US20170152323A1 - Anti-inflammatory molecules with tissue-targeting functions - Google Patents
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- US20170152323A1 US20170152323A1 US14/997,849 US201614997849A US2017152323A1 US 20170152323 A1 US20170152323 A1 US 20170152323A1 US 201614997849 A US201614997849 A US 201614997849A US 2017152323 A1 US2017152323 A1 US 2017152323A1
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Definitions
- the present disclosure relates to the field of pharmaceuticals; more particularly, to multi-functional molecular constructs, e.g., those having targeting and effector elements for delivering the effector (e.g., therapeutic drug) to targeted sites.
- multi-functional molecular constructs e.g., those having targeting and effector elements for delivering the effector (e.g., therapeutic drug) to targeted sites.
- antibodies can neutralize or trap disease-causing mediators, which may be cytokines or immune components present in the blood circulation, interstitial space, or in the lymph nodes.
- the neutralizing activity inhibits the interaction of the disease-causing mediators with their receptors.
- fusion proteins of the soluble receptors or the extracellular portions of receptors of cytokines and the Fc portion of IgG which act by neutralizing the cytokines or immune factors in a similar fashion as neutralizing antibodies, have also been developed as therapeutic agents.
- Fc-mediated mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytolysis (CMC), are not the intended mechanisms for the antibodies.
- Some therapeutic antibodies bind to certain surface antigens on target cells and render Fc-mediated functions and other mechanisms on the target cells.
- the most important Fc-mediated mechanisms are antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytolysis (CMC), which both will cause the lysis of the antibody-bound target cells.
- ADCC antibody-dependent cellular cytotoxicity
- CMC complement-mediated cytolysis
- Some antibodies binding to certain cell surface antigens can induce apoptosis of the bound target cells.
- Antibodies can also serve as carriers of cytotoxic molecules or other therapeutic agents without the antibodies' serving obvious therapeutic effector functions. In general, those antibodies bind to “tumor-associated” antigens on target cells, but cannot cause cell lysis by themselves. Antibodies specific for CD19 and CD22 on B lymphomas are well known. For many years, those antibodies have been explored as carriers for cytotoxic agents, including radioactive nuclides with very short half-lives, such as 90 Y, 131 I, and 177 Lu. Some antibodies have also been studied as targeting agents for liposomes loaded with cytotoxic drugs, such as doxorubicin, paclitaxel, and amphotericin B.
- ADC antibody drug conjugates
- the cytotoxic drug molecules are linked non-selectively to cysteine or lysine residues in the antibody, thereby resulting in a heterogeneous mixture of ADCs with different numbers of drug molecules per ADC.
- This approach leads to some safety and efficacy issues.
- the first FDA-approved ADC, gemtuzumab ozogamicin, for treating acute myelogenous leukemia is now withdrawn from the market due to unacceptable toxicity.
- the bi-valent or multivalent antibodies may contain two or more antigen-binding sites.
- a number of methods have been reported for preparing multivalent antibodies by covalently linking three or four Fab fragments via a connecting structure.
- antibodies have been engineered to express tandem three or four Fab repeats.
- the present disclosure is directed to a fragment crystallizable (Fc)-based molecular construct that has at least one targeting element and at least one effector element linked, directly or indirectly, to a CH2-CH3 domain of an immunoglobulin.
- Fc fragment crystallizable
- the design of the present Fc-based molecular construct allows for numerous combinations of a wide range of targeting and effector elements.
- the present Fc-based molecular construct may serve as a platform for constructing multi-valent molecules.
- the Fc-based molecular construct comprises a pair of CH2-CH3 segments of an IgG.Fc, a first pair of effector elements, and a first pair of targeting elements.
- the present Fc-based molecular constructs are intended to be used in the treatment of immune diseases (in particular, autoimmune diseases) or osteoporosis.
- the first pair of effector elements consists of two effector elements, in which each of the two effector elements is an antibody fragment specific for tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukin-17 (IL-17), IL-17 receptor (IL-17R), IL-1, IL-6, IL-6R, IL-12/IL-23, B cell activating factor (BAFF), or a receptor activator of nuclear factor kappa-B ligand (RANKL); or a soluble receptor of TNF- ⁇ or IL-1.
- TNF- ⁇ tumor necrosis factor- ⁇
- IL-17 interleukin-17
- IL-17R IL-17 receptor
- IL-1 IL-6
- IL-6R IL-12/IL-23
- BAFF B cell activating factor
- RNKL nuclear factor kappa-B ligand
- the first pair of targeting elements consists of two targeting elements, in which each of the two targeting elements is an antibody fragment specific for ⁇ -aggrecan, collagen I, collagen II, collagen III, collagen V, collagen VII, collagen IX, collagen XI, or osteonectin.
- each of the two targeting elements is an antibody fragment specific for ⁇ -aggrecan, collagen I, collagen II, collagen III, collagen V, collagen VII, collagen IX, collagen XI, or osteonectin.
- the first pair of effector elements is linked to the N-termini of the pair of CH2-CH3 segments
- the first pair of targeting elements is linked to the C-termini of the pair of CH2-CH3 segments, and vice versa.
- the first pair of effectors elements and the first pair of targeting elements is both in the form of single-chain variable fragments (scFvs)
- the first pair of targeting elements is linked to the N-termini of the first pair of effector elements in a tandem or diabody configuration, thereby forming a pair of bispecific scFvs that are linked to the N-termini of the pair of CH2-CH3 segments.
- the pair of CH2-CH3 segments is derived from human IgG heavy chain ⁇ 4 or human IgG heavy chain ⁇ 1.
- the first pair of effector elements or the first pair of the targeting elements takes a Fab configuration (i.e., consisting of the V H -CH1 domain and the V L -C ⁇ domain); this Fab fragment is linked to the N-termini of the first and second heavy chains, so that the Fc-based molecular construct adopts an IgG configuration.
- the pair of elements that is not in the Fab configuration is linked to the C-termini of the pair of CH2-CH3 segments.
- the Fc-based molecular construct further comprises a second pair of effector elements, which consists of two additional effector elements that are both selected from the group described above for the effector elements.
- the elements of the second pair of effector elements are different from those of the first pair of effector elements.
- the second pair of effector elements is linked to the free C-termini of the CH2-CH3 segments.
- the present Fc-based molecular construct further comprises a second pair of targeting elements, in which the two targeting elements are both selected from the group described above regarding the targeting elements.
- the elements of the second pair of targeting elements are different from those of the first pair of targeting elements.
- the second pair of targeting elements is linked to the free C-termini of the CH2-CH3 segments.
- the targeting elements and effector elements described above can be combined as desired, so as to attain the intended therapeutic effect.
- Some exemplary combination of the effector element(s) and targeting element(s) for treating immune diseases are provided in the appended claims and discussed in the description section bellow.
- the present disclosure is directed to methods for treating various diseases.
- the methods involve the step of administrating an effective amount of the Fc-based molecular constructs according to the first aspect and any of the associated embodiments, to a subject in need of such treatment.
- the present method is directed to the treatment of an immune disease; in particular, an autoimmune disease.
- the autoimmune disease is rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.
- the effector element is an antibody fragment specific for TNF- ⁇ , IL-12/IL-23, IL-1, IL-17, or IL-6, while the targeting element may be an antibody fragment specific for collagen II, collagen IX, collagen XI, or ⁇ -aggrecan.
- the autoimmune disease is psoriasis.
- the effector element is an antibody fragment specific for TNF- ⁇ , IL-12/IL-23, or IL-17
- the targeting element is an antibody fragment specific for collagen I or collagen VII.
- the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, or Sjögren's Syndrome.
- the effector element is an antibody fragment specific for BAFF
- the targeting element is an antibody fragment specific for collagen I, or collagen VII.
