WO2022244838A1 - 分子のin vivo薬物動態を予測する方法 - Google Patents
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/77—Internalization into the cell
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
Definitions
- the present invention relates to methods for measuring in vitro pharmacokinetics of molecules, methods for predicting in vivo pharmacokinetics of molecules, methods for screening molecules, and the like.
- mice are used to evaluate the pharmacokinetics (PK) required in the development process of pharmaceuticals such as antibody drugs.
- PK pharmacokinetics
- Non-Patent Documents 1 to 3 a method using the results of in vitro assays using cells has been known.
- Grevys et al. used human fetal Fc receptor (FcRn)-expressing cells (HMEC1-hFcRn) in a human microvascular endothelial cell line (HMEC1), and named it the HERA assay (human endothelial cell-based recycling assay). It discloses a method for measuring the amount of IgG antibody extracellularly excreted via FcRn in vitro and predicting its half-life in transgenic mice (Non-Patent Document 1). Jaramillo et al.
- Non-Patent Document 2 Madin-Darby canine kidney cells expressing human FcRn or rat FcRn, and measured the transcytosis activity, that is, the activity of the antibody to permeate the cells via FcRn. It is disclosed that the in vivo clearance of antibodies was ranked according to the results (Non-Patent Document 2). Similar to the method of Jaramillo et al., Chung et al. also performed transcytosis activity using cells expressing human FcRn in MDCK cells, and found a correlation between the measurement results and in vivo clearance in humans. (Non-Patent Document 3).
- an object of the present invention is to provide a method for predicting the in vivo pharmacokinetics of a molecule with higher sensitivity and more accuracy than ever before based on the results of in vitro pharmacokinetic measurements.
- the present inventors diligently investigated the cause of the insufficient accuracy of predicting in vivo pharmacokinetics based on in vitro pharmacokinetics with conventional methods. As a result, they found that prediction accuracy is low in conventional methods due to insufficient uptake of molecules into cells, and that prediction accuracy is improved by increasing the amount of uptake of molecules into cells. The present inventors completed the present invention by further research based on these findings.
- a method for measuring the in vitro pharmacokinetics of a molecule comprising the steps of: (a) contacting the molecule with a cell expressing FcRn in an aqueous medium so that the molecule is taken up by the cell so that the uptake amount is higher than 0.068 pmol/2 ⁇ 10 5 cells, a step having at least one characteristic selected from the following (i) to (iii); (i) the contact time between the molecule and the cell is 5 hours or longer; (ii) the cell is not washed under acidic conditions after contact with the molecule; and (iii) the cell expresses the target of the molecule on the cell surface; measuring in vitro pharmacokinetics, including The above method, wherein said molecule comprises an FcRn binding domain.
- the cells are CHO cells, HEK293 cells, COS-1 cells, COS-7 cells, MDCK cells, HMEC1 cells, HELA cells, HepG2 cells, or BaF cells the method of.
- the cells are liver parenchymal cells, liver non-parenchymal cells, liver sinusoidal endothelial cells, Kupffer cells, human umbilical vein endothelial cells, peripheral blood mononuclear cells PBMC, macrophages, mononuclear cells, B cells, T cells,
- [8] In vitro pharmacokinetics are the excretion amount from the cell into the culture medium, the excretion rate from the cell into the culture medium, the internalization rate, the amount of transcytosis, the Kp value, the intracellular molecule reduction rate, FcRn or the rate of binding to a target, or the rate of dissociation from FcRn or a target.
- FcRn is human FcRn, monkey FcRn, minipig FcRn, rat FcRn, mouse FcRn, rabbit FcRn, dog FcRn, or guinea pig FcRn.
- a method of predicting the in vivo pharmacokinetics of a molecule comprising: (a') a step of measuring in vitro pharmacokinetics by the method according to any one of [1] to [14], and (b') the measured value or in vitro evaluation parameter obtained in step (a') to predict the in vivo pharmacokinetics when the molecule is administered to a living body. [16] The method of [15], wherein the in vivo pharmacokinetics is bioavailability, volume of distribution, blood unbound fraction, clearance, urinary excretion rate, blood concentration half-life, or mean residence time. .
- a method of screening a molecule comprising: (a'') providing two or more different molecules that bind to the same target; (b'') measuring the in vitro pharmacokinetics of each of the two or more molecules prepared in step (a'') by the method described in any one of [1] to [14]; and (c') ') comparing the measured values or in vitro evaluation parameters for each of the two or more molecules obtained in step (b'') with each other and selecting the molecules that showed the desired values.
- the in vivo pharmacokinetics of molecules can be predicted with higher sensitivity and more accuracy than ever before, based on the results of in vitro pharmacokinetic measurements. Therefore, it becomes possible to easily and highly accurately predict the in vivo pharmacokinetics of a large number of candidate substances in the early stages of drug development. Moreover, the present invention can contribute to reducing the number of experimental animals used by reducing the number of in vivo pharmacokinetic tests. Furthermore, the present invention can contribute to the development of drugs with higher pharmacological effects by providing a method for efficiently screening drugs having desired pharmacokinetics.
- Figure 2 shows the results of mouse plasma pharmacokinetic evaluation of antibodies with different Fc regions (H237-G1d, H237-F1847m, H237-F1886m, H237-F1927m, and H237-F890).
- Black solid line black circle is H237-G1d
- black short dashed line black triangle is H237-F1847m
- black solid line white circle is H237-F1886m
- black long dashed line black square is H237-F1927m
- black solid line white triangle is H237- F890 is shown respectively.
- the results of measuring the in vitro cell uptake of antibodies having different Fc regions are shown. Each antibody was taken up by hFcRn-hIL6R-CHO cells or hFcRn-CHO cells at 37°C for 24 hours, and after washing with cold 2% FBS-containing PBS, the amount of uptake into the cells is shown. The results of measuring the cellular uptake of antibodies with different Fc regions over time are shown.
- FIG. 2 shows temporal changes in the intracellular residual amount and the amount excreted into the medium of antibodies having different Fc regions. After each antibody was taken up by the cells at 37°C for 24 hours, the medium was replaced with fresh medium and incubated for up to 4 hours.
- Black solid line black circle is H237-G1d
- black short dashed line black triangle is H237-F1847m
- black solid line white circle is H237-F1886m
- black long dashed line black square is H237-F1927m
- black solid line white triangle is H237- F890 is shown respectively.
- Figure 2 shows the correlation between the clearance index calculated in Example 4 and plasma half-life (a) or clearance (b) in mice.
- a first aspect of the present invention relates to a method for measuring in vitro pharmacokinetics of a molecule (hereinafter also referred to as the measuring method of the present invention).
- in vivo pharmacokinetics refers to a series of processes of absorption, distribution, metabolism, and excretion in vivo after administration of a drug (i.e., the molecule of the present invention). Refers to changes in the concentration (amount) of the drug. After administration of a drug, parallel processes of absorption, distribution, metabolism, and excretion occur in vivo.
- the basic pharmacokinetic (PK) parameters to decompose and describe these processes are (1) bioavailability (F), (2) volume of distribution (Vd or V), (3) ) fraction unbound in blood (fuB), (4) clearance (CL), and (5) cumulative amount of drug excreted in urine (Ae) have been established. (Biometrics Vol.
- PK parameters include blood concentration half-life (t 1/2 ), mean residence time (MRT), area under the first moment-time curve (AUMC), elimination rate constant (kel), post-dose zero time point concentration (C0 ) are known.
- in vitro pharmacokinetics refers to the behavior of a target molecule measured by contacting the target molecule with cells under artificially constructed conditions outside the body.
- “In vitro pharmacokinetics” includes, for example, intracellular to extracellular excretion rate, intracellular to extracellular excretion rate, internalization rate, transcytosis amount, Kp value, intracellular molecule reduction rate, FcRn or It can be expressed by, but not limited to, the rate of binding to a target, or the rate of dissociation from FcRn or a target.
- the amount of excretion (Efflux amount) from the inside of the cell to the outside of the cell is determined by exchanging the aqueous medium (e.g., medium, buffer, etc.) with one that does not contain the target molecule after contacting the target molecule with the cell for a predetermined time. It is determined by measuring the amount of the molecule of interest that is extracellularly excreted from the cells by detecting the molecule of interest in an aqueous medium.
- the discharge rate (Efflux rate) from the inside of the cell to the outside of the cell is determined by measuring the Efflux amount of the target molecule per unit time.
- the internalization rate is determined by contacting a molecule of interest with a cell for a predetermined period of time and measuring the amount of the molecule of interest that is taken up into the cell from the outside (eg, from medium, buffer, etc.) per unit time.
- cells that have been in contact with a molecule of interest for a predetermined period of time are acidified (pH less than 6.0, e.g. 0 or less, pH 3.5 or less, or pH 3.0 or less) to remove molecules of interest bound to the cell surface.
- the amount of the target molecule taken up (internalized) into cells can be measured more accurately.
- the amount of transcytosis is determined by measuring the amount of permeation from one side of the cell sheet to the other.
- the Kp value is known as the tissue-to-plasma drug concentration ratio (i.e., the ratio of the concentration of the molecule of interest between tissue and plasma) for in vivo pharmacokinetics, but is herein referred to as in vitro pharmacokinetics.
- tissue-to-plasma drug concentration ratio i.e., the ratio of the concentration of the molecule of interest between tissue and plasma
- in vitro pharmacokinetics refers to the ratio of concentrations of the molecule of interest between the cells and the aqueous medium (eg, culture medium). Kp values are determined by measuring the amount in cells and the amount in aqueous media.
- the Kp value as in vitro pharmacokinetics is a value calculated by (amount in cells)/(amount in aqueous medium).
- Intracellular molecule reduction rate is determined by exchanging the aqueous medium (e.g., medium, buffer solution, etc.) with one that does not contain the target molecule after contacting the target molecule with the cell for a predetermined time, and then detecting the target molecule in the cell. It is determined by measuring the amount of the molecule of interest that is depleted from the cell per unit time.
- the rate of FcRn or target binding is determined by contacting the molecule of interest with the cell for a predetermined short period of time (eg, seconds to minutes) and measuring the amount of molecule of interest bound to the FcRn or target per unit time. be.
- the rate of dissociation from FcRn or target is measured by contacting the molecule of interest with the cell for a given period of time (e.g., a time sufficient to reach equilibrium) followed by an aqueous medium (e.g., medium, buffer, etc.) free of the molecule of interest. It is determined by measuring the amount of the target molecule discharged into the aqueous medium per unit time by detecting the target molecule in the aqueous medium after exchanging with the substance.
- the contacting of the target molecule with the cell and the release of the target molecule into the aqueous medium are performed at a temperature at which the internalization of the target molecule into cells is inhibited (e.g., 4°C or lower). be able to.
- a "molecule” (also referred to as “a molecule in the present invention”) is taken up by a cell used in the assay method of the present invention, and within the cell is an intracellular organelle on an endosome. It has the property of being excreted outside the cell via the Fc receptor (FcRn) molecule. Such properties are due to the fact that the molecule contains an FcRn binding domain.
- FcRn Fc receptor
- FcRn is one of the receptors that recognize the Fc region of IgG antibodies.
- FcRn is expressed in the fetal placenta and is responsible for the transcytosis of IgG from the mother to the fetus.It is also expressed in the vascular endothelium, intestinal epithelial cells, and blood cells in adults, It is known that it is responsible for exocytosis and transcytosis from cells (Nature Reviews Immunology Vol. 7, p. 715-725 (2007)).
- Human FcRn is a dimeric protein consisting of a light chain called the ⁇ 2m subunit and a heavy chain called the ⁇ subunit with a transmembrane domain, and its structure resembles major histocompatibility complex (MHC) class I molecules. is doing. This FcRn dimer further dimers and binds to a single molecule of IgG (Annual Review of Cell and Developmental Biology Vol. 12, p. 181-220 (1996)). Unlike other IgG antibody Fc receptors, FcRn exhibits pH-dependent binding through electrostatic interactions between anionic residues on its ⁇ 2 domain and the CH2-CH3 hinge region of IgG. is known (Nature Reviews Immunology Vol. 7, p. 715-725 (2007)).
- IgG taken into cells by pinocytosis binds with high affinity to FcRn, escapes degradation in lysosomes, and then under neutral conditions (pH 7.4). It dissociates when it moves to the cell surface.
- This pH-dependent binding mode enables transcytosis and exocytosis of IgG, which contributes to the transport of IgG from the mother to the fetus and the extension of the blood half-life of IgG in vivo (approximately 20 days).
