US20220267450A1 - Compositions and methods for treatment of thyroid eye disease - Google Patents

Compositions and methods for treatment of thyroid eye disease Download PDF

Info

Publication number
US20220267450A1
US20220267450A1 US17/501,362 US202117501362A US2022267450A1 US 20220267450 A1 US20220267450 A1 US 20220267450A1 US 202117501362 A US202117501362 A US 202117501362A US 2022267450 A1 US2022267450 A1 US 2022267450A1
Authority
US
United States
Prior art keywords
antibody
seq
sequence
amino acid
acid sequence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US17/501,362
Other languages
English (en)
Inventor
Vahe Bedian
Peter Harwin
Tomas Kiselak
Angela SHE
Jonathan Violin
Yang Zhao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Viridian Therapeutics Inc
Original Assignee
Vahe Bedian
Viridian Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=81208791&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20220267450(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to US17/501,362 priority Critical patent/US20220267450A1/en
Application filed by Vahe Bedian, Viridian Therapeutics Inc filed Critical Vahe Bedian
Assigned to VAHE BEDIAN reassignment VAHE BEDIAN ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KISELAK, Tomas, HARWIN, Peter, SHE, Angela, ZHAO, YANG, VIOLIN, Jonathan, BEDIAN, VAHE
Assigned to Viridian Therapeutics, Inc. reassignment Viridian Therapeutics, Inc. CORRECTIVE ASSIGNMENT TO CORRECT THE THE ASSIGNEE NAME AND CITY PREVIOUSLY RECORDED AT REEL: 058379 FRAME: 0480. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: KISELAK, Tomas, HARWIN, Peter, SHE, Angela, ZHAO, YANG, VIOLIN, Jonathan, BEDIAN, VAHE
Publication of US20220267450A1 publication Critical patent/US20220267450A1/en
Priority to US17/822,978 priority patent/US11548951B1/en
Priority to US18/150,514 priority patent/US12404335B2/en
Priority to US18/364,620 priority patent/US20240043546A1/en
Priority to US18/942,051 priority patent/US12595309B2/en
Priority to US19/242,715 priority patent/US20250313639A1/en
Priority to US19/242,725 priority patent/US12600788B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • 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
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/524—CH2 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • 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
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • TAO thyroid-associated ophthalmopathy
  • TED thyroid eye disease
  • GO Graves' ophthalmopathy or orbitopathy
  • thyrotoxic exophthalmos dysthyroid ophthalmopathy
  • TAO is divided into two types. Active TAO, which typically lasts 1-3 years, is characterized by an ongoing autoimmune/inflammatory response in the soft tissues of the orbit. Active TAO is responsible for the expansion and remodeling of the ocular soft tissues. The autoimmune/inflammatory response of active TAO spontaneously resolves and the condition transitions into inactive TAO. Inactive TAO is the term used to describe the long-term/permanent sequelae of active TAO. The cause of TAO is unknown.
  • TAO is typically associated with Graves' hyperthyroidism, but can also occur as part of other autoimmune conditions that affect the thyroid gland and produce pathology in orbital and periorbital tissue, and, rarely, the pretibial skin (pretibial myxedema) or digits (thyroid acropachy).
  • TAO is an autoimmune orbitopathy in which the orbital and periocular soft tissues are primarily affected with secondary effects on the eye and vision.
  • the eyes are forced forward (bulge) out of their sockets—a phenomenon termed proptosis or exophthalmos.
  • TAO may precede, coincide with, or follow the systemic complications of dysthyroidism.
  • the ocular manifestations of TAO include upper eyelid retraction, lid lag, swelling, redness (erythema), conjunctivitis, and bulging eyes (exophthalmos or proptosis), chemosis, periorbital edema, and altered ocular motility with significant functional, social, and cosmetic consequences.
  • Hyaluronic acid is produced by fibroblasts residing within the orbital fat and extraocular muscles, and its synthesis in vitro is stimulated by several cytokines and growth factors, including IL-1beta, interferon-gamma, platelet-derived growth factor, thyroid stimulating hormone (TSH) and insulin-like growth factor I (IGF-I).
  • cytokines and growth factors including IL-1beta, interferon-gamma, platelet-derived growth factor, thyroid stimulating hormone (TSH) and insulin-like growth factor I (IGF-I).
  • IGF-IR insulin-like growth factor I receptor
  • IGF-IR is a widely expressed heterotetrameric protein involved in the regulation of proliferation and metabolic function of many cell types. It is a tyrosine kinase receptor comprising two subunits. IGF-IRalpha contains a ligand-binding domain while IGF-IRbeta is involved in signaling and contains tyrosine phosphorylation sites.
  • an antibody, or antigen binding fragment thereof, comprising a sequence as provided for herein comprising a sequence as provided for herein.
  • the antibody comprises a VL sequence as set forth in SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 79, or 86; and a VH sequence as set forth in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 80, or 83.
  • the antibody or antibody fragment comprises: (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 32; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 33; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 34; or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence SEQ ID NO: 29; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 30; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 31; or variants of any of the foregoing.
  • the antibody or antibody fragment comprises: (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 38; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 39; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 40; or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence SEQ ID NO: 35; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 36; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 37; or variants of any of the foregoing.
  • the antibody or antibody fragment comprises: (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 44; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 45; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 46; or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence SEQ ID NO: 41; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 42; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 43; or variants of any of the foregoing.
  • the antibody or antibody fragment comprises: (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 50; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 51; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 52; or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence SEQ ID NO: 47; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 48; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 49; or variants of any of the foregoing.
  • the antibody comprises a V L sequence as set forth in SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 79, or 86, or a variant thereof. In some embodiments, the antibody comprises a V H sequence as set forth in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 80, or 83, or a variant thereof.
  • the antibody comprises a sequence of SEQ ID NO: 65-72, 78, 82, or 85, or a variant thereof.
  • the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 3 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 83. In some embodiments, the antibody comprising a light chain variable region having the amino acid sequence of SEQ ID NO: 13 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 14.
  • the antibody comprises a light chain having a an amino acid sequence of SEQ ID NO: 93 and a heavy chain amino acid sequence of SEQ ID NO: 92.
  • the antibody comprises a light chain having a an amino acid sequence of SEQ ID NO: 93 and a heavy chain amino acid sequence of SEQ ID NO: 95.
  • the a variant of any antibodies provided herein are provided so long as the CDRs remain constant as compared to the parental (non-variant) sequence provided for herein.
  • methods of treating or reducing the severity of, thyroid-associated ophthalmopathy (TAO), or a symptom thereof comprising administering to a subject an antibody as provided for herein or a pharmaceutical composition comprising the same.
  • TAO thyroid-associated ophthalmopathy
  • methods of inhibiting IGF-1 stimulated receptor phosphorylation on a cell comprising contacting the cell with an as provided for herein, or a pharmaceutical composition comprising the same.
  • methods of treating thyroid eye disease in a subject comprising administering an as provided for herein, or a pharmaceutical composition comprising the same to the subject, wherein the antibody has a serum concentration in the subject of at least, or about, 70 ⁇ g/ml, 75 ⁇ g/ml, 80 ⁇ g/ml, 85 ⁇ g/ml, 90 ⁇ g/ml, 95 ⁇ g/ml, 100 ⁇ g/ml, or 105 ⁇ g/ml at least 1, 2, or 3 week after administration.
  • methods of inhibiting IGF-1 induced receptor autophosphorylation in a cell by at least 95%, 96%, 97%, 98%, or 99% or by 100% are provided, the method comprising contacting the cell with an antibody as provided for herein, or a pharmaceutical composition comprising the same.
  • embodiments are provided for any of the methods provided for herein, wherein the antibody, or an antigen binding fragment thereof, is administered in a pharmaceutical composition that additionally comprises a pharmaceutically acceptable diluent or excipient or carrier.
  • the pharmaceutical composition further comprises one or more pharmaceutically active compounds for the treatment of TAO.
  • the pharmaceutical composition further comprises corticosteroids; rituximab or other anti-CD20 antibodies; tocilizumab or other anti-IL-6 antibodies; or selenium, infliximab or other anti-TNFalpha antibodies or a thyroid-stimulating hormone receptor (TSHR) inhibitor.
  • TSHR thyroid-stimulating hormone receptor
  • FIG. 5A and FIG. 5B illustrate various properties of antibodies as provided for herein.
  • Proptosis and exophthalmos are used interchangeably and refer to the forward projection, displacement, bulging, or protrusion of the eye anteriorly out of the orbit. Owing to the rigid bony structure of the orbit with only anterior opening for expansion, any increase in orbital soft tissue contents taking place from the side or from behind will displace the eyeball forward.
  • Proptosis or exophthalmos can be the result of a several disease processes including infections, inflammations, tumors, trauma, metastases, endocrine lesions, vascular diseases & extra orbital lesions.
  • TAO TED or GO
  • Exophthalmos can be either bilateral, as is often seen in TAO (TED or GO), or unilateral (as is often seen in an orbital tumor).
  • the Fc region comprises a S228P and a L235E mutation.
  • the antibody comprises a L234F, L235E, and P331S mutation.
  • the Fc region comprises M252Y, S254T, T256E, S228P and L235E mutations.
  • the Fc region comprises S228P, L235E, M428L, and N434S mutations.
  • the Fc region comprises the M428L and N434S mutations.
  • the Fc region comprises the L234F, L235E, P331S, M252Y, S254T, and T256E mutations.
  • the Fc region comprises the sequence selected from:
  • a “Fab' fragment” contains one light chain and a portion or fragment of one heavy chain that contains the VH domain and the C H 1 domain and also the region between the C H 1 and C H 2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab′ fragments to form a F(ab′) 2 molecule.
  • the “Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.
  • a “bivalent antibody” comprises two antigen binding sites. In some instances, the two binding sites have the same antigen specificities. However, bivalent antibodies may be bispecific (see below).
  • diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy chain variable domain (V H ) connected to a light chain variable domain (V L ) in the same polypeptide chain (V H -V L or V L -V H ).
  • V H heavy chain variable domain
  • V L light chain variable domain
  • the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.
  • Diabodies are described more fully in, e.g., EP 404,097; WO 93/11161; and Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448.
  • Holliger and Hudson (2005) Nat. Biotechnol. 23:1126-1136 For a review of engineered antibody variants generally see Holliger and Hudson (2005) Nat. Biotechnol. 23:1126-1136.
  • the term “monoclonal antibody”, as used herein, refers to population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts.
  • conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, that are often specific for different epitopes.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • the “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.
  • Fully human antibody refers to an antibody that comprises human immunoglobulin protein sequences only.
  • a fully human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell.
  • mouse antibody refers to an antibody that comprises mouse immunoglobulin sequences only.
  • a fully human antibody may contain rat carbohydrate chains if produced in a rat, in a rat cell, or in a hybridoma derived from a rat cell.
  • rat antibody refers to an antibody that comprises rat immunoglobulin sequences only.
  • human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).
  • variable regions of each light/heavy chain pair form the antibody binding site.
  • an intact antibody has two binding sites.
  • the two binding sites are, in general, the same.
  • CDRs provide the majority of contact residues for the binding of the antibody to the antigen or epitope.
  • CDRs of interest can be derived from donor antibody variable heavy and light chain sequences, and include analogs of the naturally occurring CDRs, which analogs also share or retain the same antigen binding specificity and/or neutralizing ability as the donor antibody from which they were derived.
  • the antibodies can take the form of a full length antibody, single-domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), a shark heavy-chain-only antibody (VNAR), a microprotein (cysteine knot protein, knottin), a DARPin; a Tetranectin; an Affibody; a Transbody; an Anticalin; an AdNectin; an Affilin; a Microbody; a peptide aptamer; an alterase; a plastic antibody; a phylomer; a stradobody; a maxibody; an evibody; a fynomer, an armadillo repeat protein, a Kunitz domain, an avimer, an atrimer, a probody, an immunobody, a triomab, a troybody; a pepbody; a vaccibody, a UniBody; A
  • the term “antigen” as used herein means any molecule that has the ability to generate antibodies either directly or indirectly or that binds to antibody. Included within the definition of “antigen” is a protein-encoding nucleic acid. An “antigen” can also refer to the binding partner of an antibody.
  • the antigen is the IGF-1R protein expressed on the surface of a cell.
  • the cell is an intact cell. An intact cell is a cell that has not been lysed or broken open with the use of detergents or other reagents. A cell that has been treated with detergents or other reagents that breaks up the cellular membrane or punches holes in a cellular membrane is not an intact cell.
  • methods are provided herein for generating an antibody that binds to a IGF-1R protein, the method comprising culturing a cell comprising a nucleic acid molecule encoding the IGF-1R antibody.
  • telomere binding refers to antibody binding to a predetermined antigen (e.g. IGF-1R) or epitope present on the antigen.
  • the antibody binds with a dissociation constant (K D ) of 10 ⁇ 7 M or less, and binds to the predetermined antigen with a K D that is at least two-fold less than its K D for binding to a non-specific antigen (e.g., BSA, casein, or another non-specific polypeptide) other than the predetermined antigen.
  • K D dissociation constant
  • an antibody recognizing IGF-1R and “an antibody specific for IGF-1R” are used interchangeably herein with the term “an antibody which binds immunospecifically to IGF-1R.”
  • Reference in the present disclosure may be made to IGF-1R.
  • the degree of specificity necessary for an anti-IGF-1R antibody may depend on the intended use of the antibody, and at any rate is defined by its suitability for use for an intended purpose.
  • the antibody, or binding compound derived from the antigen-binding site of an antibody, of the contemplated method binds to its antigen (IGF-1R), with an affinity that is at least two fold greater, at least ten times greater, at least 20-times greater, or at least 100-times greater than the affinity with any other antigen.
  • the term “homolog” means protein sequences having between 40% and 100% sequence homology or identity to a reference sequence. Percent identity between two peptide chains can be determined by pair wise alignment using the default settings of the AlignX module of Vector NTI v.9.0.0 (Invitrogen Corp., Carslbad, Calif.).