- the autoimmune disease is an inflammatory bowel disease, such as Crohn's disease or ulcerative colitis.
- the effector element is an antibody fragment specific for TNF- ⁇
- the targeting element is an antibody fragment specific for collagen III or collagen V.
- the effector element for treating osteoporosis comprises an antibody fragment specific for RANKL, while the targeting element comprises an antibody fragment specific for collagen I or osteonectin.
- FIGS. 1A to 1F are schematic diagrams illustrating Fc-based molecular constructs according to various embodiments of the present disclosure.
- FIGS. 2A and 2B are schematic diagrams illustrating Fc-based molecular constructs according to various embodiments of the present disclosure.
- FIG. 3 shows the SDS-PAGE analysis of (scFv ⁇ CII)-(scFv ⁇ TNF- ⁇ )-hIgG4Fc.
- FIGS. 4A and 4B show the ELISA results analyzing the binding of (scFv ⁇ CII)-(scFv ⁇ TNF- ⁇ )-hIgG4Fc to collagen II and TNF- ⁇ .
- FIGS. 5A and 5B respectively show the SDS-PAGE and ELISA analysis of the 2-chain (scFv ⁇ CII)-(scFv ⁇ TNF- ⁇ )-hIgG4.Fc-(scFv ⁇ IL-17).
- FIGS. 6A and 6B respectively show the SDS-PAGE and ELISA analysis of 2-chain (soluble TNF- ⁇ receptor)-IgG1.CH2-CH3-scFv ⁇ collagen II.
- FIG. 7 shows the SDS-PAGE analysis of the 2-chain fusion protein containing intact antibody for human TNF- ⁇ and scFv specific for collagen II.
- FIGS. 8A and 8B respectively show the SDS-PAGE and ELISA analyses of the 2-chain fusion protein containing intact antibody for human IL-17 and scFv specific for collagen VII.
- FIGS. 9A and 9B respectively show the SDS-PAGE and ELISA analysis of scFv ⁇ collagen VII-IgG4.CH2-CH3-scFv ⁇ BAFF.
- FIGS. 10A and 10B respectively show the SDS-PAGE and ELISA analyses of the 2-chain fusion protein containing intact antibody for human BAFF and scFv specific for collagen VII.
- FIGS. 11A and 11B respectively show the SDS-PAGE and ELISA analyses of the 2-chain (scFv ⁇ SPARC)-(scFv ⁇ RANKL)-hIgG4.Fc molecular construct.
- FIGS. 12A and 12B respectively show the SDS-PAGE and ELISA analyses of the 2-chain fusion protein containing intact antibody for human RANKL and scFv specific for human osteonectin.
- FIG. 13 shows the immunostaining of mouse epiphyseal bone with (scFv ⁇ CII)-(scFv ⁇ TNF- ⁇ )-hIgG4Fc and 2-chain (scFv ⁇ CII)-(scFv ⁇ TNF- ⁇ )-hIgG4.Fc-(scFv ⁇ IL-17).
- FIG. 14 shows the immunostaining of mouse epiphyseal bone with 2-chain (soluble TNF- ⁇ receptor)-IgG1.CH2-CH3-scFv ⁇ collagen II.
- FIG. 15 shows bio-distribution of fluorescence-labeled (scFv ⁇ SPARC)-(scFv ⁇ RANKL)-hIgG4Fc in vivo in BALB/c mice.
- phrases “at least one of A, B, and C”, “at least one of A, B, or C” and “at least one of A, B and/or C,” as use throughout this specification and the appended claims, are intended to cover A alone, B alone, C alone, A and B together, B and C together, A and C together, as well as A, B, and C together.
- each molecular construct comprises a targeting element (T) and an effector element (E), and these molecular constructs are sometimes referred to as “T-E molecules”, “T-E pharmaceuticals” or “T-E drugs” in this document.
- the term “targeting element” refers to the portion of a molecular construct that directly or indirectly binds to a target of interest (e.g., a receptor on a cell surface or a protein in a tissue) thereby facilitates the transportation of the present molecular construct into the interested target.
- the targeting element may direct the molecular construct to the proximity of the target cell.
- the targeting element specifically binds to a molecule present on the target cell surface or to a second molecule that specifically binds a molecule present on the cell surface.
- the targeting element may be internalized along with the present molecular construct once it is bound to the interested target, hence is relocated into the cytosol of the target cell.
- a targeting element may be an antibody or a ligand for a cell surface receptor, or it may be a molecule that binds such antibody or ligand, thereby indirectly targeting the present molecular construct to the target site (e.g., the surface of the cell of choice).
- the localization of the effector (therapeutic agent) in the diseased site will be enhanced or favored with the present molecular constructs as compared to the therapeutic without a targeting function.
- the localization is a matter of degree or relative proportion; it is not meant for absolute or total localization of the effector to the diseased site.
- the term “effector element” refers to the portion of a molecular construct that elicits a biological activity (e.g., inducing immune responses, exerting cytotoxic effects and the like) or other functional activity (e.g., recruiting other hapten tagged therapeutic molecules), once the molecular construct is directed to its target site.
- the “effect” can be therapeutic or diagnostic.
- the effector elements encompass those that bind to cells and/or extracellular immunoregulatory factors.
- the effector element comprises agents such as proteins, nucleic acids, lipids, carbohydrates, glycopeptides, drug moieties (both small molecule drug and biologics), compounds, elements, and isotopes, and fragments thereof.
- first, second, third, etc. may be used herein to describe various elements, components, regions, and/or sections, these elements (as well as components, regions, and/or sections) are not to be limited by these terms. Also, the use of such ordinal numbers does not imply a sequence or order unless clearly indicated by the context. Rather, these terms are simply used to distinguish one element from another. Thus, a first element, discussed below, could be termed a second element without departing from the teachings of the exemplary embodiments.
- link refers to any means of connecting two components either via direct linkage or via indirect linkage between two components.
- polypeptide refers to a polymer having at least two amino acid residues. Typically, the polypeptide comprises amino acid residues ranging in length from 2 to about 200 residues; preferably, 2 to 50 residues. Where an amino acid sequence is provided herein, L-, D-, or beta amino acid versions of the sequence are also contemplated. Polypeptides also include amino acid polymers in which one or more amino acid residues are an artificial chemical analogue of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers.
- amino acids joined by a peptide linkage or by other, “modified linkages” e.g., where the peptide bond is replaced by an ⁇ -ester, a ⁇ -ester, a thioamide, phosphonamide, carbomate, hydroxylate, and the like.
- conservative substitutions of the amino acids comprising any of the sequences described herein are contemplated.
- one, two, three, four, or five different residues are substituted.
- the term “conservative substitution” is used to reflect amino acid substitutions that do not substantially alter the activity (e.g., biological or functional activity and/or specificity) of the molecule.
- conservative amino acid substitutions involve substitution one amino acid for another amino acid with similar chemical properties (e.g., charge or hydrophobicity).
- Certain conservative substitutions include “analog substitutions” where a standard amino acid is replaced by a non-standard (e.g., rare, synthetic, etc.) amino acid differing minimally from the parental residue. Amino acid analogs are considered to be derived synthetically from the standard amino acids without sufficient change to the structure of the parent, are isomers, or are metabolite precursors.
- polypeptides comprising at least 80%, preferably at least 85% or 90%, and more preferably at least 95% or 98% sequence identity with any of the sequences described herein are also contemplated.
- Percentage (%) amino acid sequence identity with respect to the polypeptide sequences identified herein is defined as the percentage of polypeptide residues in a candidate sequence that are identical with the amino acid residues in the specific polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percentage sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
- sequence comparison between two polypeptide sequences was carried out by computer program Blastp (protein-protein BLAST) provided online by National Center for Biotechnology Information (NCBI).
