WO2024148240A1 - ANTICORPS ANTI-IL-11Rα POUR LE TRAITEMENT DE L'ORBITOPATHIE THYROÏDIENNE - Google Patents
ANTICORPS ANTI-IL-11Rα POUR LE TRAITEMENT DE L'ORBITOPATHIE THYROÏDIENNE Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
-
- 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
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- 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
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Definitions
- the TED is progressing in the patient.
- a patient in an intolerant/relapsed/refractory disease state has TED that progresses more aggressively in the patient than prior to the TED therapy.
- TED progression is indicated by a worsening of one or more of the clinical signs of TED, an increased CAS score, and/or an increased VISA score, relative to the clinical signs, CAS scores, and/or VISA scores from prior to the TED therapy.
- the potency of the presently claimed antibodies and/or their different mechanism of action relative to the prior (now refractory) TED therapy can provide clinical advantages in treating a progressing disease state, including a more aggressively progressing disease state.
- the regression of proptosis is an increase in proptosis from the maximal response to the prior teprotumumab therapy.
- a relapsed TED patient is identified by an initial response to the teprotumumab therapy measured by a reduction in CAS score, that is then subsequently reversed after a period of time despite continued treatment with the same teprotumumab therapy.
- a refractory patient is identified by a lack of improvement in proptosis. In some embodiments, the lack of improvement in proptosis is less than about 2mm. In some embodiments, a refractory patient is identified by little to no change in CAS score.
- the at least one additional TED therapy is administered prior to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered simutaneously to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered sequentially to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered within the same composition as the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure. In some embodiments, the at least one additional TED therapy is administered in a separate composition as the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure.
- IGF-1R antibody is administered about 1 to about 5 times during the the treatment with the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure.
- the IGF-1R inhibitor therapy e.g. IGF-1R antibody
- the IGF-1R inhibitor therapy is administered about 1 to about 6 times during the the treatment with the anti-ILl IRa antibodies or antigen- binding fragments of the disclosure.
- the IGF-1R inhibitor therapy e.g.
- the IL-1 IRa antibody, or antigen binding fragment thereof binds to an epitope that spans residues 115-134 in IL-1 IRa.
- an exemplary antibody of the disclosure that exhibits such binding comprises the V H CDR1, V H CDR2, and V H CDR3 sequences of SEQ ID NOs: 25-27, respectively, and the V L CDR1, V L CDR2, and V L CDR3 sequences of SEQ ID NOs: 28-30, respectively.
- an exemplary antibody of the disclosure that exhibits such binding comprises the V H sequence of SEQ ID NO: 201, and the V L sequence of SEQ ID NOs: 202.
- the V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 193
- the V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 194
- the V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 195
- the V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 196
- the V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 197
- the V L comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 198
- the V H comprises a sequence at least 80, 85, 90, 95, 97, 98, 99, or
- the IL-1 IRa antibody, or antigen binding fragment thereof is selected from an Fv fragment, a single chain Fv (scFv) polypeptide, an adnectin, an anticalin, an aptamer, an avimer, a camelid antibody, a designed ankyrin repeat protein (DARPin), a minibody, a nanobody, and a unibody.
- Fv fragment a single chain Fv (scFv) polypeptide
- adnectin an anticalin
- an aptamer an avimer
- camelid antibody a designed ankyrin repeat protein (DARPin)
- DARPin ankyrin repeat protein
- the composition has a purity of at least about 80%, 85%, 90%, 95%, 98%, or 99% on a protein basis with respect to the antibody or antigen binding fragment, and is substantially aggregate- and endotoxin-free.
- the composition has reduced or undetectable heterogeneity of N-linked glycosylation (optionally relative to the TS7 and 8E2 antibodies), optionally in the V L CDR3 sequence.
- the pharmaceutical composition is a sterile, injectable solution, optionally suitable for intravenous, intramuscular, subcutaneous, or intraperitoneal administration.
- administering the pharmaceutical composition to the patient improves one or more clinical signs of TED.
- the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), extraocular muscle (EOM) dysfunction optionally hypotropia (downward deviation) and/or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival injection, excessive extracellular matrix accumulation in orbital tissue, and chemosis (conjunctival edema).
- administering the pharmaceutical composition to the patient improves the Clinical Activity Score (CAS) of the patient, optionally by at least one, two, three, four, or five points, optionally to a CAS of 3 or less, 2 or less, or 1 or less.
- administering the pharmaceutical composition to the patient improves the VISA score of the patient, optionally by at least one, two, three, four, or five points, optionally to a VISA or 4 or less, 3 or less, 2 or less, or 1 or less.
- administering the pharmaceutical composition to the patient reduces levels of IL-1 IRa or IL-11 in the blood or tissue around the patient’s eye.
- FIG. 2 shows hyaluronan release by orbital fibroblasts that were preincubated with media alone (no antibody control) or mAb5 (10 pg/mL) for 1 hour and then stimulated with human recombinant IL-11 (1.1, 3.3 or 10 ng/mL) for an additional 96 hours.
- FIG. 3 shows cell proliferation by orbital fibroblasts that were preincubated with media alone (no antibody control) or mAb5 (10 pg/mL) for 1 hour and then stimulated with human recombinant IL-11 (1.1, 3.3 or 10 ng/mL) for an additional 96 hours.
- FIGS. 4A-4C show the dose-dependent effects of IL-11, with mAb5 (10 ng/mL, hatched) and without mAb5 (solid), on hyaluronan release from orbital fibroblasts from patient sample #2 (FIG. 4A, no prior TED therapy), patient sample #1 (FIG. 4B, prior teprotumumab therapy), and patent sample #3 (FIG. 4C, prior corticosteroid therapy).
- FIGS. 5A-5C show the effects of mAb5 at 3. 10, 30 and lOOpg/mL on IL-11
- FIG. 16 shows a partial sequence of IL-1 IRa with the epitope of mAb5 shown.
- Epitope mapping of mAb5 was carried using two mass spectrometry methods.
- the epitope identified by HDX-MS is shown in bold text spanning mature IL- 1 IRa residues 115-134.
- Crosslinks identified by XL-MS are indicated at positions S138, S 147, KI 51, SI 62 and T165 indicating these residues are at, or close to, the mAb5 epitope.
- FIGS. 17A-17B demonstrates that anti-IL-1 IRa mAb5 is effective at inhibition of IL11 and hyper IL-11 signaling.
- Amino acid analogs include modified forms of naturally and non-naturally occurring amino acids. Such modifications can include, for example, substitution or replacement of chemical groups and moieties on the amino acid or by derivatization of the amino acid.
- Amino acid mimetics include, for example, organic structures which exhibit functionally similar properties such as charge and charge spacing characteristic of the reference amino acid. For example, an organic structure which mimics arginine (Arg or R) would have a positive charge moiety located in similar molecular space and having the same degree of mobility as the e-amino group of the side chain of the naturally occurring Arg amino acid.