  • the antibody, or antigenic binding fragment thereof has, at least 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% homology or identity to a sequence described herein.
  • the antibody has conservative substitutions as compared to a sequence described herein. Exemplary conservative substitutions are illustrated in Table 1 and are encompassed within the scope of the disclosed subject matter.
  • the conservative substitution may reside in the framework regions, or in antigen-binding sites, as long they do not adversely affect the properties of the antibody. Substitutions may be made to improve antibody properties, for example stability or affinity. Conservative substitutions will produce molecules having functional and chemical characteristics similar to those molecules into which such modifications are made. Exemplary amino acid substitutions are shown in the table below.
  • variants of the proteins and peptides provided herein are provided.
  • a variant comprises a substitution, deletions, or insertion.
  • the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) substitutions.
  • the substitutions can be conservative substitutions.
  • the substitution is non-conservative.
  • the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) deletions.
  • the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) insertions.
  • the substitutions, deletions, or insertions are present in the CDRs provided for herein. In some embodiments, the substitutions, deletions, or insertions are not present in the CDRs provided for herein.
  • antibodies include murine, murine-human and human-human antibodies produced by hybridoma or recombinant techniques known in the art.
  • Antibodies can also be produced in human, a mouse, sheep, a rat, a rabbit, a shark, a llama, or a chicken. In some embodiments, the antibody is produced in a chicken.
  • the antibodies can also be produced in or other small animals.
  • epitope is meant to refer to that portion of any molecule capable of being recognized by and bound by an antibody at one or more of the Ab's antigen binding regions.
  • Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three dimensional structural characteristics as well as specific charge characteristics.
  • Example of epitopes include, but are not limited to, the residues described herein that form IGF-1R epitopes.
  • the epitope is only present in a non-denatured protein. In some embodiments, the epitope is only present in a denatured protein.
  • the hybrid cells are formed by the fusion of a non-human antibody-producing cell, typically a spleen cell of an animal immunized against either natural or recombinant antigen, or a peptide fragment of the antigen protein sequence.
  • a non-human antibody-producing cell typically a spleen cell of an animal immunized against either natural or recombinant antigen, or a peptide fragment of the antigen protein sequence.
  • the non-human antibody-producing cell can be a B lymphocyte obtained from the blood, spleen, lymph nodes or other tissue of an animal immunized with the antigen.
  • the second fusion partner which provides the immortalizing function, can be a lymphoblastoid cell or a plasmacytoma or myeloma cell, which is not itself an antibody producing cell, but is malignant.
  • Fusion partner cells include, but are not limited to, the hybridoma SP2/0-Ag14, abbreviated as SP2/0 (ATCC CRL1581) and the myeloma P3X63Ag8 (ATCC TIB9), or its derivatives. See, e.g., Ausubel infra, Harlow infra, and Colligan infra, the contents of which references are incorporated entirely herein by reference.
  • the antibodies can be generated according the examples provided herein. Once the sequences are known, the antibodies can also be generated according to known methods. The antibodies can also be converted to different types, such as being converted to Human IgGs and the like. By converting the antibodies to a human antibody, a human subject should not identify the antibodies as foreign. The conversion of a non-human IgG antibody to a human IgG antibody is well known and can routinely be done once the native sequence is known. As discussed herein, the antibodies can be modified according to known methods. Such methods are described in, for example, Riechmann L, Clark M, Waldmann H, Winter G (1988). Reshaping human antibodies for therapy”.
  • the antibody-producing cell contributing the nucleotide sequences encoding the antigen-binding region of the chimeric antibody can also be produced by transformation of a non-human, such as a primate, or a human cell.
  • a non-human such as a primate, or a human cell.
  • a B lymphocyte which produces the antibody can be infected and transformed with a virus such as Epstein-Barr virus to yield an immortal antibody producing cell (Kozbor et al., Immunol. Today 4:72 79 (1983)).
  • the B lymphocyte can be transformed by providing a transforming gene or transforming gene product, as is well-known in the art. See, e.g., Ausubel infra, Harlow infra, and Colligan infra, the contents of which references are incorporated entirely herein by reference.
  • the cell fusions are accomplished by standard procedures well known to those skilled in the field of immunology. Fusion partner cell lines and methods for fusing and selecting hybridomas and screening for mAbs are well known in the art. See, e.g., Ausubel infra, Harlow infra, and Colligan infra, the contents of which references are incorporated entirely herein by reference.
  • the antibody is a MAb which binds to IGF-1R. In some embodiments, the antibody binds to amino acids of an epitope of the IGF-1R.
  • the antibody comprises a sequence as provided for herein.
  • the sequences of the antibodies can be modified to yield human IgG antibodies.
  • the conversion of the sequences provided herein can be modified to yield other types of antibodies.
  • the CDRs can also be linked to other antibodies, proteins, or molecules to create antibody fragments that bind to IGF-1R. This can be in the form of an antibody drug conjugate (“ADC”), a multi-specific molecule, or a chimeric antigen receptor.
  • ADC antibody drug conjugate
  • the CDRs and antibody sequences provided herein also be humanized or made fully human according to known methods.
  • the sequences can also be made into chimeric antibodies as described herein.
  • the antibody comprises an amino acid sequence comprising a sequence provided for herein or a fragment thereof. In some embodiments, the antibody comprises one or more amino acid sequences as provided herein, an antigen binding fragments, thereof, or a human IgG variant thereof. “A human IgG variant thereof” refers to an antibody that has been modified to be a human IgG when the starting antibody is not a human IgG antibody.
  • the nucleic acid sequence encoding an antibody described herein can be genomic DNA or cDNA, or RNA (e.g. mRNA) which encodes at least one of the variable regions described herein.
  • RNA e.g. mRNA
  • a convenient alternative to the use of chromosomal gene fragments as the source of DNA encoding the V region antigen-binding segment is the use of cDNA for the construction of chimeric immunoglobulin genes, e.g., as reported by Liu et al. (Proc. Natl. Acad. Sci., USA 84:3439 (1987) and J. Immunology 139:3521 (1987), which references are hereby entirely incorporated herein by reference.
  • a cDNA encoding a V region antigen-binding segment able to detect, bind, to or neutralize a IGF-1R antigen can be provided using known methods based on the use of the amino acid sequences provided herein. Because the genetic code is degenerate, more than one codon can be used to encode a particular amino acid (Watson, et al., infra). Using the genetic code, one or more different oligonucleotides can be identified, each of which would be capable of encoding the amino acid.
  • the probability that a particular oligonucleotide will, in fact, constitute the actual XXX-encoding sequence can be estimated by considering abnormal base pairing relationships and the frequency with which a particular codon is actually used (to encode a particular amino acid) in eukaryotic or prokaryotic cells expressing an antibody or fragment.
  • Such “codon usage rules” are disclosed by Lathe, et al., J. Molec. Biol. 183:1 12 (1985). Using the “codon usage rules” of Lathe, a single oligonucleotide, or a set of oligonucleotides, that contains a theoretical “most probable” nucleotide sequence capable of encoding an antibody variable or constant region sequences is identified.
  • variable regions described herein can be combined with any type of constant region including a human constant region or murine constant region.
  • Human genes which encode the constant (C) regions of the antibodies, fragments and regions can be derived from a human fetal liver library, by known methods.
  • Human C regions genes can be derived from any human cell including those which express and produce human immunoglobulins.
  • the human C H region can be derived from any of the known classes or isotypes of human H chains, including gamma, ⁇ , ⁇ , ⁇ or ⁇ , and subtypes thereof, such as G1, G2, G3 and G4.
  • the choice of C H region will be guided by the desired effector functions, such as complement fixation, or activity in antibody-dependent cellular cytotoxicity (ADCC).
  • the C H region is derived from gamma 1 (IgG1), gamma 3 (IgG3), gamma 4 (IgG4), or ⁇ (IgM).
  • the human C L region can be derived from either human L chain isotype, kappa or lambda.
  • the antibody comprises a Fc domain.
  • the Fc domain comprises a mutation to extend the half-life of the antibody.
  • the Fc domain comprises a mutation such as those described in U.S. Pat. No. 7,670,600, which is hereby incorporated by reference in its entirety.
  • the constant region comprises a mutation at position at amino acid residue 428 relative to a wild-type human IgG constant domain, numbered according to the EU numbering index of Kabat.
  • an antibody comprising a mutation that corresponds to residue 428 can have an increased half-life compared to the half-life of an IgG having the wild-type human IgG constant domain.
  • the mutation is a substitution of the native residue with a threonine, leucine, phenylalanine or serine.
  • the antibody further comprises one or more amino acid substitutions relative to the corresponding wild-type human IgG constant domain at one or more of amino acid residues 251-256, 285-290, 308-314, 385-389, and 429-436, numbered according to the Kabat EU numbering index.
  • the specific mutations or substitutions at these positions are described in U.S. Pat. No. 7,670,600, which is hereby incorporated by reference in its entirety.
  • Human immunoglobulin C regions can be obtained from human cells by standard cloning techniques (Sambrook, et al. (Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (1989) and Ausubel et al., eds. Current Protocols in Molecular Biology (1987 1993)).
  • Human C region genes are readily available from known clones containing genes representing the two classes of L chains, the five classes of H chains and subclasses thereof.
  • Chimeric antibody fragments, such as F(ab′) 2 and Fab can be prepared by designing a chimeric H chain gene which is appropriately truncated.
  • a chimeric gene encoding an H chain portion of an F(ab′) 2 fragment would include DNA sequences encoding the CH 1 domain and hinge region of the H chain, followed by a translational stop codon to yield the truncated molecule.
  • the antibodies, murine, human, humanized, or chimeric antibodies, fragments and regions of the antibodies described herein are produced by cloning DNA segments encoding the H and L chain antigen-binding regions of a IGF-1R antigen specific antibody, and joining these DNA segments to DNA segments encoding C H and C L regions, respectively, to produce murine, human or chimeric immunoglobulin-encoding genes.
  • a fused chimeric gene which comprises a first DNA segment that encodes at least the antigen-binding region of non-human origin, such as a functionally rearranged V region with joining (J) segment, linked to a second DNA segment encoding at least a part of a human C region.
  • cDNA encoding the antibody V and C regions the method of producing the antibody according to some of the embodiments described herein involve several steps, as exemplified below: 1. isolation of messenger RNA (mRNA) from the cell line producing an anti-IGF-1R antigen antibody and from optional additional antibodies supplying heavy and light constant regions; cloning and cDNA production therefrom; 2. preparation of a full length cDNA library from purified mRNA from which the appropriate V and/or C region gene segments of the L and H chain genes can be: (i) identified with appropriate probes, (ii) sequenced, and (iii) made compatible with a C or V gene segment from another antibody for a chimeric antibody; 3.
  • mRNA messenger RNA
  • the term “about” is intended to mean ⁇ 5% of the value it modifies. Thus, about 100 means 95 to 105.
  • the antibodies described herein are used to detect the presence of the antigen.
  • the present antibody can be used in any device or method to detect the presence of the antigen.
  • the antibodies provided for herein may also be conjugated to a chemical moiety.
  • the chemical moiety may be, inter alia, a polymer, a radionuclide or a cytotoxic factor. In some embodiments, this can be referred to as an antibody drug conjugate.
  • the chemical moiety is a polymer which increases the half-life of the antibody molecule in the body of a subject.
  • Suitable polymers include, but are not limited to, polyethylene glycol (PEG) (e.g., PEG with a molecular weight of 2 kDa, 5 kDa, 10 kDa, 12 kDa, 20 kDa, 30 kDa or 40 kDa), dextran and monomethoxypolyethylene glycol (mPEG).
  • PEG polyethylene glycol
  • mPEG monomethoxypolyethylene glycol
  • DTPA diethylenetriaminpentaacetic acid
  • chemical moieties include, but are not limited to, anti-mitotics, such as calicheamicins (e.g. ozogamicin), monomethyl auristatin E, mertansine, and the like.
  • Other exmaples include, but are not limited to, biologically active anti-microtubule agents, alkylating agents and DNA minor groove binding agents. Other examples of are provided herein and below.
  • the chemical moiety can be linked to the antibody through a linking group (maleimide), a cleaveble linker, such as a cathepsin cleavable linkers (valine-citrulline), and in some embodiments, one or more spacers (e.g. para-aminobenzylcarbamate).
  • a linking group maleimide
  • a cleaveble linker such as a cathepsin cleavable linkers (valine-citrulline)
  • one or more spacers e.g. para-aminobenzylcarbamate
  • the antibodies and antibody fragments may also be conjugated with fluorescent or chemilluminescent labels, including fluorophores such as rare earth chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanate, phycoerythrin, phycocyanin, allophycocyanin, o-phthaladehyde, fluorescamine, 152 Eu, dansyl, umbelliferone, luciferin, luminal label, isoluminal label, an aromatic acridinium ester label, an imidazole label, an acridimium salt label, an oxalate ester label, an aequorin label, 2,3-dihydrophthalazinediones, biotin/avidin, spin labels and stable free radicals.
  • fluorophores such as rare earth chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanate, phycoerythrin,
  • the antibody molecules may also be conjugated to a cytotoxic factor such as diptheria toxin, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins and compounds (e.g., fatty acids), dianthin proteins, Phytoiacca americana proteins PAPI, PAPII, and PAP-S, Momordica charantia inhibitor, curcin, crotin, Saponaria officinalis inhibitor, mitogellin, restrictocin, phenomycin, and enomycin.
  • a cytotoxic factor such as diptheria toxin, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins and compounds (e.g., fatty acids), dian
  • any method known in the art for conjugating the antibody molecules of the invention to the various moieties may be employed, including those methods described by Hunter, et al., (1962) Nature 144:945; David, etal., (1974) Biochemistry 13:1014; Pain, etal., (1981) J. Immunol. Meth. 40:219; and Nygren, J., (1982) Histochem. and Cytochem. 30:407. Methods for conjugating antibodies are conventional and very well known in the art.
  • the antibodies provided herein can also be incorporated into a chimeric antigen receptor (“CAR”) that can be used, for example, in a CAR-T cell.
  • CAR chimeric antigen receptor
  • the extracellular domain of the CAR can be an antibody as provided for herein.
  • the antibody is in a scFv format.
  • CAR-T cells are a type of treatment in which a patient's T cells are modified so they will attack the cells that are expressing IGF-1R. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cells is added in the laboratory. In some embodiments, the receptor binds to IGF-1R using the binding regions of the antibodies provided for herein.
  • the CAR-T cells comprising the IGF-1R antibody can then be used to treat a condition, such as those provided for herein.