- FcRn-binding domains include, for example, antibody heavy chain constant regions (Fc regions) and fragments thereof.
- Fc regions antibody heavy chain constant regions
- albumin Another example of an FcRn binding domain is albumin and fragments thereof. It is known from the literature (J. Exp. Med. (2003) 197(3), 315-322) that albumin binds to FcRn.
- the FcRn-binding domain may contain mutations as long as it can bind to FcRn in an endosomal pH environment of less than pH 6.5.
- Fc-binding domains containing mutations include, but are not limited to, the mutated Fc regions of antibodies described in, for example, WO 2012/133782 A1, WO 2013/046704 A2, and WO 2017/046994 A1.
- a molecule in the present invention may further have the property of binding to a target (ie, target binding activity) or the property of catalyzing a reaction on the target (ie, enzymatic activity or catalytic activity).
- Molecules with target binding activity may function as agonists or antagonists. Having these properties, the molecule has a target binding domain or a catalytic domain.
- the molecule according to the invention comprises a target binding domain. Thereby, uptake into cells expressing the target on the cell surface may be increased.
- target refers to another molecule or structure that binds to the molecule of the present invention, or another molecule or structure that is catalyzed by the molecule of the present invention.
- Targets include proteins, nucleic acids, sugar chains, and the like.
- a “target” may also be called an antigen, a receptor, a substrate, etc., depending on the relationship with the molecule in the present invention.
- target-binding domain is not particularly limited as long as it can bind to the target, and domains with any structure can be used.
- target-binding domains include antigen-binding domains of antibodies, Avimers (International Publications WO2004/044011, WO2005/040229) containing about 35 amino acid modules (A domains) contained in various cell membrane proteins in vivo, Adnectin containing the 10Fn3 domain in fibronectin, which is a glycoprotein to be expressed (International Publication WO2002/032925), Affibody that scaffolds the IgG-binding domain consisting of 58 amino acids of Protein A (International Publication WO1995/001937), and a repeating sequence of 33 amino acids DARPins (Designed Ankyrin Repeat proteins) containing ankyrin repeat (AR) as a backbone (International Publication WO2002/020565), neutrophil gelatinase-associated lipocalin (NGAL), etc.
- DARPins Designed Ankyrin Repeat proteins
- an antigen-binding domain may be provided by one or more variable domains of an antibody.
- the antigen binding domain comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH).
- the target binding domain comprises antibody heavy and/or light chain variable regions.
- the target binding domain comprises or consists of the heavy and light chain variable regions of an antibody.
- the catalytic domain includes the catalytic domain in enzymes.
- the molecule in the present invention comprises an FcRn-binding domain and a target-binding domain, more preferably an antibody Fc region and heavy and light chain variable regions.
- Molecules in the present invention include pharmaceuticals and their candidates.
- pharmaceuticals and their candidates for example, in addition to proteins such as antibodies, which are the molecules described in the Examples, peptide compounds, nucleic acids, toxins, viruses, nanoparticles/microparticles, etc. Examples include DDS formulations, but are not limited to these as long as they can bind to FcRn.
- they may be prepared by conventional methods using techniques known in the art, depending on the type. According to the measurement method of the present invention, the in vitro pharmacokinetics of these molecules can be measured in the same manner as in the examples of the present application, and the in vivo pharmacokinetics can be predicted.
- protein refers to a polymer of amino acids linked via peptide bonds, and may also include peptide compounds.
- a protein may be naturally occurring or non-naturally occurring, such as a recombinant protein. Proteins include, for example, cytokines, physiologically active peptides, biological enzymes, antibodies, or variants thereof.
- antibody refers to an immunoglobulin that is natural or produced by partial or complete synthesis. Antibodies can be isolated from natural sources such as plasma or serum in which they naturally occur, culture supernatants of antibody-producing hybridoma cells, or can be partially or completely isolated by using techniques such as genetic recombination. can be synthesized. Examples of antibodies preferably include the immunoglobulin isotypes (ie, IgG, IgA, IgD, IgE, and IgM) and their isotypic subclasses.
- the antibody in the measuring method of the present invention is IgG.
- Antibodies can be either polyclonal antibodies or monoclonal antibodies.
- artificially modified genetically modified antibodies such as chimeric antibodies, humanized antibodies, and human antibodies, can be used for the purpose of reducing heterologous antigenicity.
- the antibody may be a bispecific antibody (bispecific antibody).
- An antibody may be a fragment of an antibody as long as it contains the "FcRn binding domain". Examples of such antibody fragments include Fc fragments, scFv-CH1-Fc, and the like.
- the "FcRn-binding domain" of an antibody is any domain capable of binding to FcRn, and includes, for example, the heavy chain constant region (Fc region) of an antibody.
- An antibody as a molecule in the present invention preferably comprises an "antigen-binding domain", more preferably comprising the heavy and light chain variable regions of the antibody. Thereby, when the cells express the antigen on the cell surface, the uptake amount of the molecules of the present invention into the cells can be increased. Methods for producing these antibodies are known to those skilled in the art (eg, WO 2013/081143, etc.).
- the "antigen" is not particularly limited in structure as long as it contains an epitope to which the antigen-binding domain binds.
- Antigens may be inorganic or organic.
- the antigen is 17-IA, 4-1BB, 4Dc, 6-keto-PGF1a, 8-iso-PGF2a, 8-oxo-dG, A1 adenosine receptor, A33, ACE, ACE-2 , activin, activin A, activin AB, activin B, activin C, activin RIA, activin RIA ALK-2, activin RIB ALK-4, activin RIIA, activin RIIB, ADAM, ADAM10, ADAM12, ADAM15, ADAM17/TACE, ADAM8, ADAM9, ADAMTS, ADAMTS4, ADAMTS5, addressin, aFGF, ALCAM, ALK, ALK-1, ALK-7, alpha-1-antitrypsin, alpha-
- T cell receptor alpha/beta TdT, TECK, TEM1, TEM5, TEM7, TEM8, TERT, testicular PLAP-like alkaline phosphatase, TfR, TGF, TGF-alpha, TGF-beta, TGF-beta Pan Specific, TGF-betaRI (ALK-5), TGF-betaRII, TGF-betaRIIb, TGF- betaRIII, TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta4, TGF-beta5, thrombin, thymus Ck-1, thyroid stimulating hormone, Tie, TIMP, TIQ, tissue factor, TMEFF2, Tmpo, TMPRSS2, TNF, TNF-alpha, TNF-alphabeta, TNF-beta2, TNFc, TNF-RI, TNF-RII, TNFRSF10A (TRAIL R1 Apo-2, DR4), TN
- the antigen capable of forming a complex with the antibody is any of the antigens exemplified above, or a combination thereof. , in other words, may be monomeric or heteromultimeric.
- heteromultimers include IL-12, including IL-12p40 and IL-12p35, IL-23, including IL-12p40 and IL-23p19 (also called IL-30B), or EBI-3 and IL27p28.
- IL-23 containing, or heterodimers such as IL-35 containing IL-12p35 and EBI-3.
- antigens also include receptors
- these receptors may exist in soluble form in biological fluids such as plasma.
- soluble receptors are also included in the antigens of the present invention.
- a non-limiting embodiment of the soluble receptor is, for example, soluble IL-6R as described by Mullberg et al. (J. Immunol. (1994) 152 (10), 4958-4968). (for example, a protein consisting of amino acids 1 to 357 in the IL-6R polypeptide sequence represented by SEQ ID NO: 1 described in WO 2013/081143).
- extracellular fluid includes components in bone and cartilage such as plasma, interstitial fluid, lymph, dense connective tissue, cerebrospinal fluid, cerebrospinal fluid, aspirate fluid, or synovial fluid, alveolar fluid (bronchopulmonary lavage), ascites, pleural effusion, pericardial effusion, cystic effusion, or intracellular fluid such as aqueous humor (aqueous humor) Other body cavity fluids) is a general term.
- antigens examples include soluble antigens and membrane antigens, and it is well known to those skilled in the art which one each antigen corresponds to. For example, it can be classified by searching individual antigens on websites such as UniProtKB (https://www.uniprot.org/) and Human Protein Atlas (https://www.proteinatlas.org/). .
- the molecule in the present invention is an antibody
- the antibody may preferably be IgG.
- the molecules in the present invention are anti-IL-6R antibodies, and more particularly can be humanized anti-IL-6R antibodies.
- nucleic acid refers to DNA, RNA, and analogues thereof, and may be natural nucleic acids or synthetic nucleic acids. Analogues include artificial nucleic acids such as PNA and LNA. Nucleic acids may be single-stranded or double-stranded. Nucleic acids may also be modified. Modified forms include those chemically modified at internucleoside linkages, bases and/or sugars, and those having modified groups at the 5' and/or 3' ends.
- Internucleoside linkage modifications include phosphodiester linkages, phosphorothioate linkages, phosphorodithioate linkages, methylphosphonate linkages, phosphoramidate linkages, non-phosphate linkages, and methylphosphonothioate linkages, or combinations thereof.
- changes to Base modifications include changes to 5-propynyluracil, 2-aminoadenine, and the like.
- Sugar modifications include changes to 2'-fluororibose, 2'-O-methyl ribose, and the like.
- Nucleic acids are sometimes referred to as siRNAs, antisense RNAs, miRNAs, shRNAs, ribozymes, or aptamers, depending on their function or use.
- Nucleic acids used in the present invention also include CpG oligonucleotides that act on Toll-like receptor 9 (TLR9) to activate innate immunity.
- TLR9 Toll-like receptor 9
- the base length of the nucleic acid may be any length that allows it to be taken up into cells via Stabilin. be.
- Stabin when the molecule in the invention is a nucleic acid, its target (or receptor) can be Stabin.
- Stabin refers to proteins belonging to the family of transmembrane proteins known as nucleic acid receptors. Two types of homologues of Stabin-1 and Stabin-2 are known in mammals, and Stabin in the present invention may be either of them.
- Stabilin-1 NCBI accession number: NP_055951.2
- Stabilin-2 NCBI accession number: NP_060034.9 are known and are expressed in LSEC, spleen, adrenal cortex, lymph nodes, and sinusoidal macrophages. have been reported to occur.
- a "peptide compound” is a compound formed by an amide bond or an ester bond of an amino acid or an amino acid analogue.
- Molecular forms of peptide compounds include linear, cyclic, and cyclic having a linear portion.
- the number of amide bonds or ester bonds (the number and length of amino acids or amino acid analogues) is not particularly limited, but when it has a linear portion, it is preferable that the combined cyclic portion and linear portion are within 30 residues. More preferably, the total number of amino acids, including the cyclization sites and the linear sites, is 13 residues or less. More preferably, the total number of amino acids is 9 or more in order to obtain high metabolic stability.
- the number of amino acids and amino acid analogs constituting the cyclic portion is preferably 5-12. Furthermore, in addition to the above description, the number of amino acids and amino acid analogs constituting the cyclic portion is more preferably 5 to 11 residues, more preferably 7 to 11 residues. 9 to 11 residues are particularly preferred.
- the number of amino acids and amino acid analogues (the number of units) in the linear portion is preferably 0-8. Furthermore, 0 to 3 are preferred. In the present application, amino acids may include amino acid analogues unless otherwise specified.
- amino acid and “amino acid analogue” that constitute a peptide compound are sometimes referred to as “amino acid residue” and “amino acid analogue residue”, respectively.
- Amino acids are ⁇ , ⁇ and ⁇ amino acids, and naturally occurring amino acids (in this application, naturally occurring amino acids refer to 20 types of amino acids contained in proteins. Specifically, Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, Pro.), and may be non-natural amino acids.
- the ⁇ -amino acid may be an L-amino acid, a D-amino acid, or an ⁇ , ⁇ -dialkylamino acid.
- Amino acid side chains are not particularly limited, but may be selected freely from alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, and cycloalkyl groups in addition to hydrogen atoms. Each may be provided with a substituent, and those substituents are also freely selected from arbitrary functional groups including, for example, N atom, O atom, S atom, B atom, Si atom, and P atom.
- amino acids and amino acid analogs that constitute peptide compounds include all corresponding isotopes. Isotopes of "amino acids” and “amino acid analogues” are those in which at least one atom is replaced with an atom with the same atomic number (number of protons) but a different mass number (sum of protons and neutrons). be.
- isotopes contained in "amino acids” and “amino acid analogues” constituting the peptide compound of the present invention include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, etc. , which include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, etc., respectively.
- amino acids with an amino group include Lys (lysine).
