WO2014125082A1 - Pharmacokinetic animal model - Google Patents
Pharmacokinetic animal model Download PDFInfo
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- WO2014125082A1 WO2014125082A1 PCT/EP2014/052944 EP2014052944W WO2014125082A1 WO 2014125082 A1 WO2014125082 A1 WO 2014125082A1 EP 2014052944 W EP2014052944 W EP 2014052944W WO 2014125082 A1 WO2014125082 A1 WO 2014125082A1
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- Prior art keywords
- hsa
- albumin
- fcrn
- human
- animal
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Classifications
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0278—Knock-in vertebrates, e.g. humanised vertebrates
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
- C07K14/765—Serum albumin, e.g. HSA
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
- A01K2217/052—Animals comprising random inserted nucleic acids (transgenic) inducing gain of function
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/072—Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/107—Rabbit
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/108—Swine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/02—Animal zootechnically ameliorated
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/76—Assays involving albumins other than in routine use for blocking surfaces or for anchoring haptens during immunisation
- G01N2333/765—Serum albumin, e.g. HSA
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/20—Screening for compounds of potential therapeutic value cell-free systems
Definitions
- the present invention relates to a method of assessing one or more (several) pharmacokinetic properties of a variant of human serum albumin (including modified albumin such as genetic fusions, conjugates and associates) using a non-primate animal species.
- the present invention also relates to animal models which are particularly suitable for assessing one or more (several) pharmacokinetic properties of human serum albumin variants or modifications thereof.
- Albumin is a protein naturally found in the blood plasma of mammals where it is the most abundant protein. It has important roles in maintaining the desired osmotic pressure of the blood and also in transport of various substances in the blood stream.
- the neonatal Fc receptor (FcRn) "Brambell” is a bifunctional molecule that contributes to maintaining a high level of immunoglobulins of isotype G (IgGs) and albumin in serum in mammals such as human beings. FcRn has been found to salvage albumin and IgG from intracellular degradation by a pH dependent mechanism thus prolonging its serum half-life. The plasma half-life of wild type human serum albumin (HSA) has been found to be approximately 19 days.
- albumin in drug delivery is well described.
- Therapeutic active agents may for example be conjugated to albumin (WO 2000/69902) or therapeutic active polypeptides may be fused genetically to albumin and expressed as chimeric proteins (WO 2001/79271 and WO 2003/59934) or small acidic or hydrophobic therapeutic active agents may associate reversibly to albumin (Kragh-Hansen et al, 2002, Biol. Pharm. Bull. 25, 695 and WO 2000/71079).
- Reversible binding to albumin can also be achieved for pharmaceutically beneficial compounds, which have little or no albumin binding properties by associating such compounds to a moiety having albumin-binding properties (Kurtzhals et al, 1997, J. Pharm. Sci.
- albumin variants A number of natural albumin variants have been described. Otagiri et al, 2009, Biol. Pharm. Bull. 32(4), 527-534, discloses 77 known albumin variants, 22 are found in domain I, 30 in domain II and 25 are found in domain III. A number of other natural variants have been identified and some of these have been analyzed for FcRn binding (Andersen et al (2010), Clinical Biochemistry 43, 367-372; Galliano et al (1993) Biochim. Biophys. Acta 1225, 27-32; Minchiotti et al (1987) Biochim. Biophys. Acta 916, 41 1 -418; Takahashi et al (1987) Proc. Natl. Acad. Sci.
- Interspecies allometric scaling is based on the assumption that there are anatomical, physiological and biochemical similarities among animals which can be described by simple mathematical models.
- a number of animals species have successfully been used in interspecies allometric scaling including mouse, rat, guinea pig, rabbit, cynomolgus monkey, baboon , rhesus monkey, dog, pig and sheep (Mahmood I. (2004) New Drug Development, Regulatory Paradigms for Clinical Pharmacology and Biopharmaceutics, Edited by Chandrahas G .
- Figure 1 shows binding of albumin variants to shFcRn. Serial dilutions of each albumin variant (10 ⁇ - 0.3 ⁇ ) were injected over immobilized shFcRn at pH 6.0.
- A HSA Wt
- B B
- HSA K573P HSA K573P
- C HSA K573F
- D HSA K573W
- E HSA K573H
- F HSA K573Y.
- FIG. 2 shows binding of albumin variants to soluble rat FcRn (srFcRn). Serial dilutions of each albumin variant (10 ⁇ -0.3 ⁇ ) were injected over immobilized srFcRn at pH 6.0.
- A HSA Wt
- B wild-type rat serum albumin
- C HSA K573P
- D HSA K573F
- E HSA K573W
- F HSA K573H
- G HSA K573Y.
- Figure 3 shows binding of albumin variants to soluble mouse serum albumin (smFcRn).
- Serial dilutions of each albumin variant (10 ⁇ -0.3 ⁇ ) were injected over immobilized smFcRn at pH 6.0, with the exception of Wt HSA (100 ⁇ -3.0 ⁇ ).
- A HSA Wt
- B MSA
- C RSA
- D HSA K573P
- E HSA K573F
- F HSA K573W
- G HSA K573H
- HSA K573Y HSA K573Y.
- Figure 4 shows binding of albumin variants to soluble rhesus macaque FcRn (srmFcRn). Serial dilutions of each albumin variant (10 ⁇ -0.3 ⁇ ) were injected over immobilized srmFcRn at pH 6.0.
- rmSA wild-type rhesus macaque serum albumin
- B MSA
- C RSA
- D HSA K573P
- E HSA K573F
- F HSA K573W
- G HSA K573H
- HSA K573Y HSA Wt.
- Figure 5 shows binding of albumin variants to soluble dog FcRn (dFcRn). Serial dilutions of albumin variants injected over immobilized soluble dog FcRn at pH 6.0.
- DSA wild-type dog serum albumin
- HSA HSA
- C HSA K500A
- D HSA K573P
- E HSA K573W
- F HSA K573F
- G HSA K573Y
- HSA K573H HSA K573H
- I rmSA
- J wild-type pig serum albumin
- PSA wild-type pig serum albumin
- K RSA
- MSA wild-type pig serum albumin
- Figure 6 shows binding of albumin variants to soluble pig FcRn (pFcRn). Serial dilutions of albumin variants injected over immobilized soluble pig FcRn at pH 6.0.
- A PSA
- B HSA
- C HSA K500A
- D HSA K573P
- E HSA K573W
- F HSA K573F
- G HSA K573Y
- H HSA K573H
- I rmSA
- J DSA
- K RSA
- MSA MSA.
- Figure 7 shows selected areas of a ClustalW alignment of FcRn HC from (human, macaque, cow, goat, sheep, camel, pig, dog, guinea pig, rabbit, rat and mouse). Amino acid residues that are identical in all sequences are indicated by ( * ), conserved substitutions are indicated by (:), and semi-conservative substitutions are indicated by (.). V52 and H161 of SEQ ID NO: 16 are highlighted in bold. The alignment parameters were Opening and end gap penalty 10, extending and separation gap penalty 0.5 using scoring matrix Blosum.
- the present invention provides a method for assessing one or more (several) pharmacokinetic properties of a variant human serum albumin (HSA) compared to wild type HSA.
- HSA human serum albumin
- the pharmacokinetic properties of molecules where the Wt HSA and variant HSA is modified by fusion, conjugation or association with a partner such as therapeutic agents, vaccines or diagnostic agents are of particular interest.
- An advantage of the present invention is that it reduces the need for primate animal models for screening of albumin containing drugs by providing a non-primate animal model that can produce profiles of one or more (several) pharmacokinetic properties that can reasonably be extrapolated to indicate what the human pharmacokinetic profiles are likely to look like.
- the animal model used in the method of the present invention is characterized in that the binding affinity of wild type HSA to the native FcRn of said animal is the same as or higher than the binding affinity of the native albumin of said animal.
- binding affinity generally refers to the strength of the sum total of the non- covalent interactions between a single binding site of a molecule (e.g., IgG or albumin) and its binding partner (e.g., an antigen or FcRn). Unless indicated otherwise, as used herein, "binding affinity” refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., albumin and FcRn).
- the affinity of a molecule (X) for its partner (Y) can generally be represented by the equilibrium dissociation constant (K D ), which is calculated as the ratio k off kon (kd/k a ). Binding affinity can be measured by methods known in the art.
- a preferred method is surface plasmon resonance (SPR) for example using a Biacore (GE Healthcare) instrument as exemplified herein.
- SPR surface plasmon resonance
- the binding affinity of endogenous pairs of FcRn and albumin generally range from 0.2 to 3.2 micro Molar
- modified or “modification” in relation to albumin means to change the albumin by adding or deleting molecules unrelated to the amino acid sequence of the albumin, e.g. removing fatty acids or adding a partner molecule.
- the albumin can in in particular be modified by conjugation, fusion or association of a partner. Changes to the amino acid sequence of the albumin (e.g. SEQ ID NO: 2) is termed variants and are not considered modifications.
- conjugation in relation to albumin refers to Wt HSA or a variant HSA or a fragment thereof which is conjugated to a conjugation partner such as a beneficial agent, e.g. a therapeutic agent and/or diagnostic agent. Conjugation can be made to the N-terminal and/or C-terminal of the albumin, but can alternatively or in addition be made to one or more (several) suitable amino acid positions within the albumin. In particular cysteine residues which are not involved in disulfide bonds are suitable for conjugation.
- WO 2010/092135 describes a variant albumin with additional cysteine residues suitable for conjugation.
- WO 2009/019314 discloses examples of techniques suitable for conjugating a conjugation partner, e.g. a therapeutic agent, to a polypeptide which techniques can also be applied to the present invention.
- page 37 to 44 of WO 2009/019314 discloses examples of compounds and moieties that may be conjugated to transferrin and these compounds and moieties may also be conjugated to an albumin variant of the present invention.