  • antibodies e.g. an anti-IGF-1R antibody
  • the antibody is a recombinant antibody that binds to a IGF-1R protein.
  • the IGF-1R protein is a human IGF-1R protein.
  • the IGF-1R protein that is recognized by the antibodies is in its native conformation (non-denatured) conformation.
  • the antibody does not specifically binds to a denatured IGF-1R protein.
  • the term “recombinant antibody” refers to an antibody that is not naturally occurring.
  • the term “recombinant antibody” refers to an antibody that is not isolated from a human subject.
  • the column that is indicated as the antibody sequence comprises the VH and VL chains of the antibody.
  • the Fc sequence can be modified or substituted for a different Fc region as provided for herein.
  • the antibody can comprise the VH and VL sequence as provided for in the tables provided for herein.
  • the antibody comprises one or more VH, HC, LC, or VL (those sequence that have a constant domain are the complete light or heavy chain) having the following sequences, or a variant thereof:
  • variable light chain as set forth in SEQ ID NO: 13 does not have the C-terminal arginine residue. This is illustrated for example, in the following sequence:
  • the antibody comprises a VL of SEQ ID NO: 98 and a VH of SEQ ID NO: 99. In some embodiments, the antibody comprises a VL of SEQ ID NO: 98 and a VH of SEQ ID NO: 99 with a Fc region comprising the M252Y, S254T, and T256E mutations. In some embodiments, the antibody comprises a VL of SEQ ID NO: 98 and a VH of SEQ ID NO: 99 with a Fc region comprising the M428L and N434S mutations.
  • the heavy chain can be linked to a Fc region, including those with mutations that can affect the half-life of the antibody.
  • Non-limiting mutations in the Fc region are provided for herein.
  • the LC and HC may be illustrated with the VH and VL domains with or without constant regions.
  • the constant regions can be replaced as provided for herein.
  • the VH and VL regions can be used to form an antibody as provided for herein.
  • the VH and the VL sequences can be in any format, including, but not limited to a scFv format where the VH and VL regions are linked with a peptide linker.
  • Examples of peptide linkers that can be used to link various peptides provided for herein include, but are not limited to: (GGGGS) n (SEQ ID NO: 73); (GGGGA) n (SEQ ID NO: 74), or any combination thereof, wherein each n is independently 1-5.
  • an antibody, or antigen binding fragment thereof is provided, wherein the antibody or antibody fragment comprises a peptide selected from the following table.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain CDR having a sequence of SEQ ID NO: 20, 21, 22, 26, 27, 28, 32, 33, 34, 38, 39, 40, 44, 45, 46, 50, 51, 52, 56, 57, 58, 62, 63, or 64.
  • an antibody, or antibody binding fragment thereof comprises a light chain having a LCDR1, a LCDR2, and a LCDR3, wherein the LCDR1 has a sequence of SEQ ID NO: 17, 23, 29, 35, 41, 47, 53, or 59 the LCDR2 has a sequence of SEQ ID NO: 18, 24, 30, 36, 42, 48, 54, or 60 and the LCDR3 has a sequence of SEQ ID NO: 19, 25, 31, 37, 43, 49, 55, 61, or 81.
  • an antibody, or antibody binding fragment thereof comprises a heavy chain having a HCDR1, a HCDR2, and a HCDR3, wherein the HCDR1 has a sequence of SEQ ID NO: 20, 26, 32, 38, 44, 50, 56, or 62 the HCDR2 has a sequence of SEQ ID NO: 21, 27, 33, 39, 45, 51, 57, or 63 and the HCDR3 has a sequence of SEQ ID NO: 22, 28, 34, 40, 46, 52, 58, or 64.
  • an antibody, or antigen binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 23; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 24; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 25; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 26; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 27; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 28; or variants of any of the foregoing.
  • an antibody, or antigen binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 29; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 30; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 31; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 32; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 33; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 34; or variants of any of the foregoing.
  • an antibody, or antigen binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 35; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 36; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 37; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 38; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 39; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 40; or variants of any of the foregoing.
  • an antibody, or antigen binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 41; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 42; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 43; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 44; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 45; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 46; or variants of any of the foregoing.
  • an antibody, or antigen binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 47; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 48; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 49; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 50; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 51; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 52; or variants of any of the foregoing.
  • an antibody, or antigen binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 53; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 54; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 55; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 56; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 57; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 58; or variants of any of the foregoing.
  • an antibody, or antigen binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 59; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 60; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 61; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 63; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 64; or variants of any of the foregoing.
  • an antibody, or antigen binding fragment thereof comprises: (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 35; the light chain CDR2 has the amino acid sequence of SEQ ID NO: 36; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 81; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 38; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 39; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 40; or variants of any of the foregoing.
  • the light chain variable region CDR1 is replaced with any of the other light chain CDR1 sequences. In some embodiments, the light chain variable region CDR2 is replaced with any of the other light chain CDR2 sequences. In some embodiments, the light chain variable region CDR3 is replaced with any of the other light chain CDR3 sequences. In some embodiments, the heavy chain variable region CDR1 is replaced with any of the other light chain CDR1 sequences. In some embodiments, the heavy chain variable region CDR2 is replaced with any of the other light chain CDR2 sequences. In some embodiments, the heavy chain variable region CDR3 is replaced with any of the other light chain CDR3 sequences.
  • the antibody, or antigen binding fragment thereof, or protein is provided that comprises a peptide having a sequence as set forth in any of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 79, or 86, and 2, 4, 6, 8, 10, 12, 14, 16, 80, or 83.
  • the antibody, or antigen binding fragment thereof comprises a sequence of, or a variant of any of the foregoing.
  • the antibody, or antigen binding fragment thereof comprises a sequence of SEQ ID NOs: 69, or a variant of any of the foregoing. In some embodiments, the antibody, or antigen binding fragment thereof, comprises a sequence of SEQ ID NOs: 70, or a variant of any of the foregoing. In some embodiments, the antibody, or antigen binding fragment thereof, comprises a sequence of SEQ ID NOs: 71, or a variant of any of the foregoing. In some embodiments, the antibody, or antigen binding fragment thereof, comprises a sequence of SEQ ID NOs: 72, or a variant of any of the foregoing.
  • an antibody, or antigen binding fragment thereof comprises a V L peptide as set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 79, or 86, or any combination thereof.
  • the V L peptide can comprise a variant of any of these sequences as provided for herein.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide as set forth in SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 80, or 83, or any combination thereof.
  • the V H peptide can comprise a variant of any of these sequences as provided for herein.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the V H peptide comprises a sequence as set forth in SEQ ID NO: 2 and the V L peptide comprises a sequence as set forth in SEQ ID NO: 1.
  • an antibody, or antigen binding fragment thereof comprises a V H peptide and a V L peptide, wherein the V H peptide comprises a sequence as set forth in SEQ ID NO: 4 and the V L peptide comprises a sequence as set forth in SEQ ID NO: 3.
  • an antibody, or antigen binding fragment thereof comprises a LC peptide as set forth in SEQ ID NOs: 1, 3, 5, 7, 9, or 11, or any combination thereof.
  • the LC peptide can comprise a variant of any of these sequences as provided for herein.
  • an antibody, or antigen binding fragment thereof comprises a HC peptide and a LC peptide, wherein the HC peptide comprises a sequence as set forth in SEQ ID NO: 4 and the LC peptide comprises a sequence as set forth in SEQ ID NO: 3.
  • the HC peptide comprising the sequence as set forth in SEQ ID NO: 4 has an additional C terminal lysine (K) residue.
  • an antibody, or antigen binding fragment thereof comprises a HC peptide and a LC peptide, wherein the HC peptide comprises a sequence as set forth in SEQ ID NO: 6 and the LC peptide comprises a sequence as set forth in SEQ ID NO: 5.
  • any of the HC peptides and the LC peptides can be combined with one another.
  • the antibody comprises a heavy and a light chain, wherein the heavy chain comprises a sequence of:
  • the light chain comprises a sequence of SEQ ID NO: 93
  • the antibody comprises a heavy chain and light chain, wherein the heavy chain comprises a sequence of SEQ ID NO: 83 and the and the light chain comprises a sequence of SEQ ID NO: 3.
  • the antibody comprises a VH sequence of SEQ ID NO: 96 and a VL sequence of SEQ ID NO: 13 or SEQ ID NO: 97. In some embodiments, the antibody comprises a VH of SEQ ID NO: 14 and a VL sequence of SEQ ID NO: 97.
  • the antibody or antigen binding fragment thereof or other proteins provided herein are admixed with a pharmaceutically acceptable carrier or excipient. See, e.g., Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, Pa. (1984).
  • Formulations of therapeutic and diagnostic agents may be prepared by mixing with acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions (see, e.g., Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al.
  • the antibodies are diluted to an appropriate concentration in a sodium acetate solution pH 5-6, and NaCl or sucrose is added for tonicity. Additional agents, such as polysorbate 20 or polysorbate 80, may be added to enhance stability.
  • Toxicity and therapeutic efficacy of the antibody compositions, administered alone or in combination with another agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index (LD 50 /ED 50 ).
  • antibodies exhibiting high therapeutic indices are desirable.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration.
  • composition of the invention is administered to a subject in accordance with the Physicians' Desk Reference 2003 (Thomson Healthcare; 57th edition (Nov. 1, 2002)).
  • the mode of administration can vary. Suitable routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, transdermal, or intra-arterial.
  • the antibody or antigen binding fragment thereof can be administered by an invasive route such as by injection.
  • the antibodies or antigen binding fragment thereof, or pharmaceutical composition thereof is administered intravenously, subcutaneously, intramuscularly, intraarterially, intra-articularly (e.g. in arthritis joints), or by inhalation, aerosol delivery.
  • Administration by non-invasive routes e.g., orally; for example, in a pill, capsule or tablet is also within the scope of the present embodiments.
  • the anti-IGF-1R antibody, or antigen binding fragment thereof is administered in combination with at least one additional therapeutic agent, such as, but not limited to any therapeutic used to treat thyroid eye disease.
  • the anti-IGF-1R antibody, or antigen binding fragment thereof is administered in combination with at least one additional therapeutic agent, such as, but not limited to a therapeutic used to treat thyroid eye disease or a condition related to the same.
  • the pharmaceutical compositions may also be administered by infusion.
  • implants and modules form administering pharmaceutical compositions include: U.S. Pat. No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Pat. No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Pat. No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments. Many other such implants, delivery systems, and modules are well known to those skilled in the art.
  • Determination of the appropriate dose is made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects.
  • Important diagnostic measures include those of symptoms of, e.g., the inflammation or level of inflammatory cytokines produced.
  • a biologic that will be used is derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the reagent.
  • chimeric, humanized and fully human antibodies are may be desirable.
  • Antibodies or antigen binding fragments thereof can be provided by continuous infusion, or by doses administered, e.g., daily, 1-7 times per week, weekly, bi-weekly, monthly, bimonthly, quarterly, semiannually, annually etc. Doses may be provided, e.g., intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscular, intracerebrally, intraspinally, or by inhalation. In some embodiments, the antibody is administered every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks. In some embodiments, the antibody is administered every four weeks. In some embodiments, the antibody is administered every five weeks. In some embodiments, the antibody is administered every seven weeks.
  • the antibody is administered every six weeks. In some embodiments, the antibody is administered every eight weeks. In some embodiments, the antibody is administered for at least 21-52 weeks or longer. In some embodiments, the antibody is administered on such a schedule for at least 21 weeks. In some embodiments, the antibody is administered on such a schedule for at least 24 weeks. In some embodiments, the antibody is administered on such a schedule for at least 32 weeks. In some embodiments, the antibody is administered on such a schedule for at least 36 weeks. In some embodiments, the antibody is administered on such a schedule for at least 40 weeks. In some embodiments, the antibody is administered on such a schedule for at least 42 weeks. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) once.
  • the antibody is administered (e.g. infusion or subcutaneous injection) once.
  • the antibody is administered (e.g. infusion or subcutaneous injection) twice. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) three times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) four times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) five times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) six times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) seven times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) eight times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) nine times.
  • the antibody is administered (e.g. infusion or subcutaneous injection) 10 times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) 11 times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) 12 times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) 13 times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) 14 times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) 15 times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) 16 times. In some embodiments, the antibody is administered (e.g. infusion or subcutaneous injection) 17 times.
  • a total weekly dose can be as provided for herein.
  • the total weekly dose is at least 0.05 ⁇ g/kg body weight, more generally at least 0.2 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 10 ⁇ g/kg, 100 ⁇ g/kg, 0.25 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 5.0 mg/ml, 10 mg/kg, 25 mg/kg, 50 mg/kg or more (see, e.g., Yang, et al. (2003) New Engl. J. Med. 349:427-434; Herold, et al. (2002) New Engl. J. Med. 346:1692-1698; Liu, et al. (1999) J. Neurol.