- amino acids with thiol groups can also be labeled with thiol-reactive fluorescent dyes. Cys (cysteine) is mentioned as such an amino acid.
- the molecule in the present invention is a peptide compound, preferably its target (or receptor) is PEPT1 or PEPT2.
- Nanoparticles and microparticles are known to be used in preparations intended for drug delivery (Drug Delivery System, commonly known as DDS). Examples include, but are not limited to, liposomes, micelles, dendrimers, nanoemulsions, iron nanoparticles, gold nanoparticles, PLGA particles (Organ Biology VOL.24 NO.1 2017, 54-60).
- molecules in the present invention include nanoparticles and microparticles bound with molecules that specifically bind to specific cells. For example, antigen-binding molecules against surface antigens of the cells can be bound to these particles. Also, molecules containing, for example, FcRn binding domains can be attached to these particles.
- the molecule in the present invention can be a nanoparticle/microparticle to which an antibody comprising an FcRn-binding domain and/or a target-binding domain is conjugated.
- the term “toxin” is not particularly limited as long as it can specifically deliver a cytotoxic agent, toxin, or radioactive isotope to specific cells and damage them.
- a molecule that specifically binds to the cell eg, an antigen-binding molecule for the cell surface antigen of the cell
- a cytotoxic agent, a toxin, or a radioactive isotope can be conjugated with a cytotoxic agent, a toxin, or a radioactive isotope to prepare a molecule.
- “Molecules that specifically bind to cells” include the aforementioned antibodies, nucleic acids, peptide compounds, and the like. Cytotoxic agents, toxins, or radioisotopes can be efficiently delivered to the cells using such molecules. As a result, the cells can be specifically injured.
- cytotoxic agents include maytansinoids (see U.S. Pat. Nos. 5,208,020, 5,416,064, and EP 0,425,235 B1); e.g. monomethyl auristatin drug moieties DE and DF (MMAE and MMAF) (U.S. Pat. No. 5,635,483). dolastatin; calicheamicin or derivatives thereof (U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710); 5,773,001 and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res.
- toxins include enzymatically active toxins or fragments thereof, including but not limited to: diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain (Pseudomonas aeruginosa).
- radioisotopes include those of 211 At, 131 I, 125 I, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P, 212 Pb and Lu.
- a virus can also be used as a molecule in the present invention.
- the in vitro kinetics of the following viruses or viral proteins or parts thereof can be measured.
- Viruses used in gene therapy include retroviruses, adenoviruses, adeno-associated viruses, herpes simplex viruses, lentiviruses, poxviruses, Epstein-Barr viruses, etc. (Adv Biomed Res. (2012) 1: 27. doi : 10.4103/2277-9175.98152), drug delivery viruses such as Red clover necrotic mosaic virus (RCNMV) (Methods Mol Biol. 2011;726:207-221).
- Viral proteins or portions thereof include partial peptides of HIV-1 tat protein, human papillomavirus L2 peptide, HBV envelope L protein, and the like.
- the measurement method of the present invention comprises the following step (a), by contacting the molecule and FcRn-expressing cells in an aqueous medium, so that the uptake amount is higher than 0.068 pmol/2 ⁇ 10 5 cells. and (b) measuring the in vitro pharmacokinetics of said molecule, including.
- step (b) does not have to be started after step (a) is completed. That is, step (b) may be started after the uptake of the molecule of the present invention into cells in step (a) is completed, or the molecule is placed in a state where it can be taken up by cells in step (a). may be started when
- the cells used in the measurement method of the present invention are not particularly limited as long as they can be contacted with the target molecule in vitro and express FcRn. It can be a cultured cell, or an established cell line. Expression of FcRn is confirmed by staining cells with a fluorescently-labeled anti-FcRn antibody, measuring fluorescence by FACS, and confirming that the histogram shifts to a higher fluorescence intensity side than a control antibody (eg isotype control antibody). For a more quantitative assessment, cells may be analyzed by liquid chromatography-mass spectrometry (LC-MS) to determine the abundance of FcRn-derived peptides.
- LC-MS liquid chromatography-mass spectrometry
- the FcRn can be the FcRn of a species whose in vivo pharmacokinetics are to be predicted, such as human FcRn, monkey FcRn, minipig FcRn, rat FcRn, mouse FcRn, rabbit FcRn, dog FcRn, guinea pig FcRn, It can be hamster FcRn, chimpanzee FcRn, marmoset FcRn, ferret FcRn, or cat FcRn.
- a species whose in vivo pharmacokinetics are to be predicted such as human FcRn, monkey FcRn, minipig FcRn, rat FcRn, mouse FcRn, rabbit FcRn, dog FcRn, guinea pig FcRn, It can be hamster FcRn, chimpanzee FcRn, marmoset FcRn, ferret FcRn, or cat FcR
- the cell can be a cell transformed to express FcRn.
- Such transformation can be performed, for example, by introducing a polynucleotide encoding FcRn into the cell.
- promoters used for expression in general animal cells can be used, for example, promoters such as CMV, PGK, RSV, CAG, EF-1 alpha, SV40, TRE, Oct3/4, Nanog. (PLoS One. 2010; 5(5): e10611). By using them, a sufficient amount of FcRn can be expressed.
- the cell can be a cell transformed to express the molecular target of the present invention on the cell surface.
- the target is a protein
- such transformation can be accomplished by introducing into the cell a polynucleotide encoding the protein.
- the higher the expression level of the target the more the amount of uptake of the molecules in the present invention into cells can be increased.
- a promoter the same one as used for expressing FcRn can be used, thereby allowing sufficient amount of target to be expressed.
- the cells used to produce the transformed cells are not particularly limited as long as they are cells to which transformation techniques such as transfection and transduction to introduce foreign genes into cells can be applied.
- Such cells include, for example, CHO cells, HEK293 cells, COS-1 cells, COS-7 cells, MDCK cells, HMEC1 cells, HELA cells, HepG2 cells, or BaF cells, and in certain embodiments It can be CHO cells.
- the cells can be endogenous FcRn-expressing cells, that is, FcRn-expressing cells without manipulation for forced expression of exogenous FcRn.
- FcRn-expressing cells include, for example, liver parenchymal cells, liver non-parenchymal cells, liver sinusoidal endothelial cells, Kupffer cells, human umbilical vein endothelial cells, peripheral blood mononuclear cells PBMC, macrophages, mononuclear cells, B cells, T cells, platelets, NK cells, neutrophils, eosinophils, basophils, granulocytes, or dendritic cells.
- the cell is a cell that expresses an endogenous protein, which is a molecular target of the present invention, on the cell surface, that is, a cell that does not undergo an operation to force expression of an exogenous target protein. It can be a surface expressing cell. Such cells can be appropriately selected according to the target protein.
- cells or cell lines with high endocytic activity may be used as cells.
- the cellular uptake of the molecule in the present invention can be increased.
- Such cells or cell lines include, for example, phagocytic cells or cell lines thereof such as macrophages, neutrophils, eosinophils, monocytes. Phagocytic cells have strong phagocytosis and high uptake capacity.
- Macrophages include, for example, liver Kupffer cells, alveolar macrophages, brain microglia, and the like.
- the cell is a cell transformed to express FcRn, more preferably a cell transformed to express FcRn and expressing the molecular target of the present invention on the cell surface. It may be a cell transformed to do.
- aqueous medium means a liquid containing water as an essential component.
- the aqueous medium is not particularly limited as long as the cells used in the assay method of the present invention do not lose cellular functions such as endocytosis and the molecule of the present invention can exist stably.
- Aqueous media include, for example, buffers such as phosphate-buffered saline (PBS) and liquid media such as Dulbecco's Modified Eagle medium (DMEM).
- PBS phosphate-buffered saline
- DMEM Dulbecco's Modified Eagle medium
- the aqueous medium may be a liquid medium from the viewpoint of reducing the load on cells.
- the uptake of the molecule into cells in the present invention involves combining the molecule with cells in an aqueous medium under conditions where the cells used do not lose cellular functions such as endocytosis. It can be done by contacting. Such conditions can be appropriately set according to the cells to be used. For example, when mammalian-derived cells such as CHO cells are used, incubation can be performed at 30-40°C, preferably 36-38°C, in a liquid medium.
- the uptake of molecules in the present invention into cells is performed in an aqueous medium at a temperature that inhibits internalization of the molecule of interest into cells (e.g., at a temperature of 4° C. or lower). This can be done by contacting the molecule with the cell in a cell. Thereby, the molecule that is bound to the cell surface but not internalized can be measured, and for example, the dissociation rate from FcRn or the target can be measured more accurately.
- molecules are taken up into cells so that the amount of uptake is higher than 0.068 pmol/2 ⁇ 10 5 cells.
- Measurement of the amount of uptake is carried out by contacting the molecules of the present invention with cells for a predetermined time according to each in vitro pharmacokinetic to be measured, and then removing the aqueous medium containing the molecules that have not been taken up by the cells, This is done by measuring the amount of the molecule internalized into the cell and/or the amount of the molecule bound to the cell surface.
- an appropriate measuring means can be used according to the molecule.
- Measurement means using antibodies, measurement means for quantifying the molecule or fragments thereof by liquid chromatography-mass spectrometry (LC-MS), and the like are included.
- LC-MS liquid chromatography-mass spectrometry
- the amount of uptake can be measured using a label attached to the molecule of the present invention.
- the molecule in the present invention is a protein
- the protein can be labeled with a fluorescent dye or the like, and the abundance of the protein can be measured using the label.
- the protein labeling method is not limited to a specific method, and can be carried out by a conventional method using techniques commonly used in the art.
- protein labeling methods include fluorescent labeling, biotin labeling, peptide tag labeling (His tag, FLAG tag, HA tag, etc.), colloidal gold labeling, magnetic bead labeling, RI (Radio Isotope; radioactive isotope) labels, and enzyme labels (HRP (Horse Radish Peroxydase), AP (Alkaline Phosphatase), etc.).
- fluorescent labels include, for example, Rhodamin, VioBlue, DyLight 405, DY-405, Alexa Fluor 405, AMCA, AMCA-X, Pacific Blue, DY-415, Royal Blue, ATTO 425, Cy2, ATTO 465 , DY-475XL, NorthernLights 493, DY-490, DyLight 488, Alexa Fluor 488, 5-FITC, 5-FAM, DY-495-X5, DY-495, Fluorescein, FITC, ATTO 488, HiLyte Flour 488, MFP488, ATTO 495, and Oyster 500.
- Higher uptake than 0.068 pmol/2 ⁇ 10 5 cells may improve the accuracy of predicting in vivo pharmacokinetics from in vitro pharmacokinetics.
- the uptake of the molecules in the present invention into cells is higher than 0.070 pmol/2 ⁇ 10 5 cells, higher than 0.080 pmol/2 ⁇ 10 5 cells, higher than 0.090 pmol/2. ⁇ 10 5 cells or higher than 0.10 pmol/2 ⁇ 10 5 cells.
- the upper limit of the amount of uptake is not particularly limited, but for example, less than 0.42 pmol/2 ⁇ 10 5 cells, less than 0.40 pmol/2 ⁇ 10 5 cells, less than 0.30 pmol/2 ⁇ 10 5 cells, less than 0.20 pmol/2 ⁇ 10 5 cells cells, or less than 0.16 pmol/2 ⁇ 10 5 cells.
- molecules are taken up into cells so that the amount taken is, for example, higher than 0.068 pmol/2 ⁇ 10 5 cells, preferably higher than 0.070 pmol/2 ⁇ 10 5 cells, and higher than 0.080 pmol/2 ⁇ 10 5 cells.
- the molecule in the present invention is a protein, and step (a) is performed such that the uptake measured using a fluorescent dye attached to the molecule is higher than 0.068 pmol/2 ⁇ 10 5 cells. can break
- step (a) has at least one feature selected from (i)-(iii): (i) the contact time between the molecule and the cell is 5 hours or longer; (ii) the cells are not washed under acidic conditions after contact with the molecule, and (iii) the cells express the target of the molecule on their cell surface.
- the contact time is 5 hours or more, e.g. , or 24 hours or longer.
- the upper limit of the contact time is not particularly limited as long as the molecule in the present invention exists stably and cellular functions such as endocytosis are not lost.
- the contact time can be, for example, 72 hours or less, 48 hours or less, or 36 hours or less. Therefore, the contact time should be 5 hours or more (e.g. hours or more) and 72 hours or less (eg, 48 hours or less, or 36 hours or less).