- Mimetics also include constrained structures so as to maintain optimal spacing and charge interactions of the amino acid or of the amino acid functional groups. Those skilled in the art know or can determine what structures constitute functionally equivalent amino acid analogs and amino acid mimetics.
- Peptide aptamers typically include a variable peptide loop attached at both ends to a protein scaffold, a double structural constraint that typically increases the binding affinity of the peptide aptamer to levels comparable to that of an antibody’s (e.g., in the nanomolar range).
- the variable loop length may be composed of about 10-20 amino acids (including all integers in between), and the scaffold may include any protein that has good solubility and compacity properties.
- the antibodies or antigen binding fragments described herein are in the form of a designed ankyrin repeat protein (DARPin).
- DARPins include a class of nonimmunoglobulin proteins that can offer advantages over antibodies for target binding in drug discovery and drug development.
- DARPins are ideally suited for in vivo imaging or delivery of toxins or other therapeutic payloads because of their favorable molecular properties, including small size and high stability.
- heavy chain dimers such as antibodies from camelids and sharks.
- Camelid and shark antibodies comprise a homodimeric pair of two chains of V-like and C-like domains (neither has a light chain). Since the V H of a heavy chain dimer IgG in a camelid does not have to make hydrophobic interactions with a light chain, the region in the heavy chain that normally contacts a light chain is changed to hydrophilic amino acid residues in a camelid. VH domains of heavy-chain dimer IgGs are called VHH domains.
- Shark Ig-NARs comprise a homodimer of one variable domain (termed a V-NAR domain) and five C-like constant domains (C-NAR domains).
- camelids the diversity of antibody repertoire is determined by the complementary determining regions (CDR) 1, 2, and 3 in the VH or VHH regions.
- the CDR3 in the camelid VHH region is characterized by its relatively long length averaging 16 amino acids (Muyldermans et al., 1994, Protein Engineering 7(9): 1129). This is in contrast to CDR3 regions of antibodies of many other species.
- the CDR3 of mouse VH has an average of 9 amino acids.
- humanized antibodies have one or more CDRs (one, two, three, four, five, six) which are altered with respect to the original antibody, which are also termed one or more CDRs “derived from” one or more CDRs from the original antibody.
- the antibodies are “chimeric” antibodies.
- a chimeric antibody is comprised of an antigen binding fragment of an antibody operably linked or otherwise fused to a heterologous Fc portion of a different antibody.
- the Fc domain or heterologous Fc domain is of human origin.
- the Fc domain or heterologous Fc domain is of mouse origin.
- the heterologous Fc domain may be from a different Ig class from the parent antibody, including IgA (including subclasses IgAl and IgA2), IgD, IgE, IgG (including subclasses IgGl, IgG2, IgG3, and IgG4), and IgM.
- the heterologous Fc domain may be comprised of CH2 and CH3 domains from one or more of the different Ig classes.
- the antigen binding fragment of a chimeric antibody may comprise only one or more of the CDRs of the antibodies described herein (e.g., 1, 2, 3, 4, 5, or 6 CDRs of the antibodies described herein), or may comprise an entire variable domain (VL, VH or both).
- effector function in the context of antibodies refers to the ability of that antibody to engage with other arms of the immune system, including for example, the activation of the classical complement pathway, or through engagement of Fc receptors.
- Complement dependent pathways are primarily driven by the interaction of Clq with the Cl complex with clustered antibody Fc domains.
- Antibody dependent cellular cytotoxicity is primarily driven by the interaction of Fc receptors (FcRs) on the surface of effector cells (natural killer cells, macrophages, monocytes and eosinophils) which bind to the Fc region of an IgG which itself is bound to a target cell.
- Fc receptors are key immune regulatory receptors connecting the antibody mediated (humoral) immune response to cellular effector functions. Receptors for all classes of immunoglobulins have been identified, including FcyR (IgG), FcsRI (IgE), FcaRI (IgA), FcpR (IgM) and FcSR (IgD). There are at least three classes of receptors for human IgG found on leukocytes: CD64 (FcyRI), CD32 (FcyRIIa, FcyRIIb and FcyRIIc) and CD16 (FcyRIIIa and FcyRIIIb).
- FcyRI is classed as a high affinity receptor (nanomolar range K D ) while FcyRII and FcyRIII are low to intermediate affinity (micromolar range K D ).
- a signaling pathway is triggered which results in the secretion of various substances, such as lytic enzymes, perforin, granzymes and tumor necrosis factor, which mediate in the destruction of the target cell.
- the level of ADCC effector function various for human IgG subtypes. Although this is dependent on the allotype and specific FcvR, in simple terms ADCC effector function is “high” for human IgGl and IgG3, and “low” for IgG2 and IgG4.
- endotoxin free or “substantially endotoxin free” relates generally to compositions, solvents, and/or vessels that contain at most trace amounts (e.g., amounts having no clinically adverse physiological effects to a subject) of endotoxin, and preferably undetectable amounts of endotoxin.
- Endotoxins are toxins associated with certain microorganisms, such as bacteria, typically gram-negative bacteria, although endotoxins may be found in gram-positive bacteria, such as Listeria monocytogenes.
- Endotoxins can be detected using routine techniques known in the art.
- the Limulus Amoebocyte Lysate assay which utilizes blood from the horseshoe crab, is a very sensitive assay for detecting presence of endotoxin.
- very low levels of LPS can cause detectable coagulation of the limulus lysate due a powerful enzymatic cascade that amplifies this reaction.
- Endotoxins can also be quantitated by enzyme-linked immunosorbent assay (ELISA).
- epitope includes any determinant, preferably a polypeptide determinant, capable of specific binding to an immunoglobulin or T-cell receptor.
- An epitope includes a region of an antigen that is bound by an antibody.
- epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl, and may in certain embodiments have specific three-dimensional structural characteristics, and/or specific charge characteristics.
- Epitopes can be contiguous or non-contiguous in relation to the primary structure of the antigen, for example, an IL-1 IRa polypeptide.
- Antigen binding can involve a CDR3 or a CDR3 pair.
- An epitope can be a linear peptide sequence (i.e., “continuous”) or can be composed of noncontiguous amino acid sequences (i.e., “conformational” or “discontinuous”).
- a binding protein can recognize one or more amino acid sequences; therefore an epitope can define more than one distinct amino acid sequence. Epitopes recognized by binding protein can be determined by peptide mapping and sequence analysis techniques well known to one of skill in the art.
- polypeptide or “protein” means one or more chains of amino acids, wherein each chain comprises amino acids covalently linked by peptide bonds, and wherein said polypeptide or protein can comprise a plurality of chains non-covalently and/or covalently linked together by peptide bonds, having the sequence of native proteins, that is, proteins produced by naturally- occurring and specifically non-recombinant cells, or genetically-engineered or recombinant cells, and comprise molecules having the amino acid sequence of the native protein, or molecules having deletions from, additions to, and/or substitutions of one or more amino acids of the native sequence.