- Blastp protein-protein BLAST
- NCBI National Center for Biotechnology Information
- X is the number of amino acid residues scored as identical matches by the sequence alignment program BLAST in that program's alignment of A and B, and where Y is the total number of amino acid residues in A or B, whichever is shorter.
- PEGylated amino acid refers to a polyethylene glycol (PEG) chain with one amino group and one carboxyl group.
- PEG polyethylene glycol
- the PEGylated amino acid has the formula of NH 2 —(CH 2 CH 2 O) n —COOH.
- n ranges from 1 to 20; preferably, ranging from 2 to 12.
- terminal refers to an amino acid residue at the N- or C-end of the polypeptide.
- terminal refers to a constitutional unit of the polymer (e.g., the polyethylene glycol of the present disclosure) that is positioned at the end of the polymeric backbone.
- free terminus is used to mean the terminal amino acid residue or constitutional unit is not chemically bound to any other molecular.
- antigen or “Ag” as used herein is defined as a molecule that elicits an immune response. This immune response may involve a secretory, humoral and/or cellular antigen-specific response.
- the term “antigen” can be a protein, a polypeptide (including mutants or biologically active fragments thereof), a polysaccharide, a glycoprotein, a glycolipid, a nucleic acid, or a combination thereof.
- antibody is used in the broadest sense and covers fully assembled antibodies, antibody fragments that bind with antigens, such as antigen-binding fragment (Fab/Fab′), F(ab′) 2 fragment (having two antigen-binding Fab portions linked together by disulfide bonds), variable fragment (Fv), single chain variable fragment (scFv), bi-specific single-chain variable fragment (bi-scFv), nanobodies, unibodies and diabodies.
- Fab/Fab′ antigen-binding fragment
- F(ab′) 2 fragment having two antigen-binding Fab portions linked together by disulfide bonds
- variable fragment Fv
- scFv single chain variable fragment
- bi-specific single-chain variable fragment bi-scFv
- nanobodies unibodies and diabodies.
- an “antibody” refers to a protein consisting of one or more polypeptides substantially encoded by immunoglobulin genes or fragments of immunoglobulin genes.
- the well-known immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as myriad immunoglobulin variable region genes.
- Light chains are classified as either kappa or lambda.
- Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD, and IgE, respectively.
- a typical immunoglobulin (antibody) structural unit is known to comprise a tetramer.
- Each tetramer is composed of two identical pairs of polypeptide chains, with each pair having one “light” chain (about 25 kDa) and one “heavy” chain (about 50-70 kDa).
- the N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
- the terms variable light chain (V L ) and variable heavy chain (V H ) refer to these light and heavy chains, respectively.
- the antibody fragment can be produced by modifying the nature antibody or by de novo synthesis using recombinant DNA methodologies.
- the antibody and/or antibody fragment can be bispecific, and can be in various configurations.
- bispecific antibodies may comprise two different antigen binding sites (variable regions).
- bispecific antibodies can be produced by hybridoma technique or recombinant DNA technique.
- bispecific antibodies have binding specificities for at least two different epitopes.
- the term “specifically binds” as used herein, refers to the ability of an antibody or an antigen-binding fragment thereof, to bind to an antigen with a dissociation constant (Kd) of no more than about 1 ⁇ 10 ⁇ 6 M, 1 ⁇ 10 ⁇ 7 M, 1 ⁇ 10 ⁇ 8 M, 1 ⁇ 10 ⁇ 9 M, 1 ⁇ 10 ⁇ 10 M, 1 ⁇ 10 ⁇ 11 M, 1 ⁇ 10 ⁇ 12 M, and/or to bind to an antigen with an affinity that is at least two-folds greater than its affinity to a nonspecific antigen.
- Kd dissociation constant
- immune disorder refers to a disorder involving deficiency of humoral immunity, deficiency of cell-mediated immunity, combined immunity deficiency, unspecified immunity deficiency, and autoimmune disease.
- treatment includes preventative (e.g., prophylactic), curative or palliative treatment; and “treating” as used herein also includes preventative (e.g., prophylactic), curative or palliative treatment.
- treating refers to the application or administration of the present molecular construct or a pharmaceutical composition comprising the same to a subject, who has a medical condition a symptom associated with the medical condition, a disease or disorder secondary to the medical condition, or a predisposition toward the medical condition, with the purpose to partially or completely alleviate, ameliorate, relieve, delay onset of, inhibit progression of, reduce severity of, and/or reduce incidence of one or more symptoms or features of said particular disease, disorder, and/or condition.
- Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition, and/or to a subject who exhibits only early signs of a disease, disorder and/or condition, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder and/or condition.
- an effective amount refers to the quantity of the present recombinant protein that is sufficient to yield a desired therapeutic response.
- An effective amount of an agent is not required to cure a disease or condition but will provide a treatment for a disease or condition such that the onset of the disease or condition is delayed, hindered or prevented, or the disease or condition symptoms are ameliorated.
- the effective amount may be divided into one, two, or more doses in a suitable form to be administered at one, two or more times throughout a designated time period.
- Effective amount will vary with such factors as particular condition being treated, the physical condition of the patient (e.g., the patient's body mass, age, or gender), the type of subject being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives. Effective amount may be expressed, for example, as the total mass of active component (e.g., in grams, milligrams or micrograms) or a ratio of mass of active component to body mass, e.g., as milligrams per kilogram (mg/kg).
- application and “administration” are used interchangeably herein to mean the application of a molecular construct or a pharmaceutical composition of the present invention to a subject in need of a treatment thereof.
- subject and patient are used interchangeably herein and are intended to mean an animal including the human species that is treatable by the molecular construct, pharmaceutical composition, and/or method of the present invention.
- subject or patient intended to refer to both the male and female gender unless one gender is specifically indicated. Accordingly, the term “subject” or “patient” comprises any mammal, which may benefit from the treatment method of the present disclosure.
- a “subject” or “patient” include, but are not limited to, a human, rat, mouse, guinea pig, monkey, pig, goat, cow, horse, dog, cat, bird and fowl.
- the patient is a human.
- mammal refers to all members of the class Mammalia, including humans, primates, domestic and farm animals, such as rabbit, pig, sheep, and cattle; as well as zoo, sports or pet animals; and rodents, such as mouse and rat.
- non-human mammal refers to all members of the class Mammalis except human.
- the present disclosure is based, at least on the construction of the T-E pharmaceuticals that can be delivered to target cells, target tissues or organs at increased proportions relative to the blood circulation, lymphoid system, and other cells, tissues or organs.
- the therapeutic effect of the pharmaceuticals is increased, while the scope and severity of the side effects and toxicity is decreased.
- a therapeutic effector is administered at a lower dosage in the form of a T-E molecule, than in a form without a targeting component. Therefore, the therapeutic effector can be administered at lower dosages without losing potency, while lowering side effects and toxicity.
- Drugs used for many diseases can be improved for better efficacy and safety, if they can be targeted to the disease sites, i.e., if they can be localized or partitioned to the disease sites more favorably than the normal tissues or organs. Following are primary examples of diseases, in which drugs can be improved if they can be preferentially distributed to the disease sites or cells.
- the diseases, conditions, and/or disorders treatable with the present method is an immune disorder; for example, an autoimmune disorder that includes, but is not limited to, psoriasis, systemic lupus erythematosus (SLE), cutaneous lupus, Sjögren's syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease.
- an immune disorder for example, an autoimmune disorder that includes, but is not limited to, psoriasis, systemic lupus erythematosus (SLE), cutaneous lupus, Sjögren's syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease.
- autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, psoriasis, Crohn's disease, inflammatory bowel diseases, and others affect connective tissues. Regardless of the etiological nature, whether it is environmental, genetic, epigenetic, or their combinations, the affected tissues are damaged by prolong inflammatory processes. It is rationalized in this invention that in bringing anti-inflammatory therapeutic agents, such as anti-TNF- ⁇ , anti-IL-17, anti-BAFF, anti-IL-6, anti-IL-12/IL-23, to the diseased connective tissues, the components of the extracellular matrix may be employed as target antigens.
- anti-inflammatory therapeutic agents such as anti-TNF- ⁇ , anti-IL-17, anti-BAFF, anti-IL-6, anti-IL-12/IL-23
- the target antigens that may be considered include the various types of collagens, laminins, elastins, fibrillins, fibronectins, and tenascins.
- Connective tissues fill in nearly all parts of the human body. However, due to the structural and functional requirements of the connective tissues in different locations, the types of those extracellular matrix components are different, providing excellent choices for target tissue specificity.
- the advantages of choosing extracellular components over cell surface antigens for targeting the anti-inflammatory therapeutic agents are that the choices of selectivity among the various types of matrix proteins and the abundant amounts of the extracellular matrix proteins. Furthermore, because cells are not used as antigenic targets, the potential harmful effects of direct binding to cells by anti-inflammatory agents can be avoided.
- TNF- ⁇ e.g., infliximab and adalimumab
- fusion proteins of TNF- ⁇ receptor and IgG.Fc e.g. etanercept
- IgG.Fc e.g. etanercept
- IL-1 interleukin-1
- anakinra anakinra
- Antibodies against the shared p40 protein of IL-12 and IL-23 are approved for psoriatic arthritis or in trials for rheumatoid arthritis.
- An antibody against IL-6 receptor (tocilizumab) is approved for rheumatoid arthritis and systemic juvenile idiopathic arthritis, and several antibodies against IL-6, e.g., sarilumab and olokizumab, are in clinical trials for treating rheumatoid arthritis.
- An antibody specific for IL-17 is approved for psoriasis and in clinical trials for rheumatoid arthritis and ankylosing spondylitis.
- infliximab can cause serious blood disorders, like leukopenia and thrombocytopenia, serious infections, lymphoma and other solid tumors, reactivation of hepatitis B and tuberculosis, and other serious problems.
- Anakinra causes frequent infections, and severe side effects on the gastrointestinal and the respiratory tracts and the blood forming organs. It is important that the serious side effects of these widely used therapeutic agents be minimized, while retaining or even enhancing their therapeutic effects.
- rheumatoid arthritis joints of the knees, fingers, toes, and other joints are affected, and in ankylosing spondylitis, joints of the spine and the sacroiliac joint of the pelvis are affected.
- the articular cartilage in the joints is a smooth cartilage that contains an extracellular matrix.
- the cartilage is avascular and approximately 60% of the weight is water and the remaining content is composed of collagens and ⁇ -aggrecan, a proteoglycan, and other matrix molecules.
- Collagen II forms the major fibril in the cartilage.
- Aggrecan is the second most abundant component in the cartilage.
- Collagen XI is bound to the surface of the collagen II fibril helping to form fibril networks and collagen IX is associated with collagen II and collagen XI.
- the cartilage has a large surface and the ⁇ -aggrecan has a structure and shape like a feather.
- the joints have also ligaments, which connect adjacent bones, such as the cruciate ligaments, and tendons, which connect muscles to the bones.
- the ligaments and tendons are formed by fibrous network of collagen types I, II, and III, and elastin and fibrillins 1 and 2.
- the present invention rationalizes that the antagonist for TNF- ⁇ , IL-1, and IL-12/IL-23 can be carried to the diseased joints by using antibody fragments, such as scFv, specific for collagen II, ⁇ -aggrecan, collagen XI or collagen IX, or alternatively, collagen I, elastin or fibrillin 1 as the targeting agent.
- a preferred anti-collagen II antibody is one that binds to native collagen II in the joints and does not bind to N-terminal and C-terminal propeptides, which are cleaved off during fibril assembly.
- a preferred anti-aggrecan antibody is one that binds to whole native ⁇ -aggrecan molecules and does not bind to fragments that are cleaved off and released into the blood circulation.
- Psoriasis involves mainly keratinocytes in part of skin in the affected patients.
- Filaggrin membrane or extracellular proteins, such as filaggrin, collagen I, which are expressed at much higher levels in the skin tissues than most of other tissues, probably can be considered as the target proteins to shuffle therapeutic agents to the skin.
- Filaggrin is present in the tight junction between cells and is probably accessible by antibodies in the diseased tissue sites.
- collagen I is also present in the bone matrix and many parts of the body, it is present in the dermis layer of the skin in abundant proportions.
- the keratinocytes are in the outmost, epidermis layer of the skin; blood vessels, sweat glands, and collagen fibers are in the middle dermis layer of the skin.
- the inner layer is hypodermis, where adipose tissues are.
- the three layers of human skin together are 2-3 mm thick. If the anti-inflammatory antibodies are delivered to the dermis layer by scFv specific for collagen I, they can diffuse into the other layers. Or, the antibodies can trap inflammatory cytokines in the three layers of the skin.
- the dermo-epidermal junction is the area of tissue that joins the epidermal and dermal layers of the skin.
- the basal cells in the stratum basale of epidermis connect to the basement membrane by the anchoring filament of hemidesmosomes.
- the cells of the papillary layer of the dermis are attached to the basement membrane by anchoring fibrils, which consist of type VII collagen.
- Type XVII collagen a transmembrane protein (also referred to as BP180) expressed on keratinocytes, is a structural component of hemidesmosomes, multiprotein complexes at the dermal-epidermal basement membrane zone that mediate adhesion of keratinocytes to the underlying membrane.
- Laminins are structural non-collagenous glycoproteins present in basement membranes. Among the many types of laminins, types 5, 6, and 10 are specific of the basal lamina present under stratified epithelia.
- SLE Systemic lupus erythematosus
- Sjögren's syndrome is an autoimmune disease, in which the immune system attacks the exocrine glands, specifically the salivary and lacrimal glands, which produce saliva and tears, respectively, resulting the symptoms of dry eyes and dry mouth, leading to infections and various other problems. Both of these diseases occur 9 times more frequently in women than in men, especially in women of child-bearing ages 15 to 35.
- SLE is a systemic autoimmune connective tissue disease and affects many organs and tissues. In general, those tissues and organs, such as the heart, lungs, bladder, and kidneys, which exhibit elasticity and can expand and contract, contain collagen network. In several types of SLE, cutaneous manifestation of inflammatory symptoms is prominent.
- belimumab For more than 50 years, not a single new therapeutic agent had been developed for SLE, until belimumab, a human monoclonal antibody specific for BAFF was developed and approved. However, the therapeutic effect of belimumab for SLE has been considered to be marginal. Belimumab causes a host of side effects, including more incidences of serious infections and deaths in the treatment group than the placebo group. Interestingly, in a phase II trial on Sjögren's syndrome, belimumab showed more successful results than in SLE.
- IFN- ⁇ Several monoclonal antibodies specific for IFN- ⁇ , including rontalizumab, sifalimumab, and anifrolumab have been studied in clinical trials for the treatment of SLE. Since IFN- ⁇ is involved in many functions, a systemic administration of an antibody against IFN- ⁇ without localized targeting to disease sites may render serious side effects.
- Anti-TNF- ⁇ (such as adalimumab) has also been approved for treating Crohn's disease and ulcerative colitis (a form of inflammatory bowel disease).
- Crohn's disease and ulcerative colitis a form of inflammatory bowel disease.
- the administration of anti-TNF- ⁇ is associated with a range of series side effects, including severe infectious diseases and B cell lymphoma. Therefore, in treating patients with Crohn's disease or ulcerative colitis with anti-TNF- ⁇ , it will be desirable to distribute the administered anti-TNF- ⁇ in favor of the intestine and colon. It has been found collagen III and type V are relatively abundant in the connective tissues in the intestine and bowel.