- the cells may be washed before the in vitro pharmacokinetic measurement in step (b) (e.g., in vitro pharmacokinetics may when measuring efflux rates, intracellular molecule depletion rates, or dissociation rates from FcRn or targets), in which case washing under acidic conditions can remove cell surface bound molecules. Therefore, by not washing under acidic conditions, the cellular uptake of the molecules of the present invention can be increased.
- acidic conditions refer to pH less than 6.0, such as pH 5.5 or less, pH 5.0 or less, pH 4.5 or less, pH 4.0 or less, pH 3.5 or less, or pH 3.0 or less.
- the contact time between the molecules of the present invention and cells is not particularly limited as long as the molecules of the present invention are present stably and cell functions such as endocytosis are not lost. For example, 5 hours. Greater than or equal to, e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours or more, 72 hours or less, 48 It can be an hour or less, or 36 hours or less.
- the cell is a cell that has been transformed to express the molecular target of the invention on its cell surface, or a cell that has not been so transformed and that is an endogenous cell that is the molecular target of the invention. It may be any cell that expresses a viral protein on the cell surface.
- the uptake of the molecule into cells can be increased. The higher the expression level of the target, the better.
- promoters commonly used for expression in animal cells such as CMV, PGK, RSV, CAG, EF-1 alpha, SV40, TRE, Oct3/4, Nanog
- a sufficient amount of the target can be expressed by using a promoter such as .
- step (a) the inclusion of at least one step selected from the following (iv) to (vii) in step (a) can increase the cellular uptake of the molecules of the present invention: (iv) adjusting the pH of the aqueous medium to 5.0 to 6.0; (v) when the molecule is an antibody, forming an immune complex (IC) between the antibody and its antigen; (vi) adding an anti-Fc antibody to the aqueous medium when said molecule comprises an Fc region; and (vii) adding an uptake enhancer to the aqueous medium.
- the molecules of the present invention are positively charged, making it easier to enter cells.
- the binding strength of the Fc region to FcRn increases in an endosomal pH environment of less than pH 6.5, so that it can easily enter cells. Therefore, by adjusting the pH of the aqueous medium to 5.0 to 6.0, the uptake amount of the molecule in the present invention into cells can be increased. Therefore, in a preferred embodiment, the molecule in the present invention comprises an Fc region and step (a) may comprise step (iv).
- uptake enhancers include uptake enhancers for proteins.
- uptake enhancers for proteins include BioPORTER® Protein Delivery Reagent (Genlantis Inc.), PULSin® Kit (Polyplus-transfection® SA), Pro-DeliverIN (OZ Biosciences), L17E Cytosolic Delivery Peptide (Peptide Research Institute, Inc.) and the like.
- Uptake-enhancing agents also include endocytosis-enhancing agents. Endocytosis promoters include, for example, okadaic acid (Drug Delivery System, 2016, Vol. 31, No. 1, p. 83-84).
- Uptake-enhancing agents also include substances that inhibit the efflux of molecules in the present invention from cells.
- Such substances include, for example, inhibitors of ABC transporters (ATP-binding cassette transporters).
- ABC transporter inhibitor those commonly used in the art can be used. abcam), erythromycin, thienylbutylisothiocyanate, and the like.
- a pharmaceutically active ingredient may be further added to the aqueous medium.
- the pharmaceutically active ingredient is not particularly limited as long as it is a drug that can be used in combination with the molecule in vivo.
- a therapeutic agent for diseases such as pericitis and hemophilia A can be mentioned.
- step (b) In the measurement of in vitro pharmacokinetics in step (b), appropriate numerical values are measured according to the type of in vitro pharmacokinetics. Measurements may be taken at specific points in time, or may be taken multiple times over time.
- the excretion when the in vitro pharmacokinetics is represented by the intracellular-to-extracellular excretion (Efflux amount), the excretion is an aqueous medium such as a medium after step (a) of the molecule of the present invention. It is determined by measuring the amount of the molecule excreted from the cell to the outside by detecting the molecule in an aqueous medium after exchanging it for one that does not contain .
- the in vitro pharmacokinetics is the intracellular-to-extracellular efflux rate (Efflux rate)
- the efflux rate includes the molecule of the present invention after step (a) in an aqueous medium such as a medium.
- the intracellular molecule depletion rate is determined after step (a) by changing an aqueous medium, such as a medium, to one that does not contain the molecules of the present invention. After the exchange, it is determined by detecting the molecule of interest in the cell and measuring the amount of the molecule of interest depleted from the cell per unit time.
- the dissociation rate from FcRn or target is determined by adding an aqueous medium, such as a medium, to the molecules of the invention after step (a). It is determined by measuring the amount of the molecule excreted into the aqueous medium per unit time by detecting the molecule in the aqueous medium after replacing it with one that does not contain it.
- Step (b) may be a step of measuring in vitro pharmacokinetics in step (a) in which the molecules of the present invention are incorporated into cells.
- In vitro pharmacokinetics so measured include, for example, internalization rate, amount of transcytosis, Kp value, rate of binding to FcRn or target, and the like.
- the internalization rate is It is determined by measuring the amount of the molecule that is taken into the cell from the outside.
- the cells contacted with the molecules of the present invention for a predetermined period of time are acidified (pH less than 6.0, e.g., pH 5.5 or less, pH 5.0 or less, pH 4.5 or less, pH 4.5 or less, pH 4.0 or lower, pH 3.5 or lower, or pH 3.0 or lower) to remove the molecules bound to the cell surface.
- acidified pH less than 6.0, e.g., pH 5.5 or less, pH 5.0 or less, pH 4.5 or less, pH 4.5 or less, pH 4.0 or lower, pH 3.5 or lower, or pH 3.0 or lower
- the amount of molecules taken up by cells over time is measured after the start of uptake, integration plot analysis is performed using the obtained measured values, and the internalization rate can be calculated from the initial slope.
- the amount of transcytosis is obtained by placing the molecule in the present invention in a state where it can be taken up by cells in step (a). is determined by measuring the amount that permeates the cell.
- cells cultured in sheets can be used.
- Commercially available products that can be used to measure the amount of transcytosis eg, Transwell® permeable supports (Corning), etc.
- the Kp value is obtained after a predetermined period of time has passed after the molecules of the present invention are placed in a state where they can be taken up by cells in step (a).
- the Kp value is calculated by (amount in cells)/(amount in aqueous medium).
- the rate of binding to FcRn or target is such that in step (a) the molecules of the invention can be taken up by cells. It is then determined by measuring the amount of FcRn or molecule of interest bound to the target per unit time.
- the measurement method of the present invention includes the following steps, (c) may further include a step of calculating in vitro evaluation parameters from the measurement results obtained in step (b).
- in vitro evaluation parameter means an index calculated from numerical values measured as in vitro pharmacokinetics. Calculation of in vitro assessment parameters facilitates evaluation of in vitro pharmacokinetics and prediction of in vivo pharmacokinetics.
- in vitro evaluation parameters include indices such as "clearance index” and "HERA index”.
- the "clearance index” is calculated by one of the following three methods based on the intracellular to extracellular excretion amount (Efflux amount).
- Method 1 Measure the amount of intracellular molecules at 0 minutes after the start of excretion and the amount of extracellular molecules at 240 minutes after the start of excretion. The value calculated by the amount of molecules) is defined as the clearance index.
- Method 2 Measure the amount of intracellular molecules at 0 minutes after the start of excretion and the amount of extracellular molecules at 120 and 240 minutes after the start of excretion (average of extracellular molecule amounts at 120 and 240 minutes )/(amount of intracellular molecule at 0 min) is defined as the clearance index.
- Method 3 Measure the amount of intracellular molecules at 0 minutes after the start of efflux and the amount of extracellular molecules at 60, 120 and 240 minutes after the start of efflux (extracellular at 60, 120 and 240 minutes). The value calculated by (average molecular amount)/(intracellular molecular amount at 0 min) is defined as the clearance index.
- a clearance index by Method 3 is calculated as an in vitro evaluation parameter.
- the "HERA index” is calculated by the following method based on the intracellular to extracellular excretion amount (Efflux amount). By incubating the molecules of the present invention with cells in a pH 6.0 buffer for 4 hours, the molecules are incorporated into the cells. The cells are then washed and a pH 7.4 buffer is added to expel the molecules from the cells. The amount of molecules ejected into the buffer (Rx) and the amount of molecules remaining inside the cell (RAx) are measured. The efflux (Rwt) and residual (RAwt) are similarly measured for a reference molecule (eg, a wild-type protein if the molecule in the present invention is a mutant protein). A value calculated by (Rx/Rwt)/(RAx/RAwt) is defined as the HERA score (Non-Patent Document 1).
- the measurement method of the present invention is a method for measuring the in vitro pharmacokinetics of an antibody, comprising the steps of: (a) contacting the antibody with FcRn-expressing cells in an aqueous medium so that the antibody is taken up by the cells so that the uptake amount is higher than 0.068 pmol/2 ⁇ 10 5 cells, A step having the following characteristics (i) to (iii), (i) the contact time between the antibody and the cell is 24 hours or longer; (ii) the cells are not washed under acidic conditions after contact with the antibody, and (iii) the cells express the target of the antibody on their cell surface.
- the in vitro assessment parameter can be the above method, wherein the in vitro assessment parameter is a clearance index.
- the measurement method of the present invention can be used for quality assurance or prediction of efficacy of pharmaceuticals containing the molecule of the present invention.
- the method of the present invention can be incorporated into a part of the manufacturing process of pharmaceuticals as a specification test for pharmaceuticals.
- the quality of pharmaceuticals can be maintained at a constant level by defining the range that should include in vitro pharmacokinetic measurement values or in vitro evaluation parameters as a standard and manufacturing products that meet that standard.
- drug efficacy can be predicted by measuring in vitro pharmacokinetics by the measuring method of the present invention.
- in some autoimmune diseases autoantibodies against self-antigens increase and attack the periphery, resulting in autoimmune reactions.
- immunoglobulin preparations that inject large amounts of human plasma-derived IgG intravenously (e.g., Hizentra (registered trademark) (CSF Behring)) has been reported, and the possibility of developing an FcRn inhibitor as a therapeutic agent for autoimmune diseases has also been reported (Folia Pharmacol. Jpn. ) 136, 280-284 (2010)).
- the prediction of drug efficacy can be the prediction of drug-drug interactions.
- step (a) the molecule of the present invention and another pharmaceutically active ingredient are brought into contact with cells, and the in vitro pharmacokinetics in the presence of the ingredient is measured to determine whether the ingredient is the molecule. It is possible to predict what kind of influence it will have on drug efficacy.
- a second aspect of the present invention relates to methods for predicting in vivo pharmacokinetics of molecules (hereinafter referred to as prediction methods of the present invention).
- the prediction method of the present invention includes the following steps (a') a step of measuring in vitro pharmacokinetics by the measurement method of the present invention, and (b') the measured value obtained in step (a') or in vitro evaluation A step of predicting in vivo pharmacokinetics when the molecule is administered to a living body from the parameters.
- Step (a') is performed according to the description in I above.
- step (b') from the measured value or in vitro evaluation parameter obtained in step (a'), the in vitro pharmacokinetic measurement value or in vitro evaluation parameter and the in vivo pharmacokinetic value are calculated in advance. Predict in vivo pharmacokinetics based on the correlation between Correlations are determined for each molecule, species, and type of in vitro and in vivo pharmacokinetics in the same manner as in the mouse specific example shown below.
- Reference molecules are molecules of the same type as the molecules of the present invention (e.g., proteins, peptide compounds, nucleic acids, toxins, viruses, DDS formulations such as nanoparticles and microparticles, etc.) and are selected from molecules having the same target. be.
- the molecule of the invention and the reference molecule are antibodies, they bind to the same antigen (preferably the same epitope).
- the reference molecule is the molecule (e.g., wild-type protein, wild-type peptide compounds, wild-type nucleic acids, etc.) and/or another molecule made similarly to the artifact.
- the number of reference molecules used for correlation determination is one or more, preferably two or more (eg, three or more, four or more, five or more, ten or more).
- in vitro pharmacokinetics of the reference molecule is measured by the measurement method of the present invention in the same way as the molecule of the present invention. If necessary, in vitro evaluation parameters are calculated from the results of in vitro pharmacokinetic measurements.
- the reference molecule was administered to FcRn-expressing mice via the tail vein, plasma antibody concentrations were measured over time up to 28 days after administration, and plasma half-life or clearance was calculated by noncompartmental model analysis. do.