- fused or “fusion” in relation to albumin refers to Wt HSA or a variant HSA or a fragment thereof which is genetically fused to a fusion partner such as a beneficial agent e.g. a therapeutic polypeptide and/or diagnostic polypeptide. Fusions are normally either made at the N-terminal or C-terminal of the albumin, or sometimes at both ends. Fusions can in principal alternatively or in addition be made within the albumin molecule, in that case it is preferred to locate the fusion partner between domains of albumin. For example, a fusion partner may be located between Domain I and Domain II and/or between Domain II and Domain III.
- fusion partners e.g. therapeutic polypeptides, that may be fused to albumin or fragments thereof, and these examples apply also to the present invention.
- association in relation to albumin refers to a composition comprising Wt HSA or variant HSA or a fragment thereof and an association partner, such as a therapeutic agent and/or diagnostic agent, bound or associated to the albumin or fragment thereof by non-covalent binding.
- An example of such an associate is an albumin and a lipid associated to the albumin by a hydrophobic interaction.
- Such associates are known in the art and they may be prepared using well known techniques. Molecules which are suitable for association with albumin are known in the art, preferably they are acidic, lipophilic and/or have electronegative features. Examples of such molecules are given in Table 1 of Kragh-Hansen et al, 2002, Biol. Pharm. Bull. 25, 695 (hereby incorporated by reference).
- WO 2000/71079 describes the association of albumin with paclitaxel and paclitaxel is included in the present invention.
- the term "native" in relation to albumin and FcRn refers to the albumin or FcRn proteins that are genetically expressed in a specific animal.
- the native albumin in a mouse is normally the endogenous mouse serum albumin corresponding to UniProt accession number P07724.
- FcRn comprises a FcRn heavy chain (HC) and a beta2 microglobulin (beta2m).
- the native FcRn in a mouse is normally the endogenous mouse FcRn HC corresponding to UniProt accession number Q61559 and mouse beta2mwith UniProt accession number Q91Z73.
- a native albumin or FcRn may however be a transgenic gene which is integrated into the genome of the animal in a stable manner and where the corresponding gene of the animal has been knocked out.
- An example is the transgenic mouse where human FcRn HC has been integrated into the genome of the mouse and the mouse FcRn HC has been knocked out (Roopenian et al (2003) J. Immunol. Vol 170, pp. 3528-3533). In such an animal the human FcRn HC would be considered to be a part of the native FcRn of the transgenic animal.
- the native FcRn may also be an FcRn variant, either naturally occurring or a variant produced by human intervention.
- An example of such a variant is a mouse FcRn (SEQ ID NO: 13) with one or more of the following mutations M73V and E184H.
- wild-type in relation to albumin or FcRn means an albumin or FcRn having the same amino acid sequence as the albumin or FcRn naturally found in an animal or in a human (the endogenous gene sequence of the animal or human). It is understood that Wt albumin or Wt FcRn is without genetic alterations produced by human intervention for example by gene knock-out/knock-in as in the production of transgenic animals.
- SEQ ID NO: 2 is a mature Wt albumin from Homo sapiens. More Wt albumins and Wt FcRn molecules are listed in Tables 1 and 3.
- sequence identity describes the relatedness between two amino acid sequences or between two nucleotide sequences.
- sequence identity describes the relatedness between two amino acid sequences or between two nucleotide sequences.
- sequence identity is determined using the Needleman- Wunsch algorithm (Needleman and Wunsch, 1970, J. Mol. Biol. 48: 443-453) as implemented in the Needle program of the EMBOSS package (EMBOSS: The European Molecular Biology Open Software Suite, Rice er a/., 2000, Trends Genet. 16: 276-277), preferably version 5.0.0 or later.
- the parameters used are gap open penalty of 10, gap extension penalty of 0.5, and the EBLOSUM62 (EMBOSS version of BLOSUM62) substitution matrix.
- therapeutic agent refers to a chemical compound, a mixture of chemical compounds, or a biological macromolecule (e.g. a peptide, protein, lipid, nucleic acid (e.g. DNA or RNA), virus) or a biological macromolecule in association with a chemical compound.
- Therapeutic agents include agents that can either prevent, improve or cure a medical condition.
- the therapeutic agent may be purified, substantially purified or partially purified.
- An “agent”, according to the present invention, also includes a radiation therapy agent and vaccines.
- HSA variant or "variant HSA” means a polypeptide derived from a human serum albumin comprising an alteration, i.e., a substitution, insertion, and/or deletion, at one or more (several) positions.
- a substitution means a replacement of an amino acid occupying a position with a different amino acid;
- a deletion means removal of an amino acid occupying a position; and
- an insertion means adding 1-3 amino acids adjacent to an amino acid occupying a position.
- the variant may also be a functional fragment of HSA. Fragments may consist of one uninterrupted sequence derived from albumin or may comprise two or more sequences derived from different parts of the albumin.
- the fragments according to the invention have a size of more than approximately 100 amino acid residues, preferably more than 150 amino acid residues, more preferred more than 200 amino acid residues, more preferred more than 300 amino acid residues, even more preferred more than 400 amino acid residues and most preferred more than 500 amino acid residues.
- a fragment corresponds to one or more (several) of the albumin domains.
- Preferred albumin domains of the invention are HSA domain I consisting of amino acid residues 1 to 194 ⁇ 1 to 15 amino acids of SEQ ID NO: 2; HSA domain II consisting of amino acid residues 192 to 387 ⁇ 1 to 15 amino acids of SEQ ID NO: 2 and HSA domain III consisting of amino acid residues 381 to 585 ⁇ 1 to 15 amino acids of SEQ ID NO: 2 or a combination of one or more (several) of these domains, e.g. domain I and II, domain II and III or domain I and III fused together.
- the altered polypeptide (variant) can be obtained through human intervention by alternation of the polynucleotide sequence encoding the HSA.
- the variant albumin is preferably at least 70%, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5% or at least 99.8% identical to SEQ ID NO: 2 and maintains at least one of the major properties of HSA.
- variants or fragments of HSA will have at least 10% (preferably at least 50%, 60%, 70%, 80%, 90% or 95%) of HSA ligand binding activity (for example bilirubin- binding) and at least 50% (preferably at least 70%, 80%, 90% or 95%) of HSA's oncotic activity, weight for weight.
- Oncotic activity also known as colloid osmotic pressure
- Oncotic activity also known as colloid osmotic pressure
- Bil iru bin binding may be measured by fluorescence enhancement at 527 nm relative to HSA.
- Bilirubin (1 .0mg) is dissolved in 50microL of 1 M NaOH and diluted to I .OmL with demineralised water. The bilirubin stock is diluted in 100mM Tris-H CI pH8.5, 1 mM E DTA to give 0.6n mol of bili rubin/m L i n a fluorometer cuvette.
- the variant may possess altered binding to FcRn when compared to the HSA.
- the variant polypeptide sequence is preferably one which is not found in nature.
- regulatory sequences means all components (e.g. nucleic acid sequences) necessary for the expression of a polynucleotide inserted into an animal. Each regulatory sequence may be native (i.e. from the same gene) or foreign (i.e. from a different gene) to the polynucleotide encoding the transgenic polypeptide. Such regulatory sequences include, but are not limited to, a leader, polyadenylation sequence, propeptide sequence, promoter, signal peptide sequence and transcription terminator. At a minimum, the regulatory sequences include a promoter, and transcriptional and translational stop signals.
- operably linked means a configuration in which a regulatory sequence is placed at an appropriate position relative to the transgenic sequence of a polynucleotide such that the regulatory sequence directs the expression of the transgenic sequence.
- Wt albumin A number of therapeutic proteins fused to Wt albumin have entered clinical development. Some examples are interferon-alpha fused to Wt albumin, GCSF fused to Wt albumin, GLP-1 fused to Wt albumin and Factor IX fused to Wt albumin.
- the test will compare the therapeutic protein alone against the therapeutic protein fused to the albumin, e.g. GLP1 and GLP1-albumin. In such a case it will be fairly easy to see a change in half-life between the molecules solely due to the difference in renal filtration irrespective of what animal model is used.
- HSA Human serum albumin
- Sequence identity was calculated using the Needleman-Wunsch algorithm as imp emented in the Needle program of EBLOSUM62 (EMBOSS suite of programs, version 6.1 .0) using gap open penalty of 10, gap extension penalty of 0.5 and selecting the no brief option to obtain the longest identity.
- pig albumin (75.1 % identity to human albumin) has a similar degree of identity to human albumin as mouse albumin (72.3% identity to human albumin), rabbit albumin (74.3% identity to human albumin) or rat albumin (73.3% identity to human albumin), while the non-human primates chimpanzee (98.9% identity to human albumin), macaque (93.3% identity to human albumin) and orangutan (98.5% identity to human albumin), have a higher degree of identity to human albumin than pig albumin.
- Human albumin is synthesized predominantly in the liver. Heptocyctes do not contain a large pool of stored intracellular albumin, rather the protein is rapidly secreted from the cell resulting in approximately 13-14g of albumin entering the intravascular space every day, equivalent to 3.7%/day of the total body albumin mass of 360g for a 70kg person.
- the normal human plasma albumin concentration is 42 ⁇ 3.5 g/L and with an average plasma volume of 2.5- 3.0L for a 70kg person, the average intravascular albumin mass is 1 13-126g ( ⁇ 120g).
- Intravascular albumin is constantly being exchanged at a rate of 4-5%/hr by transport across the endothelium with the 240g extravascular albumin pool, resulting in a total body albumin mass of 360g for a 70kg person.
- Extravascular albumin returns to the vascular compartment by drainage through the lymphatic system.
- total exchangeable pool 295g
- 65g 65g is not in free exchange.
- Approximately 80% of the total extravascular pool is equally divided between the muscle and the skin.
- a mass of albumin equivalent to that entering the intravascular space (13-14g) is catabolised from the intravascular space every day.