- isolated polypeptide or protein referred to herein means that a subject protein (1) is free of at least some other proteins with which it would typically be found in nature, (2) is essentially free of other proteins from the same source, e.g., from the same species, (3) is expressed by a cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (5) is not associated (by covalent or non-covalent interaction) with portions of a protein with which the “isolated protein” is associated in nature, (6) is operably associated (by covalent or non-covalent interaction) with a polypeptide with which it is not associated in nature, or (7) does not occur in nature.
- Such an isolated protein can be encoded by genomic DNA, cDNA, mRNA or other RNA, of may be of synthetic origin, or any combination thereof.
- the isolated protein is substantially free from proteins or polypeptides or other contaminants that are found in its natural environment that would interfere with its use (therapeutic, diagnostic, prophylactic, research or otherwise).
- the “purity” of any given agent (e.g., antibody) in a composition may be defined.
- certain compositions may comprise an agent that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% pure on a protein basis or a weight-weight basis, including all decimals and ranges in between, as measured, for example and by no means limiting, by high performance liquid chromatography (HPLC), a well-known form of column chromatography used frequently in biochemistry and analytical chemistry to separate, identify, and quantify compounds.
- HPLC high performance liquid chromatography
- reference sequence refers generally to a nucleic acid coding sequence, or amino acid sequence, to which another sequence is being compared. All polypeptide and polynucleotide sequences described herein are included as references sequences, including those described by name and those described in the Tables and the Sequence Listing.
- Certain embodiments include biologically active “variants” and “fragments” of the polypeptides (e.g., antibodies) described herein, and the polynucleotides that encode the same. “Variants” contain one or more substitutions, additions, deletions, and/or insertions relative to a reference polypeptide or polynucleotide (see, e.g., the Tables and the Sequence Listing).
- a variant polypeptide or polynucleotide comprises an amino acid or nucleotide sequence with at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% , 99% or more sequence identity or similarity or homology to a reference sequence, as described herein, and substantially retains the activity of that reference sequence.
- sequences that consist of or differ from a reference sequences by the addition, deletion, insertion, or substitution of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60,70, 80, 90, 100, 110, 120, 130, 140, 150 or more amino acids or nucleotides and which substantially retain the activity of that reference sequence.
- the additions or deletions include C-terminal and/or N-terminal additions and/or deletions.
- sequence identity or, for example, comprising a “sequence at least 50% identical to,” as used herein, refer to the extent that sequences are identical on a nucleotide-by- nucleotide basis or an amino acid-by-amino acid basis over a window of comparison.
- a “percentage of sequence identity” may be calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, I) or the identical amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Vai, Leu, He, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gin, Cys and Met) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.
- the identical nucleic acid base e.g., A, T, C, G, I
- the identical amino acid residue e.g., Ala, Pro, Ser, Thr, Gly, Vai, Leu, He, Phe, Tyr, Trp, Lys,
- solubility refers to the property of an agent (e.g., antibody) provided herein to dissolve in a liquid solvent and form a homogeneous solution. Solubility is typically expressed as a concentration, either by mass of solute per unit volume of solvent (g of solute per kg of solvent, g per dL (100 mL), mg/ml, etc.), molarity, molality, mole fraction or other similar descriptions of concentration.
- the maximum equilibrium amount of solute that can dissolve per amount of solvent is the solubility of that solute in that solvent under the specified conditions, including temperature, pressure, pH, and the nature of the solvent.
- solubility is measured at physiological pH, or other pH, for example, at pH 5.0, pH 6.0, pH 7.0, pH 7.4, pH 7.6, pH 7.8, or pH 8.0 (e.g., about pH 5-8).
- solubility is measured in water or a physiological buffer such as PBS or NaCl (with or without NaPO 4 ).
- solubility is measured at relatively lower pH (e.g., pH 6.0) and relatively higher salt (e.g., 500mM NaCl and 10mM NaPO 4 ).
- solubility is measured in a biological fluid (solvent) such as blood or serum.
- the temperature can be about room temperature (e.g., about 20, 21, 22, 23, 24, 25°C) or about body temperature (37°C).
- an agent has a solubility of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90 or 100 mg/ml at room temperature or at 37°C.
- a “subject” or a “subject in need thereof’ or a “patient” or a “patient in need thereof’ includes a mammalian subject such as a human subject.
- substantially or “essentially” means nearly totally or completely, for instance, 95%, 96%, 97%, 98%, 99% or greater of some given quantity.
- Statistical significance it is meant that the result was unlikely to have occurred by chance. Statistical significance can be determined by any method known in the art. Commonly used measures of significance include the p-value, which is the frequency or probability with which the observed event would occur, if the null hypothesis were true. If the obtained p-value is smaller than the significance level, then the null hypothesis is rejected. In simple cases, the significance level is defined at a p-value of 0.05 or less.
- “Therapeutic response” refers to improvement of symptoms (whether or not sustained) based on administration of one or more therapeutic agents.
- treatment of a subject (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of a disease or disorder.
- Treatment includes, but is not limited to, administration of a pharmaceutical composition, and may be performed either prophylactically or subsequent to the initiation of a pathologic event or contact with an etiologic agent.
- prophylactic treatments which can be directed to reducing the rate of progression of the disease or condition being treated, delaying the onset of that disease or condition, or reducing the severity of its onset.
- “Treatment” or “prophylaxis” does not necessarily indicate complete eradication, cure, or prevention of the disease or condition, or associated symptoms thereof.
- wild-type refers to a gene or gene product (e.g., a polypeptide) that is most frequently observed in a population and is thus arbitrarily designed the “normal” or “wild-type” form of the gene.
- Embodiments of the present disclosure relate to methods of treating thyroid eye disease (TED) in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and an antibody, or an antigen binding fragment thereof, that binds to human interleukin-11 receptor subunit a (IL-1 IRa).
- Thyroid eye disease is the most common inflammatory orbital disorder and is associated with autoimmune thyroid dysfunction. It is a progressive disorder with symptoms and signs that may cause significant facial disfigurement and visual disability, but rarely blindness.
- TED has numerous risk factors, including being of the female sex, being of middle age, and smoking, which not only increases the development of TED, but also reduces the efficacy of therapy (see, for example, Wang et al., Ther Clin Risk Manag. 15: 1305-1318, 2019). Treatment with radioactive iodine is another exemplary risk factor for TED is (see, for example, Sikder and Weinberg, Ophthalmologica. 224(4): 199-203, 2010).
- a diagnosis of TED is made by one of two criteria (see, for example, Bartley and Gorman, Am J Ophthalmol. 119(6):792-5, 1995). For example, if eyelid retraction is evident, the additional presence of abnormal thyroid function or regulation, exophthalmos, optic nerve dysfunction, or extraocular muscle (EOM) involvement provides the diagnosis, after excluding confounding causes. If eyelid retraction is absent, then diagnosis is made via exophthalmos, optic nerve dysfunction, or EOM involvement in the setting of abnormal thyroid function or regulation. In many instances, TED is associated with Graves’ disease. [0126] Thus, in certain embodiments, the patient has one or more clinical signs of TED.