- In vivo pharmacokinetics in the prediction method of the present invention are not particularly limited, and examples include bioavailability, volume of distribution, blood unbound fraction, clearance, urinary excretion rate, blood concentration half-life, or mean residence time.
- the in vivo pharmacokinetics is clearance or plasma half-life and the in vitro assessment parameter is clearance index.
- the living organism can be a human, monkey, minipig, rat, mouse, rabbit, dog, guinea pig, hamster, chimpanzee, marmoset, ferret, or cat.
- the living body is a non-human animal, such as a monkey, minipig, rat, mouse, rabbit, dog, or guinea pig. .
- the prediction method of the present invention in vitro studies can predict in vivo pharmacokinetics such as plasma half-life and clearance. Therefore, the prediction method of the present invention can be used as an alternative to in vivo pharmacokinetic studies using animals. As a result, the number of in vivo pharmacokinetic tests and the number of experimental animals used can be reduced, and the present invention is also useful from the viewpoint of animal ethics.
- a third aspect of the present invention relates to a molecular screening method (hereinafter referred to as the screening method of the present invention).
- the screening method of the present invention comprises the following steps (a''): preparing two or more different molecules that bind to the same target; (b'') measuring the in vitro pharmacokinetics of each of the two or more molecules prepared in step (a'') by the measurement method of the present invention; and (c'') in step (b'') Comparing the resulting measured values or in vitro assessment parameters for each of the two or more molecules with each other and selecting the molecules that exhibit the desired values.
- Each of the two or more molecules in step (a'') is the molecule in the present invention described in I above.
- the two or more molecules are of the same type of molecule, have the same target, and are different from each other.
- the two or more molecules are antibodies, they can be different variants from the same parent antibody.
- the step (b'') is performed according to the description of I above for each of the two or more molecules.
- step (c'') molecules that exhibit desirable in vitro pharmacokinetic measurements or in vitro evaluation parameter values are selected. Desirable values may vary depending on the type of in vitro pharmacokinetics, but may be, for example, values that indicate higher FcRn or target binding activity.
- Desirable values may vary depending on the type of in vitro pharmacokinetics, but may be, for example, values that indicate higher FcRn or target binding activity.
- the in vitro pharmacokinetics are intracellular-to-extracellular excretion rate, intracellular-to-extracellular excretion rate, transcytosis amount, or intracellular molecule reduction rate, the higher the value, the more FcRn-binding activity. is high.
- In vitro pharmacokinetics is also the rate of internalization, and when cells express the target, higher values indicate higher binding activity with the target.
- Each selected molecule can be used for applications (medicine, etc.) depending on its characteristics, and may be subjected to further testing.
- molecules with desired characteristics can be selected without conducting in vivo pharmacokinetic tests.
- the number of in vivo pharmacokinetic tests and the number of experimental animals used can be reduced, and the present invention is also useful from the viewpoint of animal ethics.
- Example 1 Mouse Plasma Pharmacokinetic Evaluation of Each Fc Variant (1-1) Characteristics of Fc Regions of Antibodies Used for Uptake Evaluation WO 2012/133782 A1, WO 2013/046704 A2, WO 2017/046994 A1, WO 2009 H237-G1d, H237-F1847m, H237-F1886m, H237-F1927m, and H237-F890, which are anti-IL-6R antibodies having the Fc described in /125825 A1, were used.
- the heavy chain sequence of H237-G1d is the amino acid sequence of SEQ ID NO: 79 of WO 2012/133782 A1.
- the heavy chain sequence of H237-F1847m is the amino acid sequence of SEQ ID NO: 50 of WO 2017/046994 A1.
- the heavy chain sequence of H237-F1886m is the amino acid sequence of SEQ ID NO: 52 of WO 2017/046994 A1.
- the heavy chain sequence of H237-F1927m is the amino acid sequence of SEQ ID NO: 54 of WO 2017/046994 A1.
- the heavy chain sequence of H237-F890 is the amino acid sequence of SEQ ID NO: 6 of WO 2013/046704 A2. Both of these light chain sequences are the amino acid sequence of SEQ ID NO: 27 of WO 2009/125825 A1.
- mice H237-G1d, H237-F1847m, H237-F1886m, H237-F1927m, and H237-F890 in mouse FcRn knockout/human FcRn transgenic mice (Tg#32, male) and 1000 mg/kg of Sanglopor (dried pH4-treated human immunoglobulin, CSL Behring) were administered to the tail vein, and blood samples were collected from the jugular vein over time from 5 minutes to 28 days later. rice field. The obtained blood was centrifuged (12000 rpm, 4° C., 5 minutes) to obtain plasma. Plasma antibody concentrations were measured using an electrochemiluminescence immunoassay (ECL) with capture and detection antibodies to the administered antibody. Using the obtained PK profile, non-compartment model analysis was performed to calculate the half-life and clearance.
- ECL electrochemiluminescence immunoassay
- H237-F1847m, H237-F1886m, and H237-F1927m showed a gradual slope in the elimination phase compared to H237-G1d and H237-F890, indicating a tendency of slower elimination from plasma.
- Table 1 shows the calculated PK parameters.
- H237-F1886m had the longest terminal half-life, and H237-F1927m and H237-F1847m were also longer than H237-G1d.
- H237-F890 showed the shortest half-life.
- H237-F1886m had the smallest clearance, and H237-F1927m and H237-F1886m were also smaller than H237-G1d.
- Example 2 Comparison of cell uptake of each Fc variant (2-1) Alexa647 labeling of Fc region variant antibody Using Alexa flour 647 labeling kit (Thermo Fisher Scientific), H237-G1d, H237-F1847m, H237 according to the attached protocol -F1886m, H237-F1927m and H237-F890 were labeled with Alexa647 (AF647).
- the concentration of each antibody and the labeling efficiency of the fluorescent substance were calculated by measuring the absorbance with Nanodrop (Thermo Fisher Scientific) and according to the formula described in the attached protocol.
- FBS-PBS FBS-containing PBS
- Fluorescence intensity of cells was measured using FACS CantoII (Becton, Dickinson and Company).
- fluorescence intensity of fluorescently labeled standard beads was also measured using Quantum MESF (Bangs Laboratories) according to the attached protocol. According to the attached protocol, a calibration curve was drawn from the geometric mean fluorescence intensity of each sample, and the amount of each antibody incorporated was calculated from the geometric mean fluorescence intensity of the sample into which each antibody had been incorporated.
- Example 3 Evaluation of Cellular Uptake of Each Fc Variant Over Time