- albumin receptors gp18 and gp30 The fate of an albumin molecule be it degradation, transport across or exchange between pools or compartments, salvage and recycling is controlled in large part by the interaction with albumin receptors gp18 and gp30, (Ghinea A. et al. (1988) J. Cell Biol. 107: 231-239; Schnitzer J. et al. (1992) J. Biol. Chem. 267: 24544-24553; Schnitzer J. et al. (1993) J. Biol. Chem. 268: 7562-7570), gp60 (Schnitzer J. et al. (1994) J. Biol. Chem. 269: 6072-6082; Minshall R. at al. (2002) Histochem. Cell. Biol.
- gp18 and gp30 are present in cultured fibroblasts, smooth muscle cells and endothelial cells; they are also distributed ubiquitously being found in heart, lung, muscle, kidney, fat, brain, adrenal, pancreas and liver.
- Damaged albumin e.g. point mutations, truncations, glycosylation mutants, oxidation or even iodination
- Damaged albumins once internalized, are degraded, a process which can be inhibited by known inhibitors of lysosomal degradation as well as inhibited gp18 and gp30 mediated damaged albumin degradation. Therefore gp18 and gp30 resemble scavenger proteins and so may mediate the high affinity binding, endocytosis and degradation of damaged albumins, but not native albumins.
- albumin In humans the long circulatory half-life of albumin is dependent upon functional interaction with FcRn and the nature of the glomerular filtration barrier which retains proteins of greater than ⁇ 60kDa in the glomerular retentate while proteins smaller than ⁇ 60kDa are filtered and appear to a progressively greater extent in the glomerular ultrafiltrate as the size of the protein decreases.
- the circulatory half-life of albumin has been shown to be impacted to various degrees by glycation, glycosylation, oxidation, structural changes and point mutations within the albumin primary sequence, especially damage affecting hydrophobicity and net charge of the molecules reduces half-life (Nakajou et al. Biochim Biophys Acta. (2003) 1623, 88-97; (Iwao Y. et al. (2006) Biochim Biophys Acta. 1764, 743-749;lwao Y et al. (2007) Biochim Biophys Acta. 1774, 1582-1590; Sheffield W. P. et al. (2000) Thrombosis Research 99, 613-621 ).
- FcRn neonatal Fc receptor
- FcRn is a heterodimeric receptor consisting of a 46kDa MHC class-l-like transmembrane heavy chain (HC) that is non-covalently associated with a 12kDa (beta2m).
- FcRn only has affinity for albumin and IgG at acidic pH (below pH6.5).
- IgG and albumin:FcRn complexes, formed at the acidic pH of the endosome, are sorted into separate vesicles, thus diverting the molecules away from the default lysosomal degradation pathway.
- albumin:FcRn complexes are recycled back to the plasma membrane surface where they encounter physiological pH and both albumin and IgG are released from FcRn wh ich is then ready to rescue more albumin and IgG, thereby increasing the plasma half-life of albumin and IgG.
- internalized proteins which are not bound to FcRn are sorted for degradation in the lysosome.
- the major FcRn binding site is localized within Di ll (381 -585), (Andersen et al (2010), Clinical Biochemistry 43,367-372).
- a model of the interaction of human albumin with human FcRn has been described.
- a number of key amino acids in albumin have been shown to be important in binding, notably histidines H464, H510 and H536 and lysine Lys500 (Andersen et al (2010), Nat. Commun. 3:610. DOI:10.1038/ ncomms1607).
- Data indicates that amino acids within Dl (1-197) of albumin contribute to the interaction of albumin with FcRn.
- albumin interacts with the FcRn HC and not the beta2munit (Andersen et al (2010), Clinical Biochemistry 43,367-372; (Andersen et al (2012) Nature Communications Vol . 3, pp. 610).
- Crystal structures of FcRn show the extracellular part of the heavy chain with an amino- terminal alphal-alpha 2 platform of eight antiparallel beta-pleated strands topped by two long alpha-helices followed by the membrane proximal alpha3-domain (reviewed in Roopenian D. C. and Akilesh, S. (2007), Nat. Rev. Immunol 7, 715-725.).
- the beta2munit is tightly bound to residues located below the alpha1-alpha2 platform and to the alpha3-domain of the heavy chain.
- the FcRn HC has been characterized from many species including human, pig, mouse, rat, rabbit and goat and they share a high degree of sequence and structural homology (see Table 3).
- Sequence identity was calculated using the Needleman-Wunsch algorithm as implemented in the Needle program of EBLOSUM62 (EMBOSS suite of programs, version 6.1 .0) using gap open penalty of 10, gap extension penalty of 0.5 and selecting the no brief option to obtain the longest identity.
- pig FcRn HC (74.6 %identity to human FcRn HC) has a similar degree of identity to human FcRn HC as mouse FcRn HC (66.9% identity to human FcRn HC), or rat FcRn HC (65.1% identity to human FcRn HC), while the non- human primates chimpanzee (97.8% identity to human FcRn HC), macaque (97% identity to human FcRn HC), Rhesus monkey (96.7% identity to human FcRn HC), gorilla (84.5% identity to human FcRn HC) and orangutan (97.5% identity to human FcRn HC), have a higher degree of identity to human FcRn HC than pig FcRn HC.
- the pharmacokinetics of HSA, including HSA variants and modifications in an animal model will be influenced by the affinity of HSA for the native animal FcRn compared to the affinity of the native animal albumin for the native animal FcRn. If the affinity of the native animal albumin for the animal FcRn is higher than the affinity of HSA for the same animal FcRn, the native animal albumin will lead to greater competition for the FcRn than would be the case in a human.
- mouse serum albumin for human FcRn was shown to be 107.5-fold higher than the affinity of human serum albumin for the mouse FcRn. In all cases, albumin and IgG could bind the FcRn at the same time (the binding was additive).
- the effect of these differential binding affinities of human albumin for mouse FcRn is that in a mouse pharmacokinetic model, wild-type human albumin, or fusions, conjugates or associates of therapeutic agents to wild-type human albumin are completely or partially excluded from interacting with the mouse FcRn due to their reduced affinity for the mouse FcRn receptor and/or by competition due to the higher abundance of the endogenous mouse albumin.
- the observed pharmacokinetic profile and the circulatory half-life of the wild-type human albumin, or fusions, conjugates or associates of therapeutic agents to wild-type human albumin is significantly compromised. Indeed when using a mouse to compare the half-life of a therapeutic agent with the same therapeutic agent fused or conjugated to HSA as was done in Muller et al (2007) Journal of Biological Chemistry vol 282 pp. 12650-12660 it will generally be possible to observe an increase in half-life of the HSA fusion. This increase may however simply be due to an increase of the molecular weight of the therapeutic agent above the threshold of renal clearance and not due to FcRn mediated rescue of the therapeutic agents fused, conjugated or associated with albumin.
- Mouse FcRn is promiscuous regarding binding specificity and binds IgG of many species
- human FcRn is more stringent, and binds only IgG of human, primate, rabbit, and guinea pig origin (Ober R. J. et al. (2001 ) Int. Immunol. 13, 1551-1559; Stein C. et al. (201 1 ) Mamm. Genome 23:259-269).
- human IgGs or monoclonal antibodies can be assessed without competition from endogenous mouse IgG in the human FcRn transgenic mouse (homozygous KO of the mouse gene and a heterozygous Kl of the human gene) (Roopenian et al (2003) J. Immunol. Vol 170, pp. 3528-3533), while in the same model the pharmacokinetics of human albumin or compounds fused, conjugated or associated with human albumin will be compromised by competition from endogenous mouse albumin from both the greater affinity of mouse albumin for human FcRn and the greater abundance of the mouse albumin compared to the human albumin fusion, conjugate or associate.
- a mouse model may be sufficient to generally observe an increase in half-life of the HSA fusion due to the increase of the molecular weight of the therapeutic agent above the threshold of renal clearance.
- an animal model is to be used to compare the half-life of a variant HSA or a modified variant HSA with Wt HSA or a modified Wt HSA the FcRn mediated rescue is important and then the competition from the native albumin will play an important role.
- the inventors have realized that when assessing pharmacokinetic differences of a variant HSA compared to wild type HSA there needs to be as little competition from the native albumin as possible. This can be achieved if HSA binds the native FcRn in a manner similar to the binding of native albumin to the same FcRn. This is naturally the case in primates where the amino acid sequences of albumin and FcRn show a high level of identity between species (see Tables 1 and 3). However, when moving to non- primate species the diversity increases and it becomes more challenging to find an animal model suitable for assessing pharmacokinetics of a variant HSA compared to wild type HSA.
- An aspect of the present invention provides a method for assessing one or more (several) pharmacokinetic properties of a variant HSA compared to wild type HSA comprising a) selecting a non-primate animal species where the binding affinity of wild type HSA to the native FcRn of said animal is the same as or higher than the binding affinity of the native albumin of said animal to said FcRn; b) administering the variant HSA to one animal and the wild type HSA to another animal of the animal species selected in a); and c) measuring one or more (several) pharmacokinetic properties of the variant HSA and the wild type HSA.
- a preferred non-primate animal species is one where the binding affinity of HSA for the native FcRn is approximately the same (1 fold ⁇ 0.15 ) as the binding affinity of the native albumin to the native FcRn.
- Such a model would very much resemble the competition that the Wt HSA or variant HSA would be subject to when injected into a human.
- the binding affinity of wild type HSA to the native FcRn of said animal is between 0.8 and 3.5 fold when compared with the binding affinity of the native albumin of said animal, more preferred between 0.9 and 3, more preferred between 1 and 2.5, more preferred between 1 and 2, more preferred between 1 and 1.5, and most preferred the binding affinity of Wt HSA is between 1 and 1.1 fold higher than the binding affinity of the native albumin of said animal.
- Another preferred non-primate animal species of the present invention is one where the binding affinity of HSA for the native FcRn would be higher than the binding affinity of the native albumin of said animal species to the native FcRn.
- the binding affinity of wild type HSA to the native FcRn of said animal is at least 1.5 fold higher than the binding affinity of the native albumin of said animal, more preferred at least 2 folder higher, more preferred at least 3 fold higher, more preferred at least 3.5 folder higher and most preferred it is at least 4 fold higher than the binding affinity of the native albumin of said animal.
- Binding affinities between albumin and native FcRn is preferably measured using a soluble FcRn heavy-chain of the selected animal species coupled to a chip and measured in by SPR e.g. using a Biacore instrument.
- the soluble FcRn HC is an alpha chain without the transmembrane domain or an FcRn HC consisting of three ectodomains (a1- a3).
- the soluble FcRn may also include amino acids from the connecting peptide of the FcRn, which is between the ectodomains and the transmembrane region of the FcRn.
- the soluble FcRn HC is co-expressed with beta2-microglobulin from the same species as described in Example 4.
- the soluble animal FcRn comprises a FcRn heavy chain and a beta2-globulin from the same animal species. More preferably the soluble FcRn are composed of soluble pig FcRn HC and pig p2-microglobulin.
- the method described in the "Materials and Methods" section is used to select a non-primate animal species in the method of the present invention with the variations in Example 4 are applied.
- a preferred non-primate animal species of the present invention is a wild type animal species expressing its wild type FcRn and wild type albumin. Wild type animals include species which have been bred by mating animals with specific naturally occurring genotypes, but does not include animals where genes actively have been knocked out or inserted by human intervention.
- a preferred non-primate wild type animal is a pig, preferably a Gottingen minipig. Pig has been recognized as an acceptable model for predictive interspecies allometric scaling (Larsen M. O. and Rolin B. (2004) ILAR Journal 45, 303-313; Zheng Y. et al. (2012) mAbs 4, 243-255; Suenderhauf C. and Parrott N. (2013) Pharm. Res. 30, 1-15).
- Example 2 of the present invention shows that the affinity of human albumin for soluble pig FcRn (spFcRn) is 2.9 fold higher than the affinity of pig albumin for soluble pFcRn.
- the affinity of selected human albumin variants for pFcRn has also been shown to have higher than the affinity of Wt HSA for pFcRn.
- the ability to differentiate between the pharmacokinetic properties of WT HSA and variant HSA in pig animal studies has been shown in Example 5.
- primate FcRn and pig, goat, sheep, cow and camel FcRn as indicated by bold letters in figure 7, is that they have a V in the position corresponding to position 52 when aligned to SEQ ID NO: 16 and an H in the position corresponding to position 161 when aligned to SEQ ID NO: 16. All other amino acids in the aligned regions are fully conserved across all the species, except for position 55, 164 and 165. At position 164 and 165 human and macaque have an R and E respectively whereas all the other species have an L and G respectively. At Position 55 the species have either an N or an S.
- the native FcRn has a histidine in the position corresponding to position 161 when aligned to SEQ ID NO: 16.
- the native FcRn has a valine in the position corresponding to position 52 when aligned to SEQ ID NO: 16.
- the native FcRn has a valine in the position corresponding to position 52 and a histidine in the position corresponding to position 161 when aligned to SEQ ID NO: 16.
- a pig animal model or a goat or sheep or cow or camel animal model is used to compare one or more (several) pharmacokinetic properties of a control molecule and a test molecule in which the control molecule comprises wild type HSA and the test molecule comprises a variant of HSA.
- transgenic animal An alternative to wild-type animal species is a transgenic animal.
- a preferred transgenic animal for use in the method of the present invention is a non-primate animal which has its wild type (endogenous) FcRn and wild type (endogenous) albumin knocked out and a human FcRn heavy chain and human serum albumin inserted into the genome.
- the human FcRn is 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 100% identical to the mature sequence of SEQ ID NO: 9 and the human HSA is 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 100% identical to SEQ ID NO: 2.
- the human FcRn heavy chain and the Wt HSA are considered to be the native FcRn and native albumin, and it is understood that there is no (or substantially no) underlying expression of the animal's endogenous wild type FcRn heavy chain and albumin.
- the double transgenic animal is a rodent or rabbit.
- the rodent is selected from mouse, guinea pig, and rat. More preferred the rodent is a double transgenic mouse.
- the animal species of the present invention may also be an animal where the Wt FcRn has been mutated such that it contains a valine in the position corresponding to position 52 and/or a histidine in the position corresponding to position 161 when aligned to SEQ ID NO: 16.
- the conserved amino acids E54, Q56 and H166 when aligned to SEQ ID NO: 16 are maintained.
- This animal species can either contain wild type (endogenous) albumin or it can be transgenic with respect to albumin, such that the endogenous albumin is knocked out and substituted with HSA.
- An example of such an animal could be a mouse with a mouse FcRn HC variant comprising a valine in position 52 and a histidine in position 161 when aligned to SEQ ID NO:16 and where the variant is at least 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99% identical to the mature sequence of SEQ I D NO:13 and the mouse also comprises a transgene HSA and preferably the native MSA expression and wt FcRn expression has been abolished.
- a further aspect of the present invention is directed to a double transgenic animal. More specifically, the transgenic animal's genome comprises a homozygous disruption in its endogenous FcRn HC gene and serum albumin gene that prevents the expression of a functional animal FcRn HC protein and functional animal serum albumin and the genome further comprises a heterologous DNA sequence encoding a human FcRn HC (hFcRn HC) and a heterologous DNA sequence encoding human serum albumin (HSA), and wherein , and wherein the animal expresses a functional hFcRn HC protein and functional HSA.
- the relevant sequences for albumin are indicated in Table 1 and the relevant FcRn HC sequences are indicated in Table 3.
- the human FcRn is 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 100% identical to the mature sequence of SEQ ID NO: 9 or to SEQ ID NO: 16, more preferred the human FcRn HC has a histidine in position 161 when aligned to SEQ ID NO: 16, and the conserved amino acids E54, Q56 and H166 when aligned to SEQ ID NO: 16 are maintained.
- the human HSA is 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 100% identical to SEQ ID NO: 2.
- the double transgenic animal is a rodent or a rabbit.
- the rodent is selected from mouse, guinea pig, and rat.
- the most preferred double transgenic animal is a mouse.
- the heterologous DNA sequences that have been inserted into the genome of the animal can be operably linked to the same or different regulatory sequences as the endogenous genes.
- the disruption of the endogenous genes can be done by replacement with the corresponding heterologous DNA (human genes).
- the disruption can however alternatively be done independently of the insertion of the heterologous DNA (transgenic human genes), allowing the heterologous DNA to be inserted in a different place of the genome than the endogenous gene.
- the generation of a mouse with transgenic human FcRn HC as native FcRn has been described in US 7,358,416.
- transgenic human serum albumin as the native albumin.
- a person skilled in the art of producing transgenic animals would, based on these two documents, be capable of producing a transgenic animal which has its wild type FcRn HC gene and wild type albumin gene knocked out and a wild type human FcRn HC DNA and wild type human serum albumin DNA inserted into the genome such that human FcRn HC and HSA is produced in the animal instead of the wild type FcRn and albumin.
- the transgenic animal is a rabbit or rodent whose genome comprises a homozygous disruption in its endogenous FcRn heavy chain gene and endogenous serum albumin gene and further comprises a heterologous DNA sequence that expresses an FcRn with a histidine in the position corresponding to position 161 when aligned to SEQ ID NO: 16 and a heterologous DNA sequence encoding human serum (HSA), where the heterologous DNA sequences are operably linked to the same or different regulatory sequences, and wherein said homozygous disruption prevents the expression of a functional rabbit or rodent FcRn HC protein and functional rabbit or rodent serum albumin, and wherein the animal expresses a functional FcRn HC protein with a histidine in position 161 when aligned to SEQ ID NO: 16 and functional HSA.
- HSA human serum
- a transgenic rabbit or rodent that expresses an FcRn with a histidine in the position corresponding to position 161 when aligned to SEQ ID NO: 16 and human albumin and which has been knocked out for the corresponding native proteins is used to compare one or more (several) pharmacokinetic properties of a control molecule and a test molecule in which the control molecule comprises wild type HSA and the test molecule comprises a variant of HSA.
- the FcRn further comprises a valine in position 52 when aligned to SEQ ID NO: 16.
- the transgene FcRn is selected from human, chimpanzee, macaque, cow, goat, sheep, camel and pig.
- the FcRn is a variant of the Wt FcRn with a H in the position corresponding to position 161 when aligned to SEQ ID NO: 16 and/or a V in the position corresponding to position 52 when aligned to SEQ ID NO: 16, and wherein the variant is at least 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99% identical to the Wt FcRn of the animal.
- the conserved amino acids E54, Q56 and H166 when aligned to SEQ ID NO: 16 are maintained.
- the method of the present invention can be used to screen variant HSA molecules to identify the in vivo effect of altered FcRn binding affinity when compared to Wt HSA.
- the variants tested in the method of the present invention have increased human FcRn binding compared to Wt HSA.
- the KD of the variant albumin is at least 2X lower than the KD of Wt HSA, more preferably the KD of the variant albumin is at least 5X, 10X, 15X or 20X, 30X, 50X, 75X lower than the KD of Wt HSA, most preferably the KD of the variant albumin is at least 100X lower than the KD of Wt HSA (the variant has one hundred times the binding affinity to human FcRn than Wt HSA). In another embodiment the variant albumin has a weaker binding to human FcRn than Wt HSA.
- the KD of the variant albumin is at least 2X higher than the KD of Wt HSA (the variant has half the binding affinity to human FcRn than Wt HSA), more preferably the KD of the variant albumin is at least 5X, 10X, 15X or 20X, 30X, 50X, 75X higher than the KD of Wt HSA, most preferably the KD of the variant albumin is at least 100X higher than the KD of Wt HSA (the variant has one hundredth the binding affinity to human FcRn than HSA).