- the most common clinical sign of TED is upper eyelid retraction, which can be unilateral or bilateral (see, for example, Bartley et al., Am J Ophthalmol. 121(3):284-290, 1996; and Smith and Hegedus, N Engl J Med. 375(16): 1552-1565, 2016).
- the wide-eyed appearance results in chronic eye exposure, especially during sleep. Initially, such can associate with foreign body sensation, dryness, and tearing. Over time, severe keratopathy may develop, which increases the risk of corneal scarring, ulceration, perforation, and endophthalmitis (see, for example, Douglas, Eye (Lond). 33(2): 183-190, 2019).
- Certain embodiments include the steps of (a) determining levels of TSI in the patient; and (c) administering the pharmaceutical composition to the patient if the levels of TSI in the patient are increased relative to a control or reference standard.
- Some embodiments include the steps of (a) determining levels of IL- 1 IRa and/or IL-11 (e.g., protein expression, mRNA expression) in blood or tissue around the patient’s eye (for example, orbital blood, orbital tissue such as orbital fibroblasts); and (b) administering the pharmaceutical composition to the patient if the levels of IL- 1 IRa and/or IL-11 in the blood or tissue around the patient’s eye are increased relative to a control or reference standard.
- IL- 1 IRa and/or IL-11 e.g., protein expression, mRNA expression
- Certain embodiments include the steps of (a) determining levels of circulatory IL-11 in the patient; and (b) administering the pharmaceutical composition to the patient if the levels of circulatory IL-11 are increased relative to a control or reference standard.
- the antibodies and antigen-binding fragments thereof of the present disclosure can be used for determining protein expression levels of IL- 1 IRa in the blood or tissue of a patient.
- the methods provided herein can combine any one or more of the diagnostic procedures to arrive at a diagnosis of TED prior to treatment with a pharmaceutical composition that comprises an anti-IL-1 IRa antibody or antigen binding fragment thereof.
- Certain embodiments include obtaining or receiving a biological sample from the subject, and performing a diagnostic assay on the sample.
- the tissue sample is a liquid biopsy (for example, a blood sample), a surgical sample, or other biopsy sample obtained from the patient, including a blood or tissue sample from around the eye of the patient (e.g., orbital blood or orbital tissue sample such as orbital fibroblasts).
- Certain embodiments of step (a) include performing a thyroid function test on a blood or other biological sample, for instance, by measuring the levels TSH, T4, and/or T3 and determining if the patient has abnormal thyroid function, for example, hyperthyroidism.
- Certain embodiments include performing a bioassay on a blood or other biological sample obtained from the patient (for example, circulatory blood, orbital blood, or orbital tissue sample such as orbital fibroblasts) to determine if the patient has increased levels of IL- 1 IRa and/or IL-11 (e.g., circulatory IL-11) relative to a reference or control.
- a “reference” include a value, amount, sequence, or other characteristic obtained from a database.
- a “reference” also includes value, amount, sequence, or other characteristic obtained from one or more control tissues, for example, a healthy tissue from one or more controls, for example, one or more control subjects (e.g., a population of control healthy subjects).
- a patient that is “intolerant” refers to an adverse event (AE) profile requiring the disconinuation of a prior TED therapy, or indicating that such discontinuation would be advisable.
- the intolerant, relapsed and/or refractory patient has active TED.
- the TED is progressing in the patient.
- a patient in an intolerant/relapsed/refractory disease state has TED that progresses more aggressively in the patient than prior to the TED therapy.
- TED progression is indicated by a worsening of one or more of the clinical signs of TED, an increased CAS score, and/or an increased VISA score, relative to the clinical signs, CAS scores, and/or VISA scores from prior to the TED therapy.
- the potency of the presently claimed antibodies and/or their different mechanism of action relative to the prior (now refractory) TED therapy can provide clinical advantages in treating a progressing disease state, including a more aggressively progressing disease state.
- the IGF-lR-inhibitor antibody is selected from teprotumumab, ganitumab, dalotuzumab, cixutumumab, and figitumumab therapy.
- the FcRn- inhibitory therapy is selected from batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab therapy.
- the CD20-inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.
- the TNF-a-inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.
- the patient is undergoing or has previously undergone a teprotumumab therapy and is intolerant, relapsed, and/or refractory to the (prior) teprotumumab therapy.
- “Relapse” refers to the recurrence of a past condition or disease state, for example, following a period of treatment-related dormancy or disease inactivity.
- a relasped TED patient is identified by an initial response to a prior teprotumumab therapy measured by a reduction in proptosis, that is subsequently regressed after a period of time despite continued treatment with the same teprotumumab therapy.
- the reduction in proptosis is greater than about 2mm.
- the regression of proptosis is an increase in proptosis back to a pretreatment baseline measurement.
- the regression of proptosis is an increase in proptosis from the maximal response to the prior teprotumumab therapy.
- a relapsed TED patient is identified by an initial response to the teprotumumab therapy measured by a reduction in CAS score, that is then subsequently reversed after a period of time despite continued treatment with the same teprotumumab therapy.
- a patient that is “refractory” to a prior teprotumumab therapy does not significantly respond to, has previously failed to respond to, or has become non-responsive (e.g., via selection) to the prior teprotumumab therapy.
- a refractory patient is identified by a lack of improvement in proptosis. In some embodiments, the lack of improvement in proptosis is less than about 2mm. In some embodiments, a refractory patient is identified by little to no change in CAS score.
- the intolerant, relapsed and/or refractory patient has active TED. In some instances, the TED is progressing in the patient.
- a patient in an intolerant/relapsed/refractory disease state has TED that progresses more aggressively in the patient than prior to the teprotumumab therapy.
- TED progression is indicated by a worsening of one or more of the clinical signs of TED, an increased CAS score, and/or an increased VISA score, relative to the clinical signs, CAS scores, and/or VISA scores from prior to the teprotumumab therapy.
- an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof is administered 3 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 4 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 5 teprotumumab half lives from the last dose of teprotumumab.
- an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof is administered 6 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 7 teprotumumab half lives from the last dose of teprotumumab. In some embodiments, an anti-IL-1 IRa antibody of the present disclosure, or antigen binding fragment thereof, is administered 8 teprotumumab half lives from the last dose of teprotumumab.
- the IGF-lR-inhibitor antibody therapy is selected from teprotumumab, ganitumab, dalotuzumab, cixutumumab, and figitumumab therapy.
- the FcRn-inhibitory therapy is selected from batoclimab (IMVT-1401), efgartigimod, nipocalimab, orilanolimab, and rozanolixizumab therapy.
- the IL-6 inhibitor therapy is selected from clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy.
- the steroid therapy is selected from methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone) therapy.
- the at least one additional TED therapy is a IGF-lR-inhibitor therapy.
- the IGF-1R inhibitor therapy is an IGF-1R antibody, e.g. teprotumumab, ganitumab, dalotuzumab, cixutumumab, or figitumumab therapy.
- the IGF-1R inhibitor therapy e.g. IGF-1R antibody
- the IGF-1R inhibitor therapy is administered simutaneously to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure.
- the IGF-1R inhibitor therapy e.g.
- the IGF-1R antibody is administered prior to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure.
- the IGF-1R inhibitor therapy e.g. IGF-1R antibody
- the IGF-1R inhibitor therapy is administered sequentially to the administration of the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure.
- the IGF-1R inhibitor therapy e.g. IGF-1R antibody
- the IGF-1R inhibitor therapy is administered within the same composition as the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure.
- the IGF-1R inhibitor therapy e.g. IGF-1R antibody
- IGF-1R antibody is administered about 1 to about 5 times during the the treatment with the anti-ILl IRa antibodies or antigen-binding fragments of the disclosure.
- the IGF-1R inhibitor therapy e.g. IGF-1R antibody
- the IGF-1R inhibitor therapy is administered about 1 to about 7 times during the the treatment with the anti- ILl IRa antibodies or antigen-binding fragments of the disclosure.
- an antibody or antigen binding fragment thereof comprises a V H sequence that comprises complementary determining region V H CDR1, V H CDR2, and V H CDR3 sequences selected from Table Al and variants thereof which bind to IL- 1 IRa; and a V L sequence that comprises complementary determining region V L CDR1, V L CDR2, and V L CDR3 sequences selected from Table Al and variants thereof which bind to IL- 1 IRa.
- an antibody comprises a V H sequence that comprises a V H CDR1, a V H CDR2, and a V H CDR3 sequence and a V L sequence that comprises a V L CDR1, a V L CDR2, and a V L CDR3 sequence, wherein all of the CDR sequences are from a single named antibody (e.g. mAbl) in Table Al.
- exemplary variants bind to IL- 1 IRa and have 1, 2, or 3 total alterations in any one or more of the individual CDRs, for example, any one or more the V H CDR1, V H CDR2, V H CDR3, V L CDR1, V L CDR2, and/or V L CDR3 sequences described herein.
- exemplary “alterations” include amino acid substitutions, additions, and deletions.
- the V H comprises a sequence least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2 and the V L comprises a sequence at least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to a sequence selected from Table A2 and is from the same single named antibody (e.g. mAbl) as the VH region, wherein any alterations are not found in the CDRs as underlined in Table A2.
- an antibody may comprise V H and V L sequences that are at least 70, 75, 80, 85, 90, 95, 97, 98, 99, or 100% identical to the respective sequences from a single named antibody (e.g. mAbl) in Table A2, wherein the antibody comprises the CDRs of said single named antibody (e.g. mAbl) as recited in Table Al.
- the Fc region is modified by phosphorylation, sulfation, acrylation, glycosylation, methylation, famesylation, acetylation, amidation, and the like, for instance, relative to a wildtype or naturally-occurring Fc region.
- the Fc region comprises wildtype or native glycosylation patterns, or alternatively, it comprises increased glycosylation relative to a native form, decreased glycosylation relative to a native form, or it is entirely deglycosylated.
- Certain variant, fragment, hybrid, or modified Fc regions may have altered effector functions, relative to a corresponding, wild-type Fc sequence.
- such Fc regions may have increased complement fixation or activation, increased Clq binding affinity, increased CDC-related activity, increased ADCC-related activity, and/or increased ADCP-related activity, relative to a corresponding, wild-type Fc sequence.
- such Fc regions may have decreased complement fixation or activation, decreased Clq binding affinity, decreased CDC-related activity, decreased ADCC-related activity, and/or decreased ADCP-related activity, relative to a corresponding, wild-type Fc sequence.
- In vivo measurements of stability or half-life can be measured in one or more bodily fluids, including blood, serum, plasma, urine, or cerebrospinal fluid, or a given tissue, such as the liver, kidneys, muscle, central nervous system tissues, bone, etc.
- modifications to an Fc region that alter its ability to bind the FcRn can alter its half-life in vivo.
- Assays for measuring the in vivo pharmacokinetic properties e.g., in vivo mean elimination half-life
- non-limiting examples of Fc modifications that alter its binding to the FcRn are described, for example, in U.S. Pat. Nos. 7,217,797 and 7,732,570; and U.S. Application Nos. US 2010/0143254 and 2010/0143254.
- an antibody or antigen binding fragment thereof has a T m of about or at least about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75°C. In some embodiments, an antibody or antigen binding fragment thereof has a T m of about 65°C or greater, for example, in PBS (phosphate buffered saline).
- suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, polypropylene glycol and mixtures thereof.
- PBS physiological saline or phosphate buffered saline
- physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, histidine, and/or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as polysorbate 20 (TWEENTM) polyethylene glycol (PEG), and poloxamers (PLURONICSTM), and the like.
- buffers such as phosphate, citrate, and other organic acids
- antioxidants including ascorbic acid
- the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by testing the compositions in model systems known in the art and extrapolating therefrom. Controlled clinical trials may also be performed. Dosages may also vary with the severity of the condition to be alleviated.
- a pharmaceutical composition is generally formulated and administered to exert a therapeutically useful effect while minimizing undesirable side effects. The composition may be administered one time, or may be divided into a number of smaller doses to be administered at intervals of time. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need.
- compositions that will be administered to a subject or patient may take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a herein described agent in aerosol form may hold a plurality of dosage units.
- Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000).
- the composition to be administered will typically contain a therapeutically effective amount of an agent described herein, for treatment of a disease or condition of interest.
- a therapeutic or pharmaceutical composition can be in the form of a solid or liquid.
- the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form.
- the carrier(s) can be liquid, with the compositions being, for example, an oral oil, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.
- the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid. Certain embodiments include sterile, injectable solutions.
- the pharmaceutical composition may be formulated into a powder, granule, gel, compressed tablet, pill, capsule, chewing gum, wafer or the like.
- a solid composition will typically contain one or more inert diluents or edible carriers.
- binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, com starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
- a liquid carrier such as polyethylene glycol or oil.
- the therapeutic or pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, gel, emulsion or suspension.
- the liquid may be for oral administration or for delivery by injection, as two examples.
- preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
- a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
- the liquid therapeutic or pharmaceutical compositions may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
- the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- Physiological saline is a preferred adjuvants
- Physiological saline
- a liquid therapeutic or pharmaceutical composition intended for either parenteral, intraocular, or oral administration should contain an amount of an agent such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of the agent of interest in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition. Certain oral therapeutic or pharmaceutical compositions contain between about 4% and about 75% of the agent of interest. In certain embodiments, therapeutic or pharmaceutical compositions and preparations are prepared so that a parenteral dosage unit contains between 0.01 to 10% by weight of the agent of interest prior to dilution.
- the therapeutic or pharmaceutical compositions may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base.
- the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
- Thickening agents may be present in a therapeutic or pharmaceutical composition for topical administration.
- the composition may include a transdermal patch or iontophoresis device.
- compositions may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug.
- the composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient.
- bases include, without limitation, lanolin, cocoa butter, and polyethylene glycol.
- the therapeutic or pharmaceutical composition may include various materials, which modify the physical form of a solid or liquid dosage unit.
- the composition may include materials that form a coating shell around the active ingredients.
- the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
- the active ingredients may be encased in a gelatin capsule.
- the therapeutic or pharmaceutical compositions in solid or liquid form may include a component that binds to agent and thereby assists in the delivery of the compound. Suitable components that may act in this capacity include monoclonal or polyclonal antibodies, one or more proteins or a liposome.
- the therapeutic or pharmaceutical composition may consist essentially of dosage units that can be administered as an aerosol.
- aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One of ordinary skill in the art, without undue experimentation may determine preferred aerosols.
- compositions provided herein can be combined with other therapeutic modalities for the treatment of TED.
- examples include supportive care (e.g., improving thyroid function, smoking cessation, supplemental selenium), corticosteroids, radiotherapy, and surgical management such as eyelid retraction repair, strabismus surgery, and orbital decompression.
- kits comprising (a) an antibody or antigen binding fragment thereof that binds to IL-1 IRa, as described herein; and optionally (b) at least one additional therapeutic agent.
- kits comprising (a) an antibody or antigen binding fragment thereof that binds to IL-1 IRa, as described herein; and optionally (b) at least one additional therapeutic agent.
- kits comprising (a) an antibody or antigen binding fragment thereof that binds to IL-1 IRa, as described herein; and optionally (b) at least one additional therapeutic agent.
- kits are in separate therapeutic compositions.
- (a) and (b) are in the same therapeutic composition.
- kits herein may also include a one or more additional therapeutic agents or other components suitable or desired for the indication being treated, or for the desired diagnostic application.
- the kits herein can also include one or more syringes or other components necessary or desired to facilitate an intended mode of delivery (e.g., stents, implantable depots, etc.).
- a patient care kit contains separate containers, dividers, or compartments for the composition(s) and informational material(s).
- the composition(s) can be contained in a bottle, vial, or syringe, and the informational material(s) can be contained in association with the container.
- the separate elements of the kit are contained within a single, undivided container.
- the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label.
- Embodiment 1-7 The method of any one of embodiments 1-1 to 1-6, wherein the patient has autoantibody stimulation of thyroid stimulating hormone receptor (TSHR).
- TSHR thyroid stimulating hormone receptor
- Embodiment 1-8 The method of any one of embodiments 1-1 to 1-7, wherein the patient has increased levels of thyroid-stimulating immunoglobulin (TSI).
- TTI thyroid-stimulating immunoglobulin
- Embodiment 1-15 The method of embodiment 1-13 or 1-14, comprising: a. determining the CAS of the patient; and b. administering the pharmaceutical composition to the patient if the CAS is 3 or more, or 4 or more, 5 or more, or 6 or more.
- Embodiment 1-16 The method of any one of embodiments 1-13 to 1-15, comprising: a. determining the VISA score of the patient; and b. administering the pharmaceutical composition to the patient if the VISA score is 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more.
- Embodiment 1-17 The method of any one of embodiments 1-13 to 1-16, comprising: a. determining thyroid function in the patient; and b. administering the pharmaceutical composition to the patient if the patient has abnormal thyroid function, optionally hyperthyroidism.
- Embodiment 1-18 The method of any one of embodiments 1-13 to 1-17, comprising: a. determining levels of thyroid-stimulating immunoglobulin (TSI) in the patient; and b. administering the pharmaceutical composition to the patient if the levels of TSI in the patient are increased relative to a control or reference standard.
- TSI thyroid-stimulating immunoglobulin
- Embodiment 1-21 The method of any one of embodiments 1-1 to 1-19, wherein the patient is undergoing or has previously undergone a TED therapy and is relapsed/refractory /intolerant to the TED therapy, optionally a patient with active TED.
- Embodiment 1-22 The method of embodiment 1-21, wherein the TED is progressing in the patient, optionally as indicated by a worsening of one or more of the clinical signs of TED, an increased CAS score, and/or an increased VISA score, relative to the clinical signs or scores from prior to the TED therapy, optionally wherein the TED is progressing more aggressively in the patient than prior to the TED therapy.
- Embodiment 1-26 The method of embodiment 1-23, wherein the IL-6 inhibitor therapy is selected from clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy.
- Embodiment 1-28 The method of embodiment 1-23, wherein the CD20-inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.
- Embodiment 1-29. The method of embodiment 1-23, wherein the TNF-a-inhibitor therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.
- Embodiment 1-30 The method of any one of embodiments 1-1 to 1-29, comprising administering the pharmaceutical composition in combination with at least one additional TED therapy.
- Embodiment 1-31. The method of embodiment 1-30, wherein the at least one additional TED therapy is selected from IGF-lR-inhibitor therapy, FcRn-inhibitor therapy, IL-6-inhibitor therapy, corticosteroid therapy, orbital radiotherapy (ORT), CD20-inhibitor therapy, and tumor necrosis factor-a (TNF-a)-inhibitor therapy.
- Embodiment 1-33 The method of embodiment 1-32, wherein the IGF-lR-inhibitor therapy is administered 1 to 7 times either simultaneously or sequentially to the administration the pharmaceutical composition comprising a pharmaceutically-acceptable carrier and an antibody, or an antigen binding fragment thereof, that binds to human IL-1 IRa.
- Embodiment 1-35 The method of embodiment 1-31, wherein the IL-6 inhibitor therapy is selected from clazakizumab, elsilimomab, levilimab, olokizumab, sarilumab, siltuximab, sirukumab, and tocilizumab therapy.
- Embodiment 1-36 The method of embodiment 1-31, wherein the steroid therapy is selected from methylprednisolone (optionally IV methylprednisolone sodium succinate), prednisolone (optionally oral prednisolone), and prednisone (optionally oral prednisone) therapy.
- methylprednisolone optionally IV methylprednisolone sodium succinate
- prednisolone optionally oral prednisolone
- prednisone optionally oral prednisone
- Embodiment 1-37 The method of embodiment 1-31, wherein the CD20-inhibitor therapy is selected from ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, and ublituximab therapy.
- Embodiment 1-39 The method of any one of embodiments 1-1 to 1-38, wherein the antibody, or antigen binding fragment thereof, binds to a fibronectin domain III of human IL- 1 IRa, or approximately residues 90-197 of SEQ ID NO: 260.
- Embodiment 1-40 The method of any one of embodiments 1-1 to 1-38, wherein the antibody, or antigen binding fragment thereof, binds to the second extracellular domain of IL- HRa.
- Embodiment 1-4 The method of embodiment 1-39, wherein the antibody, or antigen binding fragment thereof, recognizes an epitope comprising the amino acid sequence of SEQ ID NO: 261.
- Embodiment 1-42 The method of embodiment 1-41, wherein the epitope comprises the residues SI 16, S125, K129, S140 and T143 of SEQ ID NO: 260.
- Embodiment 1-43 The method of any one of embodiments 1-1 to 1-42, wherein the antibody, or antigen binding fragment thereof, comprises: a. a heavy chain variable region (V H ) that comprises complementary determining region V H CDR1, V H CDR2, and V H CDR3 amino acid sequences selected from Table Al and variants thereof which specifically bind to IL-1 IRa; and b. a light chain variable region (V L ) that comprises complementary determining region V L CDR1, V L CDR2, and V L CDR3 amino acid sequences selected from Table Al and variants thereof which specifically bind to IL-1 IRa.
- V H heavy chain variable region
- V L a light chain variable region
- Embodiment 1-44 The method of embodiment 1-43, wherein:
- V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 1-3, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 4-6, respectively;
- V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 7-9, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 10-12, respectively;
- V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 13-15, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 16-18, respectively;
- the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 19-21, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 22-24, respectively;
- V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 34-39, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 40-42, respectively;
- V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 79-81, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 82-84, respectively;
- V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 91-93, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 94-96, respectively;
- V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 121-123, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 124-126, respectively;
- the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 127-129, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 130-132, respectively;
- V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 139-141, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 142-144, respectively;
- V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 169-171, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 172-174, respectively;
- V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 175-177, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 178-180, respectively; [0280] the V H CDR1, V H CDR2, and V H CDR3 amino acid sequences comprise SEQ ID NOs: 181-183, respectively, and the V L CDR1, V L CDR2, and V L CDR3 amino acid sequences comprise SEQ ID NOs: 184-186, respectively; or
- the V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 227
- the V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 228;
- the V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 229
- the V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 230;
- the V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 243
- the V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 244;
- the V H comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 249
- the V L comprises an amino acid sequence at least 80, 85, 90, 95, 97, 98, 99, or 100% identical to SEQ ID NO: 250;
- Embodiment 1-49 The method of any one of embodiments 1-1 to 1-48, wherein the antibody, or antigen binding fragment thereof, comprises an IgA (including subclasses IgAl and IgA2), IgD, IgE, IgG (including subclasses IgGl, IgG2, IgG3, and IgG4), or IgM Fc domain, optionally a human Fc domain, or a hybrid and/or variant thereof.
- IgA including subclasses IgAl and IgA2
- IgD including subclasses IgAl and IgA2
- IgG including subclasses IgGl, IgG2, IgG3, and IgG4
- IgM Fc domain optionally a human Fc domain, or a hybrid and/or variant thereof.
- Embodiment 1-50 The method of embodiment 1-49, wherein the antibody, or antigen binding fragment thereof, comprises an IgG Fc domain with high effector function in humans, optionally an IgGl or IgG3 Fc domain.
- Embodiment 1-51 The method of embodiment 1-49, wherein the antibody, or antigen binding fragment thereof, comprises an IgG Fc domain with low effector function in humans, optionally an IgG2 or IgG4 Fc domain.
- Embodiment 1-52 The method of embodiment 1-49, wherein the antibody, or antigen binding fragment thereof, comprises a human IgGl or IgG4 Fc domain, optionally selected from Table Fl
- Embodiment 1-53 The method of any one of embodiments 1-1 to 1-52, wherein the antibody, or antigen binding fragment thereof, is a monoclonal antibody.
- Embodiment 1-54 The method of any one of embodiments 1-1 to 1-53, wherein the antibody, or antigen binding fragment thereof, is a humanized antibody, optionally wherein the antibody, or antigen binding fragment thereof, is a humanized monoclonal antibody that comprises a human IgG4 Fc domain with an S228P mutation (EU numbering).
- Embodiment 1-56 The method of any one of embodiments 1-1 to 1-55, wherein the composition has a purity of at least about 80%, 85%, 90%, 95%, 98%, or 99% on a protein basis with respect to the at least one antibody or antigen binding fragment, and is substantially aggregate- and endotoxin-free.
- Embodiment 1-57 The method of any one of embodiments 1-1 to 1-56, wherein the composition has reduced or undetectable heterogeneity of N-linked glycosylation (optionally relative to the TS7 and 8E2 antibodies), optionally in the V L CDR3 sequence.
- Embodiment 1-58 The method of any one of embodiments 1-1 to 1-57, wherein the pharmaceutical composition is a sterile, injectable solution, optionally suitable for intravenous, intramuscular, subcutaneous, or intraperitoneal administration.
- Embodiment 1-59 The method of any one of embodiments 1-1 to 1-58, wherein administering the pharmaceutical composition to the patient improves one or more clinical signs of TED.
- Embodiment 1-60 The method of embodiment 1-59, wherein the one or more clinical signs are selected from upper eyelid retraction (unilateral or bilateral), exophthalmos (bulging eyes), lagophthalmos (incomplete eye closure), extraocular muscle (EOM) dysfunction optionally hypotropia (downward deviation) and/or esotropia (inward deviation), eyelid edema, eyelid erythema, conjunctival injection, excessive extracellular matrix accumulation in orbital tissue, and chemosis (conjunctival edema).
- EOM extraocular muscle
- Embodiment 1-62 The method of any one of embodiments 1-59 to 1-61, wherein the administering the pharmaceutical composition to the patient improves the VISA score of the patient, optionally by at least one, two, three, four, or five points, optionally to a VISA or 4 or less, 3 or less, 2 or less, or 1 or less.
- Embodiment 1-63 The method of any one of embodiments 1-1 to 1-62, wherein administering the pharmaceutical composition to the patient reduces levels of IL-1 IRa and/or IL-11 in blood or tissue around the patient’s eye, optionally in orbital fibroblasts.
- Example 1 IL-1 IRa Expression is Elevated in TED-Derived Fibroblasts
- Flow cytometry was performed to compare IL-1 IRa expression on primary fibroblasts derived from orbital tissue of a thyroid eye disease (TED) patient relative to that of primary fibroblasts derived from eye tissue of a non-TED individual.
- the antibody mAb5 was used to detect IL-11R levels on the cell surface.
- FIGS. 1A-1C high levels of IL-1 IRa expression were detected on fibroblasts from diseased tissue relative to fibroblasts from normal tissue (FIG. 1C). This result evidences that inhibitory anti-IL-1 IRa antibodies have therapeutic utility in the treatment of TED, for example, by inhibiting IL- 1 IRa activity in the tissue around the eye of TED patients.
- Example 2 Anti-IL-1 IRa Antibody Blocks IL-11 Stimulated HA Release and Cell Proliferation in Orbital Cells from TED Patients
- fibroblasts were isolated from orbital tissue of patients with Thyroid eye disease (TED) and then stimulated in culture with recombinant human IL-11 in the presence and absence of the IL- 1 IRa blocking antibody, mAb5. The effects of these treatments were measured on hyaluronic acid (HA) release and cell proliferation, two events that are linked to TED pathogenesis.
- TED Thyroid eye disease
- mAb5 hyaluronic acid
- tissue were minced into 1-2 mm pieces, placed in 6 well culture dishes containing 3 mL of growth media (high glucose Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 20% fetal bovine serum and 1% penicillin/ streptomycin; all from Gibco Laboratories, New York, USA), and incubated at 37 °C with 5% CO 2 .