- an AF647-labeled antibody was added to a final concentration of 50 ⁇ g/mL. 100 ⁇ L/well in a -well plate. The plate was then allowed to react over time at 37° C. for up to 24 hours with agitation. Then, the cells were ice-cooled, cold 2% FBS-containing PBS was added, and the cells were washed once with FBS-PBS or a medium (Acid) adjusted to pH 3.0. Cells were then recovered by centrifugation (1000 g, 3 min).
- Fluorescence intensity of cells was measured using FACS CantoII.
- fluorescence intensity of fluorescently labeled standard beads was also measured using Quantum MESF (Bangs Laboratories) according to the attached protocol. According to the attached protocol, a calibration curve was drawn from the geometric mean fluorescence intensity of each sample, and the amount of each antibody incorporated was calculated from the geometric mean fluorescence intensity of the sample into which each antibody had been incorporated.
- Example 4 Time-course evaluation of the amount of intracellular antibodies and the amount of efflux into the medium of each Fc variant (4-1)
- Time - course evaluation of the amount of intracellular antibodies and the amount of efflux into the medium AF647-labeled antibody was added to 50 ⁇ L of the cell solution containing hFcRn-hIL6R-CHO cells to a final concentration of 50 ⁇ g/mL, and adjusted to 100 ⁇ L/well in a 96-well plate. After that, it was incubated at 37°C for 24 hours. After that, the cells were ice-cooled, the cold 2% BSA-containing medium was added and removed, 100 ⁇ L of fresh 2% BSA-containing medium was added, the reaction was allowed to continue at 37° C.
- FIG. 4(a) A time-dependent decrease in the amount of intracellular antibodies was confirmed for all antibodies.
- the H237-F890 intracellular antibody level remained high.
- FIG. 4(b) shows the time transition of the amount of antibody excreted into the medium. It was confirmed that all antibodies were rapidly excreted until about 30 minutes after the start of excretion, and then reached a plateau. Up to 10 minutes after the start of excretion, the graphs for all antibodies showed similar slopes. -G1d showed the lowest amount.
- Example 5 Correlation Between Clearance Index and In Vivo Pharmacokinetics
- the present invention it is possible to predict the in vivo pharmacokinetics of a large number of drug candidate substances more easily and accurately than before.
- the present invention can contribute to the reduction of the number of experimental animals used, the development of drugs with higher pharmacological effects, and the like.
Abstract
Description
Grevysらは、ヒト微小血管内皮細胞株(HMEC1)にヒト胎児性Fc受容体(FcRn)を発現させた細胞(HMEC1-hFcRn)を用い、HERAアッセイ(human endothelial cell-based recycling assay)と名付けた手法により、in vitroでIgG抗体がFcRnを介して細胞外に排出される量を測定し、トランスジェニックマウスにおける半減期を予測する方法を開示している(非特許文献1)。
Jaramilloらは、Madin-Darbyイヌ腎臓(MDCK)細胞にヒトFcRnまたはラットFcRnを発現させた細胞を用い、抗体がFcRnを介して当該細胞を透過する活性、すなわちトランスサイトーシス活性を測定したこと、それにより抗体のin vivoクリアランスのランク付けを行ったことを開示している(非特許文献2)。
Chungらも、Jaramilloらの方法と同様に、MDCK細胞にヒトFcRnを発現させた細胞を用いてトランスサイトーシス活性をし、その測定結果とヒトにおけるin vivoクリアランスとの間に相関関係が見られたことを開示している(非特許文献3)。
例えば、Grevysらの方法では、in vitroの測定結果から算出したHERAスコア((RX/RWT)/(RAX/RAWT):Rは所定の時間内に細胞に取り込まれたタンパク質が細胞外に放出される量を表し、RAは残存量を表し、Xは目的のタンパク質(変異体)を表し、WTは結果の標準化に用いた親タンパク質を表す。)とin vivo薬物動態との相関がみられたのは、比較する抗体同士の薬物動態の差が大きい場合に限られる。また、11日を超えるような、長い血中半減期を有する抗体のin vivo薬物動態を予測できることは示されていない。
またJaramilloらの方法では、Fc改変抗体の場合には、in vitroのトランスサイトーシス活性(flux)の逆数とin vivoクリアランスとの間に相関関係が見られたものの、in vivoクリアランスの差が小さい抗体同士を比較する場合、in vitroの測定結果からin vivoクリアランスを予測できる精度は得られていなかった(非特許文献2の図6A参照)。また、抗原が異なる抗体について分析した結果では、in vitroのデータとin vivoのデータとの間に相関関係は見られなかった(非特許文献2の図6B参照)。
Chungらの方法においても、in vivoクリアランスの差が小さい抗体同士を比較する場合、in vitroの測定結果からin vivoクリアランスを予測できる精度は得られていなかった。
したがって、本発明の目的は、in vitro薬物動態の測定結果に基づき、従来よりも高い感度で、より正確に、分子のin vivo薬物動態を予測する方法などを提供することにある。
[1]分子のin vitro薬物動態を測定する方法であって、以下の工程、
(a)分子とFcRnを発現する細胞とを水性媒体中で接触させることにより、取り込み量が0.068 pmol/2×105cellsより高くなるように前記分子を前記細胞に取り込ませる工程であって、下記(i)~(iii)から選択される少なくとも1つの特徴を有する、工程、
(i)前記分子と前記細胞との接触時間が5時間以上である、
(ii)前記分子と接触させた後の前記細胞を酸性条件下で洗浄しない、および
(iii)前記細胞が、前記分子の標的を細胞表面に発現している、ならびに
(b)前記分子のin vitro薬物動態を測定する工程、
を含み、
前記分子は、FcRn結合ドメインを含む、前記方法。
[2]分子が、FcRn結合ドメインおよび標的結合ドメインを含む抗体である、[1]に記載の方法。
[3]前記細胞が、FcRnを発現するように形質転換された細胞である、[1]または[2]に記載の方法。
[4]前記細胞が、前記分子の標的を細胞表面に発現するように形質転換された細胞である、[1]~[3]のいずれかに記載の方法。
[5]前記細胞が、CHO細胞、HEK293細胞、COS-1細胞、COS-7細胞、MDCK細胞、HMEC1細胞、HELA細胞、HepG2細胞、またはBaF細胞である、[3]または[4]に記載の方法。
[6]前記細胞が、肝臓実質細胞、肝臓非実質細胞、肝類洞内皮細胞、クッパー細胞、ヒト臍帯静脈内皮細胞、末梢血単核球PBMC、マクロファージ、単核球、B細胞、T細胞、血小板、NK細胞、好中球、好酸球、好塩基球、顆粒球、または樹状細胞である、[1]または[2]に記載の方法。
[7]取り込み量が0.10 pmol/2×105cellsより高くなるように前記分子を前記細胞に取り込ませる、[1]~[6]のいずれかに記載の方法。
[8]in vitro薬物動態が、細胞内から培養液中への排出量、細胞内から培養液中への排出速度、内在化速度、トランスサイトーシス量、Kp値、細胞内分子減少速度、FcRnまたは標的への結合速度、あるいはFcRnまたは標的からの解離速度である、[1]~[7]のいずれかに記載の方法。
[9]FcRnが、ヒトFcRn、サルFcRn、ミニブタFcRn、ラットFcRn、マウスFcRn、ウサギFcRn、イヌFcRn、またはモルモットFcRnである、[1]~[8]のいずれかに記載の方法。
[10]以下の工程、
(c)工程(b)で得られた測定結果から、in vitro評価パラメーターを算出する工程
をさらに含む、[1]~[9]のいずれかに記載の方法。
[11]in vitro評価パラメーターが、クリアランスインデックスまたはHERAスコアである、[10]に記載の方法。
[12]前記分子を含む医薬品の品質確保または薬効の予測のために使用される、[1]~[11]のいずれかに記載の方法。
[13]前記分子の標的が、膜タンパク質である、[1]~[12]のいずれかに記載の方法。
[14]前記分子の標的が、ヒトIL6受容体である、[13]に記載の方法。
[15]分子のin vivo薬物動態を予測する方法であって、
(a’)[1]~[14]のいずれかに記載の方法により、in vitro薬物動態を測定する工程、および
(b’)工程(a’)で得られた測定値またはin vitro評価パラメーターから、前記分子を生体に投与した場合のin vivo薬物動態を予測する工程
を含む、前記方法。
[16]in vivo薬物動態が、バイオアベイラビリティ、分布容積、血中非結合形分率、クリアランス、尿中排泄率、血中濃度半減期、または平均滞留時間である、[15]に記載の方法。
[17]生体が、ヒト、サル、ミニブタ、ラット、マウス、ウサギ、イヌ、またはモルモットである、[15]または[16]に記載の方法。
[18]動物を用いた薬物動態試験の代替として使用される、[15]~[17]のいずれかに記載の方法。
[19]分子のスクリーニング方法であって、
(a’’)同一の標的に結合する異なる2以上の分子を準備する工程、
(b’’)工程(a’’)で準備した2以上の分子それぞれについて、[1]~[14]のいずれかに記載の方法により、in vitro薬物動態を測定する工程、および
(c’’)工程(b’’)で得られた、2以上の分子それぞれについての測定値またはin vitro評価パラメーターを相互に比較し、望ましい値を示した分子を選択する工程
を含む、前記方法。
また本発明は、in vivo薬物動態試験の回数を削減することにより、実験動物の使用数削減に貢献することができる。
さらに本発明は、所望の薬物動態を有する薬剤を効率よくスクリーニングする方法を提供することにより、より薬理効果の高い医薬品の開発に貢献することができる。
本発明の第一の態様は、分子のin vitro薬物動態を測定する方法に関する(以下、本発明の測定方法とも称する)。
薬剤が投与された後、生体内では、吸収(absorption)、分布(distribution)、代謝(metabolism)、および排泄(excretion)の過程が並行して進行する。これらの過程を分解して記述するための基本的な薬物動態(PK)パラメーターとして、(1)バイオアベイラビリティ(bioavailability: F)、(2)分布容積(volume of distribution: VdまたはV)、(3)血中非結合形分率(fraction unbound in blood: fuB)、(4)クリアランス(clearance: CL)、および(5)尿中排泄率(cumulative amount of drug excreted in urine: Ae)が確立されている(計量生物学 Vol. 36, Special Issue, S 3-S 18 (2015))。バイオアベイラビリティの指標として、血中濃度-時間曲線下面積(AUC)、最高血中濃度(Cmax)、最高血中濃度到達時間(Tmax)などが知られている。分布容積の指標として、定常状態における分布容積(Vss)などが知られている。その他のPKパラメーターとして、血中濃度半減期(t1/2)、平均滞留時間(MRT)、1次モーメント時間曲線下面積(AUMC)、消失速度定数(kel)、投与後ゼロ時点濃度(C0)などが知られている。
細胞内から細胞外への排出量(Efflux量)は、対象分子を細胞と所定の時間接触させた後、水性媒体(例えば培地、緩衝液など)を対象分子を含まないものに交換したのち、水性媒体中の対象分子を検出することにより、細胞から細胞外に排出される対象分子の量を測定することで決定される。
細胞内から細胞外への排出速度(Efflux速度)は、単位時間あたりの対象分子のEfflux量を測定することで決定される。
内在化速度は、対象分子を細胞と所定の時間接触させ、単位時間あたりに細胞外から(例えば培地、緩衝液などから)細胞に取り込まれる対象分子の量を測定することで決定される。好ましい態様において、対象分子と所定の時間接触させた細胞は、対象分子の量の測定前に、酸性(pH6.0未満、例えばpH5.5以下、pH5.0以下、pH4.5以下、pH4.0以下、pH3.5以下、またはpH3.0以下)の水性媒体で洗浄され、細胞表面に結合している対象分子が除去される。それにより、細胞内に取り込まれた(内在化された)対象分子の量をより正確に測定することができる。
トランスサイトーシス量は、細胞シートに対して一方の側から他方の側への透過量を測定することで決定される。例えば、トランズウェル(登録商標)システム(Corning)などを用いて測定することができる(非特許文献2および3参照)。
Kp値は、in vivo薬物動態に関しては組織-血漿間薬物濃度比(すなわち、組織と血漿との間の対象分子の濃度の比率)として知られているが、本明細書中においてin vitro薬物動態に関しては、細胞と水性媒体(例えば培地)との間の対象分子の濃度の比率をいう。Kp値は、細胞中の量および水性媒体中の量を測定することで決定される。本明細書中、in vitro薬物動態としてのKp値は、(細胞中の量)/(水性媒体中の量)により算出される値である。
細胞内分子減少速度は、対象分子を細胞と所定の時間接触させた後、水性媒体(例えば培地、緩衝液など)を対象分子を含まないものに交換したのち、細胞内の対象分子を検出することにより、単位時間あたりに細胞から減少する対象分子の量を測定することで決定される。