- the method of the present invention can in particular be used to select a variant HSA for use in a pre-clinical trial, where the variant HSA has improved one or more (several) pharmacokinetic properties when compared with wild type HSA.
- the variant HSA has a longer half-life than wild type HSA.
- the present invention also relates to variant HSA molecules as such, which have been selected using the method of the present invention.
- a variant HSA with one or more (several) improved pharmacokinetic properties when compared with wild type HSA that are selected for use in a pre-clinical trial is encompassed by the present invention.
- Improved pharmacokinetic properties are properties which are changed compared to Wt HSA and which will result in an advantage in relation to for example administration regime, dose, targeting, or treatment effectiveness compared to Wt HSA.
- Preferred is a variant HSA that has a longer half-life than Wt HSA.
- the method of the present invention can also be used to assay the effect of modifications to HSA or variant HSA.
- the method may be used to assess the effect of a) various linkers between a partner, such as a therapeutic agent, and HSA (both fusion linkers and conjugation linkers) or b) the position in HSA to which conjugation or fusion is made or c) the chemistry used for conjugation of the partner.
- a partner such as a therapeutic agent
- HSA both fusion linkers and conjugation linkers
- This list is not exhaustive and the skilled person will know how to use the method of the present invention to assess other modification effects.
- modifications to HSA may affect FcRn binding as seen with some of the natural occurring damages like glycosylation and oxidation described above.
- the present model is therefore relevant for assessing one or more (several) pharmacokinetic properties of modifications to Wt HSA and variant HSA, since these modifications may affect the FcRn binding of the Wt or variant HSA.
- the Wt HSA and variant HSA are modified by adding an additional functionality.
- the additional functionality can take the form of a partner molecule for example a therapeutic agent, diagnostic agent, targeting molecule that can ensure delivery of the HSA to specific cells in a human, a purification tag or identification tag like His, FLAG, GST, or fluorescence markers.
- the variant and wild type HSA modified by fusion, conjugation or association with a partner.
- the partner is a therapeutic agent, including vaccines.
- the modification should be identical for both molecules, for example in the form of a fusion, conjugation or association to the same partner.
- the animal model is used to assess the effect on one or more (several) of the pharmacokinetic properties of a selected partner, e.g. therapeutic agent, and the method of joining the partner to the control and test molecule is assessed.
- the control molecule can for example be Wt HSA joined to the partner and the test molecule is a variant HSA joined to the same partner at the same position.
- the method of joining the albumin and the selected partner can for example be one or more (several) of a) to c) mentioned above.
- the partner is conjugated at different positions on the albumin.
- the positions are identical for both control and test molecule, so if for example position 1 and 34 in WT HSA (SEQ ID NO:2) is tested for conjugation, the same position is tested in the variant HSA using the same partner, thereby testing the effect of the different positions on FcRn binding.
- the partner is conjugated with different conjugation technologies to the albumin control and test molecules.
- the conjugation technology or chemistry used is identical for both control and test molecule, so if for example one or more maleimide groups are tested for conjugation, the same groups are tested in the variant HSA using the same partner, thereby testing the effect of the different-conjugation techniques on FcRn binding.
- the partner is fused with or without different linkers at the C- terminal and/or N-terminal of the albumin.
- the linkers are identical for both control and test molecules.
- the linker peptide between the fused portions (albumin and partner) provides greater physical separation between the moieties and thus maximizes the accessibility of the fusion partner, e.g. the therapeutic agent, for instance, for binding to its cognate receptor.
- the linker peptide may consist of amino acids such that it is flexible or more rigid.
- the partner e.g. therapeutic agent
- the partner is fused to the N-terminal of the albumin.
- the partner, e.g. therapeutic agent is fused to the C-terminal of the albumin.
- the albumin fusion polypeptides of the invention may have the following formula R2-R1 ; R1-R2; R2-R1-R2; R2-L-R1 -L-R2; R1-L-R2; R2-L-R1 ; or R1- L-R2-L-R1 , wherein R1 is at least one fusion partner sequence (including fragments or variants thereof), and not necessarily the same polypeptide, L is a linker and R2 is an albumin sequence (including fragments or variants thereof).
- linkers include (GGGGS) N or (GGGS) N or (GGS)N, wherein N is an integer greater than or equal to 1 and wherein G represents glycine and S represents serine.
- the linkers may have a varying length from 1 to 50 amino acids, preferably from 3 to 40 amino acids, more preferably from 5 to 35 amino acids, even more preferably from 7 to 30 amino acids and most preferably from 10 to 25 amino acids.
- a fusion polypeptide can further comprise a cleavage site between the fusion partner and the albumin, e.g. in the form of a cleavable linker. The site may be cleaved upon secretion of the fusion polypeptide, releasing the two polypeptides.
- the linker may alternatively be cleavable, e.g. by a protease which exists in the patient, such that the fusion partner moiety is released from the albumin within the patient, potentially in relation to an activation event.
- protease driven activation event is the coagulation cascade (WO 91/09125, WO 2007/090584 and WO 2007/144173).
- cleavage sites include, but are not limited to, the sites disclosed in Martin et al., 2003, J. Ind. Microbiol. Biotechnol. 3: 568-576; Svetina et al., 2000, J. Biotechnol. 76: 245-251 ; Rasmussen-Wilson et al., 1997, Appl. Environ. Microbiol.
- the present invention also includes modified variant HSA such as a variant HSA which is fused, conjugated or associated with a therapeutic agent, where the fusion, conjugation or association is selected by a method of the present invention.
- modified variant HSA such as a variant HSA which is fused, conjugated or associated with a therapeutic agent, where the fusion, conjugation or association is selected by a method of the present invention.
- a variant HSA fused, conjugated or associated with a partner e.g. therapeutic agent
- a variant HSA fused, conjugated or associated with a partner e.g. therapeutic agent
- a partner e.g. therapeutic agent
- More preferred is a variant HSA fused, conjugated or associated with a partner, e.g. therapeutic agent, , that has a longer half-life than wild type HSA fused, conjugated or associated with the same partner, e.g. therapeutic agent.
- Variant HSA and the modified variant HSA of the present invention may be formulated into a pharmaceutical composition comprising the variant HSA and an excipient.
- One way of formulating variant HSA or modified variant HSA can be as nanoparticles or microparticles.
- the incorporation of a partner, e.g. therapeutic agent, into an albumin particle has for example been described in WO 00/71079. Techniques for incorporation of a molecule into nano- or microparticles are known in the art.
- fusion partner polypeptides and/or conjugates and/or associates may comprise one or more (several) of: 4-1 BB ligand, 5-helix, A human C-C chemokine, A human L105 chemokine, A human L105 chemokine designated huL105_3.
- Complement Component C1q C Adenoid- expressed chemokine (ADEC), aFGF; FGF-1 , AGF, AGF Protein, albumin, an etoposide, angiostatin, Anthrax vaccine, Antibodies specific for collapsin, antistasin, Anti-TGF beta family antibodies, antithrombin III, AP -1 ; ACRP-30; Famoxin, apo-lipoprotein species, Arylsul
- SMIP Small Modular ImmunoPharmaceutical
- dAb Fab' fragments, F(ab')2, scAb, scFv or scFv fragment
- IP- 10 Interferon gamma-inducible protein
- interferons such as interferon alpha species and sub-species, interferon beta species and sub-species, interferon gamma species and sub-species
- interferons such as interferon alpha species and sub-species, interferon beta species and sub-species, interferon gamma species and sub-species
- interferons such as interferon alpha species and sub-species, interferon beta species and sub-species, interferon gamma species and sub-species
- Interleukin 6, Interleukin 8 (IL-8) receptor Interleukin 8 receptor B, lnterleukin-1 alpha, l
- Thrombopoietin derivative2 Thrombopoietin derivative3, Thrombopoietin derivative4, Thrombopoietin derivatives, Thrombopoietin derivative6, Thrombopoietin derivative?, Thymus expressed chemokine (TECK), Thyroid stimulating Hormone, tick anticoagulant peptide, Tim-1 protein, TNF-alpha precursor, TNF-R, TNF-RII; TNF p75 Receptor; Death Receptor, tPA, transferrin, transforming growth factor beta, Troponin peptides, Truncated monocyte chemotactic protein 2 (6-76), Truncated monocyte chemotactic protein 2 (6-76), Truncated RANTES protein (3-68), tumour necrosis factor, Urate Oxidase, urokinase, Vasopressin (Neurophysin II), VEGF R-3; flt-4, VEGF Re
- anticalin(s), adnectin(s), fibrinogen fragment(s), nanobodies such as camelid nanobodies, infestin, and/or any of the molecules mentioned in WO01/79271 (particularly page 9 and/or Table 1 ), WO 2003/59934 (particularly Table 1 ), WO03/060071 (particularly Table 1 ) or WO01/079480 (particularly Table 1 ) (each incorporated herein by reference in their entirety).
- conjugates may comprise one or more (several) of chemotherapy drugs such as: 13-cis-Retinoic Acid, 2-CdA, 2-Chlorodeoxyadenosine, 5-Azacitidine, 5-Fluorouracil, 5- FU , 6-Mercaptopurine, 6-MP, 6-TG, 6-Thioguanine, A, Abraxane, Accutane ® , Actinomycin-D, Adriamycin ® , Adrucil ® , Agrylin ® , Ala-Cort ® , Aldesleukin, Alemtuzumab, ALIMTA, Alitretinoin, Alkaban-AQ ® , Alkeran ® , All-transretinoic Acid, Alpha Interferon, Altretamine, Amethopterin, Amifostine, Aminoglutethimide, Anagrelide, Anandron ® , Anastrozole, Arabinosylcytosine, Ara-C, Ara
- Paclitaxel or Paclitaxel Protein-bound Pamidronate, Panitumumab, Panretin ® , Paraplatin ® , Pediapred ® , PEG I nterferon , Pegaspargase, Pegfilgrasti m, PEG-INTRONTM, PEG-L- asparaginase, PEMETREXED, Pentostatin, Phenylalanine Mustard, Platinol ® , Platinol-AQ ® , Prednisolone, Prednisone, Prelone ® , Procarbazine, PROCRIT ® , Proleukin ® , Prolifeprospan 20 with Carmustine Implant, Purinethol ® , R, Raloxifene, Revlimid ® , Rheumatrex ® , Rituxan ® , Rituximab, Roferon-A ® (Interferon Alfa-2a), Rubex ® , Rubidomycin hydrochlor
- fusion partners, conjugation partners and/or molecules for inclusion in a nanoparticle, associate or composition according to the invention include: acromegaly drugs e.g. somatuline, lanreotide, octreotide, Sandostatin; antithrombotics e.g. bivalirudin, Angiomax, dalteparin, Fragmin, enoxaparin, Lovenox, Drotrecogin alfa (e.g. Activated), Xigris, heparin; assisted reproductive therapy compounds e.g. choriogonadotropin, Ovidrel, follitropin, alpha/beta; enzymes e.g.