- denosumab An antibody specific for RANKL (CD254), the ligand of RANK (RANK, receptor activator of nuclear factor ⁇ B), denosumab, is approved for the treatment of osteoporosis.
- RANKL the ligand of RANK
- RANK receptor activator of nuclear factor ⁇ B
- denosumab An antibody specific for RANKL (CD254), the ligand of RANK (RANK, receptor activator of nuclear factor ⁇ B), denosumab, is approved for the treatment of osteoporosis.
- the development of denosumab represents a major advancement in the care for osteoporosis.
- the administration of denosumab causes common side effects, such as infections of the urinary and respiratory tracts, cataracts, constipation, rashes, and joint pain. It is hence desirable that the therapeutic agent is carried preferentially to the bone.
- RANKL is a membrane protein, belonging to the tumor necrosis factor ligand family. RANKL is detected at high levels in the lung, thymus, and lymph nodes. It is also detected at low levels in the bone marrow, stomach, peripheral blood, spleen, placenta, leukocytes, heart, thyroid and skeletal muscle. Since IgG anti-RANKL, such as denosumab, can serve a therapeutic agent for osteoporosis, the molecular constructs of this invention should provide as better therapeutic agents than IgG anti-RANKL.
- Another target for antibodies for the treatment of osteoporosis is sclerostin, encoded by SOST gene.
- the glycoprotein is produced and secreted by osteocytes and negatively regulates osteoblastic bone formation.
- the loss or defective mutation of SOST gene causes progressive bone thickening.
- a defective mutation in the SOST gene increases bone formation.
- Antibodies against sclerostin cause increased bone formation, bone mineral density, and stronger bones.
- immunoglobulin antibody can serve as the base of a targeting or effector element, and its corresponding effector or targeting element can be incorporated at the C-terminal of its two heavy ⁇ chains in the form of scFv domains.
- two-chain IgG.Fc is used as the base of the molecular platform.
- Each of the polypeptide chain is fused with one or two targeting and one or two effector elements, for a total of two to three elements on each chain.
- the T-E molecule with an Fc-based configuration will have a total of four to six elements (e.g., scFv, growth factor, or cytokines).
- the Fc portion of the molecular constructs also carries Fc-mediated effector functions, ADCC, and/or complement-mediated activation. While in certain other applications, such Fc-mediated effector functions are avoided.
- targeting elements are positioned at the N- or C-terminus. If the effector elements function by binding to a cell surface component, such as CD3, CD16a, PD-1, PD-L1, or CTLA-4, they should also be positioned at the terminus. If the effector elements function by binding to and neutralizing soluble factors, such as VEGF, TNF- ⁇ , IL-17, or BAFF, they can be positioned between a terminal targeting or effector element and CH2-CH3.
- a cell surface component such as CD3, CD16a, PD-1, PD-L1, or CTLA-4
- both the effector element and the targeting element carried by the CH2-CH3 segment (or CH2-CH3 chain) are mostly comprised of amino acid residues, and for the sake of discussion, these molecular constructs are referred to anti-inflammatory molecules with tissue-targeting functions or anti-inflammatory Fc-based molecular construct.
- the effector element may be an antibody fragment or a soluble receptor, while the targeting element is also an antibody fragment.
- FIG. 1A is a schematic diagram illustrating an Fc-based molecular construct 800A according to certain embodiments of the present disclosure.
- the Fc-based molecular construct 800A comprises two identical CH2-CH3 chains 810, a first pair of effector elements E1 linked to the N-termini of the CH2-CH3 chains 810, and a first pair of targeting elements T1 linked to the C-termini of the CH2-CH3 chains 810.
- both the targeting element T1 and effector element E1 are antibody fragments.
- the CH2-CH3 chains are adopted from human immunoglobulins ⁇ 1 or ⁇ 4.
- ⁇ 1 is chosen, when Fc-mediated functions, such as antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated activity (inflammatory activation or target cell lysis), are desired.
- ADCC antibody-dependent cellular cytotoxicity
- complement-mediated activity inflammatory activation or target cell lysis
- the Fc-based molecular construct 800B illustrated in FIG. 1B is quite similar to the Fc-based molecular construct 800A of FIG. 1A in structure, except that the two effector elements E1 are respectively linked to the C-termini of the CH2-CH3 chains 810, while the two targeting effectors are respectively linked to the C-termini of the CH2-CH3 chains 810.
- both the effector elements and targeting elements are linked to the N-termini of the CH2-CH3 chains.
- the effector element and the targeting element are in the form of single-chain variable fragments (scFvs)
- the effector element and the targeting element may be linked in a tandem or diabody configuration, thereby forming a bispecific scFv that is linked to the N-terminus of the CH2-CH3 chain.
- the Fc-based molecular construct 800C ( FIG. 1C ) comprises an Fc portion, and accordingly, each CH2-CH3 chain 810 has a T1-E1 bispecific scFv linked to the N-terminus thereof.
- the anti-inflammatory Fc-based molecular constructs can also use a soluble receptor (e.g., the soluble receptor of TNF- ⁇ or IL-1) as the effector element, according to certain embodiments.
- the Fc-based molecular construct 800D ( FIG. 1D ) may have two effector elements E1 respectively linked to the N-termini of the CH2-CH3 chains 810, and two targeting elements T1 respectively linked to the C-termini of the CH2-CH3 chains 810. It is also possible that the effector elements and the targeting elements are respectively arranged at the C- and N-termini of the CH2-CH3 chains; see, for example, the Fc-based molecular construct 800E of FIG. 1E .
- the first pair of effector elements or the first pair of the targeting elements takes a Fab configuration (i.e., consisting of the V H -CH1 domain and the V L -C ⁇ domain); this Fab fragment is linked to the N-termini of the CH2-CH3 chains, so that the Fc-based molecular construct adopts an IgG configuration.
- the pair of elements that is not in the Fab configuration may be linked to the C-termini of the pair of CH2-CH3 segments.
- each of the two targeting elements T1 comprises the V H -CH1 domain 820 and the V L -C ⁇ domain 825, thereby forming a Fab configuration 830 that is linked to the N-termini of the CH2-CH3 chains 810, so that the Fc-based molecular construct 800F adopts the IgG configuration.
- the pair of effector elements E1 is linked to the C-termini of the pair of CH2-CH3 chains 810.
- the present Fc-based molecular construct may carry a total of six elements at most.
- the additional elements may be a second pair of effector elements or a second pair of targeting elements.
- the Fc-based molecular construct 900A ( FIG. 2A ) comprises a second pair of targeting elements T2.
- the targeting elements T1 and T2 are linked in a tandem or diabody configuration to form a bispecific scFv that is linked to the N-terminus of the CH2-CH3 chain 910, and the effector element E1 is linked to the C-terminus of the CH2-CH3 chain 910.
- the Fc-based molecular construct 900B comprises a second pair of effector elements E2.
- the effector element E1 and E2 are linked in a tandem or diabody configuration to form a bispecific scFv that is linked to the N-terminus of the CH2-CH3 chain 910, and the targeting element T1 is linked to the C-terminus of the CH2-CH3 chain 910.
- the effector element is an scFv specific for TNF- ⁇
- the targeting element is an scFv specific for collagen II or collagen IX, or ⁇ -aggrecan.
- each of the two effector elements is an scFv specific for IL-17, while the targeting element is an scFv specific for collagen I or collagen VII.
- each of the two effector elements is an scFv specific for BAFF, and the targeting element is an scFv specific for collagen I or collagen VII.
- each of the two effector elements is an scFv specific for TNF- ⁇
- the targeting element is an scFv specific for collagen III or collagen V.