FcRnまたは標的への結合速度は、対象分子を細胞と所定の短い時間(例えば数秒間~数分間)接触させ、単位時間当たりにFcRnまたは標的に結合した対象分子の量を測定することで決定される。
FcRnまたは標的からの解離速度は、対象分子を細胞と所定の時間(例えば平衡状態に達するのに十分な時間)接触させた後、水性媒体(例えば培地、緩衝液など)を対象分子を含まないものに交換したのち、水性媒体中の対象分子を検出することにより、単位時間あたりに水性媒体中に排出される対象分子の量を測定することで決定される。好ましい実施形態において、対象分子と細胞との接触および対象分子の水性媒体中への放出は、対象分子の細胞内への内在化が抑制される温度(例えば4℃又はそれ以下の温度)で行うことができる。
ヒトFcRnはβ2mサブユニットと呼ばれる軽鎖と、膜貫通領域を持つαサブユニットと呼ばれる重鎖からなる二量体タンパク質であり、その構造は主要組織適合遺伝子複合体(MHC)クラスI分子に類似している。このFcRn二量体は更にダイマー化し、一分子のIgGと結合する(Annual Review of Cell and Developmental Biology Vol. 12, p. 181-220 (1996))。FcRnは、他のIgG抗体Fc受容体とは異なり、自身のα2ドメイン上のアニオン残基とIgGのCH2-CH3ヒンジ領域との静電的相互作用を介したpH依存的な結合性を示すことが知られている(Nature Reviews Immunology Vol. 7, p. 715-725 (2007))。
pH6.5未満であるエンドソーム内においては、ピノサイトーシスにより細胞内に取り込まれたIgGはFcRnと高親和性で結合し、ライソソームでの分解から逃れ、その後中性条件下(pH7.4)の細胞表面へ移動したところで解離する。このpH依存的な結合様式が、IgGのトランスサイトーシスやエキソサイトーシスを可能にしており、母親からの胎児へのIgGの輸送や、生体内IgGの血中半減期延長(約20日)に寄与している(Protein Cell Vol. 9(1), p. 15-32 (2018))。
FcRn結合ドメインは、pH6.5未満であるエンドソーム内のpH環境下でFcRnと結合し得る限り、変異を含んでいてもよい。変異を含むFc結合ドメインとしては、例えば、WO 2012/133782 A1、WO 2013/046704 A2、およびWO 2017/046994 A1に記載された抗体の変異Fc領域が挙げられるが、これらに限定されない。
本明細書中、抗原結合ドメインは一または複数の抗体の可変ドメインより提供され得る。好ましくは、抗原結合ドメインは抗体軽鎖可変領域(VL)と抗体重鎖可変領域(VH)とを含む。こうした抗原結合ドメインの例としては、「scFv(single chain Fv)」、「単鎖抗体(single chain antibody)」、「Fv」、「scFv2(single chain Fv 2)」、「Fab」または「F(ab')2」等が好適に挙げられる。
特定の態様において、標的結合ドメインは、抗体の重鎖および/または軽鎖の可変領域を含む。好ましい態様において、標的結合ドメインは、抗体の重鎖および軽鎖の可変領域を含むか、またはそれらからなる。
抗体の「FcRn結合ドメイン」は、FcRnに結合することができればよく、例えば、抗体の重鎖定常領域(Fc領域)が挙げられる。
本発明における分子としての抗体は、「抗原結合ドメイン」を含むことが好ましく、抗体の重鎖および軽鎖の可変領域を含むことがより好ましい。それにより、細胞が抗原を細胞表面に発現している場合、本発明における分子の細胞への取り込み量が増加し得る。
これらの抗体を作製する方法は当業者において公知である(例えば、WO 2013/081143など)。
核酸は、その機能または用途に応じて、siRNA、アンチセンスRNA、miRNA、shRNA、リボザイム、またはアプタマーと呼ばれることもある。本発明において用いられる核酸には、Toll 様受容体9(TLR9)に作用して自然免疫を活性化させるCpGオリゴヌクレオチドも含まれる。
核酸の塩基長は、Stabilinを介して細胞に取り込まれ得る長さであればよく、例えば4~100塩基長、10~50塩基長、10~40塩基長、または10~30塩基長の範囲である。
本明細書中、Stabilinとは、核酸受容体として知られる膜貫通タンパク質のファミリーに属するタンパク質をいう。哺乳動物においては、Stabilin-1およびStabilin-2の2種類の相同体が知られており、本発明においてStabilinはそれらのいずれであってもよい。ヒトにおいては、Stabilin-1(NCBI accession number: NP_055951.2)およびStabilin-2(NCBI accession number: NP_060034.9)が知られており、LSEC、脾臓、副腎皮質、リンパ節、および類洞マクロファージにおいて発現していることが報告されている。
アミド結合あるいはエステル結合の数(アミノ酸又はアミノ酸類縁体の数・長さ)は特に限定されないが、直鎖部を有する場合、環状部と直鎖部を併せて30残基以内が好ましい。環化部位と直鎖部位を併せた総アミノ酸数は13残基以下であることがより好ましい。高い代謝安定性を獲得するためには、総アミノ酸数が9以上であることがより好ましい。上記に加えて環状部を構成するアミノ酸及びアミノ酸類縁体の数は5~12であることが好ましい。さらに、上の記載に加えて環状部を構成するアミノ酸及びアミノ酸類縁体の数はより好ましくは5~11、さらに7~11残基が好ましい。特に9~11残基が好ましい。直鎖部のアミノ酸及びアミノ酸類縁体の数(ユニットの数)は0~8であることが好ましい。さらに、0~3が好ましい。尚、本願では特に限定しない限り、アミノ酸にはアミノ酸類縁体も含まれる場合があるものとする。
アミノ酸とはα、βおよびγアミノ酸であり、天然型アミノ酸(本願では天然型アミノ酸とはタンパク質に含まれる20種類のアミノ酸を指す。具体的にはGly、Ala、Ser、Thr、Val、Leu、Ile、Phe、Tyr、Trp、His、Glu、Asp、Gln、Asn、Cys、Met、Lys、Arg、Proを指す。)に限定されず、非天然型アミノ酸であってもよい。α-アミノ酸の場合、L型アミノ酸でもD型アミノ酸でもよく、α,α-ジアルキルアミノ酸でもよい。アミノ酸側鎖の選択は特に制限を設けないが、水素原子の他にも例えばアルキル基、アルケニル基、アルキニル基、アリール基、ヘテロアリール基、アラルキル基、シクロアルキル基から自由に選択される。それぞれには置換基が付与されていてもよく、それら置換基も例えば、N原子、O原子、S原子、B原子、Si原子、P原子を含む任意の官能基の中から自由に選択される(すなわち、置換されていてもよいアルキル基、アルケニル基、アルキニル基、アリール基、ヘテロアリール基、アラルキル基、シクロアルキル基など)。
ペプチド化合物を構成する「アミノ酸」、「アミノ酸類縁体」にはそれぞれに対応する全ての同位体を含む。「アミノ酸」、「アミノ酸類縁体」の同位体は、少なくとも1つの原子が、原子番号(陽子数)が同じで,質量数(陽子と中性子の数の和)が異なる原子で置換されたものである。本発明ペプチド化合物を構成する「アミノ酸」、「アミノ酸類縁体」に含まれる同位体の例としては、水素原子、炭素原子、窒素原子、酸素原子、リン原子、硫黄原子、フッ素原子、塩素原子などがあり、それぞれ、2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F、36Cl等が含まれる。
好ましい実施形態において、本発明における分子には、特定の細胞に特異的に結合する分子を結合させたナノ粒子・マイクロ粒子が含まれる。例えば、当該細胞の表面抗原に対する抗原結合分子をこれらの粒子に結合させることができる。また、例えば、FcRn結合ドメインを含む分子をこれらの粒子に結合させることができる。一実施形態において、本発明における分子は、FcRn結合ドメインおよび/または標的結合ドメインを含む抗体を結合させたナノ粒子・マイクロ粒子であり得る。
細胞傷害剤の例として、メイタンシノイド(米国特許第5,208,020号、第5,416,064号、および欧州特許第0,425,235号B1参照);例えばモノメチルオーリスタチン薬剤部分DEおよびDF(MMAEおよびMMAF)(米国特許第5,635,483号および第5,780,588号および第7,498,298号参照)などのオーリスタチン;ドラスタチン;カリケアマイシンまたはその誘導体(米国特許第5,712,374号、第5,714,586号、第5,739,116号、第5,767,285号、第5,770,701号、第5,770,710号、第5,773,001号、および第5,877,296号;Hinman et al., Cancer Res. 53:3336-3342 (1993);ならびにLode et al., Cancer Res. 58:2925-2928 (1998) 参照);ダウノマイシンまたはドキソルビシンなどのアントラサイクリン(Kratz et al., Current Med. Chem. 13:477-523 (2006);Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006);Torgov et al., Bioconj. Chem. 16:717-721 (2005);Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000);Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002);King et al., J. Med. Chem. 45:4336-4343 (2002);および米国特許第6,630,579号参照);メトトレキサート;ビンデシン;ドセタキセル、パクリタキセル、ラロタキセル、テセタキセル、およびオルタタキセルなどのタキサン;トリコテセン;ならびにCC1065が挙げられる。
毒素の例としては、これらに限定されるものではないが以下を含む酵素的に活性な毒素またはその断片が挙げられる:ジフテリアA鎖、ジフテリア毒素の非結合活性断片、外毒素A鎖(緑膿菌 (Pseudomonas aeruginosa) 由来)、リシンA鎖、アブリンA鎖、モデシンA鎖、アルファ-サルシン、シナアブラギリ (Aleurites fordii) タンパク質、ジアンチンタンパク質、ヨウシュヤマゴボウ (Phytolacca americana) タンパク質(PAPI、PAPIIおよびPAP-S)、ツルレイシ(momordica charantia) 阻害剤、クルシン (curcin)、クロチン、サボンソウ (saponaria officinalis) 阻害剤、ゲロニン、ミトゲリン(mitogellin)、レストリクトシン、フェノマイシン、エノマイシン、ならびにトリコテセン。
放射性同位元素の例としては、211At、131I、125I、90Y、186Re、188Re、153Sm、212Bi、32P、212PbおよびLuの放射性同位体が挙げられる。
(a)分子とFcRnを発現する細胞とを水性媒体中で接触させることにより、取り込み量が0.068 pmol/2×105cellsより高くなるように前記分子を前記細胞に取り込ませる工程、および
(b)前記分子のin vitro薬物動態を測定する工程、
を含む。
工程(a)の特定の実施形態において、本発明における分子の細胞への取り込みは、対象分子の細胞内への内在化が抑制される温度(例えば4℃又はそれ以下の温度)で、水性媒体中で当該分子と細胞とを接触させることによって行い得る。それにより、細胞表面に結合しているが内在化していない当該分子を測定対象とすることができ、例えば、FcRnまたは標的からの解離速度をより正確に測定し得る。
(i)前記分子と前記細胞との接触時間が5時間以上である、
(ii)前記分子と接触させた後の前記細胞を酸性条件下で洗浄しない、および
(iii)前記細胞が、前記分子の標的を細胞表面に発現している。
(iv)水性媒体のpHを5.0~6.0に調整する工程、
(v)前記分子が抗体である場合において、当該抗体とその抗原との間で免疫複合体(IC)を形成させる工程、
(vi)前記分子がFc領域を含む場合において、水性媒体に抗Fc抗体を添加する工程、および
(vii)水性媒体に取り込み促進剤を添加する工程。
取り込み促進剤には、エンドサイトーシス促進剤も含まれる。エンドサイトーシス促進剤としては、例えば、オカダ酸(Drug Delivery System 2016年31巻1号 p. 83-84)などが挙げられる。
取り込み促進剤には、本発明における分子の細胞からの排出を阻害する物質も含まれる。そのような物質としては、例えば、ABCトランスポーター(ATP-binding cassette transporters)の阻害剤が挙げられる。ABCトランスポーターの阻害剤としては、当該分野において一般的に使用されるものを利用することができ、例えば、MRP2の阻害剤として知られるMK571、CeefourinTM 1(abcam社製)、CeefourinTM 2(abcam社製)、エリスロマイシン、チエニルブチルイソチオシアネートなどが挙げられる。
一実施形態において、in vitro薬物動態が細胞内から細胞外への排出速度(Efflux速度)である場合、排出速度は、工程(a)の後、培地などの水性媒体を本発明における分子を含まないものに交換したのち、水性媒体中の当該分子を検出することにより、単位時間あたりの当該分子の排出量を測定することで決定される。
一実施形態において、in vitro薬物動態が細胞内分子減少速度によって表される場合、細胞内分子減少速度は、工程(a)の後、培地などの水性媒体を本発明における分子を含まないものに交換したのち、細胞内の当該分子を検出することにより、単位時間あたりに細胞から減少する当該分子の量を測定することで決定される。
一実施形態において、in vitro薬物動態がFcRnまたは標的からの解離速度によって表される場合、FcRnまたは標的からの解離速度は、工程(a)の後、培地などの水性媒体を本発明における分子を含まないものに交換したのち、水性媒体中の当該分子を検出することにより、単位時間あたりに水性媒体中に排出される当該分子の量を測定することで決定される。
一実施形態において、in vitro薬物動態が内在化速度によって表される場合、内在化速度は、工程(a)において本発明における分子が細胞に取り込まれ得る状態に置かれたのち、単位時間あたりに細胞外から細胞に取り込まれる当該分子の量を測定することで決定される。好ましい態様において、本発明における分子と所定の時間接触させた細胞は、当該分子の量の測定前に、酸性(pH6.0未満、例えばpH5.5以下、pH5.0以下、pH4.5以下、pH4.0以下、pH3.5以下、またはpH3.0以下)の水性媒体で洗浄され、細胞表面に結合している当該分子が除去される。また例えば、取り込みの開始後に経時的に細胞に取り込まれた分子の量を測定し、得られた測定値を用いてIntegration plot解析を行い、初期の傾きから内在化速度を算出することができる。
一実施形態において、in vitro薬物動態がトランスサイトーシス量によって表される場合、トランスサイトーシス量は、工程(a)において本発明における分子が細胞に取り込まれ得る状態に置かれたのち、当該分子が細胞を透過する量を測定することで決定される。この目的のために、シート状に培養した細胞を用いることができる。トランスサイトーシス量測定に用いられ得る市販の製品(例えばトランズウェル(登録商標)パーミアブルサポート(Corning)など)を用いてもよい。
一実施形態において、in vitro薬物動態がKp値によって表される場合、Kp値は、工程(a)において本発明における分子が細胞に取り込まれ得る状態に置かれ、所定の時間が経過したのち、当該分子の細胞中の量および水性媒体中の量を測定することで決定される。Kp値は、(細胞中の量)/(水性媒体中の量)により算出される。
一実施形態において、in vitro薬物動態がFcRnまたは標的への結合速度によって表される場合、FcRnまたは標的への結合速度は、工程(a)において本発明における分子が細胞に取り込まれ得る状態に置かれたのち、単位時間あたりにFcRnまたは標的に結合した当該分子の量を測定することで決定される。