- acromegaly drugs e.g. somatuline, lanreotide, octreotide, Sandostatin
- antithrombotics e.g. bivalirudin, Angiomax, dalteparin, Fragmin, enoxaparin
- hyaluronidase Hylenex
- diabetes drugs e.g. exenatide, Byetta, glucagon, insulin, liraglutide, albiglutide, GLP-1 agonists, exendin or an exendin analog
- compounds useful in diagnosis e.g. protirelin, Thyrel TRH Thypinone, secretin (e.g. synthetic human), Chirhostim, thyrotropin (e.g. alpha), Thyrogen' erythropoiesis drugs e.g. Darbepoetin alfa, Aranesp, Epoetin alfa, Epogen, Eprex, drugs for the treatment of genetic defects e.g.
- pegademase drugs for the treatment of growth failure e.g. Adagen, mecasermin, rinfabate, drugs for the treatment of cystic fibrosis e.g. Dornase alfa, Pulmozyme, drugs for the treatment of metaoblic disorders e.g. Agalsidase beta, Fabrazyme, alglucosidase alpha, Myozyme, Laronidase, Aldurazyme, drugs for the treatment of genital wart intralesional e.g. Interferon alfa- n3, Alferon N, drugs for the treatment of granulomatous disease e.g.
- Interferon gamma-1 b Actimmune; drugs for the treatment of growth failure e.g. pegvisomant, Somavert, somatropin, Genotropin, Nutropin, Humatrope.Serostim, Protropin; drugs for the treatment of heart failure e.g. nesiritide, Natrecor; drugs for the treatment of hemophilia e.g. a coagulation factor e.g. Factor VIII , Helixate FS, Kogenate FS, Factor IX, BeneFIX, Factor Vila, Novoseven, desmopressin, Stimate, DDAVP; hemopoetic drugs e.g.
- growth failure e.g. pegvisomant, Somavert, somatropin, Genotropin, Nutropin, Humatrope.Serostim, Protropin
- drugs for the treatment of heart failure e.g. nesiritide, Natrecor
- G-CSF Filgrastim
- Neupogen Oprelvekin
- Neumega Pegfilgrastim
- Neulasta Sargramostim
- Leukine drugs for the treatment of hepatitis C e.g. Interferon alfa-2a, Roferon A, Interferon alfa-2b, Intron A, Interferon alfacon-1 , Infergen, Peginterferon alfa-2a, Pegasys, Peginterferon alfa-2b, PEG-lntron
- drugs for the treatment of HIV e.g. enfuvirtide, Fuzeon
- Fabs e.g.
- Fab antithrombin
- Abciximab ReoPro
- monoclonal antibodies e.g. Daclizumab, Zenapax
- antiviral monoclonal antibodies e.g. Palivizumab, Synagis
- monoclonal antibodies for the treatment of asthma e.g. Omalizumab, Xolair
- monoclonal antibodies for use in diagnostic imaging e.g. Arcitumomab, CEA-Scan, Capromab Pendetide, ProstaScint, Satumomab Pendetide, OncoScint CR/OV
- Fabs for use in diagnostic imaging e.g.
- Nofetumomab, Verluma iimmuno-supressant monoclonal antibodies e.g. Basiliximab, Simulect, Muromonab-CD3, Orthoclone OKT3; monoclonal antibodies for the treatment of malignancy e.g. Alemtuzumab, Campath, Ibritumomab tiuxetan, Zevalin, Rituximab, Rituxan, Trastuzumab, Herceptin; monoclonal antibodies for the treatment of rheumatoid arthritis (RA) e.g.
- RA rheumatoid arthritis
- MS multiple sclerosis
- palifermin, Kepivance drug for the treatment of dystonia e.g., neurotoxin, Botulinum Toxin Type A, BOTOX, BOTOX Cosmetic, Botulinum Toxin Type B, MYOBLOC; drugs for the treatment of osteoporosis e.g. teriparatide.Forteo; drugs for the treatment of psoriasis e.g. Alefacept, Amevive; drugs for the treatment of RA e.g. abatacept, Orencia, Anakinra, Kineret, Etanercept, Enbrel; thrombolytics e.g.
- Alteplase Activase, rtPA, Anistreplase, Eminase, Reteplase, Retavase, Streptokinase, Streptase, Tenecteplase, TNKase, Urokinase, Abbokinase, Kiniytic; drugs for the treatment of osteoporosis e.g. calcitonin (e.g. salmon), Miacalcin, Fortical, drugs for the treatment of skin ulcers e.g. Becaplermin, Regranex, Collagenase, Santyl.
- drugs for the treatment of osteoporosis e.g. calcitonin (e.g. salmon), Miacalcin, Fortical, drugs for the treatment of skin ulcers e.g. Becaplermin, Regranex, Collagenase, Santyl.
- albumin conjugates for example but not limited to Levemir®, Kurtzhals P et al. Biochem. J. 1995; 312:725-731
- the present invention provides a method to assess one or more (several) pharmacokinetic properties of a variant HSA compared to wild type HSA using a non- primate animal model.
- "Pharmacokinetics" is understood as the determination of the fate of substances administered externally to a living organism.
- Routes of administration can, for example, be oral, enteral (rectal), mucosal or parenteral.
- the administration is parenteral.
- Preferred parenteral administration routes are selected from intravenous, intramuscular, subcutaneous or intrapleural administration.
- the preferred pharmacokinetic property or properties measured are selected from half-life, volume of distribution, bioavailability, area under the curve (AUC), clearance rate and immunogenicity.
- the preferred pharmacokinetic property measured in relation to albumin, albumin variants and fragments and modifications thereof is half-life.
- the half-life of HSA is generally measured by injecting a model animal subcutaneously, intramuscularly or intravenously with a relevant HSA sample (e.g. Wt HSA, or variant HSA or modified HSA).
- a relevant HSA sample e.g. Wt HSA, or variant HSA or modified HSA.
- enteral (rectal) or mucosal delivery other administration routes can be selected.
- the dose can be varied depending on the animal model, a dose between 1 to 100mg/kg, preferably 5 to 50 mg/kg, preferably from 10 to 40 mg/kg, more preferably from 15 to 30 mg/kg will generally be appropriate unless the molecule is very large then the dose may be increased.
- Blood samples are collected from the animals before injection and at subsequent intervals. The intervals will depend on the animal model as the half-life is expected to vary with the size of the animal (see Table 2).
- sampling times can for example be 12, 24, 72, 168, 240 and 300 hours post injection.
- the sampling times can for example be 2, 4, 8, 12, 16, 20, 24, 28 and 32 days. The skilled person will generally know which sampling times are appropriate based on the molecules and the animal.
- the plasma can be separated from the samples and stored at -80°C.
- the amount of HSA sample remaining in the serum can be analyzed e.g. by ELISA, mass spectrometry or eso Scale Discovery (MSD).
- plates coated with antibody directed to the therapeutic agent or detection tag can be used to capture the various albumin molecules and a secondary detection antibody (e.g. either directed towards HSA or alternate epitope of the therapeutic agent or detection tag) is added to quantitate the amount of HSA present in the sample or alternately radiolabeled albumin molecules may be used to quantify the amount of albumin remaining in the serum (in all cases the means of detections should not alter the engagement of the albumin with the FcRn receptor in its characteristic manner.
- the references sited in Table 2 describe various methods of measuring half-life of albumin in different animal models. Methods using radioactive labeling of the albumin are less preferred since this is an additional modification to the albumin or variant and may therefore influence the half-life of the albumin.
- a method for assessing one or more (several) pharmacokinetic properties of a variant HSA compared to wild type HSA comprising
- non-primate animal species is a wild type animal or a transgenic animal.
- transgenic animal is a double transgenic rabbit or a double transgenic rodent, preferably a mouse, guinea pig or rat
- transgenes are human albumin and an FcRn with a histidine in the position corresponding to position 161 when aligned to SEQ ID NO: 16.
- transgene FcRn is selected from human, chimpanzee, macaque, cow, goat, sheep, camel and pig.
- the one or more (several) pharmacokinetic properties measured are selected from half-life, volume of distribution, AUC, bioavailability, clearance rate and immunogenicity. 18. The method according to any of the preceding embodiments, wherein the pharmacokinetic property measured is half-life.
- transgene FcRn is selected from human, chimpanzee, macaque, sheep, cattle and pig.
- control molecule is Wt HSA joined to the partner and the test molecule is a variant HSA joined to the same partner using the same method of joining the molecules.
- a transgenic rabbit or rodent whose genome comprises a homozygous disruption in its endogenous FcRn heavy chain gene and endogenous serum albumin gene that prevents the expression of a functional rabbit or rodent FcRn HC protein and functional rabbit or rodent serum albumin and the genome further comprises a heterologous DNA sequence that expresses an FcRn with a histidine in the position corresponding to position 161 when aligned to SEQ ID NO: 16 and a heterologous DNA sequence encoding human serum (HSA)and wherein said homozygous disruption, and wherein the animal expresses a functional FcRn HC protein with a histidine in position 161 when aligned to SEQ ID NO: 16 and functional HSA.
- HSA human serum
- a transgenic animal whose genome comprises a homozygous disruption in its endogenous FcRn HC gene and serum albumin gene that prevents the expression of a functional animal FcRn HC protein and functional animal serum albumin and the genome further comprises a heterologous DNA sequence encoding a human FcRn HC (hFcRn HC) and a heterologous DNA sequence encoding human serum albumin (HSA), and wherein the animal expresses a functional hFcRn HC protein and functional HSA.
- hFcRn HC human FcRn HC
- HSA human serum albumin
- the FcRn HC comprises SEQ ID NO: 16
- transgenic animal according to any one of embodiments 37 to 39, wherein the human HSA is 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 100% identical to SEQ ID NO: 2.
- transgenic animal according to any one of embodiments 37 to 40, wherein the animal or rodent is a mouse.
- transgenic animal according to any one of embodiments 36 to 41 , wherein the heterologous DNA replaces the endogens gene and thereby disrupts them
- transgenic animal according to any one of embodiments 36 to 41 , wherein the disruption of the endogens gene is done independently of the insertion of the heterologous
- the albumins used in the present examples were in the mature form. Serum albumin from human, mouse, rabbit and sheep were produced recombinantly using sequences provided from publicly available databases (see sequences below) using the production method as described for the variants in WO 2012/059486 methods 1 (hereby incorporated by reference). Serum albumins from dog, pig, cynomolgus macaque, guinea pig and rat were prepared using the same methods.
- HSA human serum albumin
- rmSA Wild type rhesus monkey serum albumin (rmSA) (SEQ ID NO: 3, mature sequence from amino acid 25 to 608).
- DSA Wild type dog serum albumin
- PSA Wild type pig serum albumin
- RSA Wild type rat serum albumin
- MSA Wild type mouse serum albumin
- GPSA Wild type guinea pig
- CSA cynomolgus macaque
- the variant HSA molecules were generated by substituting the native K573 with P, F, W, H or Y or the native HSA K500 with A.
- the K500A variant is known not to bind to human FcRn (a null binder).
- the variants were prepared as described in WO 201 1/051489 Example 1 , method 3 and 4 (hereby incorporated by reference).
- the variant HSA molecules with the following substitutions T83N+N111 E+K573P was prepared as described in WO 2013/135896 Example 1 (hereby incorporated by reference).
- the variant HSA molecule with the following substitutions E492G+K573P+K574H+Q580K was prepared as described in PCT/EP2013/073426 Example 1 , method 2 (hereby incorporated by reference).
- Albumin and albumin variants with a c-myc tag were generated to enable detection of human albumin and human albumin variants in monkey and pig since antibodies towards HSA cannot distinguish native rmSA and native PSA from HSA.
- the c-myc tag was added by fusing the epitope with the sequence EQKLISEEDL to the N-terminal end of the albumin sequence, for details see Example 3.
- Truncated versions of the three ectodomains (a1-a3) of FcRn HC cDNAs from rhesus monkey, rat, pig and dog were synthesized by Genscript, and subcloned into the same vector system using the restriction sites Xhol (NEB) and Hind II I (NEB). All vectors also contain a cDNA encoding human p2-microglobulin and the Epstein-Barr virus origin of replication (on ' P). Soluble GST-tagged FcRn molecules were produced in adherent human embryonic kidney 293E cells, and secreted receptors were purified using a GSTrap column as described (Berntzen et al. (2005) J Immunol Methods 298, 93-104).
- srmFcRn - rhesus monkey
- pFcRn pig
- smFcRn corresponds to amino acid 21 to 293 of SEQ ID NO: 13
- rat corresponds to amino acid 23 to 292 of SEQ ID NO: 14
- human p2-microglobulin is indicated in SEQ I D NO: 15 (mature sequence from amino acids 21 to 1 19).
- guinea pig corresponds to amino acid 25 to 298 of SEQ ID NO: 17
- CynoFcRn - cynomolgus macaque
- cynomolgus macaque p2-microglobulin is indicated in SEQ I D NO: 21 (mature sequence from amino acids 21 to 1 19)
- CM5 sensor chips were coupled with soluble FcRn from one of the following species, human (sh FcRn), rat (srFcRn), mouse (sm FcRn), rhesus monkey (srmFcRn), dog (d FcRn ) or pig (pFcRn) (- 900 - 2500 resonance units (RU)) using GE Healthcare amine coupling chemistry as per the manufacturer's instructions.
- the coupling was performed by injecting 2 or 1 0 g/ml FcRn in 1 0 mM sodium acetate pH 5.0 (GE healthcare).
- Phosphate buffer (67 mM phosphate buffer, 0.15 M NaCI, 0.005% Tween 20 ) at pH 6.0) was used as running buffer and dilution buffer. Regeneration of the surfaces were done using injections of HBS-EP buffer (0.01 M HEPES, 0.15 M NaCI, 3 mM EDTA, 0.005% surfactant P20) at pH 7.4 (GE Healthcare). For determination of binding kinetics, serial dilutions of albumin (10-0.3 ⁇ ) were injected over immobilized receptors at a constant flow rate (50 ⁇ /min) at 25 °C. I n all experiments, data were zero adjusted and the reference cell subtracted.
- Plasma samples were diluted 1 : 10 in PBST then mixed with 10% Gottingen mini pig sodium citrate plasma or female cynomolgus monkey sodium citrate plasma (SeraLab catalog no. PSCGOF-444-M-32556 and PSCF-1 18-M-32555, respectively) in PBST.
- a standard curve with a top concentration of 1000ng/ml_ and twelve 2-fold dilution points was included on each plate with purified c-myc HSA diluted in 10% mini pig plasma or cynomolgus monkey plasma in PBST. Plates were incubated at room temperature (RT) for 1 h then washed as above.
- HSA and variant HSA The binding affinity of HSA and variant HSA to soluble FcRn from human, mouse, rat and rhesus monkey was analyzed and the HSA binding was compared with the binding of the native albumin.
- HSA variants showed considerably improved binding to human FcRn at acidic pH compared to Wt, and the increase was mainly due to slower dissociation rates.
- HSA binds very weakly to rat and mouse FcRn when compared to the native albumins. Consequently, rat or mouse albumin will out-compete HSA for the binding to rat or mouse FcRn. For this reason rat and mouse are not desired animal models for assessing one or more (several) pharmacokinetic properties of HSA in vivo.
- HSA has a measurable binding affinity to rhesus monkey FcRn, and the binding is 1.3 fold better that the binding of the native rhesus monkey albumin. This indicates that rhesus monkey is a suitable animal model for pharmacokinetic studies of HSA and HSA variants since the native rhesus monkey albumin will not out-compete HSA for FcRn binding.
- the kinetic values represent the average of duplicates.
- HSA binds dog FcRn with an affinity that is 6.8 times lower than the binding affinity of native dog albumin. Consequently, it is highly likely that dog albumin will out-compete HSA binding to dog FcRn. For this reason dog is not a desired animal model for assessing one or more (several) pharmacokinetic properties of HSA in vivo.
- HSA has binding affinity to pig FcRn that is 2.9 fold higher than the binding of the native pig albumin. This indicates that pig is a suitable animal model for pharmacokinetics studies of HSA and HSA variants since the native pig albumin, even though present in excess amounts compared to HSA, will not outcompete HSA for pFcRn binding.
- HSA and HSA variants were expressed using standard molecular biology techniques, such as described in Sambrook, J. and D.W. Russell, 2001 (Molecular Cloning: a laboratory manual, 3rd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y).
- the objective was to secrete from yeast, wild-type (Wt) human albumin and variant human albumins incorporating the modifications K573P, or E492G+K573P+K574H+Q580K or T83N+N1 1 1 E+K573P which incorporated a c-myc epitope at the N-terminal end of the mature albumin sequence.
- Secretion from yeast was enabled by the use of a prepro leader sequence, k n ow n a s t h e modified fusion leader (mFL with the amino acid sequence MKWVFIVSILFLFSSAYS), incorporating a further modification to the pro region (amino acids RSLD).
- the modified fusion leader was further modified by the inclusion of the amino acid sequence EEAEAEAESSRLKR including the Kex2p dibasic (KR) cleavage site 12568and a c-myc epitope with the sequence EQKLISEEDL inserted at the N-terminal end of the albumin sequence.
- All expression cassettes comprise the S. cerevisiae PRB1 promoter and a modified S. cerevisiae ADH1 terminator (mADHt)
- Plasmids encoding Wt albumin and the variants have previously been described (see reference in the Materials and Methods section).
- the plasmids where similarly digested to completion with BglW/SacW and the large 8.585kb fragment isolated and replaced with the analogous 0.26kb BglWISacW fragment encoding the modified fusion leader sequence MKWVFIVSILFLFSSAYS RSLDEEAEAEAESSRLKREQKLISEEDL.
- Expression plasmids were generated in vivo (i.e. via homologous recombination in S. cerevisiae; a technique referred to as gap repair or in vivo cloning- see Orr-Weaver & Szostak. 1983. Proc. Natl. Acad. Sci. USA. 80:4417-4421 ).
- the modified plasmids comprising the c-myc tag were digested to completion with Nsi ⁇ IPvu ⁇ and the 7.41 kb fragments isolated. 100ng of the 4 isolated fragments were mixed individually with 100ng /4cc65l/6amHI-digested pDB3936 (disclosed in WO 2010/092135) and used to directly transform S.
- Strain A is a derivative of S. cerevisiae DYB7 (Payne et al (2008) Applied and Environmental Microbiology Vol 74(24): 7759-7766) with four copies of PDI integrated into the genome. Transformation of Strain A was achieved using the Sigma Yeast Transformation kit as described in WO201 1/051489.
- yeast transformants in shake flask culture the preparation of yeast trehalose stocks and fed-batch fermentation of the c-myc tagged albumin and albumin variants were essentially done as also described in WO 2011/051489 Example 1 (hereby incorporated by reference), with the modification that BMMS broth (0.17% (w/v) yeast nitrogen base without amino acid and ammonium sulphate (Difco), 37.8mM ammonium sulphate, 36 mM citric acid, 126mM disodium hydrogen orthophosphate pH6.5, 2% (w/v) sucrose, adjusted to pH 6.5 with NaOH) was used in both cases.
- BMMS broth 0.17% (w/v) yeast nitrogen base without amino acid and ammonium sulphate (Difco)
- 37.8mM ammonium sulphate 36 mM citric acid
- 126mM disodium hydrogen orthophosphate pH6.5 2% (w/v) sucrose, adjusted to pH 6.5 with NaOH
- a second purification step of the c-myc tagged albumin and albumin variants was performed using AlbuPureTM matrix chromatography (ProMetic Biosciences) followed by DE-FF as described in (Evans et al. (2010) Protein Expression and Purification Volume 73, Issue 2, Pages 1 13-124) followed by purification on Sephacryl S200 high resolution gel filtration (GE Healthcare) as to reduce the level of a +2058 Da miscleaved leader to below 5% (w/v).
- Example 4 Binding kinetics of albumins towards pig, cyno and guinea pig FcRn
- HSA binding affinity of HSA, variant HSA albumin and c-myc tagged HSA to FcRn from pig, cynomolgus macaque and guinea pig was analyzed and the HSA binding was compared with the binding of the native albumin (pig or guinea pig).
- the soluble FcRn receptors were synthesized by GeneArt and expressed in HEK cells.
- the soluble FcRn contained a HIS-tag on the C-terminal of the Beta-chain instead of a GST on the heavy chain and the beta-chain used was the native beta-chain of the animal (see Materials and Method section for the corresponding sequences).
- the soluble FcRn was purified by a HIS trap column followed by an additional purification using an IgG column.
- the soluble FcRn receptor was diluted to 20 g/ml_.
- the phosphate buffer used as running buffer in the SPR assay was at pH 5.5 instead of pH 6.0.
- Albumins were diluted in the range of 20 ⁇ to 0.156 ⁇ and flowed at 30 ⁇ - ⁇ ) ⁇ . 1 :1 Langmuir or Steady state model was used.
- Wt HSA and PSA binding affinities to pig FcRn are comparable.
- the binding affinities are somewhat lower than expected and may be due to the quality of the soluble receptor not being as high as expected.
- the 0.9 fold difference between native pig albumin and Wt HSA however still indicates that pig is a suitable animal model for pharmacokinetics studies of HSA and HSA variants since the native pig albumin, even though present in excess amounts compared to HSA, will not outcompete HSA for pFcRn binding.
- the c-myc tag appears to affect the binding of Wt HSA to the pig FcRn, however at such low affinity (high KD) very little disturbance in the molecule may affect the binding.
- the c-myc tag appears to either enhance binding (K573P) or not affect it. All HSA variants bind to pig FcRn with greater affinity than Wt HSA and PSA.
- HSA variant T83N + N 1 1 1 E+K573P has the fastest association to pig FcRn and HSA variant E492G+K573P+K574H+Q580K forms the most stable complexes (slowest off rate(kd)).
- Wt HSA and pig SA bind very poorly to guinea pig FcRn. Fusion of a c-myc tag to the albumins appears to inhibit binding.
- the guinea pig SA has the highest affinity to guinea pig FcRn when compared to Wt pig and human SA as well as human albumin variants. For this reason guinea pig is not a desired animal model for assessing one or more (several) pharmacokinetic properties of HSA in vivo.
- PK studies were performed in 8 female Gottingen minipigs (Ellegaard Gottingen Minipigs A/S, Soro Landevej 302, DK-4261 Dalmose). At start of the acclimatisation period the minipigs were about 5 months old and had a body weight of 7.8 - 9.7 kg. The animals were divided into 4 groups with 2 animals per group.
- N-terminally C-myc tagged Wt HSA, N-terminally C-myc tagged albu m i n varia nt K573P, N-terminally C-myc tagged albumin variant E492G+K573P+K574H+Q580K a n d N-terminally C-myc tagged albumin variant T83N+N111 E+K573P were given i.v. via a venflon in an ear vein to two animals in a dose of 1 mg/kg (0.2 ml/kg) of a dose solution of 5 mg/ml according to table 8:
- Table 8 Dose administration table for pig PK study
- Two ml (2ml) blood samples were collected from a jugular vein into sodium citrate test tubes at the following intervals: pre-dose, 0.25, 2, 8, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 360, 408, 456, and 504 hours after dosing.
- Blood samples were kept on ice for max 20 min. before centrifugation at 4°C, 1 0 min. , 2000 G.
- Plasma was immediately transferred from each sample to three appropriately labelled 750 ⁇ _ Micronic tubes, approximately 250 ⁇ in each and eventually remaining plasma shared between the three tubes, and placed in racks. The plasma samples were stored at -80°C until assayed.
- the human albumin variants E492G+K573P+K574H+Q580K and T83N+N1 11 E+K573P showed a 1.8 and 1.7 fold longer half-life, respectively, compared to Wt human albumin. This clearly indicates that half-life extension of albumin variants can be compared to the half-life of Wt HSA and a clear differentiation in the half-life between a variant HSA and Wt HSA can be observed with the current model.
- PK studies were performed in 8 female cynomolgus macaques (Huntingdon Life Sciences , H u ntingdon Research Centre . Wool ley Road , Alconbu ry. H u ntingdon . Cambridgeshire PE28 4HS. UK). At sta rt of the accl i matisation period the cynomolgus macaques were 2.5 - 3.0 years old and had a body weight of 2.5 - 3.5kg. The animals were divided into 4 groups with 2 animals per group.
- N-terminally C-myc tagged Wt HSA, N-terminally C-myc tagged album in variant K573P, N-terminally C-myc tagged albumin variant E492G+K573P+K574H+Q580K a n d N-terminally C-myc tagged albumin variant T83N+N1 1 1 E+K573P were given i.v. via a saphenous vein to two animals in a dose of 1 mg/kg (1 ml/kg) of a dose solution of 1 mg/ml according to table 10.
- Plasma samples of 0.8mL were drawn from unanaesthetized animals via suitable vein puncture using a sterile lancet into HLS standard tubes with Sodium citrate 3.8% (0.13M) at the following intervals: Pre-dose, 0.25, 2, 8, 24, 48, 72, 96, 120, 144, 192, 240, 288, 336, 384, 432, 480, 528, 576, 624, 720, 816, 912, 1008, 1 104 and 1200 hours after dosing. Samples were mixed thoroughly by inversion and immediately placed on wet ice for a maximum of 10 minutes prior to centrifugation (2000 x g for 10 minutes at 4°C). Plasma was pipetted into labelled 1.4 mL Micronic tubes, snap frozen on dry ice and kept at - 80°C. The plasma samples were stored at -80°C until assayed.
- the human albumin variants K573P, E492G+K573P+K574H+Q580K and T83N+N111E+K573P showed a 1.6, 2.1 and 2.4 fold longer half-life, respectively, compared to Wt human albumin
- the prolongation in half-life is a result of decreased clearance rate which in turn reflects increased AUC.
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Abstract
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US15/973,330 US20190113519A1 (en) | 2013-02-16 | 2018-05-07 | Pharmacokinetic animal model |
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DK (1) | DK2956002T3 (en) |
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Cited By (4)
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WO2018096396A1 (en) * | 2016-11-22 | 2018-05-31 | University Of Oslo | Albumin variants and uses thereof |
WO2020092202A2 (en) | 2018-10-29 | 2020-05-07 | Biogen Ma Inc. | Humanized and stabilized fc5 variants for enhancement of blood brain barrier transport |
WO2021044362A1 (en) | 2019-09-06 | 2021-03-11 | Novartis Ag | Therapeutic fusion proteins |
WO2024089258A1 (en) | 2022-10-28 | 2024-05-02 | Aarhus Universitet | Albumin conjugated to cpg oligodeoxynucleotides as super-boosters of immune response |
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UY35463A (en) | 2013-03-15 | 2014-10-31 | Biogen Idec Inc | FC-FACTOR IX POLYPEPTIDE FORMULATIONS IX. |
WO2017029407A1 (en) | 2015-08-20 | 2017-02-23 | Albumedix A/S | Albumin variants and conjugates |
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US10896749B2 (en) | 2017-01-27 | 2021-01-19 | Shire Human Genetic Therapies, Inc. | Drug monitoring tool |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2018096396A1 (en) * | 2016-11-22 | 2018-05-31 | University Of Oslo | Albumin variants and uses thereof |
WO2020092202A2 (en) | 2018-10-29 | 2020-05-07 | Biogen Ma Inc. | Humanized and stabilized fc5 variants for enhancement of blood brain barrier transport |
WO2021044362A1 (en) | 2019-09-06 | 2021-03-11 | Novartis Ag | Therapeutic fusion proteins |
WO2024089258A1 (en) | 2022-10-28 | 2024-05-02 | Aarhus Universitet | Albumin conjugated to cpg oligodeoxynucleotides as super-boosters of immune response |
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AU2014217831A1 (en) | 2015-07-16 |
KR20150118123A (en) | 2015-10-21 |
DK2956002T3 (en) | 2017-12-11 |
WO2014125082A9 (en) | 2014-10-16 |
EP2956002B1 (en) | 2017-09-06 |
EP2956002A1 (en) | 2015-12-23 |
US20190113519A1 (en) | 2019-04-18 |
US20160033523A1 (en) | 2016-02-04 |
EP3318124A3 (en) | 2018-05-30 |
ES2648591T3 (en) | 2018-01-04 |
EP3318124A2 (en) | 2018-05-09 |
CN105007722A (en) | 2015-10-28 |
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