- the two effector elements are in the form of a Fab specific for RANKL, and the targeting element is an scFv specific for collagen I or osteonectin.
- the targeting element is an scFv specific for collagen I or osteonectin.
- such molecular construct may take the configuration of any of those depicted in FIGS. 1A-1C and 1F .
- the first pair of effector elements includes an scFv specific for TNF- ⁇ and an scFv specific for IL-17, while the first pair of targeting elements includes an scFv specific for collagen II and an scFv specific for collagen IX.
- the first pair of effector elements includes an scFv specific for TNF- ⁇ and an scFv specific for IL-17, while the first pair of targeting elements includes an scFv specific for collagen I and an scFv specific for collagen VII.
- each of the two effector elements is an scFv specific for BAFF, and the targeting element is an scFv specific for collagen I or collagen VII.
- each of the two effector elements is an scFv specific for RANKL
- the targeting element is an scFv specific for collagen I or osteonectin.
- the two effector elements are in the form of a Fab antibody specific for TNF- ⁇ , while the targeting element is an scFv specific for collagen II or collagen IX.
- the two effector elements are in the form of a Fab antibody specific for IL-17, and the targeting element is an scFv specific for collagen I or collagen VII.
- the two effector elements are in the form of a Fab antibody specific for BAFF, and the targeting element is an scFv specific for collagen I or collagen VII.
- the two effector elements are in the form of a Fab antibody specific for TNF- ⁇ , and the targeting element is an scFv specific for collagen III or collagen V.
- the essence of this invention is the rationalization and conception of the specific combination or pairing of the targeting and effector elements.
- the adoption of Fc-fusion configuration in the molecular constructs is a preferred embodiment. It is conceivable for those skilled in the arts to link the pairs of targeting and effector elements of this invention employing other molecular platforms, such as peptides, proteins (e.g., albumin), polysaccharides, polyethylene glycol, and other types of polymers, which serve as a structural base for attaching multiple molecular elements.
- Another aspect of the present disclosure is directed to the use of the anti-inflammatory Fc-based molecular constructs discussed above in PART I.
- anti-inflammatory Fc-based molecular constructs used for treating various immune disorders contain an antibody fragment (e.g., scFv, Fab, and the like) specific for collagen II, collagen XI, or ⁇ -aggrecan used as targeting elements and an antibody fragment (e.g., scFv, Fab, and the like) specific for TNF- ⁇ and IL-17 as effector elements.
- an antibody fragment e.g., scFv, Fab, and the like
- an antibody fragment e.g., scFv, Fab, and the like
- the present treatment method involves the administration of a suitable anti-inflammatory Fc-based molecular construct to a subject in need of such treatment.
- a suitable anti-inflammatory Fc-based molecular construct for treating various immune disorders, in particular, autoimmune diseases, are discussed below.
- each effector element of the anti-inflammatory Fc-based molecular construct is an antibody fragment specific for TNF- ⁇ , IL-12/IL-23, IL-1, IL-17, or IL-6, while each targeting element is an antibody fragment specific for collagen II, collagen IX, collagen XI, or ⁇ -aggrecan.
- each effector element of the first pair of effector elements is an scFv specific for TNF- ⁇
- each targeting element of the first pair of targeting elements is an antibody fragment specific for collagen II.
- the effector element is an scFv specific for TNF- ⁇ , while the targeting element is an antibody fragment specific for collagen IX.
- the effector element is an scFv specific for TNF- ⁇ , while the targeting element is an antibody fragment specific for ⁇ -aggrecan.
- the above-mentioned anti-inflammatory Fc-based molecular constructs may have the configuration of 800A, 800B, or 800C discussed above.
- Another anti-inflammatory Fc-based molecular construct for treating rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis comprises two effector elements that are in the form of a Fab antibody specific for TNF- ⁇ .
- both targeting elements of the first pair of targeting elements is scFvs specific for collagen II or scFvs specific for collagen IX. Configurations of these Fc-based molecular constructs are illustrated in FIG. 1F , for example.
- the anti-inflammatory Fc-based molecular construct may comprise effector elements of an antibody fragment specific for TNF- ⁇ , IL-12/IL-23, or IL-17, and targeting elements of an antibody fragment specific for collagen I or collagen VII.
- the effector elements are scFvs specific for IL-17, while the targeting elements are scFvs specific for collagen I.
- the effector elements are scFvs specific for IL-17, while the targeting elements are scFvs specific for collagen VII.
- These anti-inflammatory Fc-based molecular constructs have the configuration of 800A, 800B, or 800C discussed above.
- Another anti-inflammatory Fc-based molecular construct for treating psoriasis comprises two effector elements that are in the form of a Fab antibody specific for IL-17.
- both targeting elements of the first pair of targeting elements is scFvs specific for collagen I or scFvs specific for collagen VII. Configurations of these Fc-based molecular constructs are illustrated in FIG. 1F , for example.
- each effector is an antibody fragment specific for BAFF
- each targeting element is an antibody fragment specific for collagen I or collagen VII.
- These anti-inflammatory Fc-based molecular constructs may have the configuration illustrated in FIGS. 1A to 1C .
- the pair of effector elements may also take the form of a Fab antibody specific for BAFF
- the pair of targeting elements may be scFvs specific for collagen I or collagen VII, which takes the configuration of the molecular construct 800F illustrated in FIG. 1F .
- each effector is an antibody fragment specific for TNF- ⁇
- each targeting element is an antibody fragment specific for collagen III or collagen V.
- Configurations of these Fc-based molecular constructs are illustrated in FIGS. 1A to 1C , for example.
- the pair of effector elements may also take the form of a Fab antibody specific for TNF- ⁇
- the pair of targeting elements may be scFvs specific for collagen III or collagen V, thereby giving the configuration illustrated in FIG. 1F .
- the present anti-inflammatory Fc-based molecular constructs are also applicable in the treatment of osteoporosis.
- the effector elements are antibody fragments specific for RANKL
- the targeting elements are antibody fragments specific for collagen I or osteonectin.
- the antibody fragments specific for RANKL may be scFvs so that the Fc-based molecular construct has the configuration illustrated in FIG. 1A to 1C , or they may take the form of a Fab so that the Fc-based molecular construct has the configuration illustrated in FIG. 1F .
- Example 1 Construction of Gene Segments Encoding 2-Chain IgG4.Fc Fusion Protein Containing scFv Specific for Human Collagen II and scFv Specific for TNF- ⁇
- Mouse B cell hybridoma II-116B3 producing anti-collagen II antibody was purchased from Developmental Studies Hybridoma Bank at the University of Iowa. Poly(A)+ RNA was reverse-transcribed with a SuperScript III RT-PCR system (Invitrogen, Waltham, USA), and first strand cDNA was synthesized. The V H and V L nucleotide and amino acid sequences of II-116B3 had not been published. To determine the sequences of variable regions of II-116B3, cDNA of V H and V L were amplified by PCR using a set of DNA primers provided by Ig-primer Sets (Novagen, Madison, USA) per the manufacturer's instructions.
- V H and V L of II6B3 monoclonal antibody specific for collagen type II are described in SEQ ID NOs: 3 and 4.
- the sequences of V L and V H of scFv specific for TNF- ⁇ were those of V L and V H of adalizumab.
- the scFv1-scFv2-CH2-CH3 (human ⁇ 4) recombinant chain was configured by fusing two scFvs, one specific for human collagen II and the other specific for human TNF- ⁇ , to the N-terminal of CH2 domain of IgG4.Fc through a flexible hinge region.
- the first scFv (specific for collagen II) had an orientation of V L -linker-V H and the second scFv (specific for TNF- ⁇ ) was in V H -linker-V L .
- V L and V H in each of the two scFv were connected by a hydrophilic linker, GSTSGSGKPGSGEGSTKG.