(c)工程(b)で得られた測定結果から、in vitro評価パラメーターを算出する工程
をさらに含み得る。
Method1:排出開始後0分における細胞内の分子の量および排出開始後240分における細胞外の分子の量を測定し、(240分における細胞外の分子の量)/(0分における細胞内の分子の量)により算出される値をクリアランスインデックスとする。
Method2:排出開始後0分における細胞内の分子の量ならびに排出開始後120分および240分における細胞外の分子の量を測定し、(120分および240分における細胞外の分子の量の平均値)/(0分における細胞内の分子の量)により算出される値をクリアランスインデックスとする。
Method3:排出開始後0分における細胞内の分子の量ならびに排出開始後60分、120分および240分における細胞外の分子の量を測定し、(60分、120分および240分における細胞外の分子の量の平均値)/(0分における細胞内の分子の量)により算出される値をクリアランスインデックスとする。
本発明における分子と細胞とをpH6.0の緩衝液中で4時間インキュベーションすることにより、当該分子を細胞内へ取り込ませる。その後、細胞を洗浄し、pH7.4の緩衝液を添加して、細胞から当該分子を排出させる。緩衝液中に排出された分子の量(Rx)および細胞内に残存する分子の量(RAx)を測定する。参照分子(例えば、本発明における分子が変異型タンパク質である場合には野生型タンパク質)についても同様に、排出量(Rwt)および残存量(RAwt)を測定する。(Rx/Rwt)/(RAx/RAwt)により算出される値をHERAスコアとする(非特許文献1)。
(a)抗体とFcRnを発現する細胞とを水性媒体中で接触させることにより、取り込み量が0.068 pmol/2×105cellsより高くなるように前記抗体を前記細胞に取り込ませる工程であって、下記(i)~(iii)の特徴を有する、工程、
(i)前記抗体と前記細胞との接触時間が24時間以上である、
(ii)前記抗体と接触させた後の前記細胞を酸性条件下で洗浄しない、および
(iii)前記細胞が、前記抗体の標的を細胞表面に発現している、
(b)前記抗体のin vitro薬物動態を測定する工程、ならびに
(c)工程(b)で得られた測定結果から、in vitro評価パラメーターを算出する工程
を含み、
前記抗体は、FcRn結合ドメインおよび標的結合ドメインを含み、
in vitro薬物動態は、細胞内から細胞外への排出量であり、
in vitro評価パラメーターは、クリアランスインデックスである、前記方法であり得る。
また本発明の測定方法によりin vitro薬物動態を測定し、それに基づきin vivo薬物動態を予測することにより、薬効を予測し得る(後述のII)。
特定の実施形態において、薬効の予測は、薬物間相互作用の予測であり得る。例えば、工程(a)において本発明における分子と薬学的に活性な他の成分とを細胞と接触させ、当該成分の存在下でのin vitro薬物動態を測定することにより、当該成分が当該分子の薬効にどのような影響を与えるかを予測することができる。
本発明の第二の態様は、分子のin vivo薬物動態を予測する方法に関する(以下、本発明の予測方法と称する)。
(a’)本発明の測定方法により、in vitro薬物動態を測定する工程、および
(b’)工程(a’)で得られた測定値またはin vitro評価パラメーターから、前記分子を生体に投与した場合のin vivo薬物動態を予測する工程
を含む。
本発明の第三の態様は、分子のスクリーニング方法に関する(以下、本発明のスクリーニング方法と称する)。
(a’’)同一の標的に結合する異なる2以上の分子を準備する工程、
(b’’)工程(a’’)で準備した2以上の分子それぞれについて、本発明の測定方法により、in vitro薬物動態を測定する工程、および
(c’’)工程(b’’)で得られた、2以上の分子それぞれについての測定値またはin vitro評価パラメーターを相互に比較し、望ましい値を示した分子を選択する工程
を含む。
(1-1)取り込み評価に用いた抗体のFc領域の特性
WO 2012/133782 A1、WO 2013/046704 A2、WO 2017/046994 A1、WO 2009/125825 A1に記載のFcを持つ抗IL-6R抗体である、H237-G1d、H237-F1847m、H237-F1886m、H237-F1927m、H237-F890を用いた。
H237-G1dの重鎖配列はWO 2012/133782 A1の配列番号:79のアミノ酸配列である。
H237-F1847mの重鎖配列はWO 2017/046994 A1の配列番号:50のアミノ酸配列である。
H237-F1886mの重鎖配列はWO 2017/046994 A1の配列番号:52のアミノ酸配列である。
H237-F1927mの重鎖配列はWO 2017/046994 A1の配列番号:54のアミノ酸配列である。
H237-F890の重鎖配列はWO 2013/046704 A2の配列番号:6のアミノ酸配列である。
これらの軽鎖配列はいずれもWO 2009/125825 A1の配列番号:27のアミノ酸配列である。
マウスFcRnノックアウト/ヒトFcRnトランスジェニックマウス(Tg#32、雄性)に、H237-G1d、H237-F1847m、H237-F1886m、H237-F1927m、およびH237-F890のいずれか1つの抗体1 mg/kgと、Sanglopor(乾燥pH4処理人免疫グロブリン、CSLベーリング)1000 mg/kgとを尾静脈投与し、5分後から28日後まで経時的に頸静脈採血を行った。得られた血液を遠心分離(12000rpm、4℃、5分)し、血漿を得た。血漿中抗体濃度は、投与抗体に対する捕獲抗体・検出抗体を使った電気化学発光免疫測定法(ECL)を用いて測定した。また、得られたPKプロファイルを用いて、Non-compartment model解析を行い、半減期およびクリアランスを算出した。
(2-1)Fc領域改変抗体のAlexa647標識
Alexa flour 647 labeling kit(Thermo Fisher Scientific)を用い、添付のプロトコルにしたがってH237-G1d、H237-F1847m、H237-F1886m、H237-F1927m、およびH237-F890をAlexa647(AF647)で標識した。各抗体の濃度、および蛍光物質の標識効率は、吸光度をNanodrop(Thermo Fisher Scientific)で測定し、添付のプロトコルに記載の計算式にしたがって算出した。
完全培地(CHO-S-SFM II(Invitrogen))中に2x105個のヒトFcRnおよびヒトIL-6Rを強制発現させたCHO細胞(hFcRn-hIL6R-CHO細胞(Chiome Bioscience);CHO細胞にCMVプロモーターを含む発現ベクター(pcDNA3.1 vector, Invitrogen)を導入して作製された。)またはヒトFcRnのみを強制発現させたCHO細胞(hFcRn-CHO細胞(Chiome Bioscience);CHO細胞にCMVプロモーターを含む発現ベクター(pcDNA3.1 vector, Invitrogen)を導入して作製された。)を含む細胞溶液50μLに、AF647標識した抗体を終濃度が50μg/mLになるように添加し、96-wellプレート中100μL/wellとした。その後、CO2インキュベーター内で37℃で24時間反応させた。その後氷冷し、細胞を冷2% FBS含有PBS(FBS-PBS)で洗浄した。細胞の蛍光強度はFACS CantoII(Becton, Dickinson and Company)を用いて測定した。
アッセイを行った細胞に加えて、Quantum MESF(Bangs Laboratories)を用い、添付のプロトコルにしたがって、蛍光標識された標品ビーズの蛍光強度も測定した。添付のプロトコルにしたがって、各標品の幾何平均蛍光強度から検量線を描き、各抗体を取り込ませた試料の幾何平均蛍光強度から、各抗体の取り込み量を算出した。
2x105個のhFcRn-hIL6R-CHO細胞を含む細胞溶液50μLに、AF647標識した抗体を終濃度が50μg/mLになるように添加し、96-wellプレート中100μL/wellとした。その後、プレートを撹拌しながら37℃で最大24時間まで経時的に反応させた。その後氷冷し、冷2% FBS含有PBSを加え、細胞をFBS-PBSもしくはpH3.0に調整した培地(Acid)で1回洗浄した。その後、遠心(1000g, 3min)により細胞を回収した。細胞の蛍光強度は、FACS CantoIIを用いて測定した。
アッセイを行った細胞に加えて、Quantum MESF(Bangs Laboratories)を用い、添付のプロトコルにしたがって、蛍光標識された標品ビーズの蛍光強度も測定した。添付のプロトコルにしたがって、各標品の幾何平均蛍光強度から検量線を描き、各抗体を取り込ませた試料の幾何平均蛍光強度から、各抗体の取り込み量を算出した。
得られた抗体取り込み量の測定値を用いてIntegration plot解析を行い、初期の傾きから内在化速度を算出した。Integration plot解析の結果を図3(c)に示す。また算出された内在化速度を表2に示す。H237-F890は、H237-G1d、H237-F1847m、H237-F1886m、およびH237-F1927mに比べて、やや高い値を示した。
(4-1)細胞内抗体量および培地中への排出量の経時的評価
2x105個のhFcRn-hIL6R-CHO細胞を含む細胞溶液50μLに、AF647標識した抗体を終濃度が50μg/mLになるように添加し、96-wellプレート中100μL/wellとした。その後、37℃で24時間インキュベーションした。その後氷冷し、冷2% BSA含有培地の添加と除去を行い、新鮮な2%BSA含有培地を100μL加え、37℃で最大4時間まで反応させ、経時的にサンプリングした。各時点の試料を遠心した後、上清を回収するとともに、細胞をFBS-PBSで洗浄した。上清中の抗体濃度は、電気化学発光免疫測定法(ECL)を用いて測定した。また、細胞の蛍光強度は、FACS CantoIIを用いて測定し、標品ビーズの蛍光強度から細胞に含まれる抗体量を算出した。
また、培地中に排出された抗体量の時間推移を図4(b)に示す。いずれの抗体も排出の開始後30分前後まで、急速に排出され、その後プラトーに達することが確認された。排出の開始後10分までは、いずれの抗体についてのグラフも同様の傾きを示したが、60分以降は、各抗体で培地中抗体量に差が見られ、H237-F1886mが最も多く、H237-G1dが最も少ない量を示した。
排出開始後0分における細胞内抗体量、および各時点までに培地中に排出された抗体量を用いて、以下に示す3通りの計算式でクリアランスインデックスを算出した。
Method1:(240分における培地中の抗体量)/(0分における細胞内の抗体量)
Method2:(120分および240分における培地中の抗体量の平均)/(0分における細胞内の抗体量)
Method3:(60分、120分、および240分における培地中の抗体量)/(0分における細胞内の抗体量)
上記の各方法で算出したクリアランスインデックスの値を表4に示す。いずれの抗体においても、0.30~0.70程度の数値となった。各抗体について3つの方法で算出した値は、概ね同程度の値を示した。抗体間の値の大小も、3つの方法で同じ傾向を示した。
実施例4で算出したクリアランスインデックスと実施例1で測定したin vivoにおける半減期またはクリアランスとの相関を評価した。結果を図5に示す。in vivoにおける半減期およびクリアランスのいずれも、クリアランスインデックスとの間に強い相関が見られた(それぞれR2=0.961およびR2=0.822)。したがって、Method1~3により算出されるクリアランスインデックスにより、in vivoにおける血漿中半減期またはクリアランスを予測可能であることが示された。
Claims (19)
- 分子のin vitro薬物動態を測定する方法であって、以下の工程、
(a)分子とFcRnを発現する細胞とを水性媒体中で接触させることにより、取り込み量が0.068 pmol/2×105cellsより高くなるように前記分子を前記細胞に取り込ませる工程であって、下記(i)~(iii)から選択される少なくとも1つの特徴を有する、工程、
(i)前記分子と前記細胞との接触時間が5時間以上である、
(ii)前記分子と接触させた後の前記細胞を酸性条件下で洗浄しない、および
(iii)前記細胞が、前記分子の標的を細胞表面に発現している、ならびに
(b)前記分子のin vitro薬物動態を測定する工程、
を含み、
前記分子は、FcRn結合ドメインを含む、前記方法。 - 分子が、FcRn結合ドメインおよび標的結合ドメインを含む抗体である、請求項1に記載の方法。
- 前記細胞が、FcRnを発現するように形質転換された細胞である、請求項1または2に記載の方法。
- 前記細胞が、前記分子の標的を細胞表面に発現するように形質転換された細胞である、請求項1~3のいずれか一項に記載の方法。
- 前記細胞が、CHO細胞、HEK293細胞、COS-1細胞、COS-7細胞、MDCK細胞、HMEC1細胞、HELA細胞、HepG2細胞、またはBaF細胞である、請求項3または4に記載の方法。
- 前記細胞が、肝臓実質細胞、肝臓非実質細胞、肝類洞内皮細胞、クッパー細胞、ヒト臍帯静脈内皮細胞、末梢血単核球PBMC、マクロファージ、単核球、B細胞、T細胞、血小板、NK細胞、好中球、好酸球、好塩基球、顆粒球、または樹状細胞である、請求項1または2に記載の方法。
- 取り込み量が0.10 pmol/2×105cellsより高くなるように前記分子を前記細胞に取り込ませる、請求項1~6のいずれか一項に記載の方法。
- in vitro薬物動態が、細胞内から培養液中への排出量、細胞内から培養液中への排出速度、内在化速度、トランスサイトーシス量、Kp値、細胞内分子減少速度、FcRnまたは標的への結合速度、あるいはFcRnまたは標的からの解離速度である、請求項1~7のいずれか一項に記載の方法。
- FcRnが、ヒトFcRn、サルFcRn、ミニブタFcRn、ラットFcRn、マウスFcRn、ウサギFcRn、イヌFcRn、またはモルモットFcRnである、請求項1~8のいずれか一項に記載の方法。
- 以下の工程、
(c)工程(b)で得られた測定結果から、in vitro評価パラメーターを算出する工程
をさらに含む、請求項1~9のいずれか一項に記載の方法。 - in vitro評価パラメーターが、クリアランスインデックスまたはHERAスコアである、請求項10に記載の方法。
- 前記分子を含む医薬品の品質確保または薬効の予測のために使用される、請求項1~11のいずれか一項に記載の方法。
- 前記分子の標的が、膜タンパク質である、請求項1~12のいずれか一項に記載の方法。
- 前記分子の標的が、ヒトIL6受容体である、請求項13に記載の方法。
- 分子のin vivo薬物動態を予測する方法であって、
(a’)請求項1~14のいずれか一項に記載の方法により、in vitro薬物動態を測定する工程、および
(b’)工程(a’)で得られた測定値またはin vitro評価パラメーターから、前記分子を生体に投与した場合のin vivo薬物動態を予測する工程
を含む、前記方法。 - in vivo薬物動態が、バイオアベイラビリティ、分布容積、血中非結合形分率、クリアランス、尿中排泄率、血中濃度半減期、または平均滞留時間である、請求項15に記載の方法。
- 生体が、ヒト、サル、ミニブタ、ラット、マウス、ウサギ、イヌ、またはモルモットである、請求項15または16に記載の方法。
- 動物を用いた薬物動態試験の代替として使用される、請求項15~17のいずれか一項に記載の方法。
- 分子のスクリーニング方法であって、
(a’’)同一の標的に結合する異なる2以上の分子を準備する工程、
(b’’)工程(a’’)で準備した2以上の分子それぞれについて、請求項1~14のいずれか一項に記載の方法により、in vitro薬物動態を測定する工程、および
(c’’)工程(b’’)で得られた、2以上の分子それぞれについての測定値またはin vitro評価パラメーターを相互に比較し、望ましい値を示した分子を選択する工程
を含む、前記方法。
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