks an important and long-awaited landmark in the development of therapeutic strategies for HA as it represents the promise of a cure, being associated with markedly reduced bleeding events whilst overcoming the demands of regular life-long administration of factor concentrates or antibodies with FVIII mimetic activity. However, the benefits of AAV gene therapy in severely affected HA patients are likely to be short-lived as clinical data from most advanced trials show a gradual decline in transgenic FVIII levels over time. The reasons for this decline in expression remain unexplained. Therefore, there is a need for improved therapeutic options for the treatment of HA, including gene therapy approaches. Summary of the Invention The inventors hypothesised that the gradual decline in transgenic FVIII levels over time seen in recent gene therapy clinical trials using AAV viral vectors, was due to the use of oversized transgenic FVIII expression cassettes reaching the packaging limits of the viral capsids used to design these AAV vectors. Their hypothesis was supported by the fact that such decline in transgene expression has not been observed in other gene therapy approaches in clinic where the transgene expression cassette is within the packaging limits of AAV capsids. In view of deficiencies in current treatments, the inventors have developed a single chain FVIII mimetic antigen binding protein (Bi8) for use in the treatment of diseases such as HA. The antigen binding protein of the invention displays FVIII mimetic activity, successfully enhances the FIXa mediated catalytic activation of FX, and displays activity fully capable of correcting the FVIII deficiency of haemophilia A plasma. The inventors then developed an improved gene therapy approach for HA that utilises the therapeutic potential of bispecific FVIII mimetics with an expression cassette encoding a single chain FVIII mimetic antigen binding protein that remains within the packaging constrains of the viral capsids used to design therapeutic AAV vectors. This approach provides an innovative solution to improve the prospects of long-term control of the bleeding diathesis in severely affected HA patients. The present invention describes an innovative strategy of gene therapy using adeno-associated viruses (AAVs) vectors to express stable transgenic expression of a coagulation Factor VIII (FVIII) mimetic antigen binding protein for the treatment of haemophilia A patients. This therapeutic approach relies on Bi8, a novel FVIII mimetic antigen binding protein designed as a tandem of single chain Fragments variable (scFvs) fused together to produce a single chain bispecific antibody. This molecular format is smaller and less complex than traditional antibodies and therefore particularly adapted to the small size of transgenic expression cassettes required for the development of AAV- based vector for gene therapy. This novel therapeutic strategy addresses current limitations in the development of AAV-based gene therapies for haemophilia A, where the large size of the human coagulation FVIII coding sequence has led to the use of oversized transgenic expression cassettes with minimal regulatory elements, which could be responsible for the progressive decline in transgene expression observed in patients enrolled in the latest trials. In addition, this non-FVIII based strategy can also provide a gene therapy solution for patients with FVIII neutralising antibodies who receive treatment with FVIII bypassing agents but are ineligible to the current gene therapy products for haemophilia A. Proof-of-concept was established in vitro to demonstrate the FVIII mimetic potential of the single chain bispecific antibody format used to design Bi8, and its ability to correct the clotting disorders in haemophilia A plasma. An AAV vector, using a liver specific transgenic expression cassette with the coding sequence of Bi8, was used to demonstrate the stable transgenic expression of the FVIII mimetic antibody and its therapeutic potential in a model of haemophilia A mice. Accordingly, in a first aspect of the invention, there is provided an antigen binding protein with FVIII mimetic activity composed of a single polypeptide chain. The invention also provides an antigen binding protein composed of a single polypeptide chain, wherein the single polypeptide chain is composed of a first antigen binding domain and a second binding domain, wherein the first antigen binding domain selectively binds coagulation FIX and second binding domain selectively binds coagulation FX, and wherein the first antigen binding domain and second binding domain each comprise a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises a light chain complementarity determining region (LCDR)1, an LCDR2 and an LCDR3, and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3; wherein the first antigen binding domain selectively binds coagulation FIX; and wherein for the second antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 7; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 9; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 10; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 11; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 12. The invention also provides a polynucleotide of no more than 5.0 kb in length comprising a nucleic acid sequence encoding the antigen binding protein as defined herein. The invention also provides a viral particle comprising the polynucleotide as defined herein. The invention also provides a composition comprising the antigen binding protein, polynucleotide or viral particle as described herein and a pharmaceutically acceptable excipient. The invention also provides an isolated host cell transformed with the polynucleotide or viral particle as defined herein. The invention also provides the antigen binding protein, polynucleotide, viral particle or composition as defined herein for use in a method of treatment. The invention also provides an AAV genome comprising a polynucleotide encoding a FVIII mimetic antigen binding protein for use in a method of gene therapy. Description of the Figures Figure 1: Design of a single chain FVIII mimetic antibody Bi8 was engineered as a single chain FVIII mimetic antibody using the format of a bispecific tandem of single chain Fragment variables (scFvs). Two scFvs targeting human coagulation FIX and FX were fused together by a flexible linker composed of Glycine – Serine repeats. A 6x Histidine motif was added in C-terminus as a tag for detection. Figure 2: Size profile of recombinant Bi8 by SDS-Page Recombinant Bi8 antibody (recBi8) was produced in mammalian cells and purified by affinity chromatography. The resulting material was analysed by SDS-Page gel stained with Coomassie blue in reducing and non-reducing condition showing a single discrete band at 54.5 kDa. Figure 3: FVIII mimetic activity of recBi8 in vitro The FVIII mimetic activity of recBi8 was evaluated in a kinetic chromogenic assay, which measure the antibody-enhanced conversion of FX into FXa by FIXa, and benchmarked against the marketed FVIII mimetic antibody emicizumab at equivalent molar concentration (40nM). Symbols indicate the mean OD value ±SEM of n=5 replicates. Control condition was performed in absence of antibody. Figure 4: Procoagulant potential of recBi8 in an activated Partial Thromboplastin Time The efficacy of recBi8 to correct the clotting defect of human haemophilia A plasma was measured in vitro. A pool of citrated normal human plasma was spiked with 200 Bethesda Units (BU) of anti-FVIII antibody to neutralise endogenous FVIII. This induced haemophilia A plasma was then spiked with 350nM of recBi8 and activated Partial Thromboplastin Time (aPTT) was measured using a silica-based trigger. Symbols represent individual clotting times values and lines indicate the mean ±SD of three replicates. **** means statistical significance with p<0.0001 in a one-way ANOVA test with Sidak’s multiple comparisons. Figure 5: Thrombin generation profile of recBi8 in haemophilia A plasma The kinetic of thrombin formation was evaluated in a thrombin generation assay. A pool of citrated normal human plasma was spiked with 200BU of anti-FVIII antibody to neutralise endogenous FVIII and further spiked with 350nM of recBi8. Thrombin generation was then trigger with a FXIa based trigger and measured in the Calibrated Automated Thrombogram (CAT) method. (A) Curves represent the average thrombogram profile for each condition in a 60min reading frame. (B) Time to peak (time to maximal thrombin generation) and endogenous thrombin potential (ETP) were extracted from the thrombogram and plotted as individual values (symbols) and mean of 4 independent replicates. ns means non-significant in a one-way ANOVA test with Sidak’s multiple comparisons. Figure 6: Design of a liver specific expression cassette encoding Bi8 for AAV vectors The cDNA sequence encoding Bi8 was cloned downstream of the hepatic control region enhancer and human alpha-1 anti-trypsin promoter (HCR-hAAT) to drive a strong liver specific expression of the transgene. (A) This expression cassette was further inserted between the Inverted Terminal Repeat (ITR) sequences of AAV serotype 2 to generate a 4.4 kb single-stranded viral transgene construct. (B) AAV vector encoding Bi8 (AAV_Bi8) were produced with the capsid of AAV8 and migrated on an alkaline gel to evaluate the integrity of the packaged transgenic DNA. Controls were performed with AAV8 vectors produced with transgene cassettes of 5.1 (high) and 4.3 (low) kbases respectively. Figure 7: Transduction and expression of AAV_Bi8 in vitro The expression and activity of Bi8 was evaluated following AAV-mediated transduction of the human hepatocyte cell line HuH7. AAV vector encoding Bi8 (AAV_Bi8) were produced with a capsid serotype of AAV8 and Huh7 cells were transduced with various multiplicity of infection (MOI) ranging from 103to 5x106vg / cells. (A) Transgenic expression of Bi8 was measure by ELISA in the cell culture supernatant 48h post infection. Symbols represent the mean ±SD of three replicates, and the dashed area indicates the lower limit of quantification. (B) The FVIII mimetic activity of AAV-derived Bi8 was evaluated in the chromogenic assay on crude supernatant samples from the highest MOI, and activity over antigen ratio was normalised to recombinant Bi8 (recBi8). Symbols are individual values and whisker plots represent the median and 25 / 75 quartiles. ns means non-significant in a non-parametric Mann-Whitney statistical assay. Figure 8: Characterisation of AAV_Bi8 vectors in a model of haemophilia A mice AAV vectors encoding the sequence of Bi8 were evaluated in vivo using a model of haemophilia A mice. A single intravenous injection in the lateral tail vein was performed with purified AAV vectors. Animals were monitored for up to 8 weeks, to evaluate expression and stability of the transgenic constructs. The procoagulant efficacy of Bi8 following AAV-mediated gene transfer was further challenged in a tail vein transection bleeding model. AAV treated mice were injected with a bolus dose of human FIX and FX and the tail vein transection was performed 5min later. Blood loss was recorded for a period of 45min post transection. Figure 9: Stable expression of Bi8 in AAV transduced animals Haemophilia A mice received a single intravenous injection of AAV_Bi8 vectors with either 4e11or 4e12vg / kg and blood draws were performed every 2 weeks. (A) Expression levels of Bi8 post infusion of AAV vectors were then measured by ELISA in plasma samples. Symbols are the mean ±SD of n=4 animals. (B) The presence anti-drug antibodies (ADAs) against Bi8 was further assessed in the plasma of AAV treated animals at 8 weeks post- infusion using a dedicated ELISA setting. Positive controls were performed by spiking plasma samples with know concentrations of a monoclonal antibody against the 6xHistidin tag of Bi8. Symbols represent the mean ±SD of 3 replicate (positive controls) or individual animals. N.D. means non-detectable and dashed area represent the lower limit of quantification in this assay. Figure 10: Therapeutic efficacy of AAV_Bi8 vectors in haemophilia A mice Haemophilia A mice received a single intravenous injection of AAV_Bi8 vectors with a dose of either 4e11, 4e12or 1.2e13vg / kg. (A) circulating plasma levels of Bi8 were then measured by ELISA at 2 weeks post-AAV infusion. Symbols represent values for individual animals and whisker plots show the median and 25 / 75 quartiles for each AAV dose. (B) The haemorrhagic phenotype of AAV-treated haemophilia A mice was then challenged in the tail vein transection model at 3 weeks post AAV infusion. Symbols represent the blood loss for each individual mice and whisker plots indicate the median and 25 / 75 quartiles for each condition. Dashed line shows of the median blood loss in non- treated haemophilia A mice. ** and **** mean statistical significance with p<0.01 and p<0.0001 respectively in a one-way ANOVA test with Sidak’s multiple comparisons. Figure 11: Half-life extension of the single chain antibody Bi8 A variant of Bi8 with extended half-life (HLE) was engineered with albumin binding capability to benefit from the FcRn recycling mechanism. A heavy chain only antibody fragment (VHH) derived from camelids and targeting human albumin was fused to the C- terminus of Bi8, downstream of the FX-targeting scFv, using a Serine – Glycine flexible linker. The 6x Histidine motif used for detection of the antibody was added in C-terminus of the albumin binding VHH. Figure 12: Characterisation of recombinant Bi8 - HLE Recombinant antibody variants for Bi8 and Bi8 – HLE were produced in mammalian cells and purified by affinity chromatography. (A) The resulting material was migrated on a SDS-Page gel stained with Coomassie blue and showed discrete bands at the expected sizes. (B) FVIII mimetic activity was further evaluated in the kinetic chromogenic assay using increasing concentrations from 0.63 to 40nM and expressed in FXa activity. Symbols indicate the mean ±SD of n=3 replicates. Control condition was performed in absence of antibody. Figure 13: AAV expression cassette encoding Bi8 – HLE (A) The cDNA sequence encoding Bi8 – HLE was cloned in the same liver-specific expression cassette used for Bi8, under the control of the (HCR-hAAT) promoter. The presence of the albumin binding VHH extended the total size of the cassette from 4.4 to 4.7 kbases. (B) AAV vectors encoding Bi8 or Bi8 - HLE were produced with the capsid serotype of AAV8, and integrity of the packaged transgenic DNA was evaluated by the alkaline gel method. Figure 14: Transduction of Huh7 cells with AAV vectors encoding Bi8 – HLE The expression and activity of Bi8 – HLE was evaluated following AAV-mediated transduction of the human hepatocyte cell line HuH7. Cells were transduced with AAV8 vectors coding for either Bi8 or Bi8 – HLE at 1x106vg / cells, and expression of the antibodies was measured by ELISA in the cell culture supernatant 48h post infection. Symbols represent individual values and bars are the mean ±SD of three replicates. ns means non-significant in a non-parametric Mann-Whitney statistical assay. Detailed Description General definitions Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this invention belongs. In general, the term “comprising” is intended to mean including but not limited to. For example, the phrase “a polynucleotide comprising a nucleic acid sequence encoding a first antigen binding domain” should be interpreted to mean that the polynucleotide has a nucleotide sequence encoding a first antigen binding domain, but the polynucleotide may contain additional nucleotides. In some embodiments of the invention, the word “comprising” is replaced with the phrase “consisting of”. The term “consisting of” is intended to be limiting. For example, the phrase “a polynucleotide consisting of a nucleic acid sequence encoding a first antigen binding domain” should be understood to mean that the polynucleotide has a nucleic acid sequence encoding a first antigen binding domain and no additional nucletides. The terms “protein” and “polypeptide” are used interchangeably herein, and are intended to refer to a polymeric chain of amino acids of any length. For the purpose of this invention, in order to determine the percent identity of two sequences (such as two polynucleotide or two polypeptide sequences), the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in a first sequence for optimal alignment with a second sequence). The nucleotide residues at nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide residue as the corresponding position in the second sequence, then the nucleotides are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions in the reference sequence x 100). Typically the sequence comparison is carried out over the length of the reference sequence. For example, if the user wished to determine whether a given (“test”) sequence is 95% identical to SEQ ID NO. 19, SEQ ID NO. 19 would be the reference sequence. For example, to assess whether a sequence is at least 80% identical to SEQ ID NO. 19 (an example of a reference sequence), the skilled person would carry out an alignment over the length of SEQ ID NO. 19, and identify how many positions in the test sequence were identical to those of SEQ ID NO. 19. If at least 80% of the positions are identical, the test sequence is at least 80% identical to SEQ ID NO. 19. If the sequence is shorter than SEQ ID NO. 19, the gaps or missing positions should be considered to be non-identical positions. The skilled person is aware of different computer programs that are available to determine the homology or identity between two sequences. For instance, a comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In an embodiment, the percent identity between two amino acid or nucleic acid sequences is determined using the Needleman and Wunsch (1970) algorithm which has been incorporated into the GAP program in the Accelrys GCG software package (available at http: / / www.accelrys.com / products / gcg / ), using either a Blosum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. For the purposes of the present invention, the term “fragment” refers to a contiguous portion of a sequence. For example, a fragment of SEQ ID NO. 19 of 50 amino acids refers to 50 contiguous amino acids of SEQ ID NO. 19. An antigen binding protein An antigen can be defined as a compound, composition, or substance that can stimulate the production of antibodies or a T cell response in an animal, including compositions that are injected or absorbed into an animal. An antigen reacts with the products of specific humoral or cellular immunity, including those induced by heterologous antigens, such as the disclosed antigens. "Epitope" or "antigenic determinant" refers to the region of an antigen to which B and / or T cells respond. In one embodiment, T cells respond to the epitope, when the epitope is presented in conjunction with an MHC molecule. Epitopes can be formed both from contiguous amino acids or non-contiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5, about 9, or about 8-10 amino acids in a unique spatial conformation. Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and nuclear magnetic resonance. Examples of antigens include, but are not limited to, peptides, lipids, polysaccharides, and nucleic acids containing antigenic determinants, such as those recognized by an immune cell. Antigens can include peptides derived from a pathogen of interest or from a cancerous cell. Exemplary pathogens include bacteria, fungi, viruses and parasites. In some preferred embodiments, the antigen is FIX or FX or antigenic fragments thereof. A “target epitope” is a specific epitope on an antigen that specifically binds an antibody of interest, such as a monoclonal antibody. In some examples, a target epitope includes the amino acid residues that contact the antibody of interest, such that the target epitope can be selected by the amino acid residues determined to be in contact with the antibody. In a preferred embodiment of the invention, the antigen binding protein comprises a first antigen binding domain, wherein the first antigen binding domain comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises a light chain complementarity determining region (LCDR)1, an LCDR2 and an LCDR3, and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3. The antigen binding proteins of the invention include antibodies. The antigen binding proteins of the invention include single chain antibodies (i.e. a full-length heavy chain and light chain); Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, Fab-Fv, Fab- dsFv, single domain antibodies (e.g. VH or VL or VHH), scFv, mono-, bi-, tri- or tetra- valent antibodies, scFv, Bis-scFv, single-domain antibodies (sdAbs), also known as VHH antibodies, nanobodies (Camelid-derived single-domain antibodies), shark IgNAR-derived single-domain antibody, diabodies, tribodies, triabodies, tetrabodies and epitope-binding fragments of any of the above (see for example Holliger P and Hudson PJ, 2005, Nat. Biotechnol., 23,: 1126-1136; Adair JR and Lawson ADG, 2005, Drug Design Reviews – Online, 2, 209-217). The methods for creating and manufacturing these antigen-binding proteins are well known in the art (see for example Verma R et al., 1998, J. Immunol. Methods, 216, 165-181). The Fab-Fv format was first disclosed in WO2009 / 040562 and the disulphide-stabilised versions thereof, the Fab-dsFv was first disclosed in WO2010 / 035012. Multi-valent antigen-binding proteins of the invention may comprise multiple specificities e.g. bispecific, or may be monospecific. The antigen binding proteins of the invention may be biparatopic. A scFv protein is a fusion protein in which a light chain variable region of an immunoglobulin and a heavy chain variable region of an immunoglobulin are bound by a linker, while in dsFvs, the chains have been mutated to introduce a disulfide bond to stabilize the association of the chains. The term also includes genetically engineered forms such as chimeric antibodies and heteroconjugate antibodies such as bispecific antibodies. See also, Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, IL); Kuby, Immunology, 3rdEd., W.H. Freeman & Co., New York, 1997. Antigen binding proteins of the invention include, but are not limited to, the following: (1) Fab, the fragment which contains a monovalent antigen-binding fragment of an antibody molecule produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain; (2) Fab', the fragment of an antibody molecule obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; two Fab' fragments are obtained per antibody molecule; (3) (Fab')2, the fragment of the antibody obtained by treating whole antibody with the enzyme pepsin without subsequent reduction; (4) F(ab')2, a dimer of two Fab' fragments held together by two disulfide bonds; (5) Fv, a genetically engineered fragment containing the variable region of the light chain and the variable region of the heavy chain expressed as two chains; and (6) single chain antibody (“SCA”), a genetically engineered molecule containing the variable region of the light chain, the variable region of the heavy chain, linked by a suitable polypeptide linker as a genetically fused single chain molecule. In an embodiment of the invention, the antigen binding protein may comprise heavy and light chain each containing a constant region and a variable region, (the regions are also known as “domains”). In several embodiments of the invention, the heavy and the light chain variable domains combine to specifically bind the antigen. In additional embodiments of the invention, only the heavy chain variable domain is required. For example, naturally occurring camelid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain (see, e.g., Hamers-Casterman et al., Nature, 363:446-448, 1993; Sheriff et al., Nat. Struct. Biol., 3:733-736, 1996). Light and heavy chain variable domains contain a “framework” region interrupted by three hypervariable regions, also called “complementarity-determining regions” or “CDRs” (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1991). The sequences of the framework regions of different light or heavy chains are relatively conserved within a species. The framework region of an antibody, that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs in three-dimensional space. The CDRs are primarily responsible for antigen binding. The sequences of the framework regions of different light or heavy chains are relatively conserved within a species. The framework region of an antibody, that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs in three- dimensional space. The CDRs of each chain are typically referred to as CDR1, CDR2, and CDR3 (from the N-terminus to C-terminus), and are also typically identified by the chain in which the particular CDR is located. Thus, a VHCDR3 is located in the variable domain of the heavy chain of the antibody in which it is found, whereas a VLCDR1 is the CDR1 from the variable domain of the light chain of the antibody in which it is found. Light chain CDRs can also be referred to as CDR L1, CDR L2 and CDR L3, or LCDR1, LCDR2 and LCDR3. Heavy chain CDRs can be referred to as CDR H1, CDR H2 and CDR H3, or HCDR1, HCDR2 and HCDR3. The residues in antibody variable domains are conventionally numbered according to IMGT (http: / / www.imgt.org). This system is set forth in Lefranc MP (1997, J, Immunol. Today, 18, 509). This numbering system is used in the present specification except where otherwise indicated. The IMGT residue designations do not always correspond directly with the linear numbering of the amino acid residues. The actual linear amino acid sequence may contain fewer or additional amino acids than in the strict IMGT numbering corresponding to a shortening of, or insertion into, a structural component, whether framework or CDR, of the basic variable domain structure. The correct IMGT numbering of residues may be determined for a given antibody by alignment of residues of homology in the sequence of the antibody with a “standard” IMGT numbered sequence. Suitable antigen binding proteins, antibodies or binding fragments thereof may be disclosed herein by the primary amino acid sequences of their heavy and light chain CDRs, their heavy and light chain variable regions, and / or their full length heavy and light chains. An antigen binding protein, antibody or binding fragment thereof may comprise one or more VH CDR sequences and alternatively or additionally one or more VL CDR sequences of said specific antigen binding protein or antibody, in addition to VL CDR1. An antigen binding protein, antibody or binding fragment thereof may comprise one, two or all three of the VH CDR sequences of a specific antigen binding protein, antibody or binding fragment thereof as described above and alternatively or additionally one, two or all three of the VL chain CDR sequences of said specific antigen binding protein, antibody or binding fragment thereof, including VL CDR1. An antigen binding protein, antibody or binding fragment thereof may comprise all six CDR sequences of a specific antigen binding protein, antibody or binding fragment as described above. A variant antigen binding protein or antibody may comprise 1, 2, 3, 4, 5, up to 10, up to 20, up to 30 or more amino acid substitutions and / or deletions from the specific sequences and fragments discussed above, whilst maintaining the activity of the antigen binding proteins or antibodies described herein. “Deletion” variants may comprise the deletion of, for example, 1, 2, 3, 4 or 5 individual amino acids or of one or more small groups of amino acids such as 2, 3, 4 or 5 amino acids. “Small groups of amino acids” can be defined as being sequential, or in close proximity but not sequential, to each other. "Substitution" variants preferably involve the replacement of one or more amino acids with the same number of amino acids and making conservative amino acid substitutions. For example, an amino acid may be substituted with an alternative amino acid having similar properties, for example, another basic amino acid, another acidic amino acid, another neutral amino acid, another charged amino acid, another hydrophilic amino acid, another hydrophobic amino acid, another polar amino acid, another aromatic amino acid, another aliphatic amino acid, another tiny amino acid, another small amino acid or another large amino acid. Some properties of the 20 main amino acids, which can be used to select suitable substituents, are as follows: Ala aliphatic, hydrophobic, neutral Met hydrophobic, neutral Cys polar, hydrophobic, neutral Asn polar, hydrophilic, neutral Asp polar, hydrophilic, charged (-) Pro hydrophobic, neutral Glu polar, hydrophilic, charged (-) Gln polar, hydrophilic, neutral Phe aromatic, hydrophobic, neutral Arg polar, hydrophilic, charged (+) Gly aliphatic, neutral Ser polar, hydrophilic, neutral His aromatic, polar, hydrophilic, Thr polar, hydrophilic, neutral charged (+) Ile aliphatic, hydrophobic, neutral Val aliphatic, hydrophobic, neutral Lys polar, hydrophilic, charged (+) Trp aromatic, hydrophobic, neutral Leu aliphatic, hydrophobic, neutral Tyr aromatic, polar, hydrophobic Preferred "derivatives" or "variants" include those in which instead of the naturally occurring amino acid the amino acid, which appears in the sequence, is a structural analog thereof. Amino acids used in the sequences may also be derivatized or modified, e.g. labelled, providing the function of the antibody is not significantly adversely affected. Derivatives and variants as described above may be prepared during synthesis of the antigen binding protein or antibody or by post-production modification, or when the antigen binding protein or antibody is in recombinant form using the known techniques of site-directed mutagenesis, random mutagenesis, or enzymatic cleavage and / or ligation of nucleic acids. Preferably variant antigen bonding proteins or antibodies have an amino acid sequence which has more than 60%, or more than 70%, e.g. 75 or 80%, preferably more than 85%, e.g. more than 90%, 95%, 96%, 97%, 98% or 99% amino acid identity to the VL and / or VH, or a fragment thereof, of an antigen binding protein or antibody disclosed herein. This level of amino acid identity may be seen across the full-length of the relevant SEQ ID NO sequence or over a part of the sequence, such as across 20, 30, 50, 75, 100, 150, 200 or more amino acids, depending on the size of the full-length polypeptide. Preferably the variant antigen binding proteins or antibodies comprise one or more of the CDR sequences as described herein. In connection with amino acid sequences, "sequence identity" refers to sequences, which have the stated value when assessed using ClustalW (Thompson JD et al., 1994, Nucleic Acid Res., 22, 4673-4680) with the following parameters: Pairwise alignment parameters -Method: slow / accurate, Matrix: PAM, Gap open penalty: 10.00, Gap extension penalty: 0.10; Multiple alignment parameters -Matrix: PAM, Gap open penalty: 10.00, % identity for delay: 30, Penalize end gaps: on, Gap separation distance: 0, Negative matrix: no, Gap extension penalty: 0.20, Residue-specific gap penalties: on, Hydrophilic gap penalties: on, Hydrophilic residues: G, P, S, N, D, Q, E, K, R. Sequence identity at a particular residue is intended to include identical residues, which have simply been derivatized. The methods of the present invention may use antibodies having specific VH and VL amino acid sequences and variants and fragments thereof, which maintain the function or activity of these VHs and VLs. References to “VH” or “VH” refer to the variable region of an immunoglobulin heavy chain, including that of an antibody fragment, such as Fv, scFv, dsFv or Fab. References to “VL” or “VL” refer to the variable region of an immunoglobulin light chain, including that of an Fv, scFv, dsFv or Fab. In some embodiments of the invention, the antigen binding protein may be an antibody comprising heavy (H) chains and light (L) chains interconnected by disulfide bonds. There are two types of light chain, lambda (λ) and kappa (κ). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. IgG1 (e.g. IgG1 / kappa) antibodies having an IgG1 heavy chain and a light chain may advantageously be used in the invention. However, other human antibody isotypes are also encompassed by the invention, including IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD and IgE in combination with a kappa or lambda light chain. Also, all animal-derived antibodies of various isotypes can be used in the invention. The antibodies can be full-size antibodies or antigen-binding fragments of antibodies, including Fab, F(ab')2, single-chain Fv fragments, or single-domain VHH, VH or VL single domains. The Fc region generally refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, and the last three constant region immunoglobulin domains of IgE and IgM. An Fc region may also include part or all of the flexible hinge N-terminal to these domains. For IgA and IgM, an Fc region may or may not comprise the tailpiece, and may or may not be bound by the J chain. For IgG, the Fc region comprises immunoglobulin domains Cgamma2 and Cgamma3 (Cγ2 and Cγ3) and the lower part of the hinge between Cgamma1 (Cγ1) and Cγ2. Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is usually defined to comprise residues C226 or P230 to its carboxyl-terminus, wherein the numbering is according to the EU index. For IgA, the Fc region comprises immunoglobulin domains Calpha2 and Calpha3 (Cα2 and Cα3) and the lower part of the hinge between Calpha1 (Cα1) and Cα2. Encompassed within the definition of the Fc region are functionally equivalent analogs and variants of the Fc region. A functionally equivalent analog of the Fc region may be a variant Fc region, comprising one or more amino acid modifications relative to the wild- type or naturally existing Fc region. Variant Fc regions will possess at least 50% homology with a naturally existing Fc region, such as about 80%, and about 90%, or at least about 95% homology. Functionally equivalent analogs of the Fc region may comprise one or more amino acid residues added to or deleted from the N- or C-termini of the protein, such as no more than 30 or no more than 10 additions and / or deletions. Functionally equivalent analogs of the Fc region include Fc regions operably linked to a fusion partner. Functionally equivalent analogs of the Fc region must comprise the majority of all of the Ig domains that compose Fc region as defined above; for example IgG and IgA Fc regions as defined herein must comprise the majority of the sequence encoding CH2and the majority of the sequence encoding CH3. Thus, the CH2domain on its own, or the CH3domain on its own, are not considered Fc region. The Fc region may refer to this region in isolation, or this region in the context of an Fc fusion polypeptide. When referring to an antigen binding protein of the invention, the binding to said protein to an antigen refers to a binding reaction which determines the presence of a target protein, peptide, or polysaccharide in the presence of a heterogeneous population of proteins and other biologics. Thus, under designated conditions, an antigen binding protein binds preferentially to a particular target protein, peptide or polysaccharide (such as FIX or FX) and does not bind in a significant amount to other proteins or polysaccharides present in the sample or subject. Specific binding can be determined by methods known in the art. With reference to an antibody antigen complex, specific binding of the antigen and antibody has a Kdof less than about 10-5Molar, 10-6Molar, 10-7Molar, such as less than about 10-7Molar, 10-8Molar, 10-9, or even less than about 10-10Molar. The terms "binding activity" and "binding affinity" are intended to refer to the tendency of an antigen-binding protein to bind or not to bind to a target. Binding affinity may be quantified by determining the dissociation constant (Kd) for an antigen-binding protein and its target. Similarly, the specificity of binding of an antigen binding protein to its target may be defined in terms of the comparative dissociation constants (Kd) of the antibody for its target as compared to the dissociation constant with respect to the antigen binding protein and another, non-target molecule. Typically, the Kd for the antibody with respect to the target will be 2-fold, preferably 5-fold, more preferably 10-fold less than the Kd with respect to the other, non- target molecule such as unrelated material or accompanying material in the environment. More preferably, the Kd will be 50-fold less, even more preferably 100-fold less, and yet more preferably 200-fold less. The value of this dissociation constant can be determined directly by well-known methods, and can be computed even for complex mixtures by methods such as those, for example, set forth in Caceci MS and Cacheris WP (1984, Byte, 9, 340-362). For example, the Kd may be established using a double-filter nitrocellulose filter binding assay such as that disclosed by Wong I and Lohman TM (1993, Proc. Natl. Acad. Sci. USA, 90, 5428- 5432) or for example, by using Octet surface plasmon resonance. One method for the evaluation of binding affinity is by ELISA. Other standard assays to evaluate the binding ability of ligands such as antibodies towards targets are known in the art, including for example, Western blots, RIAs, and flow cytometry analysis. The binding kinetics (e.g. binding affinity) of the antibody also can be assessed by standard assays known in the art, such as surface plasmon resonance, for example by Biacore™ system analysis. In one embodiment the antigen binding protein is a monoclonal antibody. Monoclonal antibodies are immunoglobulin molecules that are identical to each other and have a single binding specificity and affinity for a particular epitope. Monoclonal antibodies (mAbs) of the present invention can be produced by a variety of techniques, including conventional monoclonal antibody methodology, for example those disclosed in “Monoclonal Antibodies: a manual of techniques”(Zola H, 1987, CRC Press) and in “Monoclonal Hybridoma Antibodies: techniques and applications” (Hurrell JGR, 1982 CRC Press). In a preferred embodiment of the invention, the antigen binding protein comprises a first antigen binding domain and a second antigen binding domain. In a preferred embodiment of the invention, the first and second antigen binding domains of the antigen binding protein are scFv proteins. In a preferred embodiment of the invention, the first and second antigen binding domains of the antigen binding protein are scFv proteins covalently linked by a peptide linker. As indicated below, the sequence of each light chain variable domain and heavy chain variable domain referred to above may differ from the given sequence. For example, the light / heavy chain variable domain may comprise a sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences as set forth in the sequence listing. Alternatively, the light / heavy chain variable domain sequence may differ at up to 10 amino acid positions, although it is preferred that fewer than 10 amino acid substitutions are present so that there may be up to 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions. As referred to above, in some embodiments, the Light Chain Variable Domains and the Heavy Chain Variable Domains comprise an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences as set forth above. For example, the Light Chain Framework Regions, the Heavy Chain Framework Regions, the Light Chain Variable Domains and the Heavy Chain Variable Domains may include at most 10, at most 9, at most 8, at most 7, at most 6, at most 5, at most 4, at most 3, at most two or at most one amino acid substitutions in the amino acid sequences as set forth above. Where there is variation in the sequences of the Light Chain Variable Domain and the Heavy Chain Variable Domain, any amino acid substitutions are preferably not in the CDRs. In particular, the Light Chain Framework Regions and / or the Heavy Chain Framework Regions of the antibodies described above may comprise an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences as set forth above. Further, the Light Chain Framework Regions and / or the Heavy Chain Framework Regions may include at most 10, at most 9, at most 8, at most 7, at most 6, at most 5, at most 4, at most 3, at most two or at most one amino acid substitutions in the amino acid sequences as set forth above. Preferably the amino acid substitutions are conservative substitutions as described above. For example, the framework regions may comprise such substitutions in order to humanise the sequence. Preferably, the framework regions are humanised. The sequence of each light chain variable domain and heavy chain variable domain of the second antigen binding domain referred to above may differ from the given sequence. For example, the light / heavy chain variable domain may comprise a sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences as set forth in the sequence listing. Alternatively, the light / heavy chain variable domain sequence may differ at up to 10 amino acid positions, although it is preferred that fewer than 10 amino acid substitutions are present so that there may be up to 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions. Preferably, there are no substitutions present in the CDRs of the heavy / light chain. Antigen binding proteins comprising the antigen binding domains can be prepared by proteolytic hydrolysis of the antibody or by expression in mammalian cells of DNA encoding the fragment. Antibody fragments can be obtained by pepsin or papain digestion of whole antibodies by conventional methods. For example, antibody fragments can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment denoted F(ab')2. This fragment can be further cleaved using a thiol reducing agent, and optionally a blocking group for the sulfhydryl groups resulting from cleavage of disulfide linkages, to produce 3.5S Fab' monovalent fragments. Alternatively, an enzymatic cleavage using pepsin produces two monovalent Fab' fragments and an Fc fragment directly (see U.S. Patent No. 4,036,945 and U.S. Patent No. 4,331,647, and references contained therein; Nisonhoff et al., Arch. Biochem. Biophys. 89:230, 1960; Porter, Biochem. J. 73:119, 1959; Edelman et al., Methods in Enzymology, Vol. 1, page 422, Academic Press, 1967; and Coligan et al. at sections 2.8.1-2.8.10 and 2.10.1-2.10.4). Other methods of cleaving antigen binding proteins and antibodies, such as separation of heavy chains to form monovalent light-heavy chain fragments, further cleavage of fragments, or other enzymatic, chemical, or genetic techniques may also be used, so long as the fragments bind to the antigen that is recognized by the intact antibody, or antigen binding protein. In a preferred embodiment, the antigen binding protein has FVIII mimetic activity and is composed of a single polypeptide chain. In a preferred embodiment, the single polypeptide chain is composed of a first antigen binding domain and a second antigen binding domain. In a preferred embodiment, the single polypeptide chain is composed of a first antigen binding domain and a second antigen binding domain, wherein the first antigen binding domain selectively binds coagulation FIX and second antigen binding domain selectively binds coagulation FX. In a preferred embodiment, the antigen binding protein comprises a first antigen binding domain that selectively binds to FIX / FIXa and a second antigen binding domain that selectively binds to FX / FXa. In a preferred embodiment, the first antigen binding domain and second antigen binding domain each comprise a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises a light chain complementarity determining region (LCDR)1, an LCDR2 and an LCDR3, and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein the first antigen binding domain selectively binds coagulation FIX; and wherein for the second antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 7; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 9; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 10; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 11; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 12; wherein the sequence of each complementarity determining region may differ from the given sequence at up to two amino acid positions. In a preferred embodiment, the first antigen binding domain and second antigen binding domain each comprise a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises a light chain complementarity determining region (LCDR)1, an LCDR2 and an LCDR3, and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein for the first antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 1; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 2; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 3; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 4; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 5; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 6; and wherein for the second antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 7; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 9; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 10; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 11; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 12; wherein the sequence of each complementarity determining region may differ from the given sequence at up to two amino acid positions. In particular embodiments, for the first antigen binding domain the light chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO: 13 and the heavy chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO: 14, and for the second antigen binding domain the light chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO: 15 and the heavy chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO: 16. In particular embodiments, the first antigen binding domain is comprised in an scFv. In particular embodiments, the second antigen binding domain is comprised in an scFv. In particular embodiments, the first antigen binding domain comprises the amino acid sequence as set forth as SEQ ID NO: 17. In particular embodiments, the second antigen binding domain comprises the amino acid sequence as set forth as SEQ ID NO: 18. In particular embodiments, the first antigen binding domain comprises the amino acid sequence as set forth as SEQ ID NO: 17 and the second antigen binding domain comprises the amino acid sequence as set forth as SEQ ID NO: 18. In particular embodiments, the antigen binding protein comprises the amino acid sequence as set forth as SEQ ID NO: 19. The Bi8 antibody referenced herein comprises the comprises the amino acid sequence as set forth as SEQ ID NO: 19. Antigen binding proteins using the single-chain tandem scFv generally have short half-lives (1-2 hours) in humans. However, fusion of antigen binding proteins using the scFv with moieties binding to proteins that interact with the neonatal Fc receptor (FcRn) pathway can extend the circulating half-life through the FcRn-mediated recycling mechanism. Expression of an antigen binding protein with a longer half-life will therefore increase steady-state levels in an embodiment where the antigen binding protein is administered by gene transfer using a viral vector such as AAV, potentially reducing the required vector dose to achieve therapeutic efficacy. Therefore, in an embodiment in the invention, the antigen binding protein is half- life extended. In a preferred embodiment, the antigen binding protein further comprises a third antigen binding domain which binds to a protein that interacts with FcRn. The skilled person would understand that alternative third antigen binding domains could be selected which directly interact with the FcRn. In particular embodiments, the third antigen binding domain binds to albumin. In particular embodiments, the third antigen binding domain comprises a CDR1, CDR2 and a CDR3 sequence, wherein the CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 42; CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 43; and CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 44. In a preferred embodiment, the third antigen binding domain comprises a VHH domain. In a preferred embodiment, the VHH domain is derived from a camelid. The skilled person would understand that suitable alternative truncated formats for the third antigen binding domain that could be used are VHH antibodies, recombinant antibodies, single chain antibodies, single chain variable fragments (scFv), variable fragments (Fv), fragment antigen-binding regions (Fab), single-domain antibodies (sdAb), nanobodies, camelids-derived single-domain antibodies, shark IgNAR-derived single- domain antibody fragments (VNAR), diabodies, triabodies, Anticalins and aptamers. In a preferred embodiment, the third antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 41. SEQ ID NO: 41 corresponds to the amino acid sequence of an Albumin targeting VHH. This Albumin targeting VHH is also referenced as “HLE” herein. In a preferred embodiment, the half-life extended antigen binding protein comprises the amino acid sequence set forth in SEQ ID NO: 40. A polynucleotide The invention provides polynucleotides of no more than 4.5 kb, 4.6 kb. 4.7 kb, 4.8 kb, 4.9 kb or 5.0 kb in length encoding FVIII mimetic antigen binding protein sequences as defined herein. The invention provides polynucleotides of no more than 5.0 kb in length encoding FVIII mimetic antigen binding protein sequences as defined herein. The terms “sequence that encodes” or “polynucleotides … encoding” refer to a nucleotide sequence comprising codons that encode the encoded polypeptide. For example, a nucleotide sequence that encodes an antigen binding protein or fragment thereof comprises codons that encode the amino acid sequence of the antigen binding protein or fragment thereof. A suitable nucleotide sequence of the invention is provided in SEQ ID NO. 21. The following Table describes codons that encode each amino acid: Amino Acid Codon Amino Codon Amino Acid Codon Acid Phenylalanine TTC Proline CCT Asparagine AAT TTT CCC AAC CCA CCG Leucine TTA Threonine ACT Lysine AAA TTG ACC AAG CTT ACA CTC ACG CTA CTG Isoleucine ATT Alanine GCT Aspartic Acid GAT ATC GCC GAC ATA GCA GCG Methionine ATG Tyrosine TAT Glutamic GAA TAC Acid GAG Valine GTT Histidine CAT Cysteine TGT GTC CAC TGC GTA GTG Serine TCT Glutamine CAA Tryptophan TGG TCC CAG TCA TCG AGT AGC Arginine CGT Glycine GGT CGC GGC CGA GGA CGG GGG AGA AGG The corresponding RNA codons will contain Us in place of the Ts in the Table above. One aspect of the present invention provides a polynucleotide comprising an antigen binding protein nucleotide sequence, wherein the antigen binding protein nucleotide sequence encodes an antigen binding protein or fragment thereof and has at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or 100% identity to SEQ ID NO. 21. In general, the antigen binding protein nucleotide sequence may be at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or 100% identical to a fragment of at least 1200, at least 1350, or at least 1530 nucleotides of SEQ ID NO. 21, and retain FVIII mimetic activity. The antigen binding protein nucleotide sequence may be at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or 100% identical to a contiguous fragment of at least 1200, at least 1350, or at least 1530 nucleotides of SEQ ID NO. 21, and retain FVIII mimetic activity. The antigen binding protein nucleotide sequence may be at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or 100% identical to SEQ ID NO 21, and retain FVIII mimetic activity. For example, the antigen binding protein nucleotide sequence may be at least 98% identical to SEQ ID NO. 21, and retain FVIII mimetic activity. In an embodiment of the invention, the antigen binding protein nucleotide sequence may be at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or 100% identical to SEQ ID NO 21, and retain FVIII mimetic activity, wherein the CDR nucleotide sequences of the first and second antigen binding domain encode the amino acid sequences set forth in SEQ ID NOs 1 to 12. In a preferred embodiment of the polynucleotide sequence of the invention the antigen binding protein nucleotide sequence encodes an antigen binding protein, wherein the antigen binding protein optionally further comprises a third antigen binding domain, wherein the third binding domain binds a protein that interacts with FcRn, and wherein the polynucleotide sequence is no more than 5.0 kb in length, such that the polynucleotide sequence can fit in a single AAV vector. In a preferred embodiment, the antigen binding protein further comprises a third antigen binding domain which binds to a protein that interacts with FcRn. The skilled person would understand that alternative third antigen binding domains could be selected which directly interact with the FcRn. In particular embodiments, the third antigen binding domain binds to albumin. In particular embodiments, the nucleic acid sequence encoding the third antigen binding domain comprising a CDR1, CDR2 and a CDR3 sequence, wherein the nucleic acid sequence encoding the CDR1 sequence is set forth in SEQ ID NO: 47; the nucleic acid sequence encoding the CDR2 sequence is set forth in SEQ ID NO: 48; and the nucleic acid sequence encoding the CDR3 sequence is set forth in SEQ ID NO: 49. In a preferred embodiment, the third antigen binding domain comprises a VHH domain. In a preferred embodiment, the VHH domain is derived from a camelid. The skilled person would understand that suitable alternative truncated formats for the third binding domain could be chosen so that the polynucleotide sequence is equal to or less than 5.0 kb in length. The skilled person would therefore select a suitable format for the third antigen binding domain that is equal to or less than 5.0 kb in length such as VHH antibodies, recombinant antibodies, single chain antibodies, single chain variable fragments (scFv), variable fragments (Fv), fragment antigen-binding regions (Fab), single- domain antibodies (sdAb), nanobodies, camelids-derived single-domain antibodies, shark IgNAR-derived single-domain antibody fragments (VNAR), diabodies, triabodies, Anticalins, aptamers and peptides. The skilled person would understand that a suitable format for the third antigen binding domain may comprise three CDR sequences, CDR1, CDR2, and CDR3. In a preferred embodiment, the nucleic acid sequence encoding the third antigen binding domain comprises the nucleic acid sequence set forth in SEQ ID NO: 46. SEQ ID NO: 46 corresponds to the nucleotide sequence of an Albumin targeting VHH. This Albumin targeting VHH is also referenced as “HLE” herein. Therefore, a suitable polynucleotide sequence of the invention comprises SEQ ID NO: 45, which corresponds to the nucleotide sequence of the antigen binding protein of the invention comprising the third antigen binding domain as described herein. The polynucleotide may further comprise a promoter / transcription regulatory element The polynucleotide may comprise a promoter. The polynucleotide may comprise a promoter that comprises a transcription regulatory element. Any appropriate transcription regulatory element may be used, such as HLP2, HLP1, LP1, HCR-hAAT, ApoE-hAAT, and LSP, which are all liver specific transcription regulatory elements. These transcription regulatory elements are described in more detail in the following references: HLP1: McIntosh J. et al., Blood 2013 Apr 25, 121(17):3335-44; LP1: Nathwani et al., Blood. 2006 April 1, 107(7): 2653–2661; HCR-hAAT: Miao et al., Mol Ther. 2000;1: 522-532; ApoE-hAAT: Okuyama et al., Human Gene Therapy, 7, 637-645 (1996); and LSP: Wang et al., Proc Natl Acad Sci U S A. 1999 March 30, 96(7): 3906–3910. The transcription regulatory element may comprise a promoter and / or an enhancer, such as the promoter element and / or enhancer element from HLP2, HLP1, LP1, HCR- hAAT, ApoE-hAAT, and LSP. Each of these transcription regulatory elements comprises a promoter, an enhancer, and optionally other nucleotides. In an embodiment, the transcription regulatory element comprises an enhancer which is the human apolipoprotein E (ApoE) hepatic locus control region (HCR; Miao et al (2000), Molecular Therapy 1(6):522), or a fragment thereof. In an embodiment, the transcription regulatory element comprises a fragment of the HCR enhancer which is a fragment of at least 80, at least 90, at least 100, less than 192, between 80 and 192, between 90 and 192, between 100 and 250, or between 117 and 192 nucleotides in length. Optionally, the fragment of the HCR enhancer is between 100 and 250 nucleotides in length. If the polynucleotide is intended for expression in the liver, the promoter may be a liver-preferred or liver-specific promoter. Optionally, the promoter is a human liver- specific promoter. A “liver-preferred promoter” is a promoter that is expressed predominantly in the liver and related tissues. For example, the skilled person can determine whether a promoter is a liver-preferred promoter by comparing expression of the polynucleotide in liver cells (such as Huh 7 cells) with expression of the polynucleotide in cells from other tissues. A “liver-specific promoter” is a promoter that provides a higher level of expression in liver cells compared to other cells in general. For example, the skilled person can determine whether a promoter is a liver-specific promoter by comparing expression of the polynucleotide in liver cells (such as Huh 7 cells) with expression of the polynucleotide in cells from other tissues. If the level of expression is higher in the liver cells, compared to the cells from other tissues, the promoter is a liver-specific promoter. In a preferred embodiment, the promoter may comprise the hepatic control region enhancer / human alpha-1 anti-trypsin promoter (HCR hAAT) complex. In a preferred embodiment, the promoter may comprise a CAG intron. In a preferred embodiment, the promoter may comprise the hepatic control region enhancer / human alpha-1 anti-trypsin promoter (HCR hAAT) complex and the CAG intron. A viral particle comprising the polynucleotide The invention further provides a viral particle comprising polynucleotides of the invention. For the purposes of the present invention, the term “viral particle” refers to all or part of a virion. For example, the viral particle comprises a recombinant genome and may further comprise a capsid. The viral particle may be a gene therapy vector. Herein, the terms “viral particle” and “vector” are used interchangeably. For the purpose of the present application, a “gene therapy” vector is a viral particle that can be used in gene therapy, i.e. a viral particle that comprises all the required functional elements to express a transgene, such as a FVIII mimetic antigen binding protein, in a host cell after administration. Suitable viral particles include a parvovirus, a retrovirus, a lentivirus or a herpes simplex virus. The parvovirus may be an adeno-associated virus (AAV). The viral particle is preferably a recombinant adeno-associated viral (AAV) vector or a lentiviral vector. More preferably, the viral particle is an AAV viral particle. The terms AAV and rAAV are used interchangeably herein. The genomic organization of all known AAV serotypes is very similar. The genome of AAV is a linear, single-stranded DNA molecule that is less than about 5,000 nucleotides in length. Inverted terminal repeats (ITRs) flank the unique coding nucleotide sequences for the non-structural replication (Rep) proteins and the structural (VP) proteins. The VP proteins (VP1, -2 and -3) form the capsid. The terminal 145 nt are self- complementary and are organized so that an energetically stable intramolecular duplex forming a T-shaped hairpin may be formed. These hairpin structures function as an origin for viral DNA replication, serving as primers for the cellular DNA polymerase complex. Following wild type (wt) AAV infection in mammalian cells the Rep genes (i.e. encoding Rep78 and Rep52 proteins) are expressed from the P5 promoter and the P19 promoter, respectively, and both Rep proteins have a function in the replication of the viral genome. A splicing event in the Rep ORF results in the expression of actually four Rep proteins (i.e. Rep78, Rep68, Rep52 and Rep40). However, it has been shown that the unspliced mRNA, encoding Rep78 and Rep52 proteins, in mammalian cells are sufficient for AAV vector production. Also in insect cells the Rep78 and Rep52 proteins suffice for AAV vector production. The recombinant viral genome of the invention may comprise ITRs. It is possible for an AAV vector of the invention to function with only one ITR. Thus, the viral genome comprises at least one ITR, but, more typically, two ITRs (generally with one either end of the viral genome, i.e. one at the 5’ end and one at the 3’ end). There may be intervening sequences between the polynucleotide and one or more of the ITRs. The polynucleotide of the invention may be incorporated into a viral particle located between two regular ITRs or located on either side of an ITR engineered with two D regions. AAV sequences that may be used in the present invention for the production of AAV vectors can be derived from the genome of any AAV serotype. Generally, the AAV serotypes have genomic sequences of significant homology at the amino acid and the nucleic acid levels, provide an identical set of genetic functions, produce virions which are essentially physically and functionally equivalent, and replicate and assemble by practically identical mechanisms. For the genomic sequence of the various AAV serotypes and an overview of the genomic similarities see e.g. GenBank Accession number U89790; GenBank Accession number J01901; GenBank Accession number AF043303; GenBank Accession number AF085716; Chiorini et al, 1997; Srivastava et al, 1983; Chiorini et al, 1999; Rutledge et al, 1998; and Wu et al, 2000. AAV serotype 1, 2, 3, 3B, 4, 5, 6, 7, 8, 9, 10, 11 or 12 may be used in the present invention. The sequences from the AAV serotypes may be mutated or engineered when being used in the production of gene therapy vectors. Optionally, an AAV vector comprises ITR sequences which are derived from AAV1, AAV2, AAV4 and / or AAV6. Preferably the ITR sequences are AAV2 ITR sequences. Herein, the term AAVx / y refers to a viral particle that comprises some components from AAVx (wherein x is a AAV serotype number) and some components from AAVy (wherein y is the number of the same or different serotype). For example, an AAV2 / 8 vector may comprise a portion of a viral genome, including the ITRs, from an AAV2 strain, and a capsid derived from an AAV8 strain. A viral particle of the invention may be a "hybrid" particle in which the viral ITRs and viral capsid are from different parvoviruses, such as different AAV serotypes. Preferably, the viral ITRs and capsid are from different serotypes of AAV, in which case such viral particles are known as transcapsidated or pseudotyped. Likewise, the parvovirus may have a "chimeric" capsid (e. g., containing sequences from different parvoviruses, preferably different AAV serotypes) or a "targeted" capsid (e. g., a directed tropism). In some embodiments, the recombinant AAV genome comprises intact ITRs, comprising functional terminal resolution sites (TRS). Such an AAV genome may contain one or two resolvable ITRs, i.e. ITRs containing a functional TRS at which site-specific nicking can take place to create a free 3’ hydroxyl group which can serve as a substrate for DNA polymerase to unwind and copy the ITR. Preferably, the recombinant genome is single- stranded (i.e., it is packaged into the viral particle in a single-stranded form). Optionally, the recombinant genome is not packaged in self-complementary configuration, i.e. the genome does not comprise a single covalently-linked polynucleotide strand with substantial self-complementary portions that anneal in the viral particle. Alternatively, the recombinant genome may be packaged in “monomeric duplex” form. “Monomeric duplexes” are described in WO 2011 / 122950. The genome may be packaged as two substantially complementary but non-covalently linked polynucleotides which anneal in the viral particle. The viral particle may further comprise a poly A sequence or polyadenylation sequence. The poly A sequence may be positioned downstream of the nucleotide sequence encoding the antigen binding protein. The poly A sequence may be a bovine growth hormone poly A sequence (bGHpA). The poly A sequence may be between 250 and 270 nucleotides in length. The poly A sequence may be downstream of the nucleotide sequence encoding the antigen binding protein and upstream of an ITR. The present invention encompasses a viral particle comprising a polynucleotide of no more than 5.0 kb in length encoding a first antigen binding domain and a second binding domain, wherein the first antigen binding domain and second binding domain each comprise a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises a light chain complementarity determining region (LCDR)1, an LCDR2 and an LCDR3, and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3; wherein for the first antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 1; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 2; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 3; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 4; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 5; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:6; and wherein for the second antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 7; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 9; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 10; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 11; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 12. The invention encompasses an AAV genome comprising a polynucleotide encoding a FVIII mimetic antigen binding protein for use in a method of gene therapy. Host cells The invention encompasses isolated host cells transformed with the polynucleotides or viral particles as defined herein. Suitable host cells include cultured human liver cells, such as Huh 7 cells. Suitable host cells for the production of antigen binding proteins or antibodies include mammalian cells or E. coli. Compositions, methods and uses In a further aspect of the invention, there is provided a composition comprising the antigen binding protein, polynucleotide or vector / viral particle of the invention and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipients may comprise carriers, diluents and / or other medicinal agents, pharmaceutical agents or adjuvants, etc. Optionally, the pharmaceutically acceptable excipients comprise saline solution. Optionally, the pharmaceutically acceptable excipients comprise human serum albumin. Preferably, the carrier is suitable for parenteral, e.g. intravenous, intraocular, intramuscular, subcutaneous, intradermal or intraperitoneal administration (e.g. by injection or infusion). In certain embodiments, a pharmaceutically acceptable carrier comprises at least one carrier selected from the group consisting of a co-solvent solution, liposomes, micelles, liquid crystals, nanocrystals, nanoparticles, emulsions, microparticles, microspheres, nanospheres, nanocapsules, polymers or polymeric carriers, surfactants, suspending agents, complexing agents such as cyclodextrins or adsorbing molecules such as albumin, surface active particles, and chelating agents. In further embodiments, a polysaccharide comprises hyaluronic acid and derivatives thereof, dextran and derivatives thereof, cellulose and derivatives thereof (e.g. methylcellulose, hydroxy-propylcellulose, hydroxy-propylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate butyrate, hydroxypropylmethyl-cellulose phthalate), chitosan and derivative thereof, [beta]-glucan, arabinoxylans, carrageenans, pectin, glycogen, fucoidan, chondrotin, dermatan, heparan, heparin, pentosan, keratan, alginate, cyclodextrins, and salts and derivatives, including esters and sulfates, thereof. Preferred pharmaceutically acceptable carriers comprise aqueous carriers or diluents. Examples of suitable aqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, buffered water and saline. Examples of other carriers include ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, or sodium chloride in the composition. A pharmaceutical composition may include a pharmaceutically acceptable anti- oxidant. These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents, which delay absorption such as aluminium monostearate and gelatin. Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The pharmaceutical composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. Sterile injectable solutions can be prepared by incorporating the active agent (e.g. antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration. Generally, dispersions are prepared by incorporating the active agent into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active agent plus any additional desired ingredient from a previously sterile-filtered solution thereof. Pharmaceutical compositions may comprise additional active ingredients as well as an therapeutic agent. Compositions of the invention may comprise one or more antigen binding proteins, polynucleotides or viral particles. They may also comprise additional therapeutic or prophylactic active agents. Depending on the route of administration, the antigen binding protein of the invention may be coated in a material to protect the antigen binding protein from the action of acids and other natural conditions that may inactivate or denature the antigen binding protein. The invention further provides an antigen binding protein, polynucleotide, vector / viral particle or composition of the invention for use in a method of treatment. Optionally the method of treatment comprises administering an effective amount of the antigen binding protein, polynucleotide or vector / viral particle of the invention to a patient. The invention further provides a method of treatment comprising administering an effective amount of the antigen binding protein, polynucleotide or vector / viral particle of the invention to a patient. The invention further provides use of the antigen binding protein, polynucleotide, vector / viral particle or composition of the invention in the manufacture of a medicament for use in a method of treatment. Optionally the method of treatment comprises administering an effective amount of the polynucleotide or vector / viral particle of the invention to a patient. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as raising the level of functional FVIII mimetic antibody in a subject (so as to lead to functional antibody production at a level sufficient to ameliorate the symptoms of haemophilia A). In therapeutic applications, the antigen binding protein, polynucleotides or composition is administered to a subject already suffering from a disorder or condition, in an amount sufficient to cure, alleviate or partially arrest the condition or one or more of its symptoms. Such therapeutic treatment may result in a decrease in severity of disease symptoms, or an increase in frequency or duration of symptom-free periods. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective amounts for a given purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. In prophylactic applications, the antigen binding protein, polynucleotide or composition is administered to a subject not yet exhibiting symptoms of a disorder or condition, in an amount sufficient to prevent or delay the development of symptoms. Such an amount is defined as a “prophylactically effective amount”. As used herein, the term "subject" includes any vertebrate, typically any mammal, such as human or horse. The subject is preferably human. The antigen binding protein of the invention, may be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and / or mode of administration will vary depending upon the desired results. Preferred routes of administration for antigen binding proteins, antibodies or compositions of the invention include intravenous, subcutaneous, intraocular, intramuscular, intradermal, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection. Administration may be rectal, oral, ocular, topical, epidermal or by the mucosal route. Administration may be local, including peritumoral, juxtatumoral, intratumoral, to the resection margin of tumors, intralesional, perilesional, by intra cavity infusion, intravesicle administration, or by inhalation. In a preferred embodiment, the pharmaceutical composition is administered intravenously or subcutaneously. A suitable dosage of the antigen binding protein of the invention may be determined by a skilled medical practitioner. Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular therapeutic agent employed, the route of administration, the time of administration, the rate of excretion of the therapeutic agent the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A suitable dose of an antigen binding protein may be, for example, in the range of from about 0.1 µg / kg to about 100 mg / kg body weight of the patient to be treated. For example, a suitable dosage may be from about 1µg / kg to about 50 mg / kg body weight per week, from about 100 µg / kg to about 25 mg / kg body weight per week or from about 10 µg / kg to about 12.5 mg / kg body weight per week. A suitable dosage may be from about 1 µg / kg to about 50 mg / kg body weight per day, from about 100 µg / kg to about 25 mg / kg body weight per day or from about 10 µg / kg to about 12.5 mg / kg body weight per day. Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Antigen binding proteins may be administered in a single dose or in multiple doses. The multiple doses may be administered via the same or different routes and to the same or different locations. Alternatively, antigen binding proteins can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency may vary depending on the half-life of the antigen binding protein in the patient and the duration of treatment that is desired. The dosage and frequency of administration can also vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage may be administered at relatively infrequent intervals over a long period of time. In therapeutic applications, a relatively high dosage may be administered, for example until the patient shows partial or complete amelioration of symptoms of disease. Combined administration of two or more agents may be achieved in a number of different ways. In one embodiment, the antigen binding protein of the invention and the other agent may be administered together in a single composition. In another embodiment, the antigen binding protein of the invention and the other agent may be administered in separate compositions as part of a combined therapy. For example, the antigen binding protein of the invention may be administered before, after or concurrently with the other agent. Optionally the method of treatment is a gene therapy. A “gene therapy” involves administering a vector / viral particle of the invention that is capable of expressing a transgene (such as a polynucleotide encoding a FVIII mimetic antigen binding protein) in the host to which it is administered. Optionally, the vector / viral particle is administered at a dose of less than 1 x 1011, less than 1 x 1012, less than 5 x 1012, less than 2 x 1012, less than 1.5 x 1012, less than 3 x 1012, less than 1 x 1013, less than 2 x 1013, or less than 3 x 1013vector genomes per kg of weight of patient. Optionally, the polynucleotide, viral particle or composition is administered in a dose of at least 4.5 x 1011, or between 4.5 x 1011and 1 x 1012vector genomes per kg of weight of patient (vg / kg). Optionally, the polynucleotide, viral particle or composition is administered in a dose of less than 5 x 1011vg / kg. Optionally, the polynucleotide, viral particle or composition is administered in a dose of between 4.5 x 1011vg / kg and 5 x 1011vg / kg, or between 4.5 x 1011vg / kg and 4.9 x 1011vg / kg. Optionally, the polynucleotide or viral particle that is administered is produced from a mammalian cell, and / or possesses characteristics which result from use of mammalian viral vector production cells and distinguish from vectors produced in insect viral vector production cells (e.g. baculovirus system). Optionally, administration of a given dose of vectors / viral particles – quantified in terms of the number of vector genomes - is achieved using qPCR to titrate vector genomes. In principle, the qPCR primers can be designed to bind any part of the recombinant vector genome which is not common to wild type genomes, but is it recommended against using primer template sequences very close to the ITRs as doing so can lead to an exaggerated vector genome titre measurement. Optionally, vector genomes are quantified by quantitative polymerase chain reaction (qPCR) utilising primers directed towards a promoter region, for example the promoter region of the transgene cassette (also sometimes known as a transgene expression cassette). Methods of performing qPCR are known to those of skill in the art. Using a real- time PCR cycler and DNA-binding dye such as SYBR Green (ThermoFisher Scientific) the amplification of nascent double-stranded amplicons can be detected in real time. Known quantities of the qPCR template genetic material (e.g. the promoter region) may then be serially diluted to create a standard curve, and sample vector genome titre interpolated from the standard curve. In an aspect, the polynucleotide, viral particle or composition of the invention is for use in achieving a stable antigen binding protein activity level in a subject. The term “stable antigen binding protein activity level” refers to an antigen binding protein activity level that maintains at or above a certain level for a continuous period of at least 5 weeks. In some embodiments, the antigen binding protein activity level maintains at or above a certain level for a continuous period of at least 10, at least 15, at least 20, at least 30, at least 40, or at least 50 weeks. The activity level of the antigen binding protein can be determined by means known to the skilled person, including monitoring for FVIII mimetic activity. The present invention encompasses a method for treating hemophilia A in a subject, the method comprising administering to the subject a therapeutically effective amount of the disclosed antigen binding protein and / or polynucleotide encoding said antigen binding protein and / or vial particle comprises said polynucleotide, thereby treating hemophilia. The present invention also relates to the disclosed antigen binding protein and / or polynucleotide encoding said antigen binding protein and / or vial particle comprises said polynucleotide for use in the treatment of hemophilia A. Further, the present invention also relates to use of the disclosed antigen binding protein and / or polynucleotide encoding said antigen binding protein and / or vial particle comprises said polynucleotide in the manufacture of a medicament for the treatment of hemophilia A. Sequence listing SEQ ID NO: 1: FIX-binding antigen binding domain LCDR 1 RNIERQ SEQ ID NO: 2: FIX-binding antigen binding domain LCDR 2 QAS SEQ ID NO: 3: FIX-binding antigen binding domain LCDR 3 QQYSDPPLT SEQ ID NO: 4: FIX-binding antigen binding domain HCDR 1 GFTFSYYD SEQ ID NO: 5: FIX-binding antigen binding domain HCDR 2 ISPSGQST SEQ ID NO: 6: FIX-binding antigen binding domain HCDR 3 ARRTGREYGGGWYFDY SEQ ID NO: 7: FX-binding antigen binding domain LCDR 1 QSLVYSDGNTY SEQ ID NO: 8: FX-binding antigen binding domain LCDR 2 KVS SEQ ID NO: 9: FX-binding antigen binding domain LCDR 3 MQGTHWPPT SEQ ID NO: 10: FX-binding antigen binding domain HCDR 1 GFTFSSYA SEQ ID NO: 11: FX-binding antigen binding domain HCDR 2 ISYDGSHK SEQ ID NO: 12: FX-binding antigen binding domain HCDR 3 ARATTAARNGLDI SEQ ID NO: 13: light chain variable region of FIX-binding antigen binding domain (CDRs in bold) DIQMTQSPSSLSASVGDRVTITCKASRNIERQLAWYQQKPGQAPELLIYQASRKESGVPDRFSGSRYGTDFTL TISSLQPEDIATYYCQQYSDPPLTFGGGTKVEIK SEQ ID NO: 14: heavy chain variable region of FIX-binding antigen binding domain (CDRs in bold) QVQLVESGGGLVQPGGSLRLSCAASGFTFSYYDIQWVRQAPGKGLEWVSSISPSGQSTYYRREVKGRFTISRD NSKNTLYLQMNSLRAEDTAVYYCARRTGREYGGGWYFDYWGQGTLVTVSS SEQ ID NO: 15: light chain variable region of FX-binding antigen binding domain (CDRs in bold) DIVMTQSPLSLHVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSG TDFTLKITRVEAEDVGVYYCMQGTHWPPTFGQGTKVEIK SEQ ID NO: 16: heavy chain variable region of FX-binding antigen binding domain (CDRs in bold) EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYAIHWVRQAPGKGLEWVAVISYDGSHKYYADSVKGRFTISRD SSKDTLYLQMNSLGAEDTAVYYCARATTAARNGLDIWGQGTTVTVSS SEQ ID NO: 17: FIX-binding scFv DIQMTQSPSSLSASVGDRVTITCKASRNIERQLAWYQQKPGQAPELLIYQASRKESGVPDRFSGSRYGTDFTL TISSLQPEDIATYYCQQYSDPPLTFGGGTKVEIKGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAA SGFTFSYYDIQWVRQAPGKGLEWVSSISPSGQSTYYRREVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA RRTGREYGGGWYFDYWGQGTLVTVSS SEQ ID NO: 18: FX-binding scFv EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYAIHWVRQAPGKGLEWVAVISYDGSHKYYADSVKGRFTISRD SSKDTLYLQMNSLGAEDTAVYYCARATTAARNGLDIWGQGTTVTVSSGGGGSGGGGSGGGGSDIVMTQSPLSL HVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKITRVE AEDVGVYYCMQGTHWPPTFGQGTKVEIK SEQ ID NO: 19: Amino acid sequence of Bi8 DIQMTQSPSSLSASVGDRVTITCKASRNIERQLAWYQQKPGQAPELLIYQASRKESGVPDRFSGSRYGTDFTL TISSLQPEDIATYYCQQYSDPPLTFGGGTKVEIKGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAA SGFTFSYYDIQWVRQAPGKGLEWVSSISPSGQSTYYRREVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA RRTGREYGGGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEVQLLESGGGVVQPGRSLRLSCAASGFTFSSY AIHWVRQAPGKGLEWVAVISYDGSHKYYADSVKGRFTISRDSSKDTLYLQMNSLGAEDTAVYYCARATTAARN GLDIWGQGTTVTVSSGGGGSGGGGSGGGGSDIVMTQSPLSLHVTLGQPASISCRSSQSLVYSDGNTYLNWFQQ RPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKITRVEAEDVGVYYCMQGTHWPPTFGQGTKVEIKHHHH HH SEQ ID NO: 20: 3xG4S linker region GGGGSGGGGSGGGGS SEQ ID NO: 21: Nucleotide sequence of Bi8 GACATCCAGATGACACAGTCACCCAGCTCACTCTCTGCCTCAGTAGGGGACCGAGTGACAATCACATGTAAGG CCTCCAGAAACATTGAGAGGCAGCTCGCATGGTACCAACAGAAGCCGGGACAGGCTCCGGAACTGCTGATTTA TCAGGCATCACGCAAGGAGAGTGGCGTCCCCGATCGGTTCTCTGGCAGTAGATACGGCACTGACTTTACACTG ACTATTTCTAGCCTTCAGCCAGAAGATATCGCTACTTACTATTGCCAGCAGTACTCCGACCCCCCGTTGACAT TTGGCGGCGGAACGAAAGTCGAAATCAAAGGCGGTGGCGGCTCTGGCGGAGGTGGCTCTGGCGGAGGCGGCAG CCAAGTGCAACTGGTCGAGTCTGGTGGCGGCCTCGTGCAGCCAGGAGGTTCACTTAGACTGTCCTGCGCTGCT AGTGGCTTTACTTTCAGCTACTACGACATCCAGTGGGTGCGCCAGGCCCCAGGGAAGGGGCTTGAGTGGGTAA GTTCTATTTCCCCATCCGGCCAGTCTACTTACTATCGGCGGGAGGTCAAAGGGAGATTCACCATCTCCCGCGA CAATTCAAAGAACACATTGTACTTGCAAATGAACTCCCTGCGCGCAGAGGACACCGCCGTCTACTATTGCGCG AGACGCACAGGGCGGGAGTACGGTGGTGGTTGGTATTTCGATTATTGGGGGCAAGGAACACTCGTAACGGTCT CATCAGGTGGCGGAGGTAGTGGAGGAGGTGGCTCTGGAGGGGGCGGTTCAGAGGTGCAGCTGTTGGAGTCTGG GGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTAT GCTATACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGTC ATAAATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAGTTCCAAGGACACGCTGTATCT GCAAATGAACAGTCTGGGAGCCGAGGACACGGCTGTGTATTACTGTGCAAGAGCAACTACTGCTGCTCGAAAT GGTCTTGATATCTGGGGGCAAGGGACCACGGTCACCGTCTCGAGTGGAGGCGGAGGGTCTGGGGGCGGCGGTA GCGGCGGAGGAGGAAGCGATATTGTGATGACCCAGTCTCCACTCTCCCTGCACGTCACCCTTGGACAGCCGGC CTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAATTGGTTTCAGCAG AGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCA GCGGCAGTGGGTCAGGCACTGATTTCACACTGAAGATCACCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTA CTGCATGCAAGGTACACACTGGCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACACCATCACCAT CACCAT SEQ ID NO: 22: Nucleotide sequence of FIX binding scFv ACATCGACATCCAGATGACACAGTCACCCAGCTCACTCTCTGCCTCAGTAGGGGACCGAGTGACAATCACATG TAAGGCCTCCAGAAACATTGAGAGGCAGCTCGCATGGTACCAACAGAAGCCGGGACAGGCTCCGGAACTGCTG ATTTATCAGGCATCACGCAAGGAGAGTGGCGTCCCCGATCGGTTCTCTGGCAGTAGATACGGCACTGACTTTA CACTGACTATTTCTAGCCTTCAGCCAGAAGATATCGCTACTTACTATTGCCAGCAGTACTCCGACCCCCCGTT GACATTTGGCGGCGGAACGAAAGTCGAAATCAAAGGCGGTGGCGGCTCTGGCGGAGGTGGCTCTGGCGGAGGC GGCAGCCAAGTGCAACTGGTCGAGTCTGGTGGCGGCCTCGTGCAGCCAGGAGGTTCACTTAGACTGTCCTGCG CTGCTAGTGGCTTTACTTTCAGCTACTACGACATCCAGTGGGTGCGCCAGGCCCCAGGGAAGGGGCTTGAGTG GGTAAGTTCTATTTCCCCATCCGGCCAGTCTACTTACTATCGGCGGGAGGTCAAAGGGAGATTCACCATCTCC CGCGACAATTCAAAGAACACATTGTACTTGCAAATGAACTCCCTGCGCGCAGAGGACACCGCCGTCTACTATT GCGCGAGACGCACAGGGCGGGAGTACGGTGGTGGTTGGTATTTCGATTATTGGGGGCAAGGAACACTCGTAAC GGTCTCATCA SEQ ID NO: 23: Nucleotide sequence of FIX binding scFv – light chain GACATCCAGATGACACAGTCACCCAGCTCACTCTCTGCCTCAGTAGGGGACCGAGTGACAATCACATGTAAGG CCTCCAGAAACATTGAGAGGCAGCTCGCATGGTACCAACAGAAGCCGGGACAGGCTCCGGAACTGCTGATTTA TCAGGCATCACGCAAGGAGAGTGGCGTCCCCGATCGGTTCTCTGGCAGTAGATACGGCACTGACTTTACACTG ACTATTTCTAGCCTTCAGCCAGAAGATATCGCTACTTACTATTGCCAGCAGTACTCCGACCCCCCGTTGACAT TTGGCGGCGGAACGAAAGTCGAAATCAAA SEQ ID NO: 24: Nucleotide sequence of FIX binding scFv – light chain CDR1 AGAAACATTGAGAGGCAG SEQ ID NO: 25: Nucleotide sequence of FIX binding scFv – light chain CDR2 CAGGCATCA SEQ ID NO: 26: Nucleotide sequence of FIX binding scFv – light chain CDR3 CAGCAGTACTCCGACCCCCCGTTGACA SEQ ID NO: 27: Nucleotide sequence of FIX binding scFv – heavy chain CAAGTGCAACTGGTCGAGTCTGGTGGCGGCCTCGTGCAGCCAGGAGGTTCACTTAGACTGTCCTGCGCTGCTA GTGGCTTTACTTTCAGCTACTACGACATCCAGTGGGTGCGCCAGGCCCCAGGGAAGGGGCTTGAGTGGGTAAG TTCTATTTCCCCATCCGGCCAGTCTACTTACTATCGGCGGGAGGTCAAAGGGAGATTCACCATCTCCCGCGAC AATTCAAAGAACACATTGTACTTGCAAATGAACTCCCTGCGCGCAGAGGACACCGCCGTCTACTATTGCGCGA GACGCACAGGGCGGGAGTACGGTGGTGGTTGGTATTTCGATTATTGGGGGCAAGGAACACTCGTAACGGTCTC ATCA SEQ ID NO: 28: Nucleotide sequence of FIX binding scFv – heavy chain CDR1 GGCTTTACTTTCAGCTACTACGAC SEQ ID NO: 29: Nucleotide sequence of FIX binding scFv – heavy chain CDR2 ATTTCCCCATCCGGCCAGTCTACT SEQ ID NO: 30: Nucleotide sequence of FIX binding scFv – heavy chain CDR3 GCGAGACGCACAGGGCGGGAGTACGGTGGTGGTTGGTATTTCGATTAT SEQ ID NO: 31: Nucleotide sequence of FX binding scFv GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCT CTGGATTCACCTTCAGTAGCTATGCTATACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGC AGTTATATCATATGATGGAAGTCATAAATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGAC AGTTCCAAGGACACGCTGTATCTGCAAATGAACAGTCTGGGAGCCGAGGACACGGCTGTGTATTACTGTGCAA GAGCAACTACTGCTGCTCGAAATGGTCTTGATATCTGGGGGCAAGGGACCACGGTCACCGTCTCGAGTGGAGG CGGAGGGTCTGGGGGCGGCGGTAGCGGCGGAGGAGGAAGCGATATTGTGATGACCCAGTCTCCACTCTCCCTG CACGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACA CCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGA CTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAGATCACCAGGGTGGAG GCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACACACTGGCCTCCGACGTTCGGCCAAGGGACCAAGG TGGAAATCAAA SEQ ID NO: 32: Nucleotide sequence of FX binding scFv – light chain GATATTGTGATGACCCAGTCTCCACTCTCCCTGCACGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGT CTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCC AAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGC ACTGATTTCACACTGAAGATCACCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTACAC ACTGGCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 33: Nucleotide sequence of FX binding scFv – light chain CDR1 CAAAGCCTCGTATACAGTGATGGAAACACCTAC SEQ ID NO: 34: Nucleotide sequence of FX binding scFv – light chain CDR2 AAGGTTTCT SEQ ID NO: 35: Nucleotide sequence of FX binding scFv – light chain CDR3 ATGCAAGGTACACACTGGCCTCCGACG SEQ ID NO: 36: Nucleotide sequence of FX binding scFv – heavy chain GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCT CTGGATTCACCTTCAGTAGCTATGCTATACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGC AGTTATATCATATGATGGAAGTCATAAATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGAC AGTTCCAAGGACACGCTGTATCTGCAAATGAACAGTCTGGGAGCCGAGGACACGGCTGTGTATTACTGTGCAA GAGCAACTACTGCTGCTCGAAATGGTCTTGATATCTGGGGGCAAGGGACCACGGTCACCGTCTCGAGT SEQ ID NO: 37: Nucleotide sequence of FX binding scFv – heavy chain CDR1 GGATTCACCTTCAGTAGCTATGCT SEQ ID NO: 38: Nucleotide sequence of FX binding scFv – heavy chain CDR2 ATATCATATGATGGAAGTCATAAA SEQ ID NO: 39: Nucleotide sequence of FX binding scFv – heavy chain CDR3 GCAAGAGCAACTACTGCTGCTCGAAATGGTCTTGATATC SEQ ID NO: 40: Amino-Acid sequence of Bi8 with HLE DIQMTQSPSSLSASVGDRVTITCKASRNIERQLAWYQQKPGQAPELLIYQASRKESGVPDRFSGSRYGTDFTL TISSLQPEDIATYYCQQYSDPPLTFGGGTKVEIKGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAA SGFTFSYYDIQWVRQAPGKGLEWVSSISPSGQSTYYRREVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA RRTGREYGGGWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEVQLLESGGGVVQPGRSLRLSCAASGFTFSSY AIHWVRQAPGKGLEWVAVISYDGSHKYYADSVKGRFTISRDSSKDTLYLQMNSLGAEDTAVYYCARATTAARN GLDIWGQGTTVTVSSGGGGSGGGGSGGGGSDIVMTQSPLSLHVTLGQPASISCRSSQSLVYSDGNTYLNWFQQ RPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKITRVEAEDVGVYYCMQGTHWPPTFGQGTKVEIKGGGG SGGGGSGGGGSEVQLVESGGGLVQAGGSLRLSCTASGRTFTPYTMGWFRQAPGKEREFVASILWSGNNRDYAD SVKGRFAISRDNAKNTAYLQMTSLKPEDTAVYYCAAGDGLGFYRSVNQYDYWGQGTQVTVSSHHHHHH SEQ ID NO: 41: Amino acid sequence of Albumin targeting VHH EVQLVESGGGLVQAGGSLRLSCTASGRTFTPYTMGWFRQAPGKEREFVASILWSGNNRDYADSVKGRFAISRD NAKNTAYLQMTSLKPEDTAVYYCAAGDGLGFYRSVNQYDYWGQGTQVTVSS SEQ ID NO: 42: CDR1 sequence of Albumin targeting VHH GRTFTPYTMG SEQ ID NO: 43: CDR2 sequence of Albumin targeting VHH SILWSGNNRDYADSVKG SEQ ID NO: 44: CDR3 sequence of Albumin targeting VHH GDGLGFYRSVNQYDY SEQ ID NO: 45: Nucleotide sequence of Bi8 with HLE GACATCCAGATGACACAGTCACCCAGCTCACTCTCTGCCTCAGTAGGGGACCGAGTGACAATCACATGTAAGG CCTCCAGAAACATTGAGAGGCAGCTCGCATGGTACCAACAGAAGCCGGGACAGGCTCCGGAACTGCTGATTTA TCAGGCATCACGCAAGGAGAGTGGCGTCCCCGATCGGTTCTCTGGCAGTAGATACGGCACTGACTTTACACTG ACTATTTCTAGCCTTCAGCCAGAAGATATCGCTACTTACTATTGCCAGCAGTACTCCGACCCCCCGTTGACAT TTGGCGGCGGAACGAAAGTCGAAATCAAAGGCGGTGGCGGCTCTGGCGGAGGTGGCTCTGGCGGAGGCGGCAG CCAAGTGCAACTGGTCGAGTCTGGTGGCGGCCTCGTGCAGCCAGGAGGTTCACTTAGACTGTCCTGCGCTGCT AGTGGCTTTACTTTCAGCTACTACGACATCCAGTGGGTGCGCCAGGCCCCAGGGAAGGGGCTTGAGTGGGTAA GTTCTATTTCCCCATCCGGCCAGTCTACTTACTATCGGCGGGAGGTCAAAGGGAGATTCACCATCTCCCGCGA CAATTCAAAGAACACATTGTACTTGCAAATGAACTCCCTGCGCGCAGAGGACACCGCCGTCTACTATTGCGCG AGACGCACAGGGCGGGAGTACGGTGGTGGTTGGTATTTCGATTATTGGGGGCAAGGAACACTCGTAACGGTCT CATCAGGTGGCGGAGGTAGTGGAGGAGGTGGCTCTGGAGGGGGCGGTTCAGAGGTGCAGCTGTTGGAGTCTGG GGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTAT GCTATACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGTC ATAAATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAGTTCCAAGGACACGCTGTATCT GCAAATGAACAGTCTGGGAGCCGAGGACACGGCTGTGTATTACTGTGCAAGAGCAACTACTGCTGCTCGAAAT GGTCTTGATATCTGGGGGCAAGGGACCACGGTCACCGTCTCGAGTGGAGGCGGAGGGTCTGGGGGCGGCGGTA GCGGCGGAGGAGGAAGCGATATTGTGATGACCCAGTCTCCACTCTCCCTGCACGTCACCCTTGGACAGCCGGC CTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGTGATGGAAACACCTACTTGAATTGGTTTCAGCAG AGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCA GCGGCAGTGGGTCAGGCACTGATTTCACACTGAAGATCACCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTA CTGCATGCAAGGTACACACTGGCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAGGGGGTGGTGGA TCAGGTGGTGGAGGAAGCGGTGGAGGGGGCTCCGAAGTGCAGCTCGTAGAATCAGGTGGTGGTCTTGTTCAAG CTGGGGGTTCACTGAGGTTGTCTTGTACTGCGAGTGGCCGAACCTTTACTCCGTACACGATGGGATGGTTTAG GCAAGCACCAGGAAAGGAGCGGGAATTTGTTGCATCTATTCTCTGGAGTGGAAACAATAGGGACTATGCAGAT AGTGTGAAGGGTCGCTTCGCCATTTCCCGGGACAATGCCAAGAACACAGCTTACCTCCAGATGACAAGCCTCA AGCCGGAGGATACAGCCGTATATTATTGCGCTGCCGGCGATGGTCTCGGGTTTTACAGAAGCGTGAATCAGTA CGACTACTGGGGACAAGGCACTCAGGTTACTGTATCAAGCCACCATCACCATCACCAT SEQ ID NO: 46: Nucleotide sequence of Albumin targeting VHH GAAGTGCAGCTCGTAGAATCAGGTGGTGGTCTTGTTCAAGCTGGGGGTTCACTGAGGTTGTCTTGTACTGCGA GTGGCCGAACCTTTACTCCGTACACGATGGGATGGTTTAGGCAAGCACCAGGAAAGGAGCGGGAATTTGTTGC ATCTATTCTCTGGAGTGGAAACAATAGGGACTATGCAGATAGTGTGAAGGGTCGCTTCGCCATTTCCCGGGAC AATGCCAAGAACACAGCTTACCTCCAGATGACAAGCCTCAAGCCGGAGGATACAGCCGTATATTATTGCGCTG CCGGCGATGGTCTCGGGTTTTACAGAAGCGTGAATCAGTACGACTACTGGGGACAAGGCACTCAGGTTACTGT ATCAAGC SEQ ID NO: 47: Nucleotide sequence of CDR1 sequence of Albumin targeting VHH GGCCGAACCTTTACTCCGTACACGATGGGA SEQ ID NO: 48: Nucleotide sequence of CDR2 sequence of Albumin targeting VHH TCTATTCTCTGGAGTGGAAACAATAGGGACTATGCAGATAGTGTGAAGGGT SEQ ID NO: 49: Nucleotide sequence of CDR3 sequence of Albumin targeting VHH GGCGATGGTCTCGGGTTTTACAGAAGCGTGAATCAGTACGACTAC Examples Example 1- Materials and Methods Production and purification of recombinant Bi8 The coding sequences of Bi8 or Bi8 – HLE were cloned in the pcDNA3.1hygro(+) expression vector for protein expression and recombinant antibodies were produced in- house using transient transfections in the mammalian Expi293 expression system (Gibco). High-density Expi293F™ cells were sub-cultured routinely at 37°C, 8% CO2and 130rpm in Expi293 expression medium. For transfections, cells were seeded the day before at 1x106viable cells per ml in Expi293 expression medium. On the following day, desired volumes of cell suspensions were transfected with pcDNA3.1hygro_Bi8 plasmid, using ExpiFectamine™ according to the manufacturer’s instructions. 16 to 18h post-transfection, cells were fed with production enhancers as per recommendations to increase protein yields, and cultures were incubated for an additional 5 days. Production supernatants were harvested clarified by both centrifugation (4000g for 20min) to remove the cells and filtration through a 0.22µm filter. Recombinant Bi8 antibodies were purified by affinity chromatography using 5mL HiTrap™ columns with the MabSelect™ PrismA resin (Cytiva) on an ÄKTA avant 25 system (Cytiva). The purified antibodies were eluted from the column at low pH with a 50mM glycine, 150mM NaCl, pH3 buffer and immediately neutralized with 2% v / v of a 2M Tris-Base solution, pH8.3. Post-purification, recombinant Bi8 was buffer exchanged HEPES buffer containing 50mM N-2-hydroxyethylpiperazine- N-2-ethane sulfonic acid, 150mM NaCl, at pH7.6 and stored at -80°C. AAV production and purification A liver specific expression cassette containing the coding sequence of Bi8 or Bi8 – HLE was inserted between the Inverted Terminal Repeat (ITR) motifs of a pAAV specific backbone (serotype 2) to generate a single-stranded transfer plasmid, and the human embryonic kidney HEK-293T cell line was used to produce the AAV vectors. The day preceding the transfection, 1.5x107cells were seeded in a 150mm culture dish with a growth media composed of high glucose DMEM (4.5g / L - Gibco) supplemented with 10% v / v foetal bovine serum (FBS). A transient co-transfection of the pAAV transfer plasmid with adenoviral helper (HGTI) and AAV8 capsid element plasmids to produce AAV vector pseudotyped with serotype 8 was performed using polyethylenimine (PEI). The transfection media was replaced with fresh production media (High glucose DMEM) 24h post-transfection, and a 2-day production step was carried-out. Both cells and supernatant were collected at the end of the production. Harvested cells were lysed by freeze / thaw cycles to extract intracellular rAAV. The cell lysate and supernatant were clarified by both centrifugation (4000g for 20min) to remove the cells debris and filtration through a 0.22µm filter before being mixed. Recombinant AAVs were purified from this preparation by affinity-chromatography using the POROS-AAVX resin (Cytiva) on an ÄKTA avant 25 system (Cytiva). AAVs were eluted in pH2.7 glycine buffer (50mM) prior to a rapid neutralisation using a 2M Tris buffer (pH8.8). The peak fractions were pooled and dialysed in phosphate buffer saline (PBS) using a 10kDa cut-off Slide-A-Lyzer cassette (Thermofisher). The post-dialysis preparation was concentrated 10-times using a 100kDa Amicon centrifugal filter (Merck- Millipore). AAV titre was quantified by qPCR with primers annealing to the polyA tail region in the expression cassettes. SDS-page migration Recombinant Bi8 samples were prepared NuPAGE LDS Sample buffer (Invitrogen) with or without the presence of NuPAGE sample reducing agent (Invitrogen) and denaturated for 10min at 90°C. 1ug of denaturated sample was loaded in a NuPAGE 4−12% bis-Tris precast gel (Invitrogen) and migration was performed between 120 and 180 V in MOPS-SDS running buffer (Invitrogen). 5uL of prestained PageRuler Protein Ladder (Thermofisher) was added in a separated well for molecular weight comparison. Migrated proteins were detected by coloration with PageBlue Protein staining solution (Thermofisher) overnight. Alkaline Gel Intregrity of the AAV-packaged transgenic DNA was evaluated by migration on a 0.8% agarose gel prepared in alkaline running buffer (50 mM NaOH, 1 mM EDTA). 30 μL of AAV preparation was mixed with 6 μL of loading buffer (300 mM NaOH, 6 mM EDTA, 30% glycerol, 1.8% SDS, xylene cyanole) and loaded on the gel. Electrophoresis was run at 10V for 17h30 at 4°C. The gel was neutralised 2h in 3 gel volumes of 0.1M Tris, pH 8.0 under gentle rocking, washed in tap water, and stained for 5min in the dark with 1 gel volume of 2x SYBRTMGold (ThermoFisher) diluted in 0.1M NaCl. Images were acquired on a ChemiDocTMimaging system (Biorad). Chromogenic assay for FVIII mimetic activity The FVIII mimetic activity of Bi8 was evaluated by measuring the FIX-mediated activation of FX into FXa, using the FXa specific S-2765 chromogenic substrate. In a polystyrene 96 flat-bottom half-well plate (Greiner Bio-one), 50uL of a coagulation factor solution containing 40uM phospholipid-TGT (Rossix AB), 280nM of plasma-derived human FX (Coagadex®, Bio Product Laboratory) and 6nM of plasma-derived human FIXa (Haematologic Technologies) in running buffer (50mM Tris-Base, 150nM NaCl, 0.1% BSA-protease free, pH 7.8) was mixed with 25uL of Bi8 at 40nM and incubated 15min at 37°C. 25uL of S-2765 chromogenic substrate (Chromogenix) diluted at 1.2mM in running buffer with 20mM CaCl2 was then added to each well and the kinetic of chromogenic conversion was immediately recorded at 405nm on a plate reader (SpectraMax m3, Molecular Devices) for 60min at 37°C (1 read / minute, 2sec shake before each read). The marketed FVIII mimetic antibody emicizumab used as a positive control was obtained from left-over vials of the commercial Hemlibra™ provided by the Katharine Dormandy Haemophilia and Thrombosis center (Royal Free hospital, London) Activated Partial Thromboplastin Time (aPTT) A citrated pool of human plasma made from at least 20 healthy volunteers was spiked with 200 Bethesda Units (BU) of a FVIII-neutralising polyclonal antibody (PAHFVIII-S, Haematologica Technologies) to removed FVIII activity. The induced haemophilia A plasma was then supplemented with 350nM of recombinant Bi8 and incubated for 15min at room temperature. Clotting time was measured on an ACL Top 700 coagulometer (Werfen Limited) using the silica-based aPTT synthaSil reagents (Werfen Limited). FXIa triggered thrombin generation assay (TGA) Thrombin generation was measured with the calibrated automated thrombogram (CAT) method on a thrombinoscope (Diagnostica stago). FVIII activity was neutralized as previously described in a pool of human plasma with 200BU of anti-FVIII antibody. The neutralised plasma was then supplemented with 350nM of recombinant Bi8 and incubated for 15min at room temperature. For each condition, 80uL of plasma was distributed in an Immulon 2HB U-bottom plate (Diagnostica Stago) and mixed with 20uL of trigger solution composed of 2.35nM of human FXIa and 100uM of phospholipid-TGT (Rossix AB) diluted in running buffer (50mM Tris-Base, 150nM NaCl, 0.1% BSA-protease free, pH 7.8). The plate was incubated for 10min at 37°C and thrombin generation was initiated by the automated injection of 20uL of pre-warmed FluCa reagent. Time to peak and Endogenous Thrombin Potential (ETP) are calculated respectively as time to maximum thrombin generation and the area under the thrombogram curve. Quantification of Bi8 expression Bi8 levels in cell supernatant and mice plasma samples were quantified using an enzyme-linked immunosorbent assay (ELISA). Polystyrene 96 flat-bottom half-well plates (Greiner Bio-one) were coated with 5 µg / mL of human FX protein (Coagadex®, Bio Product Laboratory) diluted in carbonate buffer (Na2CO312.2 mM, NaHCO335 mM, pH 9.6) overnight at 4 °C. Plates were washed 3 times in TBS.T (50 mM Tris-Base, 150 mM NaCl, 0.1% Tween20, pH 7.8) and non-specific binding sites were saturated with TBS.T + 3% BSA for 1 h at 37 °C. Following a 3x wash step, samples were diluted in TBS.T + 1% BSA and incubated for 2 h at 37 °C. Unbound samples were washed 3x in TBS.T and bound antibodies were detected by the 6xhistidine tag motif using a HRP-labelled monoclonal anti-His tag antibody (clone J099B12, Biolegend) diluted 1:2500 in TBS.T + 1% BSA and incubated for 2 h at 37 °C. After a final 3x wash step, the plates were incubated with slow kinetic 3,3′,5,5′-tetramethylbenzidine (TMB) substrate and colour was allowed to develop for 5−15 min. The reaction was stopped by the v / v addition of 2 M H2SO4, and optical density was read at 450 nm within 30 min on a SpectraMax m3 (Molecular Devices). The standard curve was established with purified recombinant B8. HuH7 models The human hepatocellular carcinoma cell line HuH7 was used as a model of human hepatocyte to evaluate the expression of Bi8 following infection with the AAV_Bi8 vector. HuH7 cells were routinely grown in high glucose DMEM Media (Sigma-Aldrich) supplemented with 10% FBS. Cells were seeded at 3x104cells per well in a flat bottom 96 well plate and incubated for 24h at 37°C with 5% CO2. On the day of transduction, AAV vectors were diluted in X-vivo media (Lonza) to reach a range of multiplicity of infection (MOI) comprised between 103and 5x106vector genome (vg) per cells. The cell supernatant was removed and replaced by 100uL of the AAV preparation and incubated for 24h. The AAV containing media was then removed and replaced with 200uL of serum free DMEM media and incubated for an additional 2 days. The supernatant was collected, clarified by centrifugation (15min at 4000g) and further used to evaluate expression levels and FVIII mimetic activity of AAV-derived Bi8. Characterisation of AAV_Bi8 vectors in haemophilia A mice. AAV vectors encoding the sequence of Bi8 were characterised in haemophilia A mice. FVIII deficient male mice, on a C57 / Bl6 genetic background, and aged 8 – 12 weeks, received a single intravenous injection in the lateral tail vein of AAV_Bi8 vector diluted in X-Vivo media (Lonza). Animals were monitored for up to 8 weeks and blood samples were taken every 2 weeks by retro-orbital puncture on 10% of 0.139M sodium citrate anticoagulant to evaluate expression of the transgenic constructs. To procoagulant potential in vivo of AAV_Bi8, treated mice were challenged 3 weeks post-AAV infusion in a tail vein transection (TVT) bleeding model as previously described in (Johansen PB et al., Haemophilia 2016). Mice were first anesthetised using gaseous isoflurane (Dechra) in a non-recovery procedure. A retro-orbital injection with a mixture of 100U / kg of both human FIX (BeneFix, Pfizer) and FX (Haematologic Technologies) was then given 5 minutes before the assay. The lateral tail vein was transected, and the severed tail was then immersed in prewarmed physiological saline (37°C), and blood was collected for 45 minutes. The volume of blood loss was quantified by measuring the amount of haemoglobin in the collection tube by spectrophotometry at 416nm and calculated from a standard curve. Anti-drug antibody ELISA assay The presence of anti-drug antibodies (ADAs) targeting Bi8 was detected in mice plasma using an ELISA method as described before. Briefly, 96 flat-bottom half-wells were coated with recombinant Bi8 at 5ug / mL overnight in carbonate buffer. Plasma samples from AAV-treated mice were diluted 1:20 in TBS.T + 1% BSA and incubated for 2h at 37 °C. Potential ADAs bound to Bi8 were then detected with an HRP-labelled goat polyclonal anti-mouse Fc (Invitrogen, A16084), diluted 1:5000 in TBS.T + 1% BSA and incubated for 2h at 37 °C. Positive controls were performed by spiking non-treated mice plasma with various concentrations of a monoclonal anti-his tag antibody (Biolegend, 652502) to simulate the presence of antibody targeting Bi8. Example 2: Design of a single chain FVIII mimetic antibody compatible with expression cassette of AAV vectors Full-size bispecific immunoglobulin G (IgGs), including the FVIII mimetic antibodies either marketed for the treatment of haemophilia A or in clinical development, are complex multimeric proteins composed of at least 3 or 4 different peptide chains that requires a precise assembly to yield a functional molecule. Their size, as well as the complexity of this assembly process makes these antibody formats poorly compatible with the design of short sized expression cassettes that would be required for a stable expression by AAV-mediated gene transfer. To address this limitation, Bi8 was engineered as small-sized single-chain FVIII mimetic antibody, which simultaneously remove the difficulties related to the size or multimeric assembly and bispecific antibodies. Single chain Fragments variable (scFv) targeting human coagulation FIX and FX were fused together by a flexible linker made of a 3x repeat of a G4S motif to form a bispecific tandem of scFv with a molecular weight of approximately 54.5 kDa (Figure 1). Following production in mammalian cell and purification by affinity chromatography, the migration pattern of a recombinant Bi8 antibody (recBi8) was evaluated in reducing and non reducing conditions by electrophoresis (Figure 2). In both conditions, recBi8 displayed a single discrete band on a Coomassie Blue gel at the expected size of a bispecific tandem of scFvs and showing only intact material. Example 3: In vitro evaluation of the FVIII mimetic potential of a recombinant Bi8 The function of FVIII mimetic antibodies is to enhance the FIXa mediated catalytic conversion of FX into activated FXa by simultaneously binding the 2 coagulation factors and is therefore likely dependant on the binding orientation between the bispecific antibody and its 2 targets. To evaluate whether the format of a bispecific tandem of scFvs used to designed Bi8 can support the catalytic reaction, its FVIII mimetic activity was measured in a kinetic chromogenic assay reproducing this enzymatic reaction (Figure 3). While in absence of bispecific antibody, little if no activation of FXa could be observed, the progressive conversion of the chromogenic substrate in presence of recBi8 demonstrated that this bispecific format displays FVIII mimetic activity and successfully enhanced the FIXa mediated catalytic activation of FX. In addition, the kinetic profile obtained with recBi8 was identical to that of positive control made with the marketed FVIII mimetic antibody emicizumab, which has already demonstrated it clinical efficacy (Figure 3). To further evaluate the magnitude of its FVIII mimetic activity, the ability of recBi8 to correct the clotting deficiency of human haemophilia A plasma was assessed in an aPTT assay. In this setting, the absence of FVIII severely increase the clotting time of haemophilia A plasma (mean ± SD; 99.8 ± 5.6 sec) when compared to a pool of healthy individuals (30.6 ± 1.8). However, when recBi8 is spiked at 350nM in haemophilia A plasma, the aPTT clotting time is significantly reduced to an average of 19.0 ± 3.2 sec, thus demonstrating the procoagulant capacity of this single chain FVIII mimetic antibody (Figure 4). In addition, the ability recBi8 to induce the formation of thrombin, a critical parameter in the coagulation cascade, was also evaluated in vitro. When spiked at the same concentration of 350nM, the presence of recBi8 successfully restored the formation of thrombin in haemophilia A plasma when coagulation was triggered with activated FXIa (Figure 5A). Interestingly, the time to peak corresponding to the time to reach the maximal level of thrombin formation was apparently reduced, but not significant, when compared to a pool of normal plasma (Figure 5B) which is a feature previously described in other FVIII mimetic antibodies. However, the endogenous thrombin potential (ETP) in presence of recBi8 was equivalent to that of the pool of normal plasma (1574 ± 239 and 1592 ± 144 nM. min respectively, mean ± SD) supporting the conclusion that recBi8 displays FVIII mimetic activity fully capable of correcting the FVIII deficiency of haemophilia A plasma (Figure 5B). Example 4: Engineering and in vitro evaluation of an AAV vector encoding the sequence of Bi8 The expression cassette used for the adaptation of Bi8 to an AAV vector approach was designed to specifically target liver transduction. The coding sequence of Bi8 was inserted downstream of the hepatic control region enhancer / human alpha-1 anti-trypsin promoter (HCR hAAT) complex which drives a strong liver specific expression of the transgene (Figure 6A). With addition of the polyadenylation region and inverted terminal repeats (ITR) required for AAV packaging, the transgenic expression cassette for Bi8 is 4.4 kbases in length, which is well within the packaging capacity of AAV capsids which can tolerate up to 5 kbases. This was confirmed, following the production and purification of AAV particles using the capsid serotype of AAV8, by evaluating the profile of packaged transgenic DNA on an alkaline gel (Figure 6B). As expected, AAV_Bi8 showed a strong band of DNA at 4.4 kbases corresponding to the intact transgenic cassette. The ability of the AAV_Bi8 vector to induce expression of a fully functional transgenic Bi8 construct was evaluated in vitro using the human hepatocyte cell line Huh7. When transduced with increasing MOI of AAV_Bi8, ranging from 103to 5x106vector genome (vg) per cells, HuH7 cells showed a dose-dependant expression of transgenic Bi8 detectable in the supernatant (Figure 7A). FVIII mimetic activity of the transgenic Bi8 produced by transduced HUH7 was further evaluated in the chromogenic assay. The bispecific antibody produced by the highest MOI of 5x106was normalised to the activity of the recombinant Bi8 produced. As expected, transgenic Bi8 obtained by AAV-mediated transduction of HuH7 cells showed fully functional FVIII mimetic activity with an activity / antigen ratio at 91.1 ± 13.5 % of the recBi8 molecule (Figure 7B). Example 5: Stable expression of Bi8 in haemophilia A mice following AAV mediated gene transfer The transgenic expression of Bi8 was assess following AAV mediated gene transfer in a model of a haemophilia A mice. Male FVIII deficient mice were dosed with a single infusion of AAV_Bi8 by intravenous injection in the tail vein, using 2 different doses of vector at 4e11and 4e12vg / kg. Treated animals were then monitored for 8 weeks to measure (Figure 8). The circulating concentration of transgenic Bi8 was measured eery 2 weeks in plasma samples. A dose dependant expression of transgenic Bi8 was observed as early as week 2 with circulating levels of respectively 5.7 ± 3.0 and 39.1 ± 10.6 nM (mean ± SD) measured in mice treated with 4e11and 4e12vg / kg of AAV_Bi8 (Figure 9A). Interestingly, for both concentrations of AAV vector, the transgenic expression of Bi8 appeared maximal from week 2 and remained stable until week 8 with no significant changes in the average circulating levels (Figure 9A). Plasma samples collected at week 8 were then used to titrate the possible presence of anti-drug antibodies (ADAs) targeting Bi8. While the positive control incubated with a commercial mouse monoclonal antibody targeting the histidine tag of Bi8 clearly showed the formation of Bi8 – antibody complexes detectable by ELISA, plasma samples from mice treated with both dose of 4e11and 4e12vg / kg remained negatives. With a lower limit of detection at 20ng / mL of ADAs, this absence of signal indicates that the prolonged exposure of haemophilia A mice to circulating levels of Bi8 did not lead to the formation of detectable ADAs (Figure 9B). Example 6: Correction of the bleeding tendency in haemophilia A mice following AAV mediated gene transfer. The therapeutic potential of AAV_Bi8 to correct bleeding was evaluated in haemophilia A mice. As previously, male FVIII deficient mice receive a single infusion of AAV_Bi8 with doses of 4e11, 4e12and 1.2e13vg / kg (Figure 8). The transgenic expression of Bi8 was measured 2 weeks post AAV infusion and showed circulating levels of the FVIII mimetic antibody at and average ±SD of 4.5 ± 2.3; 47.4 ± 16.0 and 178.8 ± 4.6 nM for the respective 3 doses (Figure 10A). The bleeding profile of AAV-treated mice was assessed in a tail vein transection (TVT) model specifically optimised for FVIII mimetic bispecific antibodies as described previously (Johansen PB et al., Haemophilia 2016; Ferriere, Peyron et al. 2020). In this model, which requires the injection of a bolus of human coagulation FIX and FX 5 min before the assay, the blood loss is recorded over a period of 45 min following the tail vein severing (Figure 8). Following the TVT induction, non-treated haemophilia A mice display a strong bleeding phenotype with blood loss of between 516.7 and 929.1 µL (median = 732.0 µL (Figure 10B)). However, all 3 cohorts of animal treated with AAV_Bi8 showed evidence of haemostatic correction of the bleeding phenotype. Indeed, most mice treated with AAVs had a reduced bleeding tendency below the 75 percentiles of the control group. The therapeutic response was dose-dependent, with significantly reduced median blood loss values of 372.0, 78.5, and 12.0 µL for the 4e11, 4e12and 1.2e13vg / kg cohorts, respectively (Figure 10B). The 1.2e13vg / kg cohort achieved blood loss levels comparable to wild-type animal, thus establishing the efficacy of AAV vectors to deliver a functional single chain FVIII mimetic antibody at therapeutic levels sufficient to correct the bleeding phenotype of haemophilia A mice. Example 7: Half-life extension of the single chain FVIII mimetic antibody Bi8 Antibodies using the single-chain tandem scFv, such as Bi8, generally have short half-lives (1-2 hours) in humans. However, fusion with moieties binding to albumin, that interact with the neonatal Fc receptor (FcRn) pathway, can extend the circulating half-life through the FcRn-mediated recycling mechanism. Expression of an antibody with a longer half-life will therefore increase steady-state levels after gene transfer, potentially reducing the required AAV vector dose to achieve therapeutic efficacy. A variant of Bi8 with extended half-life (Bi8 – HLE) was developed by fusion of an albumin-binding heavy chain only antibody fragment (VHH), derived from camelids, to the C-terminus part of the single-chain FVIII mimetic antibody. The VHH was connected downstream of the FX-targeting scFv with a 3x repeat of a G4S motif to produce a trispecific single-chain antibody of approximately 69.0 kDa (Figure 11). The migration pattern of both recombinant Bi8 and Bi8 – HLE, produced in mammalian cells, was evaluated by SDS-Page electrophoresis. A single discrete band could be observed at the expected size for both constructs, and only showed the intact antibody (Figure 12A). The FVIII mimetic activity of Bi8 – HLE was further evaluated using the chromogenic assay previously described. Increasing concentrations of Bi8 – HLE in the assay led to a dose- dependant activation of FX into FXa (Figure 12B). In addition, the FVIII mimetic activity of Bi8 – HLE was comparable to that of the parental Bi8 antibody, thus demonstrating that the biological activity of the FVIII mimetic antibody is not affected by the presence of the albumin-binding VHH fused in C-terminus position (Figure 12B). Example 8: In vitro evaluation of AAV vectors encoding Bi8 – HLE The coding sequence of Bi8 – HLE was cloned using the same liver-specific expression cassette previously used for the parental Bi8, and under the control of the HCR hAAT promoter complex (Figure 6A). Presence of the albumin-binding VHH fused in C- terminus of the single-chain bispecific antibody extended the total size of the transgenic cassette to 4.7 kbases, which remains within the packaging capabilities of AAV capsids (Figure 13A). Indeed, following the production of AAV vectors using the capsid serotype of AAV8 and coding for either Bi8 or Bi8 - HLE, we confirmed the integrity of the packaged DNA by electrophoresis on an alkaline gel. Both constructs showed a single band of DNA at 4.4 and 4.7 kbases respectively, corresponding to the intact expression cassette (Figure 13B). The ability of recombinant AAV vectors to induce expression of Bi8 or Bi8 – HLE was further tested in the HuH7 cell model. In cells exposed to a single dose of AAV vectors at 1x106vg / cell, the concentration of antibody detected in the supernatant 48h post transduction was in a comparable range between Bi8 and the Bi8 – HLE variant, with a mean ±SD of 92.7±63.8 and 173.7±77.0 pM respectively (Figure 14). This result suggests that AAV-mediated expression of Bi8 in a cellular system is not affected by the presence of the albumin-binding element, and highlights the therapeutic potential of this construct for an AAV-based gene therapy inducing the expression of a single-chain FVIII mimetic antibody with extended half-life. Embodiments 1. A viral particle comprising a polynucleotide of no more than 5.0 kb in length encoding a first antigen binding domain and a second binding domain, wherein the first antigen binding domain and second binding domain each comprise a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises a light chain complementarity determining region (LCDR)1, an LCDR2 and an LCDR3, and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3; wherein for the first antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 1; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 2; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 3; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 4; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 5; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:6; and wherein for the second antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 7; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 9; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 10; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 11; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 12. 2. The viral particle of embodiment 1, wherein the polynucleotide encodes a single chain Fv protein (scFv) comprising the first antigen binding domain and a single chain Fv protein comprising the second antigen binding domain. 3. The viral particle of embodiment 1 or 2, wherein in the first antigen binding domain the light chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO: 13 and the heavy chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO: 14, and wherein in the second antigen binding domain the light chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO: 15 and the heavy chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO: 16. 4. An antigen binding protein composed of a single polypeptide chain, wherein the single polypeptide chain is composed of a first antigen binding domain and a second binding domain, wherein the first antigen binding domain selectively binds coagulation FIX and second binding domain selectively binds coagulation FX, and wherein the first antigen binding domain and second binding domain each comprise a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises a light chain complementarity determining region (LCDR)1, an LCDR2 and an LCDR3, and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3; wherein the first antigen binding domain selectively binds coagulation FIX; and wherein for the second antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 7; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 9; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 10; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 11; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 12. 5. The antigen binding protein of embodiment 4, wherein the first antigen binding domain comprises an scFv and the second antigen binding domain comprises an scFv.