  • the antibody has a serum concentration in the subject of at least, or about, 10 ⁇ g/ml or 20 ⁇ g/ml or 50 ⁇ g/ml, 70 ⁇ g/ml, 75 ⁇ g/ml, 80 ⁇ g/ml, 85 ⁇ g/ml, 90 ⁇ g/ml, 95 ⁇ g/ml, 100 ⁇ g/ml, or 105 ⁇ g/ml at least 1, 2, or 3 weeks after administration.
  • inhibitor or “treat” or “treatment” includes a postponement of development of the symptoms associated with a disorder and/or a reduction in the severity of the symptoms of such disorder.
  • the terms further include ameliorating existing uncontrolled or unwanted symptoms, preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms.
  • the terms denote that a beneficial result has been conferred on a vertebrate subject with a disorder, disease or symptom, or with the potential to develop such a disorder, disease or symptom.
  • therapeutically effective amount refers to an amount of the antibody, or antigen binding fragment thereof, that, when administered alone or in combination with an additional therapeutic agent to a cell, tissue, or subject, is effective to cause a measurable improvement in one or more symptoms of a disease or condition or the progression of such disease or condition.
  • a therapeutically effective dose further refers to that amount of the binding compound sufficient to result in at least partial amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
  • a therapeutically effective dose refers to that ingredient alone.
  • a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • An effective amount of a therapeutic will result in an improvement of a diagnostic measure or parameter by at least 10%; usually by at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably by at least 50%.
  • An effective amount can also result in an improvement in a subjective measure in cases where subjective measures are used to assess disease severity.
  • an amount is a therapeutically effective amount if it is an amount that can be used to treat or ameliorate a condition as provided for herein.
  • subject as used throughout includes any organism, such as an animal, including a mammal (e.g., rat, mouse, dog, cat, rabbit) and, for example, a human.
  • a subject can be also be referred to as a patient.
  • the subject is a subject in need thereof.
  • a subject that is “in need thereof” refers to a subject that has been identified as requiring treatment for the condition that is to be treated and is treated with the specific intent of treating such condition.
  • the conditions can be, for example, any of the conditions described herein.
  • an isolated antibody binds an epitope on a IGF-1R protein, or other protein described herein, and displays in vitro and/or in vivo IGF-1R inhibiting or therapeutic activities
  • the antibodies or antigen binding fragments thereof, capable of inhibiting IGF-1R function are suitable both as therapeutic agents for treating IGF-1R-associated conditions in humans and animals. These conditions include thyroid eye disease. According, methods of treating such conditions are also provided, wherein the method comprises administering an antibody, or antigen binding fragment thereof, to the subject with such a condition.
  • the antibodies used are compatible with the recipient species such that the immune response to the MAbs does not result in an unacceptably short circulating half-life or induce an immune response to the MAbs in the subject.
  • Treatment of individuals may comprise the administration of a therapeutically effective amount of the antibodies described herein.
  • the antibodies can be provided in a kit, such as those provided herein.
  • the antibodies can be used or administered alone or in admixture with another therapeutic, analgesic, or diagnostic agent, such as provided for herein.
  • another therapeutic, analgesic, or diagnostic agent such as provided for herein.
  • the dosage of administered agent will vary depending upon such factors as the patient's age, weight, height, sex, general medical condition, previous medical history, etc.
  • An antibody capable treating a condition associated with IGF-1R activity or use to treat a IGF-1R related pathology, is intended to be provided to subjects in an amount sufficient to affect a reduction, resolution, or amelioration in the IGF-1R related symptom or pathology.
  • a pathology includes, thyroid eye disease and the like
  • methods of treating a subject with a IGF-1R mediated disorder comprise administering a pharmaceutical composition comprising an antibody, or antigen binding fragment thereof, as provided herein.
  • the disorder is thyroid eye disease.
  • the antibodies, or antigen binding fragments thereof can be administered with other therapeutics. These can be administered simultaneously or sequentially.
  • the antibodies, or antigen binding fragments thereof may be used to treat thyroid eye disease. In some embodiments, the antibodies, or antigen binding fragments thereof, may be used to treating or reduce the severity of, thyroid-associated ophthalmopathy (TAO), or a symptom thereof.
  • TAO thyroid-associated ophthalmopathy
  • methods or uses are provided to reduce proptosis in an eye in a subject with thyroid-associated ophthalmopathy (TAO).
  • TAO thyroid-associated ophthalmopathy
  • the subject is a subject how has previously been treated with a different antibody than those provided herein.
  • CAS Clinical Activity Score
  • TAO thyroid-associated ophthalmopathy
  • methods or uses are provided to reduce proptosis by at least 2 mm and b) reducing the clinical activity score (CAS) in a subject with thyroid-associated ophthalmopathy (TAO).
  • CAS clinical activity score
  • TEO thyroid-associated ophthalmopathy
  • Clinical Activity Score refers to the protocol described and scored according to Table 2. According to this protocol, one point is given for the presence of each of the parameters assessed in the Table below. The sum of all points defines clinical activity and provides the CAS, where 0 or 1 constitutes inactive disease and 7 severe active ophthalmopathy.
  • Parameters for calculating Clinical Activity Score Item No. Parameter 1 Spontaneous retrobulbar pain 2 Pain on attempted eye movements (upward, side to side, and downward gazes; sometimes termed gaze evoked orbital pain 3 Eyelid swelling 4 Eyelid erythema (redness) 5 Conjunctival redness 6 Chemosis (swelling/edema of the conjunctiva) 7 Swelling of caruncle or pila
  • the CAS consists of seven components: spontaneous retrobulbar pain, pain on attempted eye movements (upward, side-to-side, and downward gazes), conjunctival redness, redness of the eyelids, chemosis, swelling of the caruncle/plica, and swelling of the eyelids.
  • Each component is scored as present (1 point) or absent (0 points).
  • the score at each efficacy assessment is the sum of all items present; giving a range of 0-7, where 0 or 1 constitutes inactive disease and 7 severe active ophthalmopathy. A change of >2 points is considered clinically meaningful.
  • Item 1 spontaneous orbital pain could be a painful, or oppressive feeling on, or behind, the globe. This pain may be caused by the rise in intraorbital pressure, when the orbital tissues volume increases through excess synthesis of extracellular matrix, fluid accumulation, and cellular infiltration and expansion.
  • Item 2 gaze evoked orbital pain, could be pain in the eyes when looking, or attempting to look, up, down or sideways, i.e., pain with upward, downward, or lateral eye movement, or when attempting eye movement. This kind of pain could arise from the stretching of the inflamed muscle(s), especially on attempted upgaze. The ‘stretching pain’ cannot be provoked by digital pressing on the eyeball, as would be expected if it were a manifestation of the raised intraorbital pressure. Both kinds of pain can be reduced after anti-inflammatory treatment. These kinds of pain are therefore considered to be directly related to autoimmune inflammation in the orbit and thus useful in assessing TAO activity.
  • TAO Swelling in TAO is seen as chemosis (edema of the conjunctiva), item no. 6 in Table 1, and swelling of the caruncle and/or plica semilunaris. Both are signs of TAO activity. Swollen eyelids can be caused by edema, fat prolapse through the orbital septum, or fibrotic degeneration. In addition to swelling, other symptoms indicative of active TAO include redness and/or pain of the conjunctiva, eyelid, caruncle and/or plica semilunaris.
  • the subject who is treated has the proptosis is reduced by at least 2 mm. In some embodiments, the subject who is treated has the proptosis is reduced by at least 3 mm. In some embodiments, the subject who is treated has the proptosis is reduced by at least 4 mm.
  • methods off treating or reducing the severity of thyroid-associated ophthalmopathy (TAO) in a subject wherein the treatment with said antibody (i) reduces proptosis by at least 2 mm in an eye; (ii) is not accompanied by a deterioration of 2 mm or more in the other (or fellow eye); and (iii) reduces the CAS in said subject to either one (1) or zero (0).
  • TAO thyroid-associated ophthalmopathy
  • methods of improving the quality of life in a subject with thyroid-associated ophthalmopathy are provided.
  • TAO thyroid-associated ophthalmopathy
  • the quality of life is measured by the Graves' Ophthalmopathy Quality of Life (GO-QoL) assessment, or either the Visual Functioning or Appearance subscale thereof.
  • the treatment results in an improvement of greater than or equal to 8 points on the GO-QoL.
  • the treatment results in an improvement on the Functioning subscale of the GO-QoL.
  • the treatment results in an improvement on the Appearance subscale of the GO-QoL.
  • the severity of the disease can be measured in the following non-limiting embodiments.
  • the distance between the lid margins are measured (in mm) with the patient looking in the primary position, sitting relaxed, and with distant fixation.
  • the measure/evaluation is either “absent/equivocal,” “moderate,” or “severe.” Redness of the eyelids is either absent or present. Redness of the conjunctivae is either absent or present. In some embodiments, conjunctival edema is either absent or present. In some embodiments, inflammation of the caruncle or plica is either absent or present. Exophthalmos is measured in millimeter using the same Hertel exophthalmometer and same intercanthal distance for an individual patient.
  • eye muscle involvement the ductions are measured in degrees. Corneal involvement is either absent/punctate or keratopathy/ulcer.
  • optic nerve involvement i.e., best-corrected visual acuity, color vision, optic disc, relative afferent pupillary defect, the condition is either absent or present.
  • visual fields are checked if optic nerve compression is suspected.
  • Mild Thyroid Eye Disease Patients whose features of thyroid eye disease have only a minor impact on daily life insufficient to justify immunosuppressive or surgical treatment. They usually have only one or more of the following: minor lid retraction ( ⁇ 2 mm), mild soft tissue involvement, exophthalmos ⁇ 3 mm above normal for race and gender, transient or no diplopia, and corneal exposure responsive to lubricants.
  • a patient can be characterized by Graves Ophthalmopathy Quality of Life (GO-QoL) score.
  • GO-QoL Graves Ophthalmopathy Quality of Life
  • proptosis or exophthalmos
  • CAS GO quality of life
  • This questionnaire is designed to determine the improved quality of life after treatment with a method disclosed herein.
  • questionnaire may determine the decreased or lack of side effects after being treated with an antibody, or an antigen binding fragment thereof, according to a method disclosed herein as compared to treatment with glucocorticoids.
  • the GO-QoL is a 16-item self-administered questionnaire divided into 2 subsets and used to assess the perceived effects of TED by the subjects on (i) their daily physical activity as it relates to visual function, and (ii) psychosocial functioning. Quality of life is evaluated with the use of the GO QoL questionnaire.
  • the GO-QoL questionnaire [C. B. Terwee et al, 1998] is completed on Day 1 and Weeks 6, 12, and 24 (or PW) during the Treatment Period, and at Months 7 and 12 (or PW) during the Follow-Up Period.
  • the methods comprise administering an antibody, such as those provided herein.
  • the antibody is administered at a dosage of about 1 mg/kg to about 5 mg/kg antibody as a first dose.
  • the antibody is administered at a dosage of about 5 mg/kg to about 10 mg/kg antibody as a first dose.
  • the antibody is administered at a dosage of about 5 mg/kg to about 20 mg/kg antibody in subsequent doses.
  • the antibody is administered in the following amounts: about 10 mg/kg antibody as a first dose; and about 20 mg/kg antibody in subsequent doses.
  • the subsequent doses are administered every three weeks for at least 21 weeks.
  • the antibody is administered in a pharmaceutical composition, such as those provided herein.
  • the pharmaceutical composition further comprises one or more pharmaceutically active compounds for the treatment of TAO.
  • the pharmaceutical composition further comprises corticosteroids; rituximab or other anti-CD20 antibodies; tocilizumab or other anti-IL-6 antibodies; or selenium, infliximab or other anti-TNFalpha antibodies or a thyroid-stimulating hormone receptor (TSHR) inhibitor.
  • TSHR thyroid-stimulating hormone receptor
  • the method provided herein comprise administering to a subject an antibody, or an antigen binding fragment thereof, that specifically binds to and inhibits IGF-IR.
  • the antibody is as provided herein.
  • Kits are also provided which are useful for carrying out embodiments described herein.
  • the present kits comprise a first container containing or packaged in association with the above-described antibodies.
  • the kit may also comprise another container containing or packaged in association solutions necessary or convenient for carrying out the embodiments.
  • the containers can be made of glass, plastic or foil and can be a vial, bottle, pouch, tube, bag, etc.
  • the kit may also contain written information, such as procedures for carrying out the embodiments or analytical information, such as the amount of reagent contained in the first container means.
  • the container may be in another container apparatus, e.g. a box or a bag, along with the written information.
  • kits for detecting IGF-1R protein in a biological sample includes a container holding one or more antibodies which binds an epitope of IGF-1R protein and instructions for using the antibody for the purpose of binding to IGF-1R protein to form an immunological complex and detecting the formation of the immunological complex such that the presence or absence of the immunological complex correlates with presence or absence of IGF-1R protein in the sample.
  • containers include multiwell plates which allow simultaneous detection of IGF-1R protein in multiple samples.
  • antibodies that bind to a IGF-1R protein are provided.
  • the antibody is isolated.
  • the antibody binds specifically.
  • the antibody binds to a IGF-1R protein that is properly folded.
  • the antibody is specific for a specific IGF-1R conformational state (open or closed).
  • the antibody binds to a IGF-1R protein in a cell membrane.
  • the antibody binds to a IGF-1R protein that is in a cell membrane in an intact cell.
  • the antibody inhibits or neutralizes the function of a IGF-1R protein.
  • the term “neutralize” means that the activity or function of the protein is inhibited.
  • the inhibition can be complete or partial.
  • the activity or function of the protein is inhibited at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99%.
  • the percent inhibition can be based upon the function or activity of the protein in the absence of the antibody.
  • the antibody inhibits the glucose transport facilitated by IGF-1R.
  • the antibody inhibits the internalization of the IGF-1R protein.
  • the antibody comprises a sequence as provided for herein or antigen binding fragment thereof. In some embodiments, the antibody comprises a heavy chain CDR or an antigen binding fragment thereof described herein. The heavy chain may be one or more of the heavy chains described herein. In some embodiments, the antibody comprises a light chain, or an antigen binding fragment thereof as described herein
  • methods of treating, inhibiting or ameliorating a IGF-1R, associated pathology comprise administering an antibody described herein or a pharmaceutical composition described herein to a subject to treat, inhibit or ameliorate a IGF-1R associated pathology.
  • the pathology is as described herein.
  • methods of detecting the presence or absence of a IGF-1R in a sample comprising contacting a sample with one or more antibodies described herein detecting the binding to a IGF-1R antigen by the antibody.
  • the detection of the binding indicates the presence IGF-1R antigen; or the absence of the detection of the binding to the IGF-1R antigen indicates the absence of the IGF-1R antigen.