- the two scFvs were connected via a flexible linker, (GGGGS) 3 .
- the sequence of the recombinant chain in the IgG4.Fc fusion protein molecular construct illustrated below is described in SEQ ID NO: 5.
- the gene-encoding sequence was placed in pcDNA3 expression cassette.
- Expi293F cells were seeded at a density of 2.0 ⁇ 10 6 viable cells/ml in Expi293F expression medium and maintained for 18 to 24 hours prior to transfection to ensure that the cells were actively dividing at the time of transfection.
- 7.5 ⁇ 10 8 cells in 255-ml medium in a 2-liter Erlenmeyer shaker flask were transfected by ExpiFectamineTM 293 transfection reagent. The transfected cells were incubated at 37° C.
- ELISA assay was performed, using adalimumab and mouse parental monoclonal antibody II-116B3 for comparison.
- ELISA plates were coated with 5 ⁇ g/mL of human type II collagen (human COL2), mouse type II collagen (mouse COL2), and chicken type II collagen (chick COL2).
- 1D11 was a human IgG1 antibody against mite allergen as an isotype control.
- Recombinant 2-chain (scFv ⁇ CII)-(scFv ⁇ TNF- ⁇ )-hIgG4.Fc fusion protein, purified anti-collagen II antibody (II-116B3) and adalimumab were detected by HRP-conjugated goat anti-human IgG4.Fc, goat anti-mouse IgG.Fc, and goat anti-human IgG1.Fc, respectively.
- the ELISA results were summarized in FIG. 4A .
- ELISA assay was performed, along with adalimumab and mouse parental monoclonal antibody II-116B3. ELISA plates were coated with 1 ⁇ g/mL of human TNF- ⁇ and 1 ⁇ g/mL of human serum albumin as a control.
- the scFv1-scFv2-CH2-CH3-scFv3 (human ⁇ 4) recombinant chain was configured by fusing three scFvs, in which the first one specific for human collagen II and the second one specific for TNF- ⁇ were fused to the N-terminal of CH2 domain of IgG4.Fc through a flexible hinge region, while the third one specific for IL-17 was fused to the C-terminal of CH3 domain.
- the V H and V L of the scFv specific for collagen II were from monoclonal antibody II-116B3; the V H and V L of the scFv specific for TNF- ⁇ were from monoclonal antibody adalimumab; V H and V L of the scFv specific for IL-17 were from secukinumab.
- the first scFv (specific for collagen II) had an orientation of V L -linker-V H
- the second scFv (specific for TNF- ⁇ ) was in the orientation of V H -linker-V L
- the third scFv (specific for IL-17) was in the orientation of V L -linker-V H .
- the V L and V H in each of the three scFv were connected by a hydrophilic linker, GSTSGSGKPGSGEGSTKG.
- the three scFv were fused via a flexible linker, (GGGGS) 3 .
- the sequence of the recombinant chain in the IgG4.Fc fusion protein molecular construct of the construct illustrated below is shown in SEQ ID NO: 6.
- the expression of the constructed genes in Expi293F cells and the purification of the expressed fusion protein were performed as in preceding Examples. Characterization of the new construct was performed with SDS-PAGE and ELISA.
- the antibody Secukinumab (Cosentyx) was purchased from Chang Gung Hospital (Taipei, Taiwan); human IL-17 was from Peprotech (NJ, USA).
- FIG. 5A shows the SDA-PAGE results, indicating that the recombinant chain of the new construct had a size of about 110 kDa, consistent with the expected size.
- FIG. 5B shows the ELISA results, indicating that the present recombinant Fc-fusion protein had the binding activity to human collagen II, human TNF- ⁇ , and human IL-17.
- the (TNF- ⁇ receptor)-CH2-CH3-scFv ⁇ collagen II (human ⁇ 1) recombinant chain was configured by fusing human TNF- ⁇ receptor, IgG1.Fc, and scFv specific for collagen II.
- the sequences of TNF- ⁇ receptor and IgG1.Fc were those of etanercept. Etanercept and scFv were fused via a flexible linker, (GGGGS) 3 .
- the sequence of the recombinant chain in the IgG4.Fc fusion protein molecular construct is shown in SEQ ID NO: 7.
- FIG. 6A shows the SDS-PAGE results, indicating that the recombinant chain in the new molecular construct had a size of about 100 kDa, consistent with the expected size (an Etanercept molecule had a molecular weight of 150 kDa and one chain of it was about 75 kDa in size; an scFv was about 27 kDa in size).
- FIG. 6B shows the ELISA results, indicating the present molecular construct bound to human TNF- ⁇ , human collagen II, and mouse collagen II.
- the IgG-scFv (human ⁇ 1) recombinant chain was configured by fusing the intact antibody specific for human TNF- ⁇ and scFv specific for collagen II (illustrated below).
- the sequences of intact antibody were those of adalimumab.
- Adalimumab and scFv were fused via a flexible linker, (GGGGS) 3 .
- the construction of the heavy and light chains of recombinant genes was built by inserting the two genes into a pG1K expression cassette with the multiple cloning site.
- To prepare the 2-chain fusion protein containing intact antibody for human TNF- ⁇ and scFv specific for collagen type II transfection of the expression vectors into Expi293F cells was performed as in preceding Examples.
- the amino acid sequence of the heavy chain of 2-chain fusion protein containing intact antibody for human TNF- ⁇ and scFv specific for collagen type II is indicated in SEQ ID NO: 8
- the amino acid sequence of the light chain of the 2-chain fusion protein is indicated in SEQ ID NO: 9.
- FIG. 7 shows the SDS-PAGE result, indicating that the heavy recombinant chain in the present extended IgG molecular construct had a size of about 75 kDa, consistent with the expected size.
- the IgG-scFv (human ⁇ 1) recombinant chain was configured by fusing the intact antibody specific for human IL-17 and scFv specific for collagen type VII (SEQ ID NO: 20).
- the sequences of the intact antibody were those of secukinumab.
- Secukinumab and the scFv were fused via a flexible linker, (GGGGS) 3 .
- the construction of the heavy and light chains of recombinant genes was built by inserting the two genes into a pG1K expression cassette with the multiple cloning site.
- the amino acid sequence of the heavy chain of 2-chain fusion protein containing intact antibody for human IL-17 and scFv specific for collagen type VII is indicated in SEQ ID NO: 10
- the amino acid sequence of the light chain of the 2-chain fusion protein is indicated in SEQ ID NO: 11.
- FIG. 8A shows the SDS-PAGE results indicating that the recombinant heavy chain of the new molecular construct had a size of 75 kDa, consistent with the expected size.
- FIG. 8B shows the ELISA results, indicating that the present molecular construct bound to human IL17 and human collagen VII. The relatively low binding to collagen VII was due to a low concentration the antigen used for coating the ELISA plates
- Example 8 Preparation of 2-Chain IgG4.Fc Fusion Protein Containing scFv Specific for Human Collagen VII and scFv Specific for BAFF
- the scFv1-CH2-CH3-scFv2 (human ⁇ 4) recombinant chain (SEQ ID NO: 12) was configured by fusing two scFv, spaced with IgG4.Fc, one specific for collagen VII and the other specific for BAFF, to the C-terminal of CH3 domain of IgG4.Fc through a flexible linker, (GGGGS) 3 (illustrated below).
- the first scFv (specific for collagen VII) had an orientation of V L -linker-V H and the second scFv (specific for BAFF) was in V H -linker-V L .
- the V L and V H in each of the two scFv were connected by a hydrophilic linker, GSTSGSGKPGSGEGSTKG.
- FIG. 9A shows the SDA-PAGE results, indicating that the recombinant chain in the new molecular construct had a size of about 80-90 kDa, consistent with or somewhat larger than the expected size.