Claims

CLAIMS 1. An antigen binding protein with FVIII mimetic activity composed of a single polypeptide chain.

2. The antigen binding protein of claim 1, wherein the single polypeptide chain comprises a first antigen binding domain and a second binding domain.

3. The antigen binding protein of claim 2, wherein the first antigen binding domain selectively binds coagulation FIX and second binding domain selectively binds coagulation FX.

4. The antigen binding protein of claim 1 and 2, wherein the first antigen binding domain and second binding domain each comprise a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises a light chain complementarity determining region (LCDR)1, an LCDR2 and an LCDR3, and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3; wherein the first antigen binding domain selectively binds coagulation FIX; and wherein for the second antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 7; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 9; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 10; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 11; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:

12.

5. The antigen binding protein of any one of claims 1 to 4, wherein the first antigen binding domain and second binding domain each comprise a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises a light chain complementarity determining region (LCDR)1, an LCDR2 and an LCDR3, andwherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3; wherein for the first antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 1; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 2; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 3; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 4; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 5; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 6; and wherein for the second antigen binding domain LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 7; LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 9; and wherein the heavy chain variable domain comprises a heavy chain complementarity determining region (HCDR)1, an HCDR2 and an HCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 10; HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 11; and HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:

12.

6. The antigen binding protein of any one of claims 1 to 5, wherein for the first antigen binding domain the light chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO: 13 and the heavy chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO: 14, and for the second antigen binding domain the light chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO: 15 and the heavy chain variable domain comprises the amino acid sequence as set forth as SEQ ID NO:

16.

7. The antigen binding protein of any one of claims 1 to 6, wherein first antigen binding domain comprises the amino acid sequence as set forth as SEQ ID NO: 17 and the second antigen binding domain comprises the amino acid sequence as set forth as SEQ ID NO: 18.

8. The antigen binding protein of any one of claims 1 to 7, wherein the antigen binding protein comprises the amino acid sequence as set forth as SEQ ID NO:

19.

9. The antigen binding protein of any one of claims 1 to 8, wherein the antigen binding protein further comprises a third antigen binding domain, wherein the third binding domain binds a protein that interacts with FcRn.

10. The antigen binding protein of claim 9, wherein the third antigen binding domain binds to albumin.

11. The antigen binding protein of claim 9 or claim 10, wherein the third antigen binding domain comprises a CDR1, CDR2 and a CDR3 sequence, wherein the CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 42; CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 43; and CDR3 comprises the amino acid sequence set forth in SEQ ID NO:

44.

12. The antigen binding protein of any one of claims 9 to 11, wherein the third antigen binding domain comprises a VHH domain.

13. The antigen binding protein of any one of claims 9 to 12, wherein the third antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO:

41.

14. The antigen binding protein of any one of claims 9 to 13, wherein the antigen binding protein comprises the amino acid sequence set forth in SEQ ID NO:

40.

15. A polynucleotide of no more than 5.0 kb in length comprising a nucleic acid sequence encoding the antigen binding protein as defined in any one of claims 1 to 14.

16. The polynucleotide of claim 15, comprising a promoter upstream of the nucleic acid sequence encoding the antigen binding protein.

17. The polynucleotide of claim 16, wherein the promoter is a liver-preferred or liver- specific promoter.

18. The polynucleotide of claim 17, wherein the liver-preferred or liver-specific promoter comprises a hepatic control region enhancer / human alpha-1 anti-trypsin promoter (HCR hAAT) complex.

19. The polynucleotide of any one of claims 15 to 18, further comprising a first ITR upstream of the promoter, and a second ITR downstream of the nucleic acid sequence encoding the antigen binding protein.

20. The polynucleotide of any one of claims 15 to 19, further comprising a polyadenylation sequence downstream of the nucleic acid sequence encoding the antigen binding protein and upstream of the second ITR.

21. The polynucleotide of any one of claims 15 to 20, wherein the nucleic acid sequence encoding the antigen binding protein encodes a single chain Fv protein (scFv) comprising the first antigen binding domain and a single chain Fv protein comprising the second antigen binding domain, optionally wherein the nucleic acid sequence encoding the antigen binding protein encodes a third antigen binding domain, wherein the third antigen binding domain binds a protein that interacts with FcRn.

22. The polynucleotide of any one of claims 15 to 21, wherein the nucleic acid sequence encoding the antigen binding protein comprises SEQ ID NO: 21 or SEQ ID NO:

45.

23. A viral particle comprising the polynucleotide as defined in any one of claims 15 to 22.

24. The viral particle of claim 23, which is an AAV viral particle, preferably wherein the capsid of the AAV is AAV8.

25. A composition comprising the antigen binding protein, polynucleotide or viral particle of any one of the preceding claims and a pharmaceutically acceptable excipient.

26. An isolated host cell transformed with the polynucleotide or viral particle of any one of claims 15 to 24.

27. The antigen binding protein, polynucleotide, viral particle or composition of any one of claims 1 to 25 for use in a method of treatment.

28. The antigen binding protein, polynucleotide, viral particle or composition for use according to claim 27, wherein the method of treatment comprises administering an effective amount of the antigen binding protein, polynucleotide, viral particle or composition of any one of claims 1 to 25 to a patient.

29. The antigen binding protein, polynucleotide, viral particle or composition for use according to claim 28, wherein the method of treatment is a method of treating haemophilia.

30. The antigen binding protein, polynucleotide, viral particle or composition for use according to claim 29, wherein the method of treatment is a method of treating haemophilia A.

31. An AAV genome comprising a polynucleotide encoding a FVIII mimetic antigen binding protein for use in a method of gene therapy, optionally wherein the FVIII mimetic antigen binding protein is defined according to any one of claims 1 to 14.

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