  • the detecting can be done with any known method, such as using a biosensor, ELISA, sandwich assay, and the like.
  • the method comprises detecting the presence of the protein in non-denaturing conditions.
  • the non-denaturing conditions can be used so that the protein of interest is detected in its native, or properly folded form.
  • methods of monitoring internalization of IGF-1R from the surface of a cell comprising contacting the cell with an anti-IGF-1R antibody as provided herein and detecting the presence of IGF-1R in the cell or on the surface of the cell.
  • the differences in cell surface expression can be measured and the internalization can be monitored and measured. This can be used, for example, to measure the effect of another molecule, such as a test agent, to modulate internalization of IGF-1R protein.
  • the antibodies provided for herein can be used to identify test agents that modulate (increase or decrease) the internalization of IGF-1R protein.
  • methods of inhibiting IGF-1 stimulated receptor phosphorylation on a cell comprise contacting the cell with an antibody as provided for herein, or a pharmaceutical composition comprising the same. In some embodiments, the contacting comprises administering to a subject the antibody or a pharmaceutical composition comprising the same. In some embodiments, the cell is a cell in the eye. In some embodiments, the subject has or is at risk of thyroid eye disease (TED). In some embodiments, the antibody has an IC50 of less than, or equal to, about 0.2 nm, 0.15 nm, 0.10 nm, 0.09 nm.
  • methods of treating thyroid eye disease in a subject comprising administering an antibody as provided for herein, or a pharmaceutical composition comprising the same to the subject, wherein the antibody has a serum concentration in the subject of at least, or about, 70 ⁇ g/ml, 75 ⁇ g/ml, 80 ⁇ g/ml, 85 ⁇ g/ml, 90 ⁇ g/ml, 95 ⁇ g/ml, 100 ⁇ g/ml, or 105 ⁇ g/ml at least 1, 2, or 3 weeks after administration.
  • the serum concentration is measured after one, two or three doses of the antibody, or the pharmaceutical composition comprising the same, are administered to the subject.
  • embodiments provided herein also include, but are not limited to:
  • Blockage of IGF-1 stimulation is measured by secretion of hyaluronan, in the presence of IGF-1R antibodies VRDN-2700, VRDN-03100, VRDN-02100, VRDN-02200, VRDN-02300, VRDN-02400, VRDN-02500, VRDN-01100, VRDN-02600, and VRDN-02301, all of which are disclosed herein.
  • Immunoglobulins are purified from the sera of patients with Graves' ophthalmopathy (GO) and tested for their ability to activate TSHR and/or IGF-1R directly, and TSHR/IGF-1R cross talk in primary cultures of GO fibroblasts.
  • GO Graves' ophthalmopathy
  • IGF-1R inhibitory antibodies such as those provided for herein, including but not limited to, VRDN-2700, VRDN-03100, VRDN-02100, VRDN-02200, VRDN-02300, VRDN-02400, VRDN-02500, VRDN-01100, VRDN-02600, and VRDN-02301, all of which are disclosed herein, are provided to the subjects.
  • the number of infusions is individualized for each subject and is based on the investigator's clinical judgment.
  • the Day 1 Visit occurs within 14 days after the final visit of the prior trial. Visit windows are ⁇ 1 day for Weeks 1 and 4, ⁇ 3 days for Weeks 3, 6, 9, 12, 15, 18, 21, and 24.
  • the follow-up period is meant for subjects who were proptosis non-responders in the prior trial only; subjects who relapsed in the prior trial did not participate in the Follow-Up Period. Visit windows during the Follow-up period are ⁇ 7 days.
  • Treatment Period is 24 weeks (6 months), during which 8 infusions of teprotumumab are administered.
  • Subjects who are proptosis non-responders are scheduled to participate in a 6-month Follow-Up Period in this extension study; subjects who relapsed in the lead-in study and are retreated in this extension study will not participate in the Follow-Up Period.
  • Efficacy assessments are performed for both eyes at each assessment time point.
  • the “study eye” i.e., the more severely affected eye
  • Both eyes are assessed for efficacy but the study eye is used to assess the primary outcome measure.
  • Efficacy is assessed by proptosis (measured as exophthalmos evaluation of the Clinical Measures of Severity using a Hertel instrument for consistency in measurement), CAS (7-item scale), diplopia (measured as part of the Clinical Measures of Severity) and Clinical Measures of Severity (including motility restriction assessments).
  • Safety is assessed via AE and concomitant medication use monitoring, immunogenicity testing, physical and ophthalmic examinations, vital signs, clinical safety laboratory evaluations (complete blood count, chemistry (including thyroid panel and HbA1C), and urinalysis), pregnancy testing (if applicable), and electrocardiograms (ECG).
  • DSMB Data Safety Monitoring Board
  • Proptosis is measured for each eye on Day 1 and Weeks 6, 12, 18, and 24 (or premature withdrawal (PW)) during the Treatment Period, and at Months 7, 9, and 12 (or PW) during the Follow-Up Period. Measurements is recorded on the Clinical Measures of Severity eCRF under exophthalmo s.
  • the antibodies are found to be effective in treating thyroid eye disease and also improving quality of life as provided for herein.
  • Cynomolgus monkeys were dosed with an antibody comprising the CDRs of VRDN-2700 with the YTE mutation in the Fc domain in an amount of 10 mg/kg by either intravenous or subcutaneous route, and samples were collected at 0.5 hr, 2 hr, 8 hr and days 1, 3, 7, 10, 14, 21, and 28 time points for PK analysis by ELISA. Teprotumumab was also administered at 10 mg/kg IV as a comparator. The results illustrated in FIG. 1 demonstrate that the antibody had a significantly higher PK as compared to Teprotumumab.
  • VRDN-1100 is an antagonist antibody to insulin-like growth factor-1 receptor (IGF-1R) under development for treatment of Thyroid Eye Disease (TED).
  • TED is driven by Thyroid Stimulating Hormone Receptor (TSHR) agonistic autoantibodies and crosstalk between TSHR and IGF-1R.
  • TSHR Thyroid Stimulating Hormone Receptor
  • TED is characterized by recruitment of fibrocytes that express IGF-1R and TSHR in orbital tissues, where they mediate deposition of hyaluronan and expansion of orbital muscle and fatl.
  • IGF-1R antagonism has been found to reverse this orbital tissue expansion and robustly relieve symptoms in TED patients2.
  • VRDN-1100 is a humanized monoclonal antibody targeting IGF-1R. The IGF-1R binding and antagonist characteristics of VRDN-1100 was analyzed.
  • SPR Surface plasmon resonance
  • VRDN-1100 was immobilized on a chip surface by amine coupling and used to capture IGF-1R-ECD, after which teprotumumab was flowed over the chip.
  • A549 human lung adenocarcinoma cells or primary human ocular choroid fibroblasts (HOCF) were incubated with varying concentrations of VRDN-1100 or teprotumumab.
  • a single dose 50 nM IgG1 isotype control was used as negative control. Unbound antibody was removed by washing, and the cells were incubated with an Alexa Fluor 488-goat anti-human antibody and a cell impermeable dye to gate live cells.
  • the median fluorescence intensity (MFI) of viable cells was measured by flow cytometry and the data were analyzed using FlowJo software. Dose curves were fitted using a non-linear regression model; log(agonist) vs response-variable slope (four parameters).
  • HOCF cells were incubated with directly labeled antibodies or IgG isotype control at 10 ug/mL.
  • the median fluorescence intensity (MFI) was measured by flow cytometry and the data were analyzed using FlowJo software.
  • Antagonism Serum starved A549 or HOCF cells were preincubated with varying concentrations of test antibody for one hour at 37° C., then stimulated by addition of 100 ng/mL (A549s) or 200 ng/mL (HOCFs) IGF-1 for 7 minutes at 37° C. Phosphorylated IGF-1R (pIGF1R) of biological duplicates was measured using the R&D Systems pIGF-1R ELISA according to the manufacturer's protocol and pIGF-1R concentrations were normalized to the lowest test antibody concentration. Dose curves were fit using a non-linear regression model; log(inhibitor) vs response-variable slope (four parameters)).
  • FIG. 2A illustrates that increasing concentrations of IGF-1R-ECD bound to anti-FC captured VRDN-1100 or teprotumumab reveal a stepwise increase in SPR signal, enabling a global fit to a binding model. Following IGF-1R washout, VRDN-1100 shows a more sustained binding interaction.
  • FIG. 2B illustrates IGF-1R-ECD bound robustly to immobilized VRDN-1100. Teprotumumab showed no binding to the IGF-1R:VRDN-1100 complex, suggesting that teprotumumab and VRDN-1100 have overlapping epitopes. The data is also illustrated in the table as shown in FIG. 2B .
  • 3F illustrates that VRDN-1100, VRDN-2700 with a M252Y, S254T, and T256E mutation in the Fc domain, and teprotumumab cause comparable levels of internalization ( ⁇ 50%) measured by reduction in membrane IGF-1R receptor levels at 37° C vs 4° C.
  • the left most bars are the isotype control
  • the second to left set of bars are teprotumumab
  • the second from the right set of bars are VRDN-1100
  • the right most set of bars are VRDN-2700.
  • CD34+,Thy-1+ orbital fibroblasts are implicated in extracellular matrix deposition and pathogenic fibrosis in TED5.
  • HOFCs were shown to express (Panel A) IGF-1R and (Panel B) TSHR, as well as (Panel C) CD34 and Thy-1, which demonstrates their ability to be used as an in vitro model system for IGF-1R function in TED.
  • FIG. 5A and FIG. 5B illustrate VRDN-1100 binding to HOCF cells, which was assessed by flow cytometry and found to have largely similar binding as teprotumumab at three different concentrations.
  • VRDN-1100 Is A Sub-Nanomolar IGF-1R Antagonist.
  • VRDN-2700 which has a M252Y, S254T, and T256E mutation in the Fc domain is a novel anti-IGF-1R antibody incorporating half-life extension modifications in its Fc region as described herein and can be used for the treatment of Thyroid Eye Disease (TED).
  • TED Thyroid Eye Disease
  • the pharmacokinetic (PK) parameters of VRDN-2700 with such Fc mutations was measured in cynomolgus monkeys to the marketed IGF-1R antibody, teprotumumab, and a PK model was constructed to project potential human dosing regimens.
  • TED is an autoimmune condition most commonly associated with Graves' disease and hyperthyroidism but can also be found in patients who are euthyroid or hypothyroid. Orbitopathy in TED is driven by Thyroid Stimulating Hormone Receptor (TSHR) agonistic autoantibodies and crosstalk between TSHR and IGF-1R. Pathological remodeling of the orbit and periorbital tissues results in varied presentations which may include dry eyes, increased lacrimation, local irritation, eyelid retraction and eventually proptosis, diplopia, and optic nerve compression, with ensuing vision loss.
  • TSHR Thyroid Stimulating Hormone Receptor
  • the underlying pathology of TED is the activation of an inflammatory cascade within the orbit, primarily due to recruitment of fibrocytes and immune cells.
  • Over-expression of IGF-1R has been demonstrated within the orbit of TED patients, and it has been surmised that IGF-1R inhibitory antibodies may disrupt the IGF-1R and TSHR cross-talk and dampen the inflammatory cascade. Indeed, IGF-1R antagonism has been demonstrated to robustly relieve much of the inflammatory symptomology that affects TED patients.
  • VRDN-2700 is a monoclonal antibody that inhibits IGF-1 mediated signaling via IGF-1R with subnanomolar potency and incorporates clinically validated Fc modifications (M252Y, S254T, and T256E) to extend half-life. This antibody was found to have a more favorable PK profile with the potential for a less burdensome treatment paradigm for patients than conventional IgG therapeutic antibodies.
  • VRDN-2700 with the Fc mutations was administered to cynomolgus monkeys by 30 min intravenous (IV) infusions at 2, 10, and 50 mg/kg, and by subcutaneous (SC) injection at 2 and 10 mg/kg. Teprotumumab at 10 mg/kg was likewise administered by 30 min IV infusion.
  • VRDN-2700 and teprotumumab levels in serum were measured using a human IgG specific ELISA assay. Data were analyzed using the WinNonlin non-compartmental model. A semi-mechanistic model incorporating target mediated drug disposition was constructed using available human and cynomolgus data. The data is illustrated below.
  • TMDD target mediated drug disposition
  • Model simulations predict that dosing of VRDN-2700 at 10 mg/kg every 3 weeks or 20 mg/kg every 6 weeks will result in Cmin of >100 ug/mL, similar to the approved teprotumumab regimen (10 mg/kg first dose followed by seven 20 mg/kg doses q3w).
  • the 10 mg/kg q3w regimen will with lower Cmax values.
  • a longer dosing interval would increase patient convenience and reduce treatment costs, while lower dose and Cmax values may potentially mitigate toxicities.
  • the model predicts that weekly subcutaneous dosing of VRDN-2700 at 300 mg fixed dose could achieve a steady-state Cmin of ⁇ 130 ug/mL, enabling at home self-administration.
  • VRDN-2700 In the event that lower Cmin values are efficacious, subcutaneous administration of VRDN-2700 at 300 mg fixed dose every other week is predicted to achieve ⁇ 50 ug/mL steady-state Cmin levels. Taken together, the extended half-life of VRDN-2700 is predicted to provide patients with a wider range of options for more convenient dosing interval and route of administration.
  • VRDN-2700 was compared to other antibodies having mutations in the Fc domain, such as the L/S mutations that are described herein.
  • the yield for the antibody with the YTE mutation in the Fc domain was approximately 80% higher than the yield of a similar antibody except that it has a L/S mutation.
  • the YTE version had fewer lower molecular weight species as compared to the LS version.
  • the YTE antibody has fewer impurities and is a more homogenous composition, which provides advantages over the antibody with the LS mutation.
  • the LS mutant formed more aggregates when being purified on a cation exchange column as compared VRDN-2700.
  • the aggregation of the LS mutant would cause significant manufacturing issues, which were not observed for VRDN-2700. Therefore, this difference in the Fc mutants for this antibody could not have been predicted or expected and leads to significant and unexpected advantages for the antibody that is referenced herein as VRDN-2700.
  • VRDN-2700 The prolonged half-life of VRDN-2700 (YTE) demonstrates that it can be used in a convenient SC injection, or as an IV infusion requiring fewer and/or less frequent treatments vs. conventional therapeutic IgG antibodies and has superior properties as compared to other Fc mutant versions of the same antibody (same variable regions).
  • the binding of VRDN-1100 with the Fc YTE mutations in the heavy chain (SEQ ID NO: 94) or C22S mutation and Fc YTE mutations in the heavy chain (SEQ ID NO: 95) to IGF-1R was evaluated in a cell based binding assay (A549 cells).
  • the light chains have a sequence of SEQ ID NO: 93.
  • the YTE Fc mutatant version of VRDN1100 was found to bind to A549 cells with an EC50 of 0.30 nm and the C22S and Fc YTE mutant had an EC50 of 0.36 nm.
  • the antibodies were also evaluated for their ability to inhibit IGF-1R autophosphorylation.
  • the YTE only mutant had an IC50 of 0.40 nm and the C22S plus YTE mutations had an IC50 of 0.37 nm.
  • the antibodies were found to be able to both bind to IGF-1R and inhibit its autophosphorylation.
  • a mutant of VRDN-1100 with a C22S mutation in the heavy chain (SEQ ID NO: 96) and a VL comprising a sequence of SEQ ID NO: 97 was evaluated for its binding to IGF-1R in a surface plasma resonance assay. Using this assay, the antibody was found to bind to IGF-1R with a k a (1/Ms) of 1.04 ⁇ 10 5 , a k d (1/s) of 2.18 ⁇ 10 ⁇ 5 , and a K D (M) of 2.10 ⁇ 10 ⁇ 10 at a pH of 7.4.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
US17/501,362 2020-10-14 2021-10-14 Compositions and methods for treatment of thyroid eye disease Abandoned US20220267450A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
US17/501,362 US20220267450A1 (en) 2020-10-14 2021-10-14 Compositions and methods for treatment of thyroid eye disease
US17/822,978 US11548951B1 (en) 2020-10-14 2022-08-29 Compositions and methods for treatment of thyroid eye disease
US18/150,514 US12404335B2 (en) 2020-10-14 2023-01-05 Compositions and methods for treatment of thyroid eye disease
US18/364,620 US20240043546A1 (en) 2020-10-14 2023-08-03 Compositions and methods for treatment of thyroid eye disease
US18/942,051 US12595309B2 (en) 2020-10-14 2024-11-08 Compositions and methods for treatment of thyroid eye disease
US19/242,725 US12600788B2 (en) 2020-10-14 2025-06-18 Compositions and methods for treatment of thyroid eye disease
US19/242,715 US20250313639A1 (en) 2020-10-14 2025-06-18 Compositions and methods for treatment of thyroid eye disease