- FIG. 9B shows the ELISA results, indicating that the new construct bound specifically to human BAFF and human collagen VII.
- the IgG-scFv (human ⁇ 1) recombinant chain was configured by fusing the intact antibody specific for human BAFF and scFv specific for collagen type VII.
- the sequences of intact antibody were those of belimumab. Belimumab and the scFv were fused via a flexible linker, (GGGGS) 3 .
- the construction of the heavy and light chains of recombinant genes was built by inserting the two genes into a pG1K expression cassette with the multiple cloning site.
- FIG. 10A shows the SDS-PAGE results, indicating that the recombinant heavy chain of the new molecular construct had a size of about 80 kDa, consistent with the expected size.
- FIG. 10B shows the ELISA results, indicating that the new extended IgG construct bound specifically to human BAFF and human collagen VII.
- Mouse B cell hybridoma AON-1 producing anti-osteonectin (SPARC) antibody was purchased from Developmental Studies Hybridoma Bank at the University of Iowa. Poly(A)+ RNA was reverse-transcribed with a SuperScript III RT-PCR system (Invitrogen), and the first strand cDNA was synthesized. The V H and V L nucleotide and amino acid sequences of AON-1 had not been published. To determine the sequences of variable regions of AON-1, cDNA of V H and V L were amplified by PCR using a set of DNA primers provided by Ig-primer Sets (Novagen) according to the manufacturer's instructions.
- V H and V L sequences of AON-1 monoclonal antibody specific for osteonectin are shown in SEQ ID NOs: 15 and 16.
- the sequences of V L and V H of scFv specific for RANKL were those of V L and V H of denosumab.
- the scFv1-scFv2-CH2-CH3 (human ⁇ 4) recombinant chain (SEQ ID NO: 17) was configured by fusing two scFv, one specific for human osteonectin and the other specific for RANKL, to the N-terminal of CH2 domain of IgG4.Fc through a flexible hinge region (illustrated below).
- the first scFv (specific for osteonectin) had an orientation of V L -linker-V H and the second scFv (specific for RANKL) was in V H -linker-V L .
- the V L and V H in each of the two scFv were connected by a hydrophilic linker, GSTSGSGKPGSGEGSTKG.
- the two scFv were fused via a flexible linker, (GGGGS) 3 .
- FIG. 11A shows the SDS-PAGE results, indicating that the recombinant chain in the new molecular construct had a size of about 80 kDa.
- FIG. 11B shows the ELISA results, indicating that the new Fc-fusion construct bound specifically to human SPARC and human RANKL.
- the IgG-scFv (human ⁇ 1) recombinant chain was configured by fusing the intact antibody specific for human RANKL and scFv specific for human osteonectin.
- the sequences of intact antibody were those of denosumab. Denosumab and the scFv were fused via a flexible linker, (GGGGS) 3 .
- the construction of the heavy and light chains of recombinant genes was built by inserting the two genes into a pG1K expression cassette with the multiple cloning site.
- FIG. 12A shows the SAS-PAGE results, indicating that the recombinant heavy chain in the extended IgG molecular construct had a size of about 80 kDa.
- FIG. 12B shows the ELISA results, indicating that the new Fc-fusion construct bound specifically to human SPARC and human RANKL.
- Example 12 Immunohistologic Chemical Analysis of 2-Chain IgG4.Fc Fusion Protein Containing scFv Specific for Human Collagen II and scFv Specific for TNF- ⁇ in Binding to Joint Cartilage
- mouse IgG blocking reagent Vector Laboratories
- mice II-116B3 and (scFv ⁇ CII)-(scFv ⁇ TNF- ⁇ )-hIgG4Fc were used at 50 ⁇ g/mL.
- Goat anti-mouse IgG Fc and goat anti-human IgG Fc were use at 1.6 ⁇ g/mL for incorporating HRP, which reacted with the subsequently added biotin-tyramide.
- biotin labels were then probed with streptavidin-HRP and chromogenically visualized with diaminobenzidine substrate (BioGenex). Sections were counterstained using hematoxylin and mounted with Leica CV5030 Coverslipper.
- FIGS. 13 panel A to 13 panel C showed the immunostaining of mouse epiphyseal bone with monoclonal antibodies II-116B3 ( FIG. 13 panel A), adalimumab ( FIG. 13 panel B), and (scFv ⁇ CII)-(scFv ⁇ TNF- ⁇ )-hIgG4Fc, i.e., the configuration illustrated in an earlier Example ( FIG. 13 panel C), followed by HRP-labeled goat anti-mouse or goat anti-human secondary antibodies and tyramide amplification.
- Type II collagen was revealed at epiphyseal articular cartilage (AC) and growth plate (GP) in FIG. 13 panel A and FIG. 13 panel C.
- Example 13 Immunohistologic Chemical Analysis of 2-Chain IgG1.Fc Fusion Protein Containing scFv Specific for Collagen II and scFv Specific for TNF- ⁇ and scFv Specific for IL-17 in Binding to Joint Cartilage
- tissue thin sections staining with the molecular construct, 2-chain (scFv ⁇ CII)-(scFv ⁇ TNF- ⁇ )-hIgG4.Fc-(scFv ⁇ IL-17) (the configuration illustrated in an earlier Example) and controls were performed as in the preceding Examples.
- FIGS. 13 panel D to 13 panel E showed the immunostaining of collagen II in mouse epiphyseal bone. 3- ⁇ m thick sections of the femoral end of mouse knee were stained with monoclonal antibodies, an anti-IL17a mouse antibody (purchased from PeproTech, NJ, USA) ( FIG. 13 panel D), and the present construct 2-chain (scFv ⁇ CII)-(scFv ⁇ TNF- ⁇ )-hIgG4.Fc-(scFv ⁇ IL-17) ( FIG. 13 panel E), followed by HRP-labeled goat anti-mouse or goat anti-human secondary antibodies and tyramide amplification. The results showed that anti-IL17 monoclonal antibody had no significant staining, while the present construct had moderately positive staining.
- Example 14 Immunohistologic Chemical Analysis of 2-Chain IgG1.Fc Fusion Protein Containing TNF- ⁇ Soluble Receptor and scFv Specific for Collagen II in Binding to Joint Cartilage
- tissue thin sections staining with the molecular construct, 2-chain (soluble TNF- ⁇ receptor)-IgG1.CH2-CH3-scFv ⁇ collagen II (the configuration illustrated in an earlier Example) and controls were performed as in the preceding Example.
- the staining procedure was the same as in preceding examples.
- the mouse epiphyseal bone tissue section samples were from the same batch.
- the results showed that the positive control II-116B3 stained strongly ( FIG. 14 panel A), etanercept had no significant staining ( FIG. 14 panel B), and the present construct stained collagen II-containing components AC and GP positively ( FIG. 14 panel C).
- Example 15 Bio-Distribution of Recombinant 2-Chain IgG4.Fc Fusion Protein Containing scFv Specific for Human Osteonectin (SPARC) and scFv Specific for RANKL Using In Vivo Imaging System
- FIG. 15 showed bio-distribution of fluorescence-labeled antibodies in vivo.
- BALB/c mice were intravenously injected with PBS (1), denosumab (2), anti-SPARC mAb (3), (scFv ⁇ SPARC)-(scFv ⁇ RANKL)-hIgG4Fc (4), and BoneTag (5). Images were captured at indicated time points using IVIS Spectrum imager and analyzed with Living Image software. Spectral unmixing was performed to distinguish tissue autofluorescence from DyLight 680 signals. The results showed that in comparison to denosumab, the present construct was distributed more similarly to anti-SPARC monoclonal antibody at 30 minutes after treatment. At longer time points, the distribution was influenced by half-lives of the reagents. Anti-SPARC and denosumab were both antibodies and had similar serum half-lives.
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