- growth media high glucose Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 20% fetal bovine serum and 1% penicillin/ streptomycin; all from Gibco Laboratories, New York, USA
- I l l was renewed every 3-4 days and tissue was maintained in culture for 2-3 weeks to allow the orbital fibroblasts to migrate out of the tissue.
- orbital fibroblasts (passage ⁇ 5) were plated in growth medium at a density of 10,000 cells/well on black, clear flat bottom, 96- well plates (Coming Costar, catalog #3603) and maintained in a humidified incubator overnight at 37 °C in 5% CO 2 . The following day, media was changed to 100 pL of starvation media (high glucose Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 1% fetal bovine serum and 1% penicillin/ streptomycin; all from Gibco Laboratories, New York, USA) for 24 hours to synchronize cells.
- starvation media high glucose Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 1% fetal bovine serum and 1% penicillin/ streptomycin; all from Gibco Laboratories, New York, USA
- recombinant IL-11 stimulated a dose-dependent increase in HA release from orbital fibroblasts (gray bars), and this was inhibited by mAb5 (lined bars) at all IL- 11 doses.
- mAb5 lined bars
- recombinant IL-11 stimulated fibroblast proliferation at all doses, and these effects were blocked by addition of mAb5.
- FIGS. 4A-4C show the dose-dependent effects of IL-11, with mAb5 (10 ng/mL, hatched) and without mAb5 (solid), on hyaluronan release from orbital fibroblasts from patient sample #2 (FIG. 4A, no prior TED therapy), patient sample #1 (FIG. 4B, prior teprotumumab therapy), and patent sample #3 (FIG. 4C, prior corticosteroid therapy).
- FIGS. 5A-5C show the effects of mAb5 at 3, 10, 30 and lOOpg/mL on IL-11 (10 ng/mL) induced HA release from orbital fibroblasts from patient samples #2, #4, and #5 (FIG. 5A; no prior TED therapy), patient sample # 1 (FIG. 5B, prior teprotumumab therapy), and patient sample #3 (FIG. 5C, prior corticosteroid therapy).
- FIGS. 6A-6C show the comparative inhibitory effects of mAb5 teprotumumab and isotype control (all at lOpg/mL) on HA release induced by lOng/mL IL-11 from orbital fibroblasts from TED patients;
- FIG. 7A-7C show the comparative effects of mAb5 teprotumumab (and isotype control antibodies (all at lOpg/mL) on proliferation of orbital fibroblasts induced by lOng/mL IL- 1 Ifrom TED patients;
- IGF-1R IGF-1 receptor
- TEPEZZA teprotumumab
- anti-IGF-lR mAb an anti-IGF-lR mAb
- FIGS. 12A-12B show that TGFP stimulation increased procollagen I release by greater than 3-fold (FIG. 12A), and that this increase was significantly inhibited by the addition of mAb5 (FIG. 12B).
- Example 4 Blocking IL-1 IRa inhibits the production of inflammatory cytokines in TED patient derived orbital fibroblasts
- the infiltration of immune cells is a key pathogenic feature of TED and an area of ongoing therapeutic drug research.
- the upregulation of cytokines including TNFa, IL-6, IL-8 and MCP-1/CCL2 is believed to promote activation of immune cells, including T cells, B cells and orbital fibroblasts leading to orbital tissue expansion and remodeling (Fallahy et al., Front Endocrinol (Lausanne). 12:654473 (2021); Lee et al., Best Pract Res Clin Endocrinol Metab. 37(2): 101620 (2023); Zhang et al., J Immunol Res. 2528046 (2022)).
- IL-11 stimulated both IL-6 and MCP-1/CCL2 release (FIG. 14A and 14C), which was not significantly increased by combination stimulation with IL-11 + IGF- 1.
- mAb5 inhibited IL-6 and MCP-1/CCL2 release under all treatment conditions whereas teprotumumab had no effect (FIG. 14).
- Example 5 Comparison of mAb5 with commercially available antibodies to IL-11 and IL- 11R
- a panel of commercially available antibodies to IL-11 and IL-11R were tested for their ability to block HA production in TED patient derived orbital fibroblasts compared to mAb5.
- the antibodies tested are shown in Table E2 below.
- These antibodies were compared directly to mAb5 using assay conditions as described in Example 2 using TED orbital fibroblasts stimulated with IL-11 and IGF-1. Cells from from 12 different tissue donors were used for all antibodies except MM09 (6 donors used), and results are shown as mean fold over vehicle conditions. The results, shown in FIG. 15, clearly demonstrate that mAb5 is more efficacious than commercially available antibodies to IL-11 or IL- HR.
- the resulting complexes were digested with 5 different proteases (trypsin, chymotrypsin, ASP-N, elastase and thermolysin and the resulting peptides, cross-linked or not, were analyzed by high-resolution mass spectrometry.
- proteases trypsin, chymotrypsin, ASP-N, elastase and thermolysin
- the resulting peptides, cross-linked or not were analyzed by high-resolution mass spectrometry.
- HDX mapping IL-1 IRa was labelled with deuterium before and after complexing with mAb5, allowing sites of differential deuterium labelling to be determined by mass spectrometry.
- Example 7 Blocking IL-11 signaling with anti-IL-1 IRa antibody is effective at inhibition of IL-11 signaling in cis and in trans
- IL-11 has been reported to be able to signal both conventionally (in cis) binding IL-
- the STAT3 Reporter (Luc) - HEK293 cell line was purchased from BPS Bioscience, catalog #79800-P and transfected with recombinant IL- 1 IRa. Cells were selected for expression of IL- 1 IRa, and a stable clone isolated which was used for further experiments. Cells were grown, passaged, and assayed as per BPS Bioscience protocols. Cells were added at 25,000 cells per well in a 96-well microtiter dish and incubated at 37 °C for 30-45 minutes in 5% CO2 humidified air.
- Results shown in FIG. 17 demonstrated that when pSTAT3 signaling was initiated by IL-11 both mAb5 (anti-IL-11R) and by an anti-IL-11 mAb with approximately equivalent potency (IC50 5.6nM for mAb5, 4.2nM for anti-IL-11). However, when stimulated with hyper IL-11 the mAb to IL-11 was ineffective whereas the potency of mAb5 was unchanged (IC50 5.4nM). This data confirms that mAb5 is effective at blocking IL-11 signaling both in cis and in trans.
- IL-11 concentrations in serum/plasma from patients with TED will be compared to healthy individuals. Differences in IL-11 and IL-11R expression in TED patient eye tissue will compared with normal eye tissue, specifically looking at fibroblasts, myoblasts and other appropriate cell types.
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Abstract
L'invention concerne des méthodes de traitement de l'orbitopathie thyroïdienne (TED) par l'administration d'un anticorps ou d'un fragment de liaison à l'antigène de celui-ci qui se lie à la sous-unité α du récepteur de l'interleukine-11 humaine (IL-11Rα).
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