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US202063091839P 2020-10-14 2020-10-14
US202163201978P 2021-05-21 2021-05-21
US202163260130P 2021-08-10 2021-08-10
US202163261742P 2021-09-28 2021-09-28
US17/501,362 US20220267450A1 (en) 2020-10-14 2021-10-14 Compositions and methods for treatment of thyroid eye disease

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US17/822,978 Continuation US11548951B1 (en) 2020-10-14 2022-08-29 Compositions and methods for treatment of thyroid eye disease

Publications (1)

Publication Number Publication Date
US20220267450A1 true US20220267450A1 (en) 2022-08-25

Family

ID=81208791

Family Applications (10)

Application Number Title Priority Date Filing Date
US17/501,362 Abandoned US20220267450A1 (en) 2020-10-14 2021-10-14 Compositions and methods for treatment of thyroid eye disease
US17/450,872 Abandoned US20220235137A1 (en) 2020-10-14 2021-10-14 Compositions and methods for treatment of thyroid eye disease
US17/501,430 Abandoned US20220267451A1 (en) 2020-10-14 2021-10-14 Compositions and methods for treatment of thyroid eye disease
US17/724,639 Abandoned US20220275096A1 (en) 2020-10-14 2022-04-20 Compositions and methods for treatment of thyroid eye disease
US17/822,978 Active US11548951B1 (en) 2020-10-14 2022-08-29 Compositions and methods for treatment of thyroid eye disease
US18/150,514 Active 2042-10-09 US12404335B2 (en) 2020-10-14 2023-01-05 Compositions and methods for treatment of thyroid eye disease
US18/364,620 Pending US20240043546A1 (en) 2020-10-14 2023-08-03 Compositions and methods for treatment of thyroid eye disease
US18/942,051 Active US12595309B2 (en) 2020-10-14 2024-11-08 Compositions and methods for treatment of thyroid eye disease
US19/242,715 Pending US20250313639A1 (en) 2020-10-14 2025-06-18 Compositions and methods for treatment of thyroid eye disease
US19/242,725 Active US12600788B2 (en) 2020-10-14 2025-06-18 Compositions and methods for treatment of thyroid eye disease

Family Applications After (9)

Application Number Title Priority Date Filing Date
US17/450,872 Abandoned US20220235137A1 (en) 2020-10-14 2021-10-14 Compositions and methods for treatment of thyroid eye disease
US17/501,430 Abandoned US20220267451A1 (en) 2020-10-14 2021-10-14 Compositions and methods for treatment of thyroid eye disease
US17/724,639 Abandoned US20220275096A1 (en) 2020-10-14 2022-04-20 Compositions and methods for treatment of thyroid eye disease
US17/822,978 Active US11548951B1 (en) 2020-10-14 2022-08-29 Compositions and methods for treatment of thyroid eye disease
US18/150,514 Active 2042-10-09 US12404335B2 (en) 2020-10-14 2023-01-05 Compositions and methods for treatment of thyroid eye disease
US18/364,620 Pending US20240043546A1 (en) 2020-10-14 2023-08-03 Compositions and methods for treatment of thyroid eye disease
US18/942,051 Active US12595309B2 (en) 2020-10-14 2024-11-08 Compositions and methods for treatment of thyroid eye disease
US19/242,715 Pending US20250313639A1 (en) 2020-10-14 2025-06-18 Compositions and methods for treatment of thyroid eye disease
US19/242,725 Active US12600788B2 (en) 2020-10-14 2025-06-18 Compositions and methods for treatment of thyroid eye disease

Country Status (18)

Country Link
US (10) US20220267450A1 (https=)
EP (1) EP4228616A4 (https=)
JP (2) JP2023545520A (https=)
KR (1) KR20230124550A (https=)
CN (3) CN116583273B (https=)
AU (1) AU2021360889A1 (https=)
CA (2) CA3195512A1 (https=)
CL (1) CL2023001052A1 (https=)
CO (1) CO2023005996A2 (https=)
CR (1) CR20230204A (https=)
DO (1) DOP2023000073A (https=)
EC (1) ECSP23034914A (https=)
IL (1) IL302068A (https=)
JO (1) JOP20230075A1 (https=)
MX (1) MX2023004280A (https=)
PE (1) PE20231202A1 (https=)
TW (2) TW202229350A (https=)
WO (2) WO2022081799A1 (https=)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230002495A1 (en) * 2020-10-14 2023-01-05 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
US12404337B2 (en) 2021-08-10 2025-09-02 Viridian Therapeutics, Inc. Compositions, doses, and methods for treatment of thyroid eye disease

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115820651B (zh) * 2022-12-06 2025-03-11 中南大学湘雅三医院 一种靶向cd34阳性眼眶成纤维细胞的核酸适配体及其应用
TW202519262A (zh) 2023-09-06 2025-05-16 美商維里迪恩醫療股份有限公司 抗ｉｇｆ－１ｒ抗體之醫藥組合物
WO2025136985A1 (en) * 2023-12-17 2025-06-26 Viridian Therapeutics, Inc. Compositions, doses, and methods for treatment of thyroid eye disease
WO2025151496A1 (en) * 2024-01-09 2025-07-17 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
WO2025151492A1 (en) * 2024-01-09 2025-07-17 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
WO2026044000A1 (en) * 2024-08-20 2026-02-26 Ethyreal Bio, Inc. Multispecific antibodies and methods of use thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220235137A1 (en) * 2020-10-14 2022-07-28 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease

Family Cites Families (149)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4447233A (en) 1981-04-10 1984-05-08 Parker-Hannifin Corporation Medication infusion pump
US4439196A (en) 1982-03-18 1984-03-27 Merck & Co., Inc. Osmotic drug delivery system
US4447224A (en) 1982-09-20 1984-05-08 Infusaid Corporation Variable flow implantable infusion apparatus
US4487603A (en) 1982-11-26 1984-12-11 Cordis Corporation Implantable microinfusion pump system
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4596556A (en) 1985-03-25 1986-06-24 Bioject, Inc. Hypodermic injection apparatus
EP0281604B1 (en) 1986-09-02 1993-03-31 Enzon Labs Inc. Single polypeptide chain binding molecules
US5260203A (en) 1986-09-02 1993-11-09 Enzon, Inc. Single polypeptide chain binding molecules
US4790824A (en) 1987-06-19 1988-12-13 Bioject, Inc. Non-invasive hypodermic injection device
US4941880A (en) 1987-06-19 1990-07-17 Bioject, Inc. Pre-filled ampule and non-invasive hypodermic injection device assembly
US4949778A (en) 1987-12-16 1990-08-21 Kawasaki Steel Corporation Immersion nozzle for continuous casting
DE3920358A1 (de) 1989-06-22 1991-01-17 Behringwerke Ag Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung
US5064413A (en) 1989-11-09 1991-11-12 Bioject, Inc. Needleless hypodermic injection device
US5312335A (en) 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
ES2259800T3 (es) 1990-06-11 2006-10-16 Gilead Sciences, Inc. Procedimientos de uso de ligandos de acido nucleico.
ATE207080T1 (de) 1991-11-25 2001-11-15 Enzon Inc Multivalente antigen-bindende proteine
US5383851A (en) 1992-07-24 1995-01-24 Bioject Inc. Needleless hypodermic injection device
US6005079A (en) 1992-08-21 1999-12-21 Vrije Universiteit Brussels Immunoglobulins devoid of light chains
DK1621554T4 (da) 1992-08-21 2012-12-17 Univ Bruxelles Immunoglobuliner blottet for lette kæder
ES2162863T3 (es) 1993-04-29 2002-01-16 Unilever Nv Produccion de anticuerpos o fragmentos (funcionalizados) de los mismos derivados de inmunoglobulinas de cadena pesada de camelidae.
SE9400088D0 (sv) 1994-01-14 1994-01-14 Kabi Pharmacia Ab Bacterial receptor structures
DE69532127T2 (de) 1994-07-20 2004-08-26 Genetics Institute, Inc., Cambridge Interaktions-fullensysteme zum nachweis von protein-interaktionen
DE19742706B4 (de) 1997-09-26 2013-07-25 Pieris Proteolab Ag Lipocalinmuteine
AUPP221098A0 (en) 1998-03-06 1998-04-02 Diatech Pty Ltd V-like domain binding molecules
GB9818110D0 (en) 1998-08-19 1998-10-14 Weston Medical Ltd Needleless injectors and other devices
US6096002A (en) 1998-11-18 2000-08-01 Bioject, Inc. NGAS powered self-resetting needle-less hypodermic jet injection apparatus and method
US6818418B1 (en) 1998-12-10 2004-11-16 Compound Therapeutics, Inc. Protein scaffolds for antibody mimics and other binding proteins
ATE320486T1 (de) 1999-05-05 2006-04-15 Phylogica Ltd Isolierung von biologischen modulatoren aus bibiotheken mit biologisch vielfältigen genfragmenten
US6794144B1 (en) 1999-05-26 2004-09-21 Licentia Ltd. Methods and materials for generating SH3 domains with tailored binding properties
SE0001877D0 (sv) 2000-05-22 2000-05-22 Klaus Mosbach Molecular imprinting
EP1332209B1 (en) 2000-09-08 2009-11-11 Universität Zürich Collections of repeat proteins comprising repeat modules
US7998681B2 (en) 2000-10-06 2011-08-16 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Diagnosis and therapy of antibody-mediated inflammatory auto-immune disorders
US8153121B2 (en) 2000-10-06 2012-04-10 Los Angeles Biomedical Research Institute at Harbor—UCLA Medical Center Diagnosis and therapy of antibody-mediated inflammatory autoimmune disorders
DE10053224A1 (de) 2000-10-26 2002-05-08 Univ Goettingen Georg August Verfahren zur Exposition von Peptiden und Polypeptiden auf der Zelloberfläche von Bakterien
US7083784B2 (en) * 2000-12-12 2006-08-01 Medimmune, Inc. Molecules with extended half-lives, compositions and uses thereof
US20040132094A1 (en) 2000-12-13 2004-07-08 Michael Etzerodt Combinatorial libraries of proteins having the scaffold structure of c-type lectinlike domains
ME00502B (me) 2001-01-05 2011-10-10 Amgen Fremont Inc Antitjela za insulinu sličan receptor faktora i rasta
AU2002323501C1 (en) 2001-08-30 2010-04-29 Biorexis Technology, Inc Modified transferrin fusion proteins
US7241444B2 (en) 2002-01-18 2007-07-10 Pierre Fabre Medicament Anti-IGF-IR antibodies and uses thereof
US20030206898A1 (en) * 2002-04-26 2003-11-06 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
EP1506286B1 (en) 2002-05-24 2014-03-19 Merck Sharp & Dohme Corp. Neutralizing human anti-igfr antibody
US8034904B2 (en) * 2002-06-14 2011-10-11 Immunogen Inc. Anti-IGF-I receptor antibody
US7538195B2 (en) 2002-06-14 2009-05-26 Immunogen Inc. Anti-IGF-I receptor antibody
AU2003282724B2 (en) 2002-10-02 2010-03-04 Catalyst Biosciences, Inc. Methods of generating and screening for proteases with altered specificity
DK1587907T3 (da) 2003-01-07 2011-04-04 Dyax Corp Kunitz-domænebibliotek
PL378812A1 (pl) 2003-02-13 2006-05-29 Pfizer Products Inc. Zastosowania przeciwciał przeciw receptorowi insulinopodobnego czynnika wzrostowego I
JP2007501021A (ja) 2003-05-30 2007-01-25 アレクシオン ファーマシューティカルズ， インコーポレイテッド 遺伝子操作された定常領域を含む、抗体および融合タンパク質
AR046071A1 (es) 2003-07-10 2005-11-23 Hoffmann La Roche Anticuerpos contra el receptor i del factor de crecimiento de tipo insulinico y los usos de los mismos
TW200526684A (en) 2003-11-21 2005-08-16 Schering Corp Anti-IGFR1 antibody therapeutic combinations
US20060008844A1 (en) 2004-06-17 2006-01-12 Avidia Research Institute c-Met kinase binding proteins
KR20080019733A (ko) * 2004-07-16 2008-03-04 화이자 프로덕츠 인코포레이티드 항-아이지에프-1알 항체를 사용하는 비-혈액학적악성종양에 대한 조합 치료
DE102004049479A1 (de) 2004-10-11 2006-04-13 Scil Proteins Gmbh Proteinkonjugate zur Verwendung in Therapie, Diagnose und Chromatographie
US8367805B2 (en) 2004-11-12 2013-02-05 Xencor, Inc. Fc variants with altered binding to FcRn
PT1828249E (pt) 2004-12-03 2011-02-25 Schering Corp Biomarcadores para a pré-selecção de pacientes para terapêutica anti-igf1r
MY146381A (en) 2004-12-22 2012-08-15 Amgen Inc Compositions and methods relating relating to anti-igf-1 receptor antibodies
NZ564098A (en) 2005-06-15 2010-04-30 Schering Corp Anti-IGF1R antibody formulations
US7612181B2 (en) 2005-08-19 2009-11-03 Abbott Laboratories Dual variable domain immunoglobulin and uses thereof
US7807409B2 (en) * 2005-10-21 2010-10-05 Roche Palo Alto Llc Method for the recombinant expression of a polypeptide
EP1957541A2 (en) 2005-11-21 2008-08-20 Laboratoires Serono SA Compositions and methods of producing hybrid antigen binding molecules and uses thereof
US20080014203A1 (en) 2006-04-11 2008-01-17 Silke Hansen Antibodies against insulin-like growth factor I receptor and uses thereof
WO2008005469A2 (en) 2006-06-30 2008-01-10 Schering Corporation Igfbp2 biomarker
US8603465B1 (en) 2006-08-07 2013-12-10 Merck Sharp & Dohme, Corp. Methods for treatment of polyposis
EP1892248A1 (en) 2006-08-21 2008-02-27 Eidgenössische Technische Hochschule Zürich Specific and high affinity binding proteins comprising modified SH3 domains of FYN kinase
EP2104501B1 (en) * 2006-12-13 2014-03-12 Merck Sharp & Dohme Corp. Methods of cancer treatment with igf1r inhibitors
EP2121018A2 (en) 2006-12-13 2009-11-25 Schering Corporation Treating cancer with anti-igf1r antibody 19d12=sch 717454
US20080226635A1 (en) 2006-12-22 2008-09-18 Hans Koll Antibodies against insulin-like growth factor I receptor and uses thereof
AR064464A1 (es) * 2006-12-22 2009-04-01 Genentech Inc Anticuerpos anti - receptor del factor de crecimiento insulinico
PL2185589T3 (pl) 2007-06-01 2016-09-30 Środki wiążące receptor regionu stałego Fc immunoglobuliny
US20110014117A1 (en) 2007-06-28 2011-01-20 Schering Corporation Anti-igf1r
US20090162359A1 (en) 2007-12-21 2009-06-25 Christian Klein Bivalent, bispecific antibodies
HRP20150279T1 (hr) 2007-12-26 2015-05-08 Xencor, Inc. Fc inaäśice s promijenjenim vezanjem na fcrn
US20100260668A1 (en) 2008-04-29 2010-10-14 Abbott Laboratories Dual Variable Domain Immunoglobulins and Uses Thereof
JP2011525180A (ja) 2008-06-16 2011-09-15 バインド バイオサイエンシズ インコーポレイテッド 治療的標的化ナノ粒子の製作に用いるためのジブロックコポリマーで官能化された標的薬の製造方法
CN102149825B (zh) 2008-07-08 2015-07-22 Abbvie公司 前列腺素e2双重可变结构域免疫球蛋白及其用途
MX2011003241A (es) 2008-09-26 2011-04-21 Schering Corp Produccion de anticuerpos con alto titulo.
US8137933B2 (en) 2008-11-12 2012-03-20 Schering Corporation Mammalian expression vector pUHAB
WO2010120599A2 (en) * 2009-04-16 2010-10-21 Merck Sharp & Dohme Corp. Compositions and methods for treating cancer
AR076508A1 (es) 2009-05-01 2011-06-15 Abbott Lab Inmunoglobulina con dominio variable dual y usos de la misma
KR101224468B1 (ko) 2009-05-20 2013-01-23 주식회사 파멥신 신규한 형태의 이중표적항체 및 그 용도
UY32808A (es) 2009-07-29 2011-02-28 Abbott Lab Inmunoglobulinas como dominio variable dual y usos de las mismas
WO2011028811A2 (en) 2009-09-01 2011-03-10 Abbott Laboratories Dual variable domain immunoglobulins and uses thereof
WO2011057064A1 (en) 2009-11-05 2011-05-12 Brian Long Igf1r inhibitor based treatment of prostate cancer
US9045536B2 (en) * 2009-12-23 2015-06-02 Merck Sharp & Dohme Corp. Cell line 3M
WO2011161119A1 (en) 2010-06-22 2011-12-29 F. Hoffmann-La Roche Ag Antibodies against insulin-like growth factor i receptor and uses thereof
UY33492A (es) 2010-07-09 2012-01-31 Abbott Lab Inmunoglobulinas con dominio variable dual y usos de las mismas
WO2012009705A1 (en) 2010-07-15 2012-01-19 Zyngenia, Inc. Ang-2 binding complexes and uses thereof
WO2013121296A1 (en) 2012-02-15 2013-08-22 Ecole Polytechnique Federale De Lausanne Erythrocyte-binding therapeutics
AU2011295968B2 (en) 2010-09-01 2017-01-05 Biogen Ma Inc. Rapid generation of anti-idiotypic antibodies
UY33707A (es) 2010-11-04 2012-05-31 Abbott Lab Inmunoglobulinas con dominio variable dual y usos de las mismas
US20120201746A1 (en) 2010-12-22 2012-08-09 Abbott Laboratories Half immunoglobulin binding proteins and uses thereof
MX342034B (es) 2011-02-28 2016-09-12 Hoffmann La Roche Proteinas monovalentes que se unen a antigenos.
AR085404A1 (es) 2011-02-28 2013-09-25 Hoffmann La Roche Proteinas de union a antigeno
AU2012255920A1 (en) * 2011-05-18 2013-11-07 Merck Sharp & Dohme Corp. Therapeutic anti-IGF1R combinations
AU2012255251B2 (en) 2011-05-18 2017-06-15 University Of Florida Research Foundation, Inc. Macrocyclic therapeutic agents and methods of treatment
KR102060389B1 (ko) 2011-05-21 2019-12-31 마크로제닉스, 인크. 사람 및 비-사람 cd3에 결합할 수 있는 cd3-결합 분자
US20130195871A1 (en) 2011-12-30 2013-08-01 Abbvie Inc. Dual variable domain immunoglobulins and uses thereof
US20150056191A1 (en) * 2012-03-30 2015-02-26 Merck Sharp & Dohme Corp. Igf1 biomarker for igf1r inhibitor therapy
WO2013169611A1 (en) 2012-05-09 2013-11-14 Merck Sharp & Dohme Corp. Compositions and methods for treating breast cancer
CA2875543A1 (en) 2012-06-21 2013-12-27 Sorrento Therapeutics, Inc. Antigen binding proteins that bind igf1r
AU2014243816B2 (en) 2013-03-13 2019-01-31 Bioasis Technologies Inc. Fragments of p97 and uses thereof
UA118029C2 (uk) * 2013-04-29 2018-11-12 Ф. Хоффманн-Ля Рош Аг Модифіковане антитіло, що зв'язується з людським fcrn, й способи його застосування
WO2014177459A2 (en) 2013-04-29 2014-11-06 F. Hoffmann-La Roche Ag Fc-receptor binding modified asymmetric antibodies and methods of use
MX364861B (es) 2013-04-29 2019-05-09 Hoffmann La Roche Anticuerpos anti-receptor del factor de crecimiento de tipo insulinico humano 1 (anti-igf-1r) con abolicion de la union al fcrn y su uso en el tratamiento de enfermedades oculares vasculares.
US10519251B2 (en) 2013-12-30 2019-12-31 Epimab Biotherapeutics, Inc. Fabs-in-tandem immunoglobulin and uses thereof
US20210138076A2 (en) 2014-01-27 2021-05-13 Molecular Templates, Inc. Cell-targeting molecules comprising shiga toxin a subunit effectors and cd8+ t-cell epitopes
HRP20190888T8 (hr) 2014-04-25 2019-10-04 Pierre Fabre Médicament Konjugat antitijela za igf-1r i lijeka i njegova upotreba u liječenju karcinoma
US20170218091A1 (en) 2014-07-03 2017-08-03 Abbvie Inc. Monovalent binding proteins
WO2016064716A1 (en) 2014-10-20 2016-04-28 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Combination therapy of tshr antagonist and igfr inhibitor
TWI769570B (zh) 2015-01-28 2022-07-01 愛爾蘭商普羅佘納生物科技有限公司 抗甲狀腺素運送蛋白抗體
TWI870335B (zh) 2015-06-12 2025-01-21 美商宏觀基因股份有限公司 變異的嵌合4d5抗體及其與抗pd-1抗體聯合用於治療癌症的應用
WO2017011773A2 (en) 2015-07-15 2017-01-19 Modernatx, Inc. Codon-optimized nucleic acids encoding antibodies
EP3448427A1 (en) 2016-04-29 2019-03-06 CureVac AG Rna encoding an antibody
EP3448874A4 (en) 2016-04-29 2020-04-22 Voyager Therapeutics, Inc. COMPOSITIONS FOR TREATING A DISEASE
CN118436801A (zh) 2016-05-20 2024-08-06 豪夫迈·罗氏有限公司 Protac抗体缀合物及其使用方法
CN109862910A (zh) * 2016-08-03 2019-06-07 小利兰·斯坦福大学托管委员会 破坏巨噬细胞上的Fc受体接合增强抗SIRPα抗体疗法的功效
CN109803679A (zh) 2016-08-30 2019-05-24 得克萨斯州大学系统董事会 在基因组重新编码生物体中生产硒代生物制剂
EP4596707A3 (en) 2016-09-19 2025-10-08 University of Southern California Non-radioactive cytotoxicity assays
DK3558369T3 (da) * 2016-12-21 2025-05-19 Cephalon Llc Antistoffer, der specifikt binder til humant il-15, og anvendelse heraf
CN106546800B (zh) 2017-01-25 2019-06-18 北京鸿智电通科技有限公司 一种应用于快充电源的充/放电电流检测电路
US10722589B2 (en) 2017-04-03 2020-07-28 Covagen Ag FGFR3 binding molecules
US10093741B1 (en) 2017-05-05 2018-10-09 Fusion Pharmaceuticals Inc. IGF-1R monoclonal antibodies and uses thereof
WO2018204872A2 (en) * 2017-05-05 2018-11-08 Fusion Pharmaceuticals Inc. Igf-1r monoclonal antibodies and uses thereof
AR112600A1 (es) 2017-05-30 2019-11-20 Teijin Pharma Ltd Anticuerpo anti-receptor de igf-i
CU24731B1 (es) 2017-10-06 2025-01-15 Prothena Biosciences Ltd Anticuerpos anti-transtiretina
WO2019084030A1 (en) 2017-10-24 2019-05-02 Genentech, Inc. (4-HYDROXYPYRROLIDIN-2-YL) -HYDROXAMATE COMPOUNDS AND METHODS OF USE
WO2019084026A1 (en) 2017-10-24 2019-05-02 Genentech, Inc. (4-HYDROXYPYRROLIDIN-2-YL) -HETEROCYCLIC COMPOUNDS AND METHODS OF USE
US20210284741A1 (en) 2018-01-24 2021-09-16 Hznp Limited Methods for the treatment of thyroid eye disease
US11208489B2 (en) * 2018-01-24 2021-12-28 Horizon Therapeutics Ireland Dac Methods for the treatment of thyroid eye disease
WO2019173352A1 (en) * 2018-03-05 2019-09-12 Hznp Limited Methods for the treatment of thyroid eye disease
WO2019183523A1 (en) 2018-03-23 2019-09-26 Genentech, Inc. Hetero-bifunctional degrader compounds and their use as modulators of targeted ubiquination (vhl)
EP3546362B1 (en) * 2018-03-28 2024-01-24 Airbus Operations GmbH Fuselage assembly for an aircraft
CA3103374A1 (en) 2018-06-29 2020-01-02 Krystal Biotech, Inc. Compositions and methods for antibody delivery
JP6958530B2 (ja) * 2018-10-10 2021-11-02 セイコーエプソン株式会社 光学モジュールおよび頭部装着型表示装置
US20220088231A1 (en) * 2018-12-03 2022-03-24 Fusion Pharmaceuticals Inc. Radioimmunoconjugates and dna damage and repair inhibitor combination therapy
FI3898668T3 (fi) * 2018-12-19 2023-11-28 Humabs Biomed Sa B-hepatiittivirusta neutraloivia vasta-aineita ja niiden käyttöjä
CN111744013B (zh) 2019-03-29 2022-07-26 江苏恒瑞医药股份有限公司 抗tigit抗体联合pd-1抑制剂治疗疾病的方法和药物组合
AU2020337958A1 (en) * 2019-08-28 2022-03-17 Horizon Therapeutics Ireland Dac Methods for the treatment of thyroid eye disease
CN113402602B (zh) 2020-03-17 2022-09-23 上海祥耀生物科技有限责任公司 一种新型冠状病毒SARS-CoV-2中和性抗体及应用
WO2021243014A1 (en) 2020-05-28 2021-12-02 Horizon Therapeutics Ireland Dac Methods for the treatment of idiopathic orbital inflammation and related conditions
TW202246339A (zh) 2021-03-03 2022-12-01 愛爾蘭商赫萊森治療愛爾蘭公司 治療甲狀腺眼疾的方法
EP4123454A1 (en) 2021-07-21 2023-01-25 Abb Schweiz Ag Validating component specifications for industrial automation systems
EP4384219A4 (en) 2021-08-10 2025-06-18 Viridian Therapeutics, Inc. COMPOSITIONS, DOSAGES AND METHODS FOR THE TREATMENT OF THYROID EYE DISEASE
US20240368282A1 (en) 2021-09-01 2024-11-07 Biosceptre (Aust) Pty Ltd Methods and compositions for stimulating immune activity
WO2023122714A2 (en) 2021-12-23 2023-06-29 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
KR20240141213A (ko) 2022-01-07 2024-09-25 비리디안 쎄라퓨틱스, 인크. 갑상선 눈 질환의 치료를 위한 조성물 및 방법
WO2023133485A2 (en) 2022-01-07 2023-07-13 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
JP2025503637A (ja) 2022-01-09 2025-02-04 クリヤ セラピューティクス， インコーポレイテッド 治療用抗ｉｇｆ－１ｒ抗体をコードする核酸の送達のためのベクター構築物およびそれを使用する方法
AU2024287547A1 (en) 2023-07-07 2026-01-22 Viridian Therapeutics, Inc. Methods of treating chronic thyroid eye disease
TW202519262A (zh) 2023-09-06 2025-05-16 美商維里迪恩醫療股份有限公司 抗ｉｇｆ－１ｒ抗體之醫藥組合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220235137A1 (en) * 2020-10-14 2022-07-28 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
US20220267451A1 (en) * 2020-10-14 2022-08-25 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
US20220275096A1 (en) * 2020-10-14 2022-09-01 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Ugradar et al ( J Neuroophthalmol 2022 Mar 1;42(1):26-34' Abstract only) *
Ugradar et al (Eye (Lond) 2022 Aug;36(8):1553-1559. doi: 10.1038/s41433-021-01593-z. Epub 2021 Jul 9) *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230002495A1 (en) * 2020-10-14 2023-01-05 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
US11548951B1 (en) * 2020-10-14 2023-01-10 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
US12404335B2 (en) 2020-10-14 2025-09-02 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
US12595309B2 (en) 2020-10-14 2026-04-07 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
US12600788B2 (en) 2020-10-14 2026-04-14 Viridian Therapeutics, Inc. Compositions and methods for treatment of thyroid eye disease
US12404337B2 (en) 2021-08-10 2025-09-02 Viridian Therapeutics, Inc. Compositions, doses, and methods for treatment of thyroid eye disease

Also Published As

Publication number Publication date
CN116583273A (zh) 2023-08-11
ECSP23034914A (es) 2023-06-30
US20230279122A1 (en) 2023-09-07
JOP20230075A1 (ar) 2023-04-13
JP2023545520A (ja) 2023-10-30
US20220267451A1 (en) 2022-08-25
US12600788B2 (en) 2026-04-14
TW202229350A (zh) 2022-08-01
JP2025143343A (ja) 2025-10-01
CN119792513A (zh) 2025-04-11
US20250313639A1 (en) 2025-10-09
AU2021360889A1 (en) 2023-06-15
US20220235137A1 (en) 2022-07-28
US20220275096A1 (en) 2022-09-01
WO2022081799A1 (en) 2022-04-21
CL2023001052A1 (es) 2023-11-17
CN116583273B (zh) 2025-01-14
CO2023005996A2 (es) 2023-05-29
DOP2023000073A (es) 2023-09-29
PE20231202A1 (es) 2023-08-17
EP4228616A4 (en) 2025-02-12
US20230002495A1 (en) 2023-01-05
US12595309B2 (en) 2026-04-07
CR20230204A (es) 2023-10-11
CA3195512A1 (en) 2022-04-21
KR20230124550A (ko) 2023-08-25
IL302068A (en) 2023-06-01
US12404335B2 (en) 2025-09-02
CN119792512A (zh) 2025-04-11
US20250382374A1 (en) 2025-12-18
US11548951B1 (en) 2023-01-10
US20250059287A1 (en) 2025-02-20
US20240043546A1 (en) 2024-02-08
CA3195590A1 (en) 2022-04-21
TW202228775A (zh) 2022-08-01
EP4228616A1 (en) 2023-08-23
WO2022081804A1 (en) 2022-04-21
MX2023004280A (es) 2023-06-23

Similar Documents

Publication Publication Date Title
US12595309B2 (en) Compositions and methods for treatment of thyroid eye disease
US12404337B2 (en) Compositions, doses, and methods for treatment of thyroid eye disease
AU2022420605A1 (en) Compositions and methods for treatment of thyroid eye disease
US20240360227A1 (en) Compositions and methods for treatment of thyroid eye disease
US20240343814A1 (en) Compositions and methods for treatment of thyroid eye disease
CN118059229A (zh) 用于治疗甲状腺眼病的组合物和方法
HK40099096A (zh) 用於治疗甲状腺眼病的组合物和方法
HK40099096B (zh) 用於治疗甲状腺眼病的组合物和方法

Legal Events

Date Code Title Description
AS Assignment

Owner name: VAHE BEDIAN, MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BEDIAN, VAHE;HARWIN, PETER;KISELAK, TOMAS;AND OTHERS;SIGNING DATES FROM 20211031 TO 20211129;REEL/FRAME:058379/0480

AS Assignment

Owner name: VIRIDIAN THERAPEUTICS, INC., MASSACHUSETTS

Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE THE ASSIGNEE NAME AND CITY PREVIOUSLY RECORDED AT REEL: 058379 FRAME: 0480. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT;ASSIGNORS:BEDIAN, VAHE;HARWIN, PETER;KISELAK, TOMAS;AND OTHERS;SIGNING DATES FROM 20211031 TO 20211129;REEL/FRAME:058806/0